Document ID: EPA-HQ-OPP-2010-0785-0002
Agency: epa
Document Type: Proposed Rule
Title: Protections for Subjects in Human Research Involving Pesticides
Posted Date: 2011-02-02T05:00Z

[Federal Register Volume 76, Number 22 (Wednesday, February 2, 2011)]
[Proposed Rules]
[Pages 5735-5755]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-1629]

[[Page 5735]]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 26

[EPA-HQ-OPP-2010-0785; FRL-8862-7]
RIN 2070-AJ76

Revisions to EPA's Rule on Protections for Subjects in Human 
Research Involving Pesticides

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: EPA proposes to amend the portions of its rules for the 
protection of human subjects of research applying to third parties who 
conduct or support research with pesticides involving intentional 
exposure of human subjects and to persons who submit the results of 
human research with pesticides to EPA. The proposed amendments would 
broaden the applicability of the rules to cover human testing with 
pesticides submitted to EPA under any regulatory statute it 
administers. They would also disallow participation in third-party 
pesticide studies by subjects who cannot consent for themselves. 
Finally the proposed amendments would identify specific considerations 
to be addressed in EPA science and ethics reviews of proposed and 
completed human research with pesticides, drawn from the 
recommendations of the National Academy of Sciences (NAS). In seeking 
comments on these proposed amendments, EPA does not imply that the 
current Federal Policy for the Protection of Human Subjects (the 
``Common Rule''), which governs research with human subjects conducted 
or supported by EPA and many other Federal departments and agencies, is 
inadequate. Indeed, the amendments proposed here would make no changes 
to the Common Rule or EPA's codification of the Common Rule. Rather, 
EPA is proposing these amendments to other portions of its regulation 
as a result of a settlement agreement, and is now seeking comment on 
these proposed amendments. The settlement agreement makes clear that 
EPA retains full discretion concerning what amendments are proposed, 
and what, if any, amendments are finalized. Furthermore, no research 
has been identified that is outside the scope of EPA's current rule, 
but that would be within the scope of these proposed amendments. EPA 
seeks comments on the need for and value of the proposed changes.

DATES: Comments must be received on or before April 4, 2011.

ADDRESSES: Submit your comments, identified by docket identification 
(ID) number EPA-HQ-OPP-2010-0785, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public 
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania 
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P), 
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South 
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only 
accepted during the Docket Facility's normal hours of operation (8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays). 
Special arrangements should be made for deliveries of boxed 
information. The Docket Facility telephone number is (703) 305-5805.
    Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2010-0785. EPA's policy is that all comments received will be included 
in the docket without change and may be made available on-line at 
http://www.regulations.gov, including any personal information 
provided, unless the comment includes information claimed to be 
Confidential Business Information (CBI) or other information whose 
disclosure is restricted by statute. Do not submit information that you 
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov Web site is an ``anonymous access'' system, 
which means EPA will not know your identity or contact information 
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov, 
your e-mail address will be automatically captured and included as part 
of the comment that is placed in the docket and made available on the 
Internet. If you submit an electronic comment, EPA recommends that you 
include your name and other contact information in the body of your 
comment and with any disk or CD-ROM you submit. If EPA cannot read your 
comment due to technical difficulties and cannot contact you for 
clarification, EPA may not be able to consider your comment. Electronic 
files should avoid the use of special characters, any form of 
encryption, and be free of any defects or viruses.
    Docket: All documents in the docket are listed in the docket index 
available at http://www.regulations.gov. Although listed in the index, 
some information is not publicly available, e.g., CBI or other 
information whose disclosure is restricted by statute. Certain other 
material, such as copyrighted material, is not placed on the Internet 
and will be publicly available only in hard copy form. Publicly 
available docket materials are available either in the electronic 
docket at http://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The hours of 
operation of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays. The Docket Facility telephone 
number is (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: Kelly Sherman, Immediate Office of the 
Director (7501P), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-8401; fax number: (703) 308-4776; e-
mail address: sherman.kelly@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you sponsor, 
conduct, review, or submit to EPA research with pesticides involving 
human subjects. Potentially affected entities may include, but are not 
limited to:
     Pesticide and other agricultural chemical manufacturers 
(NAICS code 325320) who sponsor or conduct human research with 
pesticides.
     Other entities (NAICS code 541710) that sponsor or conduct 
human research with pesticides, and Institutional Review Boards who 
review human research with pesticides to ensure it meets applicable 
standards of ethical conduct.
    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in this unit could also be 
affected. The North American Industrial Classification System (NAICS) 
codes are provided to assist you and others in determining whether this 
action might apply to certain entities. If you have any questions 
regarding the applicability of this action to a particular entity, 
consult the person listed under FOR FURTHER INFORMATION CONTACT.

B. What should I consider as I prepare my comments for EPA?

    1. Submitting CBI. Do not submit confidential business information 
(CBI)

[[Page 5736]]

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 copy of the comment that does not contain the information 
claimed as CBI must be submitted for inclusion in the public docket. 
Information so marked will not be disclosed except in accordance with 
procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When submitting comments, 
remember to:
    a. Identify the document by docket ID number and other identifying 
information (subject heading, Federal Register date and page number).
    b. Follow directions. The Agency may ask you to respond to specific 
questions or organize comments by referencing a Code of Federal 
Regulations (CFR) part or section number.
    c. Explain why you agree or disagree; suggest alternatives and 
substitute language for your requested changes.
    d. Describe any assumptions and provide any technical information 
and/or data that you used.
    e. If you estimate potential costs or burdens, explain how you 
arrived at your estimate in sufficient detail to allow for it to be 
reproduced.
    f. Provide specific examples to illustrate your concerns and 
suggest alternatives.
    g. Explain your views as clearly as possible, avoiding the use of 
profanity or personal threats.
    h. Make sure to submit your comments by the comment period deadline 
identified.

II. Background

A. What would the proposed amendments do?

    The proposed amendments would change the 2006 rule, published in 
the Federal Register issue of February 6, 2006 (71 FR 6138) (FRL-7759-
8), subsequently amended on June 23, 2006 (71 FR 36171) (FRL-8071-6), 
and codified at 40 CFR part 26, in the following substantive respects:
     By broadening the applicability of 40 CFR part 26, 
subparts K, L, M, and Q, so these subparts would apply not only to 
research submitted to or considered by EPA under the pesticide laws, 
but also to research involving a ``pesticide'' (as defined in the 
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 
136(u)) which is submitted to or considered by EPA under any other 
regulatory statute it administers.
     By incorporating the definition of ``pesticide'' from 
FIFRA, as a substance or mixture of substances intended for pesticidal 
effect.
     By deleting from 40 CFR part 26, subpart K, all references 
to consent on behalf of a subject in research involving intentional 
exposure to a pesticide by a subject's ``legally authorized 
representative.''
     By incorporating into 40 CFR part 26, subparts P and Q, 
factors to be considered by EPA and the Human Studies Review Board 
(HSRB) in their review of proposed and completed research, derived from 
the recommendations of NAS in its 2004 Report to EPA, and from the 
Nuremberg Code.
    The amendments proposed here would make no changes to the Federal 
Policy for the Protection of Human Subjects (the ``Common Rule''), 
which governs research with human subjects conducted or supported by 
EPA and many other Federal departments and agencies. EPA's codification 
of the Common Rule appears as subpart A in 40 CFR part 26.
    Subparts B, C, and D of 40 CFR part 26 would also be unchanged by 
these proposed amendments. These subparts categorically prohibit any 
EPA research involving intentional exposure to any substance of human 
subjects who are children or pregnant or nursing women (40 CFR part 26, 
subpart B), and provide extra protections for pregnant women and for 
children who are the subjects of observational research conducted or 
supported by EPA (40 CFR part 26, subparts C and D).
    The proposed amendments would retain without substantive change the 
core provisions of the 2006 rule applying to the conduct of human 
pesticide research by third parties--i.e., research neither conducted 
nor supported by EPA or another Common Rule Federal department or 
agency. These substantively unchanged provisions:
     Categorically prohibit new research involving intentional 
exposure of pregnant or nursing women or of children to a pesticide (40 
CFR part 26, subpart L).
     Apply the provisions of the Common Rule to third-party 
human research involving intentional exposure of non-pregnant, non-
nursing adults to a pesticide (40 CFR part 26, subpart K).
     Require submission to EPA of proposals for new covered 
research before it is initiated (40 CFR part 26, subpart K, Sec.  
26.1125).
     Require persons who submit to EPA reports of completed 
human research on pesticides to document the ethical conduct of that 
research (40 CFR part 26, subpart M).
     Establish an independent HSRB to review and advise EPA 
concerning both proposals for new human research involving intentional 
exposure to a pesticide and reports of completed research on which EPA 
proposes to rely in its actions (40 CFR part 26, subpart P).
    The proposed amendments would make only minor editorial revisions 
to 40 CFR part 26, subpart O, which defines administrative actions 
available to EPA to address non-compliance with 40 CFR part 26, 
subparts A through L.
    The proposed amendments would retain the essential structure of 40 
CFR part 26, subpart P, which defines the processes of EPA and HSRB 
review of proposed and completed research. The amendments, however, 
would also add substantial new clarifying language to 40 CFR part 26, 
subpart P, as discussed in detail in Unit IV.C. of this document.
    The proposed amendments would retain the essential structure of 40 
CFR part 26, subpart Q, which defines the standards to be applied when 
EPA proposes to rely on data from completed research involving 
intentional exposure of human subjects to a pesticide. The amendments, 
however, would also add substantial new clarifying language to 40 CFR 
part 26, subpart Q, as discussed in detail in Unit IV.D. of this 
document.
    The proposed amendments would not change the provision in 40 CFR 
part 26, subpart Q, forbidding EPA to rely on any otherwise 
unacceptable research involving intentional exposure of human subjects 
to a pesticide, except under extremely restrictive conditions. These 
conditions require a public review by HSRB, an opportunity for public 
comment, and a showing by EPA that to do so would result in a more 
protective regulatory standard than could be justified without reliance 
on the unethical research.

B. What is the agency's authority for taking this action?

    The legal authority for the 2006 rule on human research is set 
forth in the preamble to that final rule (71 FR 6138, February 6, 2006) 
(FRL-7759-8). These proposed amendments to that rule rest upon the same 
legal authority. In particular, the legal authority for expanding the 
2006 rule to cover research involving the intentional exposure of a 
human subject to a pesticide submitted under any EPA

[[Page 5737]]

regulatory statute is provided by section 201 of the Department of the 
Interior, Environment, and Related Agencies Appropriations Act, 2006, 
Public Law 109-54 (2006 Appropriations Act), and FIFRA.
    The 2006 Appropriations Act directly mandates that EPA promulgate a 
rule on ``third-party intentional dosing human toxicity studies for 
pesticides * * *'' without limiting the rule to pesticide studies 
submitted under FIFRA or section 408 of the Federal Food, Drug, and 
Cosmetic Act (FFDCA) (21 U.S.C. 346a).
    Additionally, under FIFRA, EPA has the authority to issue 
regulations as to both unregistered and registered pesticides used in 
research involving the intentional exposure of a human subject, whether 
or not that research is conducted for submission under FIFRA. Section 
3(a) of FIFRA authorizes EPA to regulate the distribution, sale, or use 
of any unregistered pesticide in any State ``[t]o the extent necessary 
to prevent unreasonable adverse effects on the environment'' (defined 
at FIFRA section 2(bb), in pertinent part, as ``any unreasonable risk 
to man or the environment, taking into account the economic, social, 
and environmental costs and benefits of the use of any pesticide''). 
EPA concludes that there would be an unreasonable risk to humans if 
unregistered pesticides were used in research involving intentional 
exposure of human subjects (or sold and distributed for such use) that 
is not already covered by the Common Rule absent compliance with the 
applicable rules in 40 CFR part 26, as proposed. The importance of 
these rules to the protection of human subjects is demonstrated in the 
2004 Report from the National Research Council of the NAS, entitled 
``Intentional Human Dosing Studies for EPA Regulatory Purposes: 
Scientific and Ethical Issues'' (2004 NAS Report) (http://www.national-academies.org).
    Section 25(a) of FIFRA authorizes EPA to ``prescribe regulations to 
carry out the provisions of [FIFRA].'' (7 U.S.C. 136w(a)). Regulations 
protecting human subjects in research involving the intentional 
exposure of human subjects to registered pesticides fall within that 
purview. FIFRA provides that a pesticide may not be registered unless 
use of the pesticide under its labeling will not cause unreasonable 
risks to humans or the environment, that a pesticide may not be used 
inconsistent with its label, and that a pesticide may not be used in 
human testing unless the subjects are fully informed regarding the 
nature, purpose, and physical and mental health consequences of the 
testing and freely volunteer. (See 7 U.S.C. 136(bb), 136a(c)(5), 
136j(a)(2)(G), 136j(a)(2)(P)). The 2006 rule and the amendments 
proposed in this document ensure that these provisions regarding use of 
registered pesticides in a manner that does not cause unreasonable risk 
and full and free consent in human testing with pesticides are 
effectuated.

III. EPA's Human Subjects Protection Rules

A. Overarching Principles

    EPA is committed to relying on scientifically sound research that 
is ethically conducted, and to transparency in its review processes and 
decision-making. EPA issued the 2006 rule to further these commitments 
and nothing in the amendments proposed in this document will change 
that. These proposed amendments can be seen as increasing the 
transparency of EPA's decision-making process by clarifying the scope 
and applicability of the requirements in 40 CFR part 26, codifying the 
scope and approach used in EPA's science and ethics reviews of human 
research involving pesticides.

B. Appropriations Act of 2006

    In August 2005, in the 2006 Appropriations Act, which appropriated 
funds for EPA and other Federal departments and agencies for FY 2006, 
Congress included at section 201 the following provision:

    None of the funds made available by this Act may be used by the 
Administrator of the Environmental Protection Agency to accept, 
consider or rely on third-party intentional dosing human toxicity 
studies for pesticides, or to conduct intentional dosing human 
toxicity studies for pesticides until the Administrator issues a 
final rulemaking on this subject. The Administrator shall allow for 
a period of not less than 90 days for public comment on the Agency's 
proposed rule before issuing a final rule. Such rule shall not 
permit the use of pregnant women, infants or children as subjects; 
shall be consistent with the principles proposed in the 2004 report 
of the National Academy of Sciences on intentional human dosing and 
the principles of the Nuremberg Code with respect to human 
experimentation; and shall establish an independent Human Subjects 
Review Board. The final rule shall be issued no later than 180 days 
after enactment of this Act.

    In response, EPA published a proposed rule in the Federal Register 
issue of September 12, 2005 (70 FR 53838) (FRL-7728-2), accepted public 
comment until December 12, 2005, and promulgated on February 6, 2006, a 
final rule which took effect on April 7, 2006 (71 FR 6138) (FRL-7759-
8). The 2006 rule, as subsequently amended on June 23, 2006, to extend 
special protections to nursing women as well (71 FR 36171) (FRL-8071-
6), is discussed in Unit III.E. and is now being further amended by 
this proposed rule.

C. EPA's 2006 Rule

    1. Summary of contents. The 2006 rule established a set of 
protections for people participating as subjects in third-party human 
research with pesticides. (In this context ``third-party'' research is 
research neither conducted (``first-party'') nor supported (``second-
party'') by EPA or another Common Rule Federal department or agency.) 
The 2006 rule bans all third-party research on pesticides involving 
intentional exposure of children or of pregnant or nursing women. It 
further forbids EPA itself to conduct or support any research involving 
intentional exposure of pregnant or nursing women or of children to any 
substance. EPA was required to promulgate the 2006 rule by the 2006 
Appropriations Act.
    The 2006 rule also extends the ethical protections in the Common 
Rule to third-party studies of non-pregnant, non-nursing adult subjects 
intentionally exposed to pesticides. The key provisions of the 2006 
rule include:
     Requiring pre-implementation submission to EPA of 
protocols and related information about proposed research to ensure any 
future studies meet high ethical standards.
     Establishing an independent HSRB to obtain expert peer 
review of both proposals for new research intended for submission to 
EPA and reports of completed human research involving intentional 
exposure on which EPA proposes to rely in an action taken under the 
pesticide laws.
     Prohibiting EPA from relying on the results of research in 
its actions under the pesticide laws unless EPA determines that the 
research meets acceptance standards derived from the recommendations in 
the 2004 NAS Report.
    2. Research with pesticides since promulgation of the 2006 rule. 
Contrary to some predictions, the 2006 rule has not led to an upsurge 
in human research with pesticides for submission to EPA under FIFRA or 
FFDCA. Since promulgation of the 2006 rule EPA has received no 
proposals at all for research on the toxicity of a pesticide to human 
subjects, and has received significantly fewer than were projected 
proposals for new research of other kinds (e.g., insect repellent 
studies). In the analyses supporting the 2006 rule, EPA estimated 33 
new intentional exposure studies would be submitted each year; in fact, 
only 26 proposals for new research on pesticides for submission to EPA 
under

[[Page 5738]]

FIFRA and FFDCA have been submitted over a span of approximately 5 
years, or just over 5 per year.
    3. Overview of HSRB reviews. EPA's experience in implementing the 
2006 rule is critical to understanding the amendments proposed in this 
document. The public meetings of HSRB have served as key milestones in 
the implementation of the 2006 rule, and the implementation of the 2006 
rule can be best characterized by summarizing what HSRB has been called 
upon to review. HSRB met for the first time in April 2006, immediately 
after the 2006 rule became effective, and has met 14 times since then, 
most recently in October 2010. At these meetings, HSRB has reviewed 
both reports of completed research and proposals for new research. 
Specifically, HSRB has reviewed:
     Completed reports of pre-2006 rule research reporting 
toxic endpoints. These have included intentional exposure toxicity 
tests initiated both before and after passage of the Food Quality 
Protection Act (FQPA) in 1996, as well as therapeutic trials of 
substances used both as drugs and as pesticides, reporting side effects 
relevant to EPA pesticide risk assessments.
     Proposals for and reports of new research involving 
intentional exposure to materials used in the research as pesticides.
    a. Pre-rule research reporting toxic endpoints. At its first two 
meetings in April and May 2006, HSRB reviewed 28 reports of pre-rule 
research conducted with 11 substances. At all its subsequent meetings 
combined the Board has reviewed 14 more such reports. Half of these 42 
reports were published; the rest were unpublished reports submitted 
directly to EPA by pesticide companies. Of the 42 reports, 37 reported 
non-therapeutic research, and 5 were published reports of therapeutic 
trials that described side effects relevant to pesticide risk 
assessments. We summarize the disposition of each of the 42 studies in 
the following paragraphs, and additional details may be accessed in the 
study specific reports available on the HSRB Web site at http://www.epa.gov/hsrb/index.htm.
    Twenty-nine of the 37 non-therapeutic studies reviewed by HSRB were 
initiated before the passage of FQPA in 1996; all reported toxic 
endpoints. EPA conducted both science and ethic reviews of these 
studies prior to submission of the studies to HSRB. EPA science 
reviewers proposed to rely on 17 of these 29 studies. HSRB found 13 of 
these 17 studies scientifically acceptable under the applicable 
standards of the 2006 rule. EPA ethics reviewers found 5 of the 17 
clearly acceptable, and deferred to HSRB concerning whether the 
shortcomings noted in the conduct of the remaining 12 studies rose to 
the level of ``significant'' deficiencies relative to prevailing 
standards of ethical research conduct. HSRB found 15 of those 17 
studies ethically acceptable under the applicable standards of the 2006 
rule--Sec.  26.1703 and Sec.  26.1704. HSRB found 1 study ethically 
unacceptable because of deficiencies in risk minimization procedures 
that could have led to serious harm to subjects, and another 
unacceptable because incomplete information provided to subjects 
concerning previous studies seriously impaired their informed consent. 
These 2 studies found by HSRB to be ethically unacceptable were among 
those also found by HSRB to be scientifically unacceptable. EPA has not 
subsequently relied on any studies deemed either scientifically or 
ethically unacceptable by HSRB.
    The 12 remaining pre-FQPA studies that EPA science reviewers had 
proposed to reject concerned dichlorvos (DDVP). These reports on the 
effects of dichlorvos had been submitted by the registrant to support a 
proposal to reduce the inter-species uncertainty factor in EPA's DDVP 
risk assessment. EPA reviewers found all 12 to be scientifically 
unacceptable to reduce the inter-species factor since a dose response 
could not be calculated due to numerous technical weaknesses. HSRB 
concurred. Because the reported research was deemed scientifically 
unacceptable for the proposed use, neither EPA nor HSRB explicitly 
reviewed its ethical conduct. EPA has not relied on any of these 12 
studies.
    Turning to the 8 post-FQPA toxicity studies that EPA presented to 
HSRB, we note that they were among a group of about 20 studies at the 
center of controversy before promulgation of the 2006 rule. Other post-
FQPA human toxicity studies were deemed by EPA science reviewers to be 
irrelevant to EPA's risk assessments, and have not been considered 
further.
    Of the eight relevant post-FQPA toxicity studies, EPA science 
reviewers found six scientifically acceptable and proposed to rely on 
them, found one more to be clearly scientifically unacceptable to set a 
point of departure because no effect was measured from the single dose 
level tested \1\, and deferred to HSRB with respect to the scientific 
acceptability of the last one. HSRB concurred that the first six 
studies were scientifically acceptable, and found both the others 
unacceptable. EPA ethics reviewers found four of the eight studies 
clearly acceptable, one clearly unacceptable, and deferred to HSRB's 
judgment whether the shortcomings noted in the conduct of the remaining 
three rose to the level of ``significant'' deficiencies relative to 
prevailing standards of ethical conduct. HSRB found all but one of 
these eight studies ethically acceptable under the applicable standards 
in the 2006 rule. Studies found either scientifically or ethically 
unacceptable by HSRB have not subsequently been relied on by EPA in any 
actions.
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    \1\ For more details on this finding, see the study report 
available on the HSRD Web site at http://www.epa.gov/hsrb/index.htm.
---------------------------------------------------------------------------

    EPA also proposed to rely on five published reports of therapeutic 
trials of materials that may be used as either drugs or as pesticide 
active ingredients. In these studies the reported toxic endpoints 
relevant to EPA pesticide risk assessments were not the main objective 
of the research, they were reported side effects of treatment when a 
test material (which is sometimes used as a pesticide) was administered 
as a medication. HSRB concurred with the EPA science reviews that these 
four studies were scientifically unacceptable, but found one study 
scientifically unacceptable for the purpose EPA proposed. EPA ethics 
reviewers and HSRB both found all five of these studies to be ethically 
acceptable under the standards of the 2006 rule.
    In summary, EPA and HSRB worked through the backlog of pre-rule 
studies of pesticide toxicity awaiting review when the 2006 rule was 
promulgated. EPA and HSRB agreed about the acceptability of these 
studies in most cases; when there was disagreement, EPA has accepted 
HSRB recommendation. Some pre-rule studies that met the scientific and 
ethical standards defined in the 2006 rule have been relied upon by EPA 
in actions under the pesticide laws, although EPA has not relied on any 
studies found unacceptable by HSRB. Meanwhile, as EPA completed the 
reassessment of tolerances mandated by FQPA, it found human toxicity 
testing to be relevant to only a handful of those assessments.
    b. New research involving intentional exposure of human subjects. 
In addition to reviewing pre-2006 rule research, HSRB has reviewed 
proposals for new research involving intentional exposure of human 
subjects. EPA developed a detailed ``framework'' for its reviews of 
these proposals (see the HSRB Web site at http://www.epa.gov/hsrb/index.htm). This framework has been used to guide all subsequent EPA 
reviews, and has

[[Page 5739]]

been refined in detail to incorporate suggestions from HSRB. A 
completed framework addressing concerns identified in the 2004 NAS 
Report and subsequently by HSRB has been attached to each EPA review of 
a proposal for new research under the 2006 rule.
    Since promulgation of the 2006 rule EPA has received no proposals 
at all for new research concerning pesticide toxicity or metabolism in 
human subjects. All submitted proposals for new research have been for 
research involving intentional exposure of human subjects to registered 
pesticides used for pesticidal purposes in the research itself. This 
has included proposals for research to measure the duration of 
effectiveness of skin-applied repellents intended to keep mosquitoes, 
ticks, and other pests away from the treated skin of human subjects, 
and for research monitoring occupational exposure of pesticide handlers 
as they mix, load, or apply pesticides in a variety of agricultural and 
non-agricultural use scenarios.
    Close scrutiny by both EPA and HSRB of proposals for new repellent 
performance testing and worker exposure monitoring studies has led to 
steady and substantial improvement both in the scientific design of 
these studies and in their provision for ethical treatment of subjects. 
These reviews have led to some delays in field research costly to the 
study sponsors, but the sponsors and investigators proposing these 
studies have learned how to design and execute them efficiently and in 
full compliance with the standards of the 2006 rule. These studies 
provide essential information about repellent performance and worker 
exposure that is not available except from well designed, ethically 
conducted research involving intentional exposure of human subjects to 
pesticides.
    i. Repellent performance studies. Repellent performance studies 
using human subjects have been required by EPA for many years to 
support registration of pesticide products bearing claims to keep 
mosquitoes, ticks, or other pests away from treated human skin. Since 
2006, HSRB has reviewed proposals for 13 new repellent performance 
studies testing a total of 29 repellent formulations. EPA and HSRB 
identified enough scientific and ethical deficiencies in their initial 
review of the first 2 such proposals that a second review was required. 
After they were revised and resubmitted, both proposals were reviewed 
favorably by EPA and HSRB. All subsequent proposals for new repellent 
performance studies have been found acceptable, with identified needed 
refinements, upon their first review by EPA and HSRB.
    Five of the 13 proposals have been for laboratory research with 
caged insects or ticks reared in the laboratory and known to be 
disease-free. The remaining studies have been for field studies of 
repellency against wild populations of insects. Three of the 13 studies 
have measured the duration of tick repellency in the laboratory--2 of 
them concurrently testing repellency to 2 species of ticks. Two more 
have measured the duration of repellency to biting flies--1 in the 
laboratory with laboratory-reared stable flies, and another in the 
field measuring repellency against black flies. The remaining 8 studies 
have measured the duration of repellency against mosquitoes--7 of them 
in the field, in areas where previous monitoring has not found evidence 
of infection of potential disease vectors among the wild insects 
present, and 1 in the laboratory with laboratory-reared, pathogen-free 
mosquitoes.
    In all these cases, HSRB has concurred with the EPA science and 
ethics reviews, in some cases recommending further refinements. One 
proposal was abandoned by its sponsor after a favorable HSRB review; 11 
more have been amended consistent with EPA and HSRB recommendations and 
executed. Reports of these 11 have been submitted to EPA and reviewed 
by EPA and HSRB. The most recent proposal is expected to be executed in 
the field in 2011.
    In one case EPA and HSRB found the execution of a completed field 
mosquito repellency test to have been 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 HSRB.
    Reports of all the other ten completed repellent performance 
studies were found both scientifically and ethically acceptable by EPA 
and HSRB as first submitted.
    ii. Studies of occupational exposure of pesticide handlers. All 
other proposals for new research submitted to EPA since promulgation of 
the 2006 rule have been for research monitoring exposure of 
professional pesticide handlers as they mix, load, or apply pesticides 
in well-defined agricultural and non-agricultural use scenarios. In 
such research, experienced workers performing their usual tasks are 
typically monitored at different sites, representing the range of 
variation in use practices, equipment, and other factors likely to 
affect exposure. Potential dermal exposure of the workers is measured 
by analyzing residues in special ``long underwear'' worn under their 
normal work clothing, and by rinsing their hands, face and neck. 
Potential inhalation exposure is measured with a portable air sampler 
worn in the breathing zone of each worker. This type of research has 
also long been required by EPA to support its assessments of worker 
risk.
    Five proposals for field monitoring of worker exposure submitted to 
EPA by an industry consortium were presented to HSRB in June 2006. 
These proposals were from the Agricultural Handlers Exposure Task Force 
(AHETF). HSRB review was highly critical, and called for substantially 
greater information from both the consortium and from EPA concerning 
the overall design of the research program, the statistical design of 
the proposed studies, the uses to which the resulting data would be put 
by EPA, and many other aspects of the proposed research. All five of 
these proposals were subsequently withdrawn so that HSRB criticisms 
could be addressed prior to resubmission.
    Since that initial review, the overall designs of the umbrella 
monitoring programs of AHETF and the designs from the Antimicrobial 
Exposure Assessment Task Force (AEATF II) have been fully documented 
and presented to HSRB. HSRB continues to review the design of 
individual monitoring studies, but the soundness of the overall 
approaches of both the AEATF II and AHETF programs have been 
established.
    Monitoring studies for four antimicrobial exposure scenarios 
submitted by the AEATF II have been presented to HSRB and approved with 
suggestions for refinements by both EPA and HSRB. These four scenarios 
involve common methods of application of antimicrobial pesticide 
products, including mopping, wiping down surfaces with a pre-soaked 
ready-to-use wipe, spraying surfaces with a pump spray and wiping them 
down with a cloth, and spraying surfaces with an aerosol product that 
does not need to be wiped off. For each scenario, monitoring of workers 
at three distinctive locations was proposed. After amendment of the 
protocols consistent with EPA and HSRB recommendations, the first three 
of these four studies have been executed; the first complete scenario 
report was submitted to EPA and reviewed by HSRB in October 2010. The 
remaining reports of completed AEATF II exposure research were 
submitted to EPA in the fall of 2010, and are scheduled for 
presentation to HSRB in early 2011.
    Monitoring studies for four agricultural exposure scenarios

[[Page 5740]]

submitted by the AHETF have been presented to HSRB and approved, again 
with suggestions for refinements by both EPA and HSRB. These scenarios 
involve application of liquid pesticides to trellis and orchard crops 
using ``air-blast'' spray equipment with closed cabs, application of 
liquid pesticides using air-blast spray equipment with open cabs, 
mixing and loading pesticides sold in water-soluble packaging into a 
wide variety of application equipment, and application of herbicides to 
rights-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 HSRB in October 2010. Reports of the remaining research 
scenarios will be submitted to EPA and presented to HSRB in 2011.

D. Legal Challenge to the 2006 Rule

    In early 2006, the Natural Resources Defense Council, Inc., 
Pesticide Action Network North American, Pineros y Campesinos Unido Del 
Noroeste, Physicians for Social Responsibility--San Francisco, Farm 
Labor Organizing Committee, ALF-CIO, and Migrant Clinicians Network 
petitioned for review of the 2006 rule in the United States Court of 
Appeals for the Second Circuit (Second Circuit Court of Appeals). (NRDC 
v. EPA, No. 06-0820-ag (2d Cir.)). The Petitioners argued that the 2006 
rule violated the 2006 Appropriations Act because it did not bar all 
pesticide research with pregnant women and children, was inconsistent 
with the 2004 NAS Report, and was inconsistent with the Nuremburg Code. 
The following paragraphs describe the Petitioner's arguments in greater 
detail.
    1. Inadequate bar against research with pregnant women and 
children. Petitioners argued that the scope of the 2006 rule's ban on 
research with pregnant women and children was unlawfully narrow because 
it was limited to studies intended for submission to EPA under FIFRA or 
FFDCA--the pesticide regulatory laws EPA administers. Petitioners 
argued that Congress's direction to EPA in the Appropriations Act to 
``not permit the use of pregnant women, infants, or children as 
subjects'' in ``intentional dosing human toxicity studies for 
pesticides'' did not allow EPA to distinguish between studies 
originally intended for publication and those intended for submission 
to EPA, or between studies with pesticides conducted for consideration 
under FIFRA or FFDCA and those conducted for consideration under the 
Safe Drinking Water Act or any other regulatory statute. Petitioners 
argued that EPA's 2006 rule violated the plain language of the 2006 
Appropriations Act on this point.
    2. Inconsistency with the 2004 NAS Report. The 2006 Appropriations 
Act required EPA's rule to be consistent with the principles proposed 
in the 2004 NAS Report. Petitioners argued that in citing the 
``principles'' of the 2004 NAS Report, Congress was referring to the 17 
recommendations in that report. Petitioners further argued that the 
2006 rule was inconsistent with several specific recommendations in the 
2004 NAS Report.
    First, Petitioners argued that the 2006 rule did not incorporate 
Recommendations 3-1 and 5-1 from the 2004 NAS Report, which recommend 
factors to be considered in the scientific evaluation of human 
research, including that such studies should have ``adequate 
statistical power'' and involve ``representative populations for the 
endpoint in question.''
    Second, Petitioners argued that the 2006 rule did not incorporate 
Recommendations 4-1 and 4-2 from the 2004 NAS Report, which suggest 
ethical considerations relevant to evaluation of human studies.
    Third, Petitioners argued that by adding qualifying language to the 
acceptance standard for pre-rule research suggested in Recommendation 
5-7 from the 2004 NAS Report, EPA made it inconsistent with the 2004 
NAS Report. Petitioners argued that EPA's addition of the word 
``significantly'' to the recommended acceptance standard, which permits 
EPA to rely on research not ``significantly'' deficient relative to 
prevailing standards, made the criterion in the 2006 rule unlawfully 
inconsistent with the recommendations in the 2004 NAS Report.
    Finally, Petitioners argued that the 2006 rule unlawfully failed to 
require provision of medical care for study participants, as suggested 
by Recommendation 5-5 from the 2004 NAS Report.
    3. Inconsistency with the Nuremberg Code. The 2006 Appropriations 
Act also required EPA's rule to be consistent with the principles in 
the Nuremberg Code pertaining to human experimentation. Petitioners 
argued that the 2006 rule was inconsistent with several principles in 
the Nuremburg Code.
    First, Petitioners argued that although the Nuremberg Code 
specifies that consent must be given by the human subject, the 2006 
rule permits consent to be given in certain situations by a legally 
authorized representative of the subject.
    Second, Petitioners argued that the 2006 rule was inconsistent with 
the Nuremberg Code principle that a test subject ``should have 
sufficient knowledge and comprehension of the elements of the subject 
matter involved as to enable him to make an understanding and 
enlightened decision.'' Petitioners argued that the 2006 rule consent 
requirements were inadequate to ensure fully informed consent in the 
context of research involving pesticides.
    Third, Petitioners argued that the 2006 rule failed to address 
adequately the Nuremberg Code principle that a subject must be ``so 
situated as to be able to exercise free power of choice, without the 
intervention of any element of force, fraud, deceit, duress, over-
reaching, or other ulterior form of constraint or coercion.'' 
Petitioners argued that the requirement of the 2006 rule that consent 
should only be sought in circumstances that ``minimize the possibility 
of coercion or undue influence'' did not address the potential for 
fraud, deceit, over-reaching, or constraint. Petitioners asserted that 
constraint was a particular problem when prisoners are used as subjects 
in human studies, and the 2006 rule did not specifically address 
research with prisoners.
    Fourth, Petitioners argued that the 2006 rule was inconsistent with 
the Nuremberg Code because it did not explicitly impose the Nuremburg 
Code's requirement that human studies be ``designed and based on the 
results of animal experimentation.''
    Finally, Petitioners argued that the 2006 rule was inconsistent 
with the Nuremberg Code principle that human testing ``should be such 
as to yield fruitful results * * * unprocurable by other methods or 
means of study, and not random and unnecessary in nature.'' Petitioners 
argued that the 2006 rule requires no inquiry into whether human 
testing is necessary given other methods of research.

E. Settlement of the Litigation

    After briefing and argument, but before a decision was rendered by 
the Second Circuit Court of Appeals, EPA and Petitioners began 
negotiations to settle the litigation. In the settlement agreement 
finalized on November 3, 2010, EPA agreed to conduct 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

[[Page 5741]]

parties and attached to the settlement agreement as Exhibit A. This 
agreement, including Exhibit A, is available in the docket for this 
action as described under ADDRESSES.
    The settlement agreement further provides that EPA will propose the 
negotiated amendments no later than January 18, 2011, and that EPA will 
take final action on the amendments no later than December 18, 2011. 
The settlement agreement, however, makes clear that EPA retains full 
discretion concerning what amendments are proposed, and what, if any, 
amendments are finalized.
    Although the wording of the amendments proposed in this document 
differs in a few details of construction and wording, they are 
substantially consistent with the regulatory language negotiated with 
Petitioners, and EPA considers these amendments to address the 
Petitioners' major arguments outlined in Unit III.D. Specifically:
     The proposed amendments would retain the scope of the 2006 
rule to cover research submitted to EPA under FIFRA or FFDCA, and 
extend that scope to cover as well research involving intentional 
exposure to a pesticide, intended for submission to EPA under any other 
regulatory statute administered by EPA.
     The proposed amendments incorporate language from each of 
the recommendations from the 2004 NAS Report cited by Petitioners in 
their challenge to the 2006 rule, as well as other pertinent 
recommendations from the 2004 NAS Report.
     The proposed amendments address Petitioners' arguments 
concerning the Nuremberg Code by dropping from 40 CFR part 26, subpart 
K, all provisions for consent by a representative, and by requiring EPA 
to consider whether subjects gave their ``free and fully informed 
consent'' to participate in a study, whether the design of proposed new 
human research takes into account the knowledge gained in earlier 
animal testing, and whether proposed new human research is necessary.
    Although these proposed amendments emerged from a settlement 
agreement, EPA believes that proposing these amendments is consistent 
with the language and purposes of the applicable statutes and because 
they further the 2006 rule's goal of ensuring that EPA does not rely on 
research involving intentional exposure of human subjects to pesticides 
that is not ethically conducted or that is not scientifically sound. 
EPA believes that many of the changes proposed in this document are 
codifications of the manner in which EPA and HSRB have interpreted and 
implemented the 2006 rule, but welcomes comment on these 
interpretations. EPA will fully re-evaluate the appropriateness of the 
proposed amendments in light of all comments received in response to 
this proposed rule before making a final determination. In particular, 
EPA seeks comment on the relative merits of the proposed changes 
compared to retaining the current scope and content (i.e., current 
wording) of the 2006 rule.

IV. Proposed Amendments, Rationale, and Request for Comment

    This unit provides a description of each proposed change, the 
rationale for the proposed change, and the anticipated effects of each 
change relative to the current regulatory text (i.e., the 2006 rule). 
EPA specifically requests comment on each of these proposed changes, as 
well as on the changes in the aggregate. In particular, EPA asks for 
comment on its conclusions regarding the effect of these proposed 
changes, including the effect of these proposed changes on the volume 
of studies covered by the rule, the likely statutes under which studies 
may be submitted, and the impact on activities covered by those other 
statutes, relative to the scope of the 2006 rule.

A. Redefining the Scope and Applicability of 40 CFR Part 26, Subparts 
K, L, M, P, and O

    1. Summary of proposed changes. EPA is proposing amendments that 
would modify the scope and applicability of several subparts of the 
2006 rule. The proposed changes would modify the criteria defining the 
types of research covered by 40 CFR part 26, subparts K, L, and M--most 
notably the criteria relating to the intentions of the sponsor or 
investigator in conducting the research or the intentions of the person 
submitting the research to EPA.
    The specific changes proposed to the scope and applicability 
sections of 40 CFR part 26, subparts K, L, M, P, and Q, are explained 
here. Although EPA does not propose to change the text of the 2006 rule 
defining the scope of 40 CFR part 26, subpart O, concerning 
``Administrative Actions for Noncompliance,'' the scope of that subpart 
would change nonetheless, because its applicability depends on the 
scope provisions in other subparts that EPA is proposing to change. 
More specifically, these changes alter the scope as follows: instead of 
covering substances under FIFRA, the proposed amendments would cover 
pesticides under all statutes.
    In general, the proposed amendments would shift the focus from 
whether the research on the substance was intended for EPA's 
consideration and use under the pesticide laws, FIFRA and FFDCA, to 
whether the research was conducted with a pesticide and was intended 
for EPA's consideration and use in connection with an action under any 
regulatory statute administered by EPA. The proposed amendments also 
would add a new section to 40 CFR part 26, subpart P, defining its 
scope and would change the scope and applicability of 40 CFR part 26, 
subpart Q, to parallel the changes in 40 CFR part 26, subpart K.
    2. Summary of anticipated effects. Although almost all studies with 
pesticides are conducted and submitted to EPA for consideration under 
FIFRA or FFDCA, it is possible that some pesticide studies may be 
considered by EPA only under other regulatory authorities and not be 
considered under FIFRA and FFDCA. If studies involving intentional 
exposure of humans to a pesticide are submitted or considered under 
other EPA regulatory statutes, with the proposed amendment, such 
studies would be subject to the same requirements that would have 
applied had they been submitted or considered under FIFRA or FFDCA. In 
proposing these amendments, EPA finds that these changes in scope are 
consistent with the focus in the 2006 Appropriations Act on intentional 
dosing human toxicity studies with pesticides.
    In sum, EPA does not believe that the several changes to the 
``scope'' sections of 40 CFR part 26, subparts K and L--Sec.  26.1101 
and Sec.  26.1201--and a new definition of ``pesticide'' at Sec.  
26.1102(c), that expand the range of human research to which these two 
subparts apply, will result in a significant increase in the number of 
studies reviewed under the rule. However, EPA recognizes that this is a 
possibility and requests comment on whether these proposed changes are 
clear about which studies would fall under the scope of the rule. EPA 
knows of no third-party research involving intentional exposure of a 
human subject to a pesticide that has ever been proposed, conducted, or 
submitted to EPA under regulatory authorities other than the pesticide 
laws. The proposed expansion of the scope of these subparts, however, 
would mean that any such studies that are proposed, conducted, or 
submitted to EPA will be governed by the same standards as pesticide 
studies submitted under FIFRA or FFDCA section 408.
    3. 40 CFR part 26, subparts K and L--basic ethical requirements and 
prohibitions applying to third-party research involving intentional 
exposure of human subjects to a pesticide.

[[Page 5742]]

    a. Current rule. Subpart K of 40 CFR part 26 extends the basic 
protections of the Common Rule to subjects in certain third-party human 
research; subpart L of 40 CFR part 26 forbids new third-party research 
involving intentional exposure of children or of pregnant or nursing 
women. In the 2006 rule these two subparts apply to ``research with a 
human subject'' which meets four criteria. First, it was initiated 
after April 7, 2006 (the effective date of the 2006 rule). Second, it 
is ``research involving intentional exposure of a human subject'' as 
defined at Sec.  26.1102(i). Third, it was conducted or supported by a 
``person'' as defined at Sec.  26.1102(j). Fourth, it was intended by 
any person conducting or supporting the research to be submitted to 
EPA, or to be held for later inspection by EPA, under the pesticide 
laws (FIFRA or FFDCA).
    The two cited definitions are critical to understanding the scope 
and applicability of subparts K and L of 40 CFR part 26. ``Research 
involving intentional exposure of a human subject,'' is defined at 
Sec.  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 Sec.  26.1102(j) to have the same 
meaning as in FIFRA section 2(s) (7 U.S.C. 136(s)), except that it 
excludes Federal agencies subject to the Common Rule and any person 
when performing research supported by a Common Rule Federal department 
or agency. This exclusion is appropriate because that research is 
covered by the Common Rule, which provides necessary and appropriate 
protections for the research subjects. Thus, research already covered 
by the standards of the Common Rule is not also subject to subparts K 
and L. These subparts, in short, apply only to ``third-party 
research''--research that is neither conducted (``first-party'') nor 
supported (``second-party'') by EPA or another Common Rule Federal 
department or agency.
    Finally, Sec.  26.1101(g) explains how EPA will approach 
determination of the intent of sponsors or investigators to submit 
research to EPA under the pesticide laws, or hold it for inspection by 
EPA under the pesticide laws.
    b. Proposed amendments, rationale, and anticipated effect. The 
amendments proposed in this document would not change the definitions 
of ``research involving intentional exposure of a human subject'' or of 
``person.'' They would add a new definition of ``pesticide'' at Sec.  
26.1102(c), and would modify the applicability provisions in Sec.  
26.1101, as explained later in this Unit of the document.
    The first of the four criteria for application of 40 CFR part 26, 
subpart K, will change to incorporate the effective date of a final 
rule amending the 2006 rule. EPA believes it would be inappropriate to 
apply these proposed amendments retroactively. For example, if post-
2006 research newly covered by an amended rule as proposed in this 
document were submitted to EPA, its acceptability should not be judged 
by its compliance with a rule promulgated after it was conducted. Until 
the 2006 rule is amended by a final rule, its provisions continue to 
apply fully to new research. Hence no sponsor or investigator subject 
to the 2006 rule would be relieved by the change in the effective date 
of any obligation to comply with 40 CFR part 26, subparts K and L, for 
research initiated between April 7, 2006, and the effective date of any 
subsequent amendments.
    The proposal would modify the second of the four criteria so that 
40 CFR part 26, subparts K and L, would apply to research involving 
intentional exposure of a human subject ``to a pesticide'' when the 
research is intended for submission to EPA under any regulatory statute 
other than FIFRA or FFDCA. The definition of ``research involving 
intentional exposure of a human subject'' would not change, nor would 
the applicability of these subparts to all new third-party research 
involving intentional exposure of human subjects which is intended for 
submission to EPA under FIFRA or FFDCA.
    In determining whether research involves intentional exposure to a 
pesticide, EPA will focus, as does the FIFRA definition of a 
``pesticide,'' on the intended use of the substance. EPA expects that 
application of this standard will nearly always be straightforward. 
However, EPA recognizes that there may be cases where making such a 
determination may not be as straightforward. EPA will apply this 
criterion as follows.
    Initially, EPA will examine the study on its face. If the study 
states that it involves the testing of a pesticide, or if the tested 
substance is used for pesticidal effect in the study, as it is in 
insect repellent efficacy testing or in monitoring exposure of 
pesticide applicators, there can be little question that the study 
involves exposure to a pesticide. If on the other hand the study 
reports testing of another type of substance, such as an industrial 
chemical, waste product, or air pollutant, then absent compelling 
evidence to the contrary, EPA will not treat the study as involving 
exposure to a pesticide.
    If it is not clear from the face of the study whether it involves 
exposure to a pesticide, EPA will look to other objective factors to 
determine whether a substance is being tested as a pesticide. Intent to 
test a substance as a pesticide could be indicated by evidence that the 
testing was conducted or supported by an entity regulated under FIFRA 
or section 408 of FFDCA; the testing was conducted for the purpose of 
attaining a FIFRA registration or FFDCA tolerance; there are not 
significant commercial uses for the substance other than as a 
pesticide; or human exposure to the substance occurs primarily from its 
use as a pesticide. Absent any such evidence, EPA will generally treat 
the study as not involving exposure to a pesticide.
    EPA expects that in most cases, the question of whether the study 
involves exposure to a pesticide will be quickly resolvable without 
looking to other objective factors such as the four identified in the 
previous paragraph. EPA believes that this would be true even for 
multiple-use substances that may be used as a pesticide and may also 
result in human exposure from other commercial uses or as a result of 
deposition in the environment as a waste product.
    A good example of how EPA will determine if studies on multi-use 
substances are studies on a pesticide is presented by sulfur dioxide 
(SO2)--a registered pesticide active ingredient used as a 
fungicide in grape culture, and also a common air pollutant. Thousands 
of tons of SO2 are released yearly into the atmosphere by 
burning of coal and other fossil fuels. In promulgating National 
Ambient Air Quality Standards (NAAQS) for SO2 under the 
Clean Air Act (CAA) in 2010, EPA relied on numerous human studies 
involving intentional exposure of subjects to SO2. Most of 
these studies on their face indicate clearly that they tested 
SO2 as an industrial air pollutant and not as a pesticide. 
The few that do not expressly state they tested SO2 as an 
air pollutant are, nonetheless, easily classified as not involving 
exposure to a pesticide, because the testing was not conducted

[[Page 5743]]

or sponsored by a pesticide registrant, the studies do not indicate 
they were performed in support of FIFRA registration, and there are 
clearly other major sources of human exposure to SO2 in 
addition to whatever pesticide exposure occurs. Thus, these studies 
would not come within the scope of the 2006 rule if the scope is 
modified as proposed.
    EPA specifically requests comment on the implications of this 
change for the volume of studies that may need to be reviewed under 
such a proposed amendment.
    The amendments proposed in this document would not change the 
applicability of 40 CFR part 26, subparts K and L, to ``persons'' or 
the definition of that term at Sec.  26.1102(j). Thus the third of the 
four criteria would not be affected by these proposed amendments.
    The fourth criterion would be broadened by the amendments proposed 
in this document beyond the scope of the 2006 rule. The 2006 rule 
applies to research with any substance, conducted with intent to submit 
its results to EPA under FIFRA or FFDCA; as proposed here, the rule 
would apply as well to research with a pesticide, conducted with intent 
to submit its results to EPA ``for consideration in connection with any 
action that may be performed under any regulatory statute administered 
by EPA'' other than FIFRA or FFDCA.
    The new element in this fourth criterion, putting aside the 
proposed amendment to refer to ``pesticides,'' is the reference to 
actions taken ``under any regulatory statute administered by EPA.'' 
Research intended for submission under FIFRA or FFDCA is covered by the 
2006 rule and would continue to be covered under proposed Sec.  
26.1101(a)(1). Proposed Sec.  26.1101(a)(2) would broaden the scope of 
subparts K and L of 40 CFR part 26 to apply as well to research 
involving intentional exposure of a human subject to a pesticide which 
is intended for submission to EPA for consideration in connection with 
any action that may be performed under any regulatory statute other 
than FIFRA or FFDCA. Such submission could be made under CAA, the Safe 
Drinking Water Act (SDWA), the Clean Water Act (CWA), the Resource 
Conservation and Recovery Act (RCRA), the Comprehensive Environmental 
Response, Compensation and Liability Act (CERCLA, or the Superfund 
law), or other similar statutes. EPA specifically seeks comment on the 
scope of this proposed change (i.e., the frequency with which it might 
be triggered, including other statutes to which the proposed change 
would apply) and the implications of the proposed changes on the 
activities governed by those other regulations. EPA seeks comment on 
the relative merits of this change compared to retaining the current 
scope of the 2006 rule. As noted, EPA does not expect that these 
wording changes will result in any substantive changes to the number or 
manner in which studies are currently reviewed.
    As an example, EPA's Office of Water has, in the past, set Maximum 
Contaminant Levels (MCLs) under the SDWA with pesticides found in 
drinking water. Under the proposed amendment to the scope of 40 CFR 
part 26, subpart K, any new third-party study involving intentional 
exposure of a human to a pesticide, and intended for submission to the 
Office of Water for consideration in setting a MCL, would now be 
subject to 40 CFR part 26, subpart K, including the requirement of 
Sec.  26.1125 for submission of the proposal for prior review by EPA 
and HSRB. EPA would note that this is a theoretical example in that it 
is unaware of any such study having been submitted with regard to a 
MCL.
    EPA actions not taken under the authority of regulatory statutes 
would not satisfy this fourth criterion. For example, an EPA comment on 
another Federal department's or agency's Environmental Impact Statement 
would not constitute an action taken under a regulatory statute, and 
research intended for submission solely for consideration in such a 
context would not be subject to 40 CFR part 26, subparts K and L.
    EPA interprets the word ``action'' in this context broadly, 
embracing both regulatory and non-regulatory actions. Regulatory 
actions include, for example, cancellation or registration of a 
pesticide, establishment of a tolerance for a pesticide residue in 
food, or establishing a MCL for a pesticide active ingredient under 
SDWA. Non-regulatory actions include, for example, risk assessments of 
pesticide active ingredients, recommended (non-binding) safe levels of 
exposure such as Health Advisory Limits when these pertain to 
pesticides, or clean-up standards for pesticides at a Superfund site.
    The amendments proposed in this document include two additional 
editorial revisions to clarify the scope sections of 40 CFR part 26, 
subparts K and L. One change would clarify the applicability of 40 CFR 
part 26, subpart K, by moving the exposition of how EPA will determine 
intent to submit from Sec.  26.1101(g), where it appears in the 2006 
rule, to Sec.  26.1101(b), immediately following the presentation of 
the four criteria. The other would amend Sec.  26.1201, the scope 
section of 40 CFR part 26, subpart L, to state simply that 40 CFR part 
26, subpart L applies to all research subject to 40 CFR part 26, 
subpart K.
    4. 40 CFR part 26, subpart M--requirement for documentation of the 
ethical conduct of completed human research submitted to EPA.
    a. Current rule. Subpart M of 40 CFR part 26 requires those who 
submit the results of human research to EPA for consideration under the 
pesticide laws to submit information documenting the ethical conduct of 
the completed research. Under the 2006 rule, 40 CFR part 26, subpart M, 
applies when a ``person'' as defined at Sec.  26.1102(j) submits after 
the effective date of the 2006 rule a report containing the results of 
any human research to EPA for consideration under the pesticide laws.
    These criteria differ from those defining coverage by 40 CFR part 
26, subparts K and L, in important ways. First, unlike other subparts 
of the 2006 rule, subpart M applies to submissions after the effective 
date of the rule of any and all human research, without regard to who 
conducted it, when, or for what purpose, or whether or not the reported 
research involved intentional exposure of a human subject. Second, 
subpart M applies only when a person (other than a Federal department 
or agency subject to the Common Rule) submits the results of human 
research to EPA. Subpart M does not apply when EPA, on its own 
initiative, retrieves published articles or otherwise obtains 
information derived from human research.
    b. Proposed amendments and rationale. EPA proposes to broaden the 
applicability of 40 CFR part 26, subpart M, by amending Sec.  26.1301, 
while leaving the substantive requirements of subpart M unchanged. 
Specifically, EPA proposes to include submissions of reports of human 
research on pesticides for consideration by EPA under regulatory 
statutes other than FIFRA or FFDCA. Under the proposed amendments, 
subpart M would apply when a ``person'' as defined at Sec.  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

[[Page 5744]]

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 Sec.  26.1117 and Sec.  
26.1125(a). This requirement is qualified by the provision that such 
records need only be provided ``[t]o the extent [the records] are 
available to the submitter and not previously provided to EPA,'' but 
any submitter not providing the information required must ``describe 
the efforts made to obtain the information.''
    To minimize the potential burden on commenters, EPA considered 
excluding from the coverage of 40 CFR part 26, subpart M, submissions 
of published scientific journal articles reporting human research, or 
of citations to such articles. In some circumstances, however, EPA 
believes it is important for submitters of even published human 
research to bear the burden of gathering the information required by 
Sec.  26.1303. Specifically, EPA believes a submitter of published 
human research who is seeking action under a regulatory statute from 
EPA that would directly benefit the submitter should be obliged to 
gather records bearing on the conduct of the research, even if the 
research is described in the public literature. For example, an 
applicant for a pesticide registration or a party petitioning for a 
pesticide tolerance should have to exercise reasonable efforts to 
obtain records of the ethical conduct of research relied on to support 
the EPA action sought, whether or not the research happens to be 
described in a scientific journal. Reasonable efforts in these 
circumstances may include seeking relevant records from the research 
administrator or the overseeing IRB. On the other hand, if a member of 
the public responds to an EPA request for information on a pesticide by 
citing or submitting a published study, EPA believes that certification 
that the submitter did not sponsor, participate in, or otherwise have 
personal knowledge of or responsibility for the referenced research 
would satisfy the submitter's obligation under 40 CFR part 26, subpart 
M.
    c. Anticipated effect. EPA's concern for the potential burden of 40 
CFR part 26, subpart M, on the public is tempered by its experience 
under the 2006 rule. Since promulgation of the 2006 rule EPA has 
received very few submissions of reports of human research on or with a 
pesticide for consideration under FIFRA or FFDCA, and EPA expects 
submissions of such studies to EPA for consideration only under other 
regulatory statutes will be even less common.
    EPA specifically requests comments on this approach to and 
interpretation of the requirements in 40 CFR part 26, subpart M. Such 
comments should address whether the proposed rule language is adequate 
to implement EPA's interpretation.
    5. 40 CFR part 26, subpart P--EPA and HSRB review of proposed and 
completed human research.
    a. Current rule. Subpart P of 40 CFR part 26 applies to EPA and 
HSRB reviews of proposals for new research involving intentional 
exposure of a human subject, and EPA and HSRB reviews of reports of 
completed research involving intentional exposure of a human subject 
and on which EPA proposes to rely in an action under the pesticide 
laws. Unlike other subparts of the 2006 rule, subpart P does not 
include a ``scope'' section; its applicability is defined only 
indirectly by references to other subparts.
    b. Proposed amendments and rationale. EPA proposes to make explicit 
the applicability of 40 CFR part 26, subpart P, in a new Sec.  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 Sec.  26.1125,'' and (2) ``reviews by EPA after [effective date 
of the amended rule] and, to the extent required by Sec.  26.1604, by 
the Human Studies Review Board, of reports of completed research 
subject to 40 CFR 26.1701.''
    c. Anticipated effect. Since 40 CFR 26.1125 is in subpart K and 40 
CFR 26.1701 is in subpart Q, the broadened scope of these subparts as 
proposed in these amendments would indirectly broaden the scope of 40 
CFR part 26, subpart P.
    6. 40 CFR part 26, subpart Q--ethical standards for assessing 
whether to rely on the results of human research in EPA actions.
    a. Current rule. Subpart Q of 40 CFR part 26 defines ethical 
standards that must be met for EPA to rely on the results of human 
research in actions taken under the pesticide laws. Specifically, 40 
CFR part 26, subpart Q, applies to EPA decisions to rely on data from 
completed studies involving intentional exposure of a human subject, 
when EPA regards the data as scientifically valid and relevant to an 
action taken under the pesticide laws.
    b. Proposed amendments and rationale. For the same reasons it is 
proposing to broaden the applicability of 40 CFR part 26, subpart K 
(discussed in Unit IV.A.1.), EPA proposes to amend Sec.  26.1701 to 
broaden the applicability of 40 CFR part 26, subpart Q. Proposed Sec.  
26.1701(a) would retain without change the applicability of 40 CFR part 
26, subpart Q, to research involving intentional exposure of human 
subjects to any substance, in the context of EPA actions taken under 
FIFRA or FFDCA. Proposed Sec.  26.1701(b) would extend the 
applicability of 40 CFR part 26, subpart Q, to research involving 
intentional exposure of human subjects to a pesticide, in the context 
of EPA actions taken under any other regulatory statute administered by 
EPA.
    EPA intends to interpret ``action'' and ``regulatory statute 
administered by EPA'' in 40 CFR part 26, subpart Q, just as these terms 
would be interpreted for 40 CFR part 26, subpart K. To make this scope 
provision consistent with the other scope provisions in this proposal, 
EPA proposes to depart from the language negotiated in the settlement 
agreement and define the scope of 40 CFR part 26, subpart Q, in terms 
of the ``research'' covered rather than the ``decisions'' covered.
    c. Anticipated effect. EPA expects this change in the scope of 40 
CFR part 26, subpart Q, to affect few, if any, EPA actions. Although 
such actions may occur in the future, EPA cannot identify any actions 
taken since 2006 under any regulatory statute other than FIFRA or FFDCA 
that relied on research involving intentional exposure of a human 
subject to a pesticide.
    As explained previously, EPA is authorized to propose this change 
because it is consistent with the 2006 Appropriations Act. This 
proposal would mean that all intentional human studies involving 
pesticides submitted to EPA would be reviewed under the same ethical 
and scientific criteria. On the other hand, EPA has also noted that it 
expects this change will affect few additional studies and may create 
some uncertainty as to what studies are covered by the rule.
    EPA specifically invites comment on the value of making this change 
and whether there are additional factors to be considered in evaluating 
the appropriateness of the change, such as the frequency with which it 
might be triggered, including other statutes to which the proposed 
change would apply, and on the clarity of the proposed changes.

B. Disallowing Consent by a Surrogate (40 CFR Part 26, Subpart K)

    1. Current rule. In the 2004 NAS Report to EPA, the NAS recommended 
use of the Common Rule as the starting point for protecting human 
subjects in research involving intentional exposure. Consistent with 
this recommendation,

[[Page 5745]]

EPA incorporated much of the text of the Common Rule into subpart K of 
40 CFR part 26, including language providing for consent for a 
subject's participation in research by the subject's ``legally 
authorized representative'' when the subject lacks the capacity to 
consent for himself or herself. The Common Rule, drafted to protect 
subjects in a wide variety of research settings, included these 
provisions to permit research in various situations, including, for 
example, research into emergency procedures to save lives of 
unconscious patients, into improved care for people suffering psychosis 
or schizophrenia, and to collect valuable data from research with other 
subjects who lacked the legal capacity to provide fully informed, fully 
voluntary consent.
    2. Proposed amendments and rationale. EPA proposes to amend 40 CFR 
part 26 by deleting from subpart K all references permitting consent by 
a subject's legally authorized representative. The sections affected 
are the definition of ``legally authorized representative'' at Sec.  
26.1102(c); the ``Criteria for IRB approval of research'' at Sec.  
26.1111; the ``General requirements for informed consent'' at Sec.  
26.1116; and the requirements for ``Documentation of informed consent'' 
at Sec.  26.1117.
    EPA proposes to disallow consent by a representative in third-party 
studies because the types of research that are conducted on pesticides 
would not use subjects for whom such a procedure is needed. (The 
research covered by 40 CFR part 26, subpart K includes research 
involving intentional exposure of non-pregnant, non-nursing adults to a 
pesticide or research involving intentional exposure of non-pregnant, 
non-nursing adults intended for submission under FIFRA or FFDCA.)
    3. Anticipated effect. EPA has never seen, and cannot envision, any 
such research in which it could be justified to enroll subjects lacking 
the capacity to consent for themselves. EPA does not propose to modify 
the provisions of 40 CFR part 26, subpart A, EPA's codification of the 
Common Rule. 40 CFR part 26, subpart A, applies to a much broader range 
of research with human subjects conducted or supported by EPA including 
research for which consent by a legally authorized representative may 
be appropriate.

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

    1. Current rule. 40 CFR part 26, subpart P, defines in largely 
procedural terms how EPA evaluates proposals for new research submitted 
under Sec.  26.1125 of 40 CFR part 26, subpart K, and how EPA is to 
review reports of completed research. Subpart P of 40 CFR part 26 also 
defines the membership and responsibilities of HSRB.
    2. Proposed amendments and rationale.
    a. Revisions to 40 CFR part 26, subpart P, generally. The proposed 
amendments to 40 CFR part 26, subpart P, include:
     A proposed new Sec.  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 Sec.  26.1125 of subpart K 
and to EPA and HSRB reviews of reports of completed research covered by 
subpart Q. This change is discussed in Unit IV.A.3.
     A proposed new Sec.  26.1602 references the definitions in 
40 CFR part 26, subpart K.
     A proposal to expand the discussion of EPA reviews of 
proposed research in Sec.  26.1603, retaining all elements of Sec.  
26.1601 from the 2006 rule, and including a new Sec.  26.1603(b) 
listing considerations to be addressed by EPA in its science reviews of 
proposed research, and a new Sec.  26.1603(c) listing considerations to 
be addressed by EPA in its ethics reviews of proposed research.
     A proposal to slightly revise discussion of EPA reviews of 
completed research, redesignating Sec.  26.1602 in 40 CFR part 26 as 
Sec.  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 Sec.  26.1603 in the 2006 rule would 
be redesignated as Sec.  26.1605, defining the membership and 
responsibilities of HSRB.
     A proposed new Sec.  26.1606 requiring HSRB in its reviews 
of proposed research to consider the same range of scientific, ethical, 
and other topics addressed by EPA in its reviews under Sec.  26.1603.
     A proposed new Sec.  26.1607 requiring HSRB in its reviews 
of completed research to consider both the scientific and ethical 
merits of the research, and to apply the appropriate acceptance 
standards in 40 CFR part 26, subpart Q.
    As indicated previously and again throughout this discussion, EPA 
requests comment on each of these proposed changes, as well as on the 
changes in the aggregate. EPA also seeks comments on particular points 
as provided in the discussion.
    b. Section 26.1603--EPA Review of proposed human research. Because 
the most significant changes proposed are the new lists in Sec.  
26.1603(b) and (c) of considerations to be addressed in EPA reviews of 
proposed new research, those proposed changes will be discussed in 
greater detail here. These proposed lists were derived primarily from 
the following recommendations in the 2004 NAS Report (reproduced 
verbatim here and referenced in the subsequent discussions):

Recommendation 3-1: Scientific Validity of Intentional Human Dosing 
Studies

    EPA should issue guidelines for determining whether intentional 
human dosing studies have been:
    a. Justified, in advance of being conducted, as needed and as 
scientifically appropriate, in that they could contribute to 
addressing an important scientific or policy question that cannot be 
resolved on the basis of animal data or human observational data;
    b. Designed in accordance with current scientific standards and 
practices to (i) address the research question, (ii) include 
representative study populations for the endpoint in question, and 
(iii) meet requirements for adequate statistical power;
    c. Conducted in accordance with recognized good clinical 
practices, including appropriate monitoring for safety; and
    d. Reported comprehensively to EPA, including the full study 
protocol, all data produced in the study (including adverse events), 
and detailed analyses of the data.

Recommendation 4-1: Value of Studies That Seek to Improve the 
Accuracy of EPA's Decisions But Do Not Provide a Public Health or 
Environmental Benefit

    EPA should consider a human dosing study intended to reduce the 
interspecies uncertainty factor (for example, a study of a biomarker 
such as cholinesterase inhibition) as conferring a societal benefit 
only if it was designed and conducted in a manner that would improve 
the scientific accuracy of EPA's extrapolation from animal to human 
data. Because the anticipated benefit would not be as great as that 
conferred by studies intended to provide a public health or 
environmental benefit, the study could be justified ethically only 
if the participants' exposure to the pesticide could reliably be 
anticipated to pose no identifiable risk or present a reasonable 
certainty of no harm to study participants.

Recommendation 5-1: Criteria for Scientific and Ethical 
Acceptability

    Studies that do not meet the highest scientific and ethical 
standards should not be carried out or accepted by EPA as input to 
the regulatory decision-making process. Necessary conditions for 
scientifically and ethically acceptable intentional human dosing 
studies include:
    a. Prior animal studies and, if available, human observational 
studies;
    b. A demonstrated need for the knowledge to be obtained from 
intentional human dosing studies;
    c. Justification and documentation of a research design and 
statistical analysis that are adequate to address an important 
scientific or policy question, including adequate power to detect 
appropriate effects;

[[Page 5746]]

    d. An acceptable balance of risks and benefits and minimization 
of risks to participants;
    e. Equitable selection of participants;
    f. Free and informed consent of participants; and
    g. Review by an appropriately constituted IRB or its foreign 
equivalent.

Recommendation 5-2: Participant Selection Criteria

    IRBs reviewing intentional human dosing studies should ensure 
that the following conditions are met in selecting research 
participants:
    a. Selection should be equitable.
    b. Selection of persons from vulnerable populations must be 
convincingly justified in the protocol, which also must justify the 
measures to be taken to protect those participants.
    c. Selection of individuals with conditions that put them at 
increased risk for adverse effects in such studies must be 
convincingly justified in the protocol, which also must justify the 
measures that investigators will use to decrease the risks to those 
participants to an acceptable level.

Recommendation 5-3: Payment for Participation

    IRBs, all relevant review boards, investigators, and research 
sponsors should ensure that payments to participants in intentional 
human dosing studies are neither so high as to constitute undue 
inducement nor so low as to be attractive only to individuals who 
are socioeconomically disadvantaged. Proposed levels of and purposes 
for remuneration (e.g., time, inconvenience, and risk) should be 
scrutinized in light of the principles of justice and respect for 
persons. Moreover, EPA, in conjunction with other Federal agencies, 
should consider developing further guidance on remuneration for 
participation in intentional human dosing studies, including 
guidance regarding whether remuneration should reflect the level of 
risk as well as the time and inconvenience involved.

Recommendation 5-5: Compensation for Research-Related Injuries

    At a minimum, sponsors of or institutions conducting intentional 
human dosing studies should ensure that participants receive needed 
medical care for injuries incurred in the study, without cost to the 
participants. In addition, EPA should study whether broader 
compensation for research-related injuries should be required.

Recommendation 6-1: IRB Review of All Studies

    EPA should require that all human research conducted for 
regulatory purposes be approved in advance by an appropriately 
constituted IRB or an acceptable foreign equivalent. Research 
conducted by EPA scientists should be reviewed by an EPA-authorized 
IRB.
    [Taken from pages 7-14 of the 2004 NAS Report (http://www.national-academies.org).]

    c. Science Reviews--Sec.  26.1603(b). The provisions in proposed 
Sec.  26.1603(b) include considerations that EPA must take into account 
when conducting its science reviews of proposed research that would be 
covered by the rule. In developing this list of considerations, EPA 
relied on recommendations 3-1 and 5-1 from the 2004 NAS Report to 
identify specific items that would be relevant to evaluating the 
scientific merit of proposed human research. How EPA developed the 
specific language for each provision follows.
     Proposed Sec.  26.1603(b)(1): Whether the research would 
be likely to produce data that address an important scientific or 
policy question that cannot be resolved on the basis of animal data or 
human observational research.
    This language is a combination of recommendations 3-1(a) and 5-1(b) 
and (c) from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). The language ``address an important scientific or policy 
question'' reflects excerpts taken from recommendation 5-1(c). The 
language ``that cannot be resolved on the basis of animal data or human 
observation research'' is taken from recommendation 3-1(a). These 
recommendations are intended to avoid unnecessary exposure for human 
subjects. If animal data or human observational research were available 
to address an important scientific or policy question, then there would 
be no scientific need for additional human research. EPA relied 
primarily on recommendation 5-1 in formulating the proposed language 
because that recommendation addresses criteria for EPA acceptance of 
human research, whereas recommendation 3-1describes topics that should 
be covered in EPA guidelines.
    Based on recommendation 5-1, EPA has phrased the proposed language 
as whether the research ``addresses'' an important scientific question 
rather than use the phraseology ``contributes to addressing'' in 
recommendation 3-1. The Agency believes its formulation is clearer and 
intends to interpret this as meaning that the research needs to be 
designed to obtain data likely to provide significant insight into 
important research questions.
    EPA requests comment on whether its reliance primarily on the 
language of recommendation 5-1(c) is appropriate here, or whether it 
should have used the ``contributes to'' language from recommendation 3-
1(a).
     Proposed Sec.  26.1603(b)(2): Whether the proposed 
research is designed in accordance with current scientific standards 
and practices to: Address the research question, include representative 
study populations for the endpoint in question, and have adequate 
statistical power to detect appropriate effects.
    Again, this language is a combination of recommendations 3-1(b) and 
5-1(c) from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). The recommendations highlight the need for adequate 
statistical power and appropriate representative study populations to 
ensure the scientific validity and reliability (and thus ethical 
conduct) of human research. To accommodate these recommendations, EPA 
is proposing to adopt language from the recommendations 3-1(b) and 5-
1(c).
    For the reason stated in the previous discussion on proposed Sec.  
26.1603(b)(1), EPA placed primary reliance on recommendation 5-1. The 
Agency notes that the proposed Sec.  26.1603(b)(2)(iii), which reflects 
the language in 5-1(c), differs from the language in 3-1(b), which says 
``meets requirements for adequate statistical power.'' The Agency 
prefers to propose the language as contained in 5-1(c) because it does 
not believe that there is one specific set of ``requirements'' with 
which to evaluate statistical power. The Agency intends to evaluate the 
statistical power of a study while focusing on the ultimate goal of 
ensuring that appropriate effects are detected rather than on some 
arbitrary and undefined set of ``requirements.''
    EPA requests comment on whether the proposed language is clear and 
specifically on this language as compared to using the language 
directly from the recommendation in the 2004 NAS Report.
     Proposed Sec.  26.1603(b)(3): Whether the investigator 
proposes to conduct the research in accordance with recognized good 
research practices, including, when appropriate, good clinical practice 
guidelines and monitoring for the safety of subjects.
    This provision reflects excerpts taken from recommendation 3-1(c) 
from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). Although the NAS focused on good clinical practice 
guidelines, the Agency is proposing to apply a broader standard 
``recognized good research practices'', which may include good clinical 
practice guidelines when appropriate. The rationale for this is that 
some human research--in fact, all human research proposed to EPA to be 
conducted since promulgation of the 2006 rule--is not conducted in 
clinical settings (e.g., field testing of repellents or worker 
exposure) and thus good clinical practice guidelines would be 
inappropriate to apply. However, there may be other general good 
research practices that the research community

[[Page 5747]]

employs to ensure scientific integrity of their studies and safety of 
the subjects that would be relevant for the Agency to consider. One 
such practice that has currently been developed is the Guidelines for 
Performance Testing of Skin-Applied Insect Repellent issued in October 
2008, and incorporated into the OCSPP harmonized test guidelines 
library in July 2010, entitled ``Product Performance Test Guidelines 
No. 810.3700: Insect Repellents to be Applied to Human Skin'' (http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series810.htm).
    EPA requests comment on this expansion and also welcomes 
suggestions for other good research practice documents that could be 
cited here as well.
    d. Ethics Reviews--Sec.  26.1603(c). The provisions in proposed 
Sec.  26.1603(c) address many important ethical concerns, including, 
among other things, identification and minimization of risks to 
participants, equitable selection of participants, and provision of 
medical care for participants. In developing this list of 
considerations, EPA relied on several recommendations from the 2004 NAS 
Report, including 4-1, 5-1, 5-2, 5-3, and 5-5 (see verbatim text 
provided in Unit IV.C.2.b.), to identify specific considerations that 
would be relevant to evaluating the ethics of proposed human research. 
Each proposed consideration is discussed below.
     Proposed Sec.  26.1603(c)(1): Whether adequate information 
is available from prior animal studies or from other sources to assess 
the potential risks to subjects in the proposed research.
    This provision reflects excerpts taken from recommendation 5-1(a) 
from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.), which recommends that animal studies be available prior to 
conducting human studies. This NAS recommendation also suggests 
consideration of human observational studies if available. When EPA 
conducts its ethics reviews, it does and will continue to consider 
whether there is adequate information from prior animal and human 
observational studies to understand the level of risk that may be 
presented to subjects of the proposed research. Although the NAS does 
not specify in its recommendation the specific purpose that the 
information from prior animal studies or from other sources, including 
human observational studies if available, serves, EPA believes its use 
of these studies to assess potential risks in evaluating the ethics of 
a human research proposal subject to this rule is reasonable and an 
integral part of determining whether the benefits of the research 
outweigh the risks of the research. The proposed language refers to 
``information * * * from prior animal studies or from other sources.'' 
EPA intends the reference to ``other sources'' to include human 
observational studies, consistent with recommendation 5-1.
    EPA requests comment on whether the proposed language is clear and 
specifically on this language as compared to using the language 
directly from the recommendation in the 2004 NAS Report.
     Proposed Sec.  26.1603(c)(2): Whether the research 
proposal adequately identifies anticipated risks to human subjects and 
their likelihood of occurrence, minimizes identified risks to human 
subjects, and identifies likely benefits of the research and their 
distribution.
    This provision is based on recommendation 5-1(d) from the 2004 NAS 
Report (see verbatim text provided in Unit IV.C.2.b.), which states 
that the necessary conditions for human research include ``an 
acceptable balance of risks and benefits and minimization of risks to 
participants.'' EPA has separated these two conditions and addresses 
minimization of risk in this paragraph and the balance of risks and 
benefits in proposed Sec.  26.1603(c)(3). In this paragraph, EPA also 
proposes to include a consideration of whether the research proposal 
adequately identifies anticipated risks to human subjects and their 
likelihood of occurrence and the likely benefits of the research and 
their distribution. These additional considerations are important in 
understanding the overall risk/benefit picture of proposed human 
research covered by this rule. EPA does not believe that adding these 
considerations will impose any additional burden on stakeholders since 
this information is typically provided with research proposals that are 
submitted to IRBs and to the Agency. EPA currently reviews human 
research proposals submitted to it under the 2006 rule with these 
considerations in mind.
    EPA requests comment on whether it is appropriate to address 
minimization of risk and the risk-benefit balance in separate 
paragraphs. EPA has chosen this approach because it interprets 
recommendation 5-1(d) as setting forth separate and independent 
considerations and, given this interpretation, believes that repeating 
the risk-benefit balance language in this paragraph would be 
duplicative and confusing. EPA also recognizes an alternative view of 
recommendation 5-1(d) is that separating the minimization of risk 
consideration from the risk-benefit balance consideration alters the 
collective context intended by recommendation 5-1(d) of the 2004 NAS 
Report. As such, EPA requests comments on both approaches as they apply 
to the proposed Sec. Sec.  26.1603(c)(2) and 26.1603(c)(3).
     Proposed Sec.  26.1603(c)(3): Whether the proposed 
research presents an acceptable balance of risks and benefits. In 
making this determination for research intended to reduce the 
interspecies uncertainty factor in a pesticide risk assessment, the 
Administrator must consider Recommendation 4-1 in the 2004 Report from 
the National Research Council of the National Academy of Sciences 
(NAS), entitled ``Intentional Human Dosing Studies for EPA Regulatory 
Purposes: Scientific and Ethical Issues.''
    This provision reflects excerpts taken from recommendations 5-1(d) 
and 4-1 from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). For each human research proposal submitted to the Agency 
that is covered by this rule, in addition to considering whether a 
study proposal minimizes risks to the human subjects, EPA is proposing 
to consider whether the proposed research presents an acceptable 
balance of risks and benefits based on, among other things, the 
information it considers under the proposed paragraphs (c)(1) and 
(c)(2) in Sec.  26.1603.
    Recommendation 5-1(d) also refers to ``the minimization of risks to 
participants.'' EPA addressed that consideration in proposed Sec.  
26.1603(c)(2). The Agency requests comment on whether another reference 
to minimization of risk is nonetheless needed in this paragraph for 
consistency with the 2004 NAS Report.
    For research that is intended specifically to reduce the 
interspecies uncertainty factor in a pesticide risk assessment, the 
Agency is proposing to consider whether that study presents an 
acceptable balance of risks and benefits in accordance with process 
laid out for evaluating that type of study in recommendation 4-1 and 
the attendant discussion in the 2004 NAS report that informs the 
application of that recommendation. EPA lacks experience in reviewing 
proposals for research intended to reduce the interspecies uncertainty 
factor. Since the promulgation of the 2006 rule, EPA has received no 
proposals for such research and, as noted in Unit IV.A.2. and A.3., EPA 
knows of no third-party research involving intentional exposure of a 
human subject to a pesticide that has ever been proposed, conducted, or

[[Page 5748]]

submitted to EPA under regulatory authorities other than the pesticide 
laws. However, EPA recognizes that this is a possibility in the future.
    The Agency asks for comment on how it should consider NAS 
recommendation 4-1, if this proposed amendment were finalized and EPA 
received a study proposal for that purpose, and, given the context of 
the proposed expansion to the scope of the 2006 rule as discussed in 
Unit IV.A., whether the proposed Sec.  26.1603(c)(3) is clear about how 
NAS recommendation 4-1 might apply to future studies.
     Proposed Sec.  26.1603(c)(4): Whether subject selection 
will be equitable.
    This provision is taken directly from recommendations 5-1(e) and 5-
2(a) from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.).
     Proposed Sec.  26.1603(c)(5): Whether subjects' 
participation would follow free and fully informed consent.
    This provision reflects excerpts taken from recommendations 5-1(f) 
from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.), which mentions free and informed consent, and the Nuremberg 
Code.\2\
---------------------------------------------------------------------------

    \2\ The Nuremburg Code states the importance of free and fully 
informed consent and describes the elements of such consent: ``The 
voluntary consent of the human subject is absolutely essential. This 
means that the person involved should have legal capacity to give 
consent; should be so situated as to be able to exercise free power 
of choice, without the intervention of any element of force, fraud, 
deceit, duress, over-reaching, or other ulterior form of constraint 
or coercion; and should have sufficient knowledge and comprehension 
of the elements of the subject matter involved as to enable him to 
make an understanding and enlightened decision * * *'' http://ohsr.od.nih.gov/guidelines/nuremberg.html.
---------------------------------------------------------------------------

    Key aspects or indicators of free and fully informed consent or 
legally effective consent are set out in detail in Sec.  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 Sec.  26.1603(c)(5) to ``free 
and fully informed consent'' emphasizes the centrality of this concept 
to the ethics evaluation process.
     Proposed Sec.  26.1603(c)(6): Whether an appropriately 
constituted Institutional Review Board or its foreign equivalent has 
approved the proposed research.
    This provision reflects excerpts taken from recommendations 5-1(g) 
and 6-1 from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). Section 26.1125 already requires third-parties covered by 
the 2006 rule to obtain IRB approval before submitting proposals to EPA 
under subpart P, and section 26.1601(c) of the current rule allows the 
Agency to consider whether foreign proposed research has undergone 
equivalent protective procedures.
     Proposed Sec.  26.1603(c)(7): If any person from a 
vulnerable population may become a subject in the proposed research, 
whether there is a convincing justification for selection of such a 
person, and whether measures taken to protect such human subjects are 
adequate.
    This provision reflects excerpts taken from recommendation 5-2(b) 
from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). EPA recognizes that some individuals who may become 
subjects in human research may be more vulnerable to coercion or undue 
influence, for example, prisoners, persons with mental disabilities, or 
economically or educationally disadvantaged persons. As such, for 
proposals in which such individuals may become a subject of the 
research, EPA is proposing to consider whether the proposal contains a 
convincing justification for the selection of those persons as well as 
whether any measures taken to protect those persons are adequate. The 
specific language of recommendation 5-2(b) states that ``IRBs * * * 
should ensure that the following conditions met in selecting research 
participants * * * (b) Selection of persons from vulnerable populations 
must be convincingly justified in the protocol, which also must justify 
the measures to be taken to protect the participants.'' In drafting 
this provision EPA rephrased recommendation 5-2(b) to convert it to 
regulatory language. In doing so, EPA first made this provision 
conditional (the ``if'' clause) because EPA does not expect that 
vulnerable populations will often be included in human research and 
there is no reason to impose a burden on researchers to justify a 
situation when it is inapplicable. EPA also substituted the requirement 
that measures taken to protect such human subjects be ``adequate'' 
instead of requiring a ``convincing justification'' for them.
    EPA requests comment on whether the proposed language is clear and 
specifically on this language as compared to using the language 
directly from recommendation 5-2(b) in the 2004 NAS Report.
     Proposed Sec.  26.1603(c)(8): If any person with a 
condition that would put them at increased risk for adverse effects may 
become a subject in the proposed research, whether there is a 
convincing justification for selection of such a person, and whether 
measures taken to protect such human subjects are adequate.
    This provision reflects excerpts taken from recommendation 5-2(c) 
from the 2004 NAS Report (see verbatim text provided in Unit 
IV.C.2.b.). Although EPA anticipates that persons with conditions that 
put them at increased risk for adverse effects would likely be screened 
from participating in human research subject to this rule, there may be 
circumstances when an exception is warranted. In those instances where 
such persons may become subjects in research covered by this rule, EPA 
is proposing to consider whether the research contains a convincing 
justification for the selection of those persons as well as whether any 
measures taken to protect those persons are adequate to decrease risks 
to an acceptable level. The specific language of recommendation 5-2(b) 
states that ``IRBs * * * should ensure that the following conditions 
met in selecting research participants * * * (c) Selection of 
individuals with conditions that put them at increased risk for adverse 
effects in such studies must be convincingly justified in the protocol, 
which also must justify the measures that investigators will use to 
decrease the risks to those participants to an acceptable level.'' For 
this provision, EPA followed a similar path in converting the NAS 
recommendation into regulatory language as it did with proposed Sec.  
26.1603(c)(7), i.e., EPA made the provision conditional and used an 
adequacy test rather than a convincing justification as to evaluating 
the measures to protect the subjects.
    EPA requests comment on whether the proposed language is clear and 
specifically on this language as compared to using the language 
directly from recommendation 5-2(c) in the 2004 NAS Report.
     Proposed Sec.  26.1603(c)(9): Whether any proposed 
payments to subjects are consistent with the principles of justice and 
respect for persons, and whether they are so high as to constitute 
undue inducement or so low as to be attractive only to individuals who 
are socioeconomically disadvantaged.
    This provision reflects excerpts taken from recommendation 5-3 from 
the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.). 
Although this provision overlaps slightly with proposed Sec. Sec.  
26.1603(c)(4) and Sec.  26.1603(c)(7), EPA is proposing to enumerate a 
specific consideration for whether the level of remuneration for

[[Page 5749]]

participation in any proposal for human research covered by this rule 
is appropriate, i.e., consistent with the principles of justice and 
respect for persons, and whether it is likely to induce participation 
from individuals from vulnerable populations and affect the equitable 
selection of subjects. In converting the affirmative statement in 
recommendation 5-3 into a ``whether'' statement for regulatory 
language, EPA dropped the recommendation's ``neither--nor'' phrasing 
because it is potentially confusing. EPA believes that, as drafted, 
this provision requires consideration of whether payments are either 
too high or too low but requests comment on this point.
    EPA requests comment on whether the proposed language is clear and 
specifically on this language as compared to using the language 
directly from recommendation 5-3 in the 2004 NAS Report.
     Proposed Sec.  26.1603(c)(10): Whether the sponsor or 
investigator would provide needed medical care for injuries incurred in 
the proposed research, without cost to the human subjects.
    This provision reflects excerpts taken from recommendation 5-5 from 
the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.). EPA 
is proposing to consider in its ethics review of proposed human 
research subject to this rule whether medical care resulting from 
participation in the research will be provided without cost to the 
human subjects.
    As noted throughout this section, EPA requests comment on whether 
the provisions of proposed Sec.  26.1603 are consistent with the 
recommendations from the 2004 NAS Report and whether the regulatory 
language chosen by EPA adequately captures EPA's intended goal and is 
otherwise clear and easily understood.

D. Revised Acceptance Standards for Completed Research (40 CFR part 26, 
subpart Q)

1. Overview
    a. Current rule. 40 CFR part 26, subpart Q, establishes standards 
governing reliance by EPA under the pesticide laws on ``scientifically 
valid and relevant data from research involving intentional exposure of 
human subjects.'' Section 26.1703 forbids EPA to rely on any research 
involving intentional exposure of a subject who was a pregnant woman, a 
nursing woman, or a child. Section 26.1704 forbids EPA to rely on 
research initiated before the effective date of the 2006 rule in the 
face of clear and convincing evidence that ``the conduct of the 
research was fundamentally unethical (e.g., the research was intended 
to seriously harm participants or failed to obtain informed consent), 
or was significantly deficient relative to the ethical standards 
prevailing at the time the research was conducted.'' Section 26.1705 
forbids EPA to rely on research initiated after the effective date of 
the 2006 rule unless EPA has ``adequate information to determine that 
the research was conducted in substantial compliance with subparts A 
through L * * *'' Section 26.1706 permits EPA to rely on the results of 
human research unacceptable under the standards of Sec. Sec.  26.1703-
26.1705 only if EPA determines, after public notice and comment and 
consultation with HSRB, that reliance on the research is necessary to 
support ``a more stringent regulatory restriction that would improve 
protection of public health * * * than could be justified without 
relying on the data.'' The Agency is not proposing to amend the 
substance of Sec.  26.1706.
    b. Summary of proposed changes. In addition to broadening the scope 
of 40 CFR part 26, subpart Q, to apply to research relied on by EPA 
under regulatory statutes other than FIFRA or FFDCA, EPA proposes to 
amend the substantive standards in Sec. Sec.  26.1703, 26.1704, and 
26.1705 for determining the acceptability of completed research 
involving intentional exposure of a human subject to a pesticide. As 
noted throughout this document, EPA requests comment on each of these 
proposed changes, as well as on the changes in the aggregate. In 
particular, EPA seeks comment on its conclusions regarding the effect 
of these proposed changes relative to the scope of the 2006 rule, 
including the effect of these proposed changes on the volume of studies 
covered by the rule, the likely statutes under which studies may be 
submitted, and the impact on activities covered by those other 
statutes.
    c. Anticipated effects. If a covered study does not meet the 
applicable standards in 40 CFR part 26, subpart Q, EPA would be 
prohibited from relying on the data in any action it takes under any of 
its regulatory authorities except under the extremely restrictive 
conditions defined in Sec.  26.1706.
2. Sec.  26.1703: Standards Applicable to all Covered Research
    a. Proposed changes and rationale. Consistent with the changes 
proposed in 40 CFR part 26, subpart P, and discussed in Unit IV.C., EPA 
proposes to add in Sec.  26.1703(a) an explicit prohibition against 
reliance on data from completed research ``unless EPA determines that 
the data are relevant to a scientific or policy question important for 
EPA decision-making, that the data were derived in a manner that makes 
them scientifically valid and reliable, and that it is appropriate to 
use the data for the purpose proposed by EPA.''
    In making this determination, EPA would be required to assess these 
four aspects of the research:
     Whether the research was designed and conducted according 
to ``appropriate scientific standards and practices prevailing at the 
time the research was conducted.''
     The extent to which the test subjects represent the 
population whose response the data will be used to predict.
     The statistical power of the data to support the 
scientific conclusions drawn by EPA.
     Whether, in a study that reports a No Observed Effect 
Level (NOEL) or a No Observed Adverse Effect Level (NOAEL), some dose 
level elicited a biological effect.
    These four aspects of the research are derived from Recommendations 
3-1 and 5-1 from the 2004 NAS Report. They do not establish fixed 
criteria for acceptance or rejection of a study, but they identify 
specific aspects of a study that EPA must consider in determining that 
it is relevant, scientifically valid and reliable, and appropriate for 
a particular use.
    b. Anticipated effect. As noted previously, 40 CFR part 26, subpart 
Q, applies to EPA decisions to rely on ``scientifically valid and 
relevant data'' from covered research. Since 2006, EPA's practice in 
reviewing reports of covered human research has been to examine 
carefully the scientific merit of the reported studies and to refuse to 
use research deemed invalid or irrelevant. EPA proposes to delete these 
factors from the scope of 40 CFR part 26, subpart Q, as defined in 
Sec.  26.1701, and to codify them as factors in Sec.  26.1703(a) to 
ensure that they remain central to determinations of scientific 
validity and relevance. If this proposed amendment is finalized, EPA 
would likely make minor revisions to its internal review procedures to 
highlight the consideration given to these four aspects of the 
research.
3. Sec.  26.1704: Acceptance Standards for Research not Subject to 
Sec.  26.1705
    a. Proposed changes and rationale. The Agency based the ethical 
acceptability standard in Sec.  26.1704 on Recommendation 5-7 from the 
2004 NAS Report, which states in relevant part:

[[Page 5750]]

    EPA should accept scientifically valid studies conducted before 
its new rules are implemented unless there is clear and convincing 
evidence that the conduct of those studies was fundamentally 
unethical (e.g., the studies were intended to seriously harm 
participants or failed to obtain informed consent) or that the 
conduct was deficient relative to then-prevailing standards.

Section 26.1704 provides in relevant part (emphasis added):

    * * * EPA shall not rely on data from any research initiated 
before [the effective date of the 2006 rule], if there is clear and 
convincing evidence that the conduct of the research was 
fundamentally unethical (e.g., the research was intended to 
seriously harm participants or failed to obtain informed consent), 
or was significantly deficient relative to the ethical standards 
prevailing at the time the research was conducted.

    EPA adopted the recommendation from the 2004 NAS Report nearly 
verbatim, with the notable insertion of the word ``significantly'' 
before ``deficient.'' EPA explained in the preamble to the 2006 rule 
(at 71 FR 6161) that this was to allow it the flexibility to consider 
the impact on subjects of any ethical shortcomings in the conduct of 
the research. EPA stated in that preamble (at 71 FR 6161) that ``EPA 
expects [the meaning of ``significantly''] to acquire greater clarity 
over time, through HSRB and public review of Agency decisions 
concerning reliance on completed human research.''
    EPA believes that greater clarity has, indeed, been achieved 
through the application of the 2006 rule by EPA and HSRB. EPA now 
proposes to revise Sec.  26.1704 by deleting the word 
``significantly,'' proposing instead to characterize explicitly the 
kinds of deficiencies that would make a study unacceptable.
    This language is derived from the advice of HSRB as they have 
applied the standard of Sec.  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, 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 Sec.  
26.1704 in a new paragraph (a) as the complement of the more detailed 
scope of Sec.  26.1705, thereby eliminating any gaps or overlap in the 
applicability of the two standards.
    b. Anticipated effect. Proposed Sec.  26.1704 would forbid EPA to 
rely on research not covered by 40 CFR part 26, subpart K, or the 
Common Rule in the face of clear and convincing evidence that its 
conduct ``placed participants at increased risk of harm (based on 
knowledge available at the time the study was conducted) or impaired 
their informed consent.'' EPA specifically requests comment on the 
incremental value of this change as well as the extent to which this 
change might inappropriately reduce EPA's access to human research.
4. Sec.  26.1705: Standards for Completed Research Conducted Under 40 
CFR Part 26 or Another Codification of the Common Rule
    a. Proposed changes and rationale. The standard in 40 CFR part 26 
applying to completed research initiated after the effective date of 
the rule is Sec.  26.1705, based on Recommendation 5-6 from the 2004 
NAS Report, which states in relevant part (italics in the original; 
footnote omitted):

    EPA should operate on the strong presumption that data obtained 
in studies conducted after implementation of the new rules that do 
not meet the ethical standards described in this report will not be 
considered in its regulatory decisions.

    EPA adapted this recommendation in its drafting of Sec.  26.1705, 
which provides in relevant part:

    EPA shall not rely on data from any research initiated after 
[the effective date of the 2006 rule] unless EPA has adequate 
information to determine that the research was conducted in 
substantial compliance with subparts A through L of this part, or if 
conducted in a foreign country, under procedures at least as 
protective as those in subparts A through L of this part.

    EPA now proposes to amend both the applicability of Sec.  26.1705 
and the substance of the standard itself. In the 2006 rule, Sec.  
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 Sec.  26.1705 standard to research subject, at the time it was 
conducted, either to subparts A through L of 40 CFR part 26 or to 
another Federal department or agency's codification of the Common Rule.
    EPA recognizes that it could in the future wish to rely on data 
from third-party research conducted after 2006 but which fell outside 
the scope of 40 CFR part 26, subpart K, and for which EPA therefore 
would not have conducted a protocol review under 40 CFR part 26, 
subpart P, before the research was conducted. For example, as discussed 
in Unit IV.A., 40 CFR part 26, subpart K, as now proposed would not 
apply to a new clinical trial evaluating the therapeutic efficacy of a 
drug that was also a pesticide. Because this research would fall 
outside the scope of 40 CFR part 26, subpart K, investigators would not 
have submitted the protocol to EPA under 40 CFR part 26, subpart K, and 
EPA and 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 Sec.  26.1705 is currently 
worded in 40 CFR part 26, such a study could only be relied on if ``EPA 
has adequate information to determine that the research was conducted 
in substantial compliance with subparts A through L.'' But because the 
protocol would not have been submitted for review by EPA and HSRB, the 
research in this example would not have been conducted in substantial 
compliance with 40 CFR part 26, subpart K.
    EPA believes that it would be inappropriate to reject otherwise 
meritorious and ethical research for failure to comply with provisions 
in 40 CFR part 26, subparts A-L that did not apply when the research 
was conducted. Thus EPA proposes to make Sec.  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 Sec.  26.1704(a) would apply 
the standard of Sec.  26.1704 to all other completed research 
considered by EPA under 40 CFR part 26, subpart Q, without regard to 
when the research was initiated.
    EPA proposes further changes to Sec.  26.1705 to help make this 
clear. Proposed Sec.  26.1705(b)(1) defines the applicable standard as 
either 40 CFR part 26, subparts A through L, or another Federal 
department or agency's codification of the Common Rule, whichever set 
of rules covered the research when it was conducted. In proposed Sec.  
26.1705(b)(2), corresponding changes are made applicable to research 
conducted in foreign countries.
    Finally, in a new paragraph (c) in Sec.  26.1705, EPA proposes to 
require substantial compliance of covered research with its protocol. A 
study reviewed as a proposal under subpart P of 40 CFR part 26 could be 
relied on only if it had been conducted in substantial compliance with 
the

[[Page 5751]]

protocol found acceptable by EPA, and if the investigator did not 
further amend or deviate from the protocol in ways that placed 
participants at increased risk of harm (based on knowledge available at 
the time the study was conducted) or impaired their informed consent. 
If a completed study was not reviewed as a proposal under 40 CFR part 
26, subpart P, the study could only be relied on if it had been 
conducted in substantial compliance with a protocol that would have 
been found acceptable, and if the investigator did not amend or deviate 
from the protocol in ways that placed participants at increased risk of 
harm (based on knowledge available at the time the study was conducted) 
or impaired their informed consent.
    b. Anticipated effect. Taken together, these proposed changes in 
Sec.  26.1705 reflect the interpretations and methods used by EPA and 
HSRB since 2006 in reviewing completed, post-rule research. Codifying 
these interpretations will ensure consistency and transparency in 
future decision-making and is consistent with the 2006 Appropriations 
Act.

E. Request for Public Comment on Possible Re-Codification of 40 CFR 
Part 26, Subparts K-Q

    1. Current rule. Subparts A-D of 40 CFR part 26 all apply to 
research with human subjects which is conducted or supported by EPA in 
its role as a research agency. Subparts K-Q of 40 CFR part 26 apply to 
pesticide research with human subjects that is conducted by regulated 
third parties, and to EPA's regulatory oversight of that research. Some 
stakeholders have suggested that this important distinction would be 
clearer if 40 CFR part 26 contained only those subparts applying to EPA 
as a research agency, and if 40 CFR part 26, subparts K-Q, were moved 
to a different section of EPA's regulations, within the range where 
other pesticide-specific regulations are found.
    2. Proposed amendments and rationale. EPA is not now proposing such 
a re-codification, but invites public comment on the idea. Although it 
would necessitate many non-substantive revisions--mainly of internal 
cross-references--re-codification would not be difficult to accomplish. 
40 CFR part 26 would retain current 40 CFR part 26, subparts A-D, and 
at least parts of current 40 CFR part 26, subpart O. A previously 
unused part within 40 CFR, within the numerical range of parts 150-180 
where other pesticide-related regulations appear, would include current 
40 CFR part 26, subparts K, L, M, O, P, and Q. 40 CFR part 26, subpart 
O, potentially applies to both EPA research and to third-party research 
and would need to be adapted to fit into both parts of a separated 
codification in 40 CFR.
    3. Anticipated effect. Although this proposed re-codification may 
better distinguish those requirements applying to EPA as a research 
agency, and those applying to third-party studies, it would only change 
the location of the regulation within 40 CFR, and would not otherwise 
have any effect on the requirements.

V. FIFRA Review Requirements

    In accordance with FIFRA section 25(a), EPA has submitted a draft 
of the proposed rule to the FIFRA Scientific Advisory Panel (SAP), the 
Secretary of Agriculture (USDA), and appropriate Congressional 
Committees. The FIFRA SAP waived its review of this proposal on October 
12, 2010, because the significant scientific issues involved have 
already been reviewed by the SAP and additional review is not 
necessary. USDA responded without comments, but participated in the 
interagency review process under Executive Order 12866.

VI. Statutory and Executive Order Reviews

A. Regulatory Planning and Review

    Under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993), this has been identified as a 
``significant regulatory action.'' Accordingly, EPA submitted the draft 
proposed rule to the Office of Management and Budget (OMB) for review 
under Executive Order 12866 and any changes made in response to OMB 
recommendations have been documented in the docket for this rulemaking 
as required by the Executive Order.
    The incremental costs of these proposed amendments both to industry 
and to EPA are expected to be negligible. EPA has not, therefore, 
prepared a new economic analysis for this rulemaking. Because no 
research has been identified that is outside the scope of the 2006 rule 
but that would be within the scope of these proposed amendments, EPA 
has no basis on which to revise the cost estimates that were provided 
in the economic analysis for the 2006 rulemaking or those most recently 
provided in the 2008 renewal of the Information Collection Request 
(ICR) for the existing regulation at 40 CFR part 26. The recent 
estimates included in the ICR are summarized in Unit VI.B. and a copy 
of the ICR is available in the docket.

B. Paperwork Reduction Act

    This action does not impose any new information collection burden 
that would require additional review or approval by OMB under the 
Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq. OMB previously 
approved the information collection requirements contained in the 
existing regulations at 40 CFR part 26 under OMB Control No. 2070-0169 
(EPA ICR No. 2195). Burden is defined at 5 CFR 1320.3(b).
    In its 2008 analysis supporting the most recent renewal of this 
ICR, EPA estimated that respondents would submit to the Agency some 34 
proposals for or reports of research involving intentional exposure of 
human subjects each year. EPA estimated that preparation of information 
required by the 2006 rule would require about 598 hours per study at a 
cost of $45,927 per study, for a total estimated annual burden for 
affected entities of 20,332 hours at an estimated cost of $1,561,518. 
In addition, EPA estimated annual submission of 20 reports of research 
requiring only documentation of ethical conduct at a cost of 12 hours/
$879 per report, or 240 hours/$17,580 per year. The total estimate of 
the annual respondent burden and cost was the sum of these two 
estimates, or 2,572 hours/$1,579,098.
    These paperwork burden and cost estimates include activities 
related to initial rule familiarization, as well as activities that 
researchers would have to perform even without the Agency's rulemaking 
in this area, such as developing a protocol and maintaining records.
    The average annual burden on EPA for reviewing each of the 34 study 
submissions was estimated to be 178 hours/$16,850 per study, or 6,052 
hours/$572,900 per year. The average annual burden on EPA for reviewing 
each of the 20 additional submissions was estimated to be 44 hours/
$3,158 per study, or 880 hours/$63,160 per year. The total estimate of 
the annual burden on EPA was the sum of these two estimates, or 6,932 
hours/$636,000 per year.
    In no year since promulgation of the 2006 rule have more than 7 
protocols been submitted to EPA by industry; the average annual rate 
has been just over 5 for the 5-year period of 2006-2010. Somewhat fewer 
completed reports have been submitted during this period, so the 
average of new protocols and finished studies has been about 11 per 
year, less than a third of the projected 34 per year covered by the 
ICR. There is no evidence to suggest an upward trend, and nothing in 
these amendments

[[Page 5752]]

is believed likely to lead to a significant change in the rate of 
protocol and study submissions.
    An agency may not conduct or sponsor, and a person is not required 
to respond to, a collection of information unless it displays a 
currently valid OMB control number. The OMB control numbers for EPA's 
regulations in 40 CFR are listed in 40 CFR part 9.

C. Small Entity Impacts

    Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA), 
5 U.S.C. 601 et seq., the Agency hereby certifies that this action will 
not have a significant adverse economic impact on a substantial number 
of small entities. Under RFA, small entities include small businesses, 
small organizations, and small governmental jurisdictions. For purposes 
of assessing the impacts of this proposed rule on small entities, small 
entity is defined in accordance with RFA section 601 as:
    1. A small business as defined by the Small Business 
Administration's (SBA) regulations at 13 CFR 121.201.
    2. A small governmental jurisdiction that is a government of a 
city, county, town, school district or special district with a 
population of less than 50,000.
    3. A small organization that is any not-for-profit enterprise which 
is independently owned and operated and is not dominant in its field.
    Because no small entities have been identified that are directly 
regulated by these proposed amendments, EPA has not attempted to reduce 
the impact of this proposed rule on small entities. Comments are 
invited on all aspects of the proposal and its impacts on small 
entities.

D. Unfunded Mandates

    This action does not impose any enforceable duty, contain any 
unfunded mandate, or otherwise have any effect on small governments 
subject to the requirements of sections 202, 203, 204, or 205 of the 
Unfunded Mandates Reform Act (UMRA), 2 U.S.C. 1531-1538. These 
amendments are unlikely to affect State, local, and tribal governments 
at all, and are likely to affect the private sector only trivially. The 
action does not contain a Federal mandate that may result in 
expenditures of $100 million or more for State, local, and tribal 
governments, in the aggregate, or the private sector in any 1 year.

E. Federalism

    This action does not have federalism implications because it is not 
expected to have substantial direct effects on the States, on the 
relationship between the national government and the States, or on the 
distribution of power and responsibilities among the various levels of 
government, as specified in Executive Order 13132, entitled Federalism 
(64 FR 43255, August 10, 1999). It makes marginal changes in the scope 
of an existing rule applying to sponsors and investigators conducting 
certain kinds of research involving human subjects, and refines the 
standards for EPA oversight of and reliance on such research.
    In the spirit of Executive Order 13132, and consistent with EPA 
policy to promote communications between EPA and State and local 
governments, EPA specifically requests comments on this proposed action 
from State and local officials.

F. Tribal Implications

    This action does not have tribal implications as specified in 
Executive Order 13175, entitled Consultation and Coordination with 
Indian Tribal Governments (65 FR 67249, November 9, 2000). This action 
is not expected to have substantial direct effects on Indian Tribes, 
will not significantly or uniquely affect the communities of Indian 
Tribal governments, and does not involve or impose any requirements 
that affect Indian Tribes. Thus, Executive Order 13175 does not apply 
to this action.

G. Children's Health Protection

    EPA interprets Executive Order 13045, entitled Protection of 
Children from Environmental Health Risks and Safety Risks (62 FR 19885, 
April 23, 1997), as applying only to those regulatory actions that 
concern health or safety risks, such that the analysis required under 
section 5-501 of the Executive Order has the potential to influence the 
regulation. This action is not subject to Executive Order 13045 because 
it does not establish an environmental standard intended to mitigate 
health or safety risks, nor is it an ``economically significant 
regulatory action'' as defined in Executive Order 12866. The 2006 rule 
applies to the conduct and review of research involving intentional 
exposure of human subjects, and prohibits the conduct of or EPA 
reliance on any such research involving subjects who are children, or 
pregnant or nursing women. These provisions would not be affected by 
the proposed amendments.

H. Affect on Energy Supply, Distribution, or Use

    This action is not a ``significant energy action'' as defined in 
Executive Order 13211, entitled Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, 
May 22, 2001), because this action is not likely to have any affect on 
the supply, distribution, or use of energy.

I. Technical Standards

    Because this action does not involve any technical standards, 
section 12(d) of the National Technology Transfer and Advancement Act 
of 1995 (NTTAA) (15 U.S.C. 272 note), does not apply to this action.

J. Environmental Justice

    This action does not entail special considerations of environmental 
justice related issues as delineated by Executive Order 12898, entitled 
Federal Actions to Address Environmental Justice in Minority 
Populations and Low-Income Populations (59 FR 7629, February 16, 1994). 
The strengthened protections for human subjects participating in 
covered research established in the 2006 rule would not be altered by 
these proposed amendments.

List of Subjects in 40 CFR Part 26

    Environmental protection, Administrative practice and procedures, 
Human research, Pesticides and pests.

    Dated: January 18, 2011.
Lisa P. Jackson,
Administrator.

    Therefore, it is proposed that 40 CFR chapter I be amended as 
follows:

PART 26--[AMENDED]

    1. The authority citation for part 26 is revised to read as 
follows:

    Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21 
U.S.C. 346a(e)(1)(C); sec. 201, Pub. L. 109-54, 119 Stat. 531; and 
42 U.S.C. 300v-1(b).

    2. Amend Sec.  26.1101 as follows:
    a. Remove paragraphs (a), (c), and (g);
    b. Redesignate paragraph (b) as (c), (f) as (g), (e) as (f), and 
(d) as (e); and
    c. Add new paragraphs (a), (b), and (d) to read as follows.

Sec.  26.1101  To what does this subpart apply?

    (a) Except as provided in paragraph (c) of this section, this 
subpart applies to all research initiated on or after [effective date 
of final rule] involving intentional exposure of a human subject to:
    (1) Any substance if, at any time prior to initiating such 
research, any person who conducted or supported such research intended 
either to submit results of the research to EPA for consideration in 
connection with any action that may be performed by EPA under the 
Federal Insecticide,

[[Page 5753]]

Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136-136y) or section 
408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 
346a), or to hold the results of the research for later inspection by 
EPA under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C. 
346a); or
    (2) A pesticide if, at any time prior to initiating such research, 
any person who conducted or supported such research intended either to 
submit results of the research to EPA for consideration in connection 
with any action that may be performed by EPA under any regulatory 
statute administered by EPA other than those statutes designated in 
paragraph (a)(1) of this section, or to hold the results of the 
research for later inspection by EPA under any regulatory statute 
administered by EPA other than those statutes designated in paragraph 
(a)(1) of this section.
    (b) For purposes of determining a person's intent under paragraph 
(a) of this section, EPA may consider any available and relevant 
information. EPA must rebuttably presume the existence of intent if:
    (1) The person or the person's agent has submitted or made 
available for inspection the results of such research to EPA; or
    (2) The person is a member of a class of people who, or whose 
products or activities, are regulated by EPA and, at the time the 
research was initiated, the results of such research would be relevant 
to EPA's exercise of its regulatory authority with respect to that 
class of people, products, or activities.
* * * * *
    (d) The Administrator retains final judgment as to whether a 
particular activity is covered by this subpart.
* * * * *
    3. In Sec.  26.1102, revise paragraphs (a) and (c) and add 
paragraph (k) to read as follows:

Sec.  26.1102  Definitions.

    (a) Administrator means the Administrator of the Environmental 
Protection Agency (EPA) and any other officer or employee of EPA to 
whom authority has been delegated.
* * * * *
    (c) Pesticide means any substance or mixture of substances meeting 
the definition in 7 U.S.C. 136(u) [Federal Insecticide, Fungicide, and 
Rodenticide Act, section 2(u)].
* * * * *
    (k) Common Rule refers to the Federal Policy for the Protection of 
Human Subjects that was established in 1991 by the Office of Science 
and Technology Policy and codified in 1991 by EPA and 14 other federal 
departments and agencies (see 56 FR 28003, June 18, 1991) and 
subsequently codified by other Federal departments and agencies. The 
Common Rule contains a widely accepted set of standards for conducting 
ethical research with human subjects, together with a set of procedures 
designed to ensure that the standards are met. Once codified by a 
Federal department or agency, the requirements of the Common Rule apply 
to research conducted or sponsored by that Federal department or 
agency. EPA's codification of the Common Rule currently appears in 40 
CFR part 26, subpart A.

Sec.  26.1111  [Amended]

    4. In Sec.  26.1111, remove from paragraph (a)(4) the phrase ``or 
the subject's legally authorized representative''.
    5. In Sec.  26.1116, revise the introductory text of the section to 
read as follows:

Sec.  26.1116  General requirements for informed consent.

    No investigator may involve a human being as a subject in research 
covered by this subpart unless the investigator has obtained the 
legally effective informed consent of the subject. An investigator must 
seek such consent only under circumstances that provide the prospective 
subject sufficient opportunity to consider whether or not to 
participate and that minimize the possibility of coercion or undue 
influence. The information that is given to the subject must be in 
language understandable to the subject. No informed consent, whether 
oral or written, may include any exculpatory language through which the 
subject is made to waive or appear to waive any of the subject's legal 
rights, or releases or appears to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
* * * * *
    6. Revise Sec.  26.1117 to read as follows:

Sec.  26.1117  Documentation of informed consent.

    (a) Informed consent must be documented by the use of a written 
consent form approved by the IRB and signed by the subject. A copy 
shall be given to the subject.
    (b) The consent form may be either of the following:
    (1) A written consent document that embodies the elements of 
informed consent required by Sec.  26.1116. This form may be read to 
the subject, but in any event, the investigator must give the subject 
adequate opportunity to read it before it is signed; or
    (2) A short form written consent document stating that the elements 
of informed consent required by Sec.  26.1116 have been presented 
orally to the subject. When this method is used, there must be a 
witness to the oral presentation. Also, the IRB shall approve a written 
summary of what is to be said to the subject. Only the short form 
itself is to be signed by the subject. However, the witness must sign 
both the short form and a copy of the summary, and the person actually 
obtaining consent must sign a copy of the summary. A copy of the 
summary must be given to the subject, in addition to a copy of the 
short form.
    7. Revise the heading for subpart L to read as follows:

Subpart L--Prohibition of Third-Party Research Involving 
Intentional Exposure to a Pesticide of Human Subjects Who Are 
Children or Pregnant or Nursing Women

    8. Revise Sec.  26.1201 to read as follows:

Sec.  26.1201  To what does this subpart apply?

    This subpart applies to any research subject to subpart K of this 
part.
    9. Revise Sec.  26.1301 to read as follows:

Sec.  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.

Sec.  26.1302  [Amended]

    10. In Sec.  26.1302 remove the word ``shall''.

Sec.  26.1502  [Amended]

    11. Amend Sec.  26.1502 as follows:
    a. In the first sentence of paragraph (a) remove the period after 
the phrase ``during an inspection.'' and add in its place a comma; and
    b. In the second sentence of paragraph (a) remove the phrase ``The 
agency'' and add in its place ``EPA''.
    c. In the last sentence of the introductory text of paragraph (b) 
remove the phrase ``the Agency'' and add in its place ``EPA''.

[[Page 5754]]

Sec.  26.1505  [Amended]

    12. In Sec.  26.1505 remove from the last sentence, the phrase 
``Sec.  26.1502(c)'' and add in its place ``Sec.  26.1502(b)(4)''.

Sec.  26.1507  [Amended]

    13. In Sec.  26.1507 remove from the last sentence, the phrase 
``The Agency'' and add in its place ``EPA''.

Sec. Sec.  26.1601 through 26.1603  [Redesignated as Sec. Sec.  26.1603 
through 26.1605]

    14. Amend subpart P by redesignating Sec. Sec.  26.1601 through 
26.1603 as Sec. Sec.  26.1603 through 26.1605.
    15. Add new Sec. Sec.  26.1601 and 26.1602 to read as follows:

Sec.  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 Sec.  26.1604, by the Human Studies Review Board 
of reports of completed research subject to 40 CFR 26.1701.

Sec.  26.1602  Definitions.

    The definitions in Sec.  26.1102 apply to this subpart as well.
    16. Amend newly redesignated Sec.  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.

Sec.  26.1603  EPA review of proposed human research.

    (a) EPA must review all proposals for new human research submitted 
under Sec.  26.1125 in a timely manner.
    (b) In reviewing proposals for new human research submitted under 
Sec.  26.1125, the EPA Administrator must consider and make 
determinations regarding the proposed research, including:
    (1) Whether the research would be likely to produce data that 
address an important scientific or policy question that cannot be 
resolved on the basis of animal data or human observational research.
    (2) Whether the proposed research is designed in accordance with 
current scientific standards and practices to:
    (i) Address the research question.
    (ii) Include representative study populations for the endpoint in 
question.
    (iii) Have adequate statistical power to detect appropriate 
effects.
    (3) Whether the investigator proposes to conduct the research in 
accordance with recognized good research practices, including, when 
appropriate, good clinical practice guidelines and monitoring for the 
safety of subjects.
    (c) In reviewing proposals for new research submitted under Sec.  
26.1125, the EPA Administrator must consider and make determinations 
regarding ethical aspects of the proposed research, including:
    (1) Whether adequate information is available from prior animal 
studies or from other sources to assess the potential risks to subjects 
in the proposed research.
    (2) Whether the research proposal adequately identifies anticipated 
risks to human subjects and their likelihood of occurrence, minimizes 
identified risks to human subjects, and identifies likely benefits of 
the research and their distribution.
    (3) Whether the proposed research presents an acceptable balance of 
risks and benefits. In making this determination for research intended 
to reduce the interspecies uncertainty factor in a pesticide risk 
assessment, the Administrator must consider Recommendation 4-1 in the 
2004 Report from the National Research Council of the National Academy 
of Sciences (NAS), entitled ``Intentional Human Dosing Studies for EPA 
Regulatory Purposes: Scientific and Ethical Issues.''
    (4) Whether subject selection will be equitable.
    (5) Whether subjects' participation would follow free and fully 
informed consent.
    (6) Whether an appropriately constituted IRB or its foreign 
equivalent has approved the proposed research.
    (7) If any person from a vulnerable population may become a subject 
in the proposed research, whether there is a convincing justification 
for selection of such a person, and whether measures taken to protect 
such human subjects are adequate.
    (8) If any person with a condition that would put them at increased 
risk for adverse effects may become a subject in the proposed research, 
whether there is a convincing justification for selection of such a 
person, and whether measures taken to protect such human subjects are 
adequate.
    (9) Whether any proposed payments to subjects are consistent with 
the principles of justice and respect for persons, and whether they are 
so high as to constitute undue inducement or so low as to be attractive 
only to individuals who are socioeconomically disadvantaged.
    (10) Whether the sponsor or investigator would provide needed 
medical care for injuries incurred in the proposed research, without 
cost to the human subjects.
    (d) With respect to any research or any class of research, the EPA 
Administrator may recommend additional conditions which, in the 
judgment of the EPA Administrator, are necessary for the protection of 
human subjects.
* * * * *
    (h) EPA must provide the submitter of the proposal copies of the 
EPA and Human Studies Review Board reviews.
    17. Amend newly redesignated Sec.  26.1604 by revising paragraph 
(a) to read as follows:

Sec.  26.1604  EPA review of completed human research.

    (a) When considering, under any regulatory statute it administers, 
data from completed research involving intentional exposure of humans 
to a pesticide, EPA must thoroughly review the material submitted under 
Sec.  26.1303, if any, and other available, relevant information and 
document its conclusions regarding the scientific and ethical conduct 
of the research.
* * * * *
    18. Add Sec. Sec.  26.1606 and 26.1607 to read as follows:

Sec.  26.1606  Human Studies Review Board review of proposed human 
research.

    In commenting on proposals for new research submitted to it by EPA, 
the Human Studies Review Board must consider the scientific merits and 
ethical aspects of the proposed research, including all elements listed 
in Sec.  26.1603(b) and (c) and any additional conditions recommended 
pursuant to Sec.  26.1603(d).

Sec.  26.1607  Human Studies Review Board review of completed human 
research.

    In commenting on reports of completed research submitted to it by 
EPA, the Human Studies Review Board must consider the scientific merits 
and ethical aspects of the completed research, and must apply the 
appropriate standards in subpart Q of this part.
    19. Revise the heading for subpart Q to read as follows:

Subpart Q--Standards for Assessing Whether To Rely on the Results 
of Human Research in EPA Actions

    20. Revise Sec. Sec.  26.1701 through 26.1705 to read as follows:
* * * * *
Sec.
26.1701 To what does this subpart apply?

[[Page 5755]]

26.1702 Definitions.
26.1703 Prohibitions applying to all research subject to this 
subpart.
26.1704 Prohibition of reliance on unethical human research with 
non-pregnant, non-nursing adults which is not subject to Sec.  
26.1705.
26.1705 Prohibition of reliance on unethical human research with 
non-pregnant, non-nursing adults initiated after April 7, 2006, and 
subject to subparts A through L of this part, or the codification of 
the Common Rule by another Federal department or agency.
* * * * *

Sec.  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.

Sec.  26.1702  Definitions.

    The definitions in Sec.  26.1102 and Sec.  26.1202 apply to this 
subpart as well.

Sec.  26.1703  Prohibitions applying to all research subject to this 
subpart.

    (a) Prohibition of reliance on scientifically invalid research. EPA 
must not rely on data from research subject to this subpart unless EPA 
determines that the data are relevant to a scientific or policy 
question important for EPA decisionmaking, that the data were derived 
in a manner that makes them scientifically valid and reliable, and that 
it is appropriate to use the data for the purpose proposed by EPA. In 
making such determinations, EPA must consider:
    (1) Whether the research was designed and conducted in accordance 
with appropriate scientific standards and practices prevailing at the 
time the research was conducted.
    (2) The extent to which the research subjects are representative of 
the populations for the endpoint or endpoints in question.
    (3) The statistical power of the data to support the scientific 
conclusion EPA intends to draw from the data.
    (4) In a study that reports only a No Observed Effect Level (NOEL) 
or a No Observed Adverse Effect Level (NOAEL), whether a dose level in 
the study gave rise to a biological effect, thereby demonstrating that 
the study had adequate sensitivity to detect an effect of interest.
    (b) Prohibition of reliance on research subject to this subpart 
involving intentional exposure of human subjects who are pregnant women 
(and therefore their fetuses), nursing women, or children. Except as 
provided in Sec.  26.1706, EPA must not rely on data from any research 
subject to this subpart involving intentional exposure of any human 
subject who is a pregnant woman (and therefore her fetus), a nursing 
woman, or a child.

Sec.  26.1704  Prohibition of reliance on unethical human research with 
non-pregnant, non-nursing adults which is not subject to Sec.  26.1705.

    (a) This section applies to research subject to this subpart that 
is not subject to Sec.  26.1705.
    (b) Except as provided in Sec.  26.1706, EPA must not rely on data 
from any research subject to this section if there is clear and 
convincing evidence that:
    (1) The conduct of the research was fundamentally unethical (e.g., 
the research was intended to seriously harm participants or failed to 
obtain informed consent); or
    (2) The conduct of the research was deficient relative to the 
ethical standards prevailing at the time the research was conducted in 
a way that placed participants at increased risk of harm (based on 
knowledge available at the time the study was conducted) or impaired 
their informed consent.
    (c) The prohibition in this section is in addition to the 
prohibitions in Sec.  26.1703.

Sec.  26.1705  Prohibition of reliance on unethical human research with 
non-pregnant, non-nursing adults initiated after April 7, 2006, and 
subject to subparts A through L of this part, or the codification of 
the Common Rule by another Federal department or agency.

    (a) This section applies to research subject to this subpart, that:
    (1) Was initiated after April 7, 2006.
    (2) Was subject, at the time it was conducted, either to subparts A 
through L of this part, or to the codification of the Common Rule by 
another Federal department or agency.
    (b) Except as provided in Sec.  26.1706, EPA must not rely on data 
from any research subject to this section unless EPA determines that 
the research was conducted in substantial compliance with either:
    (1) All applicable provisions of subparts A through L of this part, 
or the codification of the Common Rule by another Federal department or 
agency; or
    (2) If the research was conducted outside the United States, with 
procedures at least as protective of subjects as those in subparts A 
through L of this part, or the codification of the Common Rule by 
another Federal department or agency.
    (c) Except as provided in Sec.  26.1706, EPA must not rely on data 
from any research subject to this section unless EPA determines that 
the research was conducted in substantial compliance with either:
    (1) A proposal that was found to be acceptable under Sec.  
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 
Sec.  26.1603(c), EPA must not rely on that data.
    (2) A proposal that would have been found to be acceptable under 
Sec.  26.1603(c), if it had been subject to review under that section, 
and no amendments to or deviations from that proposal placed 
participants at increased risk of harm (based on knowledge available at 
the time the study was conducted) or impaired their informed consent.
    (d) The prohibition in this section is in addition to the 
prohibitions in Sec.  26.1703.

Sec.  26.1706  [Amended]

    21. In paragraph (d) of Sec.  26.1706 remove the word ``publishes'' 
and add in its place the phrase ``has published''.

[FR Doc. 2011-1629 Filed 2-1-11; 8:45 am]
BILLING CODE 6560-50-P