Document ID: EPA-HQ-OPP-2010-0785-0037
Agency: epa
Document Type: Rule
Title: Protections for Subjects in Human Research Involving Pesticides
Posted Date: 2013-02-14T05:00Z

[Federal Register Volume 78, Number 31 (Thursday, February 14, 2013)]
[Rules and Regulations]
[Pages 10538-10546]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-03456]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 26

[EPA-HQ-OPP-2010-0785; FRL-9353-4]
RIN 2070-AJ76

Protections for Subjects in Human Research Involving Pesticides

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: EPA is finalizing narrowly tailored amendments to 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 
amendments broaden the applicability of the rules to cover human 
testing with pesticides submitted to EPA under any regulatory statute 
it administers. The amendments also disallow participation in third-
party pesticide studies by subjects who cannot consent for themselves. 
Finally, the amendments 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). The amendments make no changes to 
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.

DATES: This rule is effective April 15, 2013.

ADDRESSES: The docket for this action, identified by docket 
identification (ID) number EPA-HQ-OPP-2010-0785, is available at http://www.regulations.gov or at the OPP Docket in the Environmental 
Protection Agency Docket Center (EPA/DC), located in the EPA West 
Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001. 
The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday 
through Friday, excluding legal holidays. The telephone number for the 
Public Reading Room is (202) 566-1744, and the telephone number for the 
OPP Docket is (703) 305-5805. Please review the visitor instructions 
and additional information about the docket available at http://www.epa.gov/dockets.

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; 
email address: sherman.kelly@epa.gov.

SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Does this action apply to me?

    You may be potentially affected by this action if you conduct or 
sponsor research that may be submitted to EPA and which involves 
intentional exposure of human subjects. The following list of North 
American Industrial Classification System (NAICS) codes is not intended 
to be exhaustive, but rather provides a guide to help readers determine 
whether this document might apply to them. Although EPA has in the past 
received such third-party research from pesticide registrants, other 
entities could submit such information to EPA.
     Pesticide and other Agricultural Chemical Manufacturing 
(NAICS code 325320) 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 (IRBs) 
who review human research with pesticides to ensure it meets applicable 
standards of ethical conduct. Under these new provisions, EPA must 
consider the ethical aspects and scientific validity and reliability of 
research in a manner that is consistent with the requirements of the 
Common Rule as codified in 40 CFR part 26, subpart A. The ``Common 
Rule'' is the name generally used to refer to the Federal Policy for 
the Protection of Human Subjects, 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.

B. What action is the agency taking?

    The amendments contained in this final rule change the 2006 rule, 
published in the Federal Register issue of February 6, 2006 (71 FR 
6138) (FRL-7759-8), subsequently amended in the Federal Register issue 
of 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

[[Page 10539]]

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 human research, 
derived from the recommendations by the National Research Council of 
NAS in its 2004 Report entitled ``Intentional Human Dosing Studies for 
EPA Regulatory Purposes: Scientific and Ethical Issues'' (hereafter, 
2004 NAS Report) to EPA.

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

    Sections 3(a) and 25(a) of FIFRA (7 U.S.C. 136a(a) and 136w(a)) and 
section 408(e)(1)(C) of the Federal Food, Drug, and Cosmetic Act 
(FFDCA) (21 U.S.C. 364a(e)(1)(C)), provide the legal authority for 
these amendments to the 2006 rule on human research.

D. What are the incremental costs and benefits of this action?

    The incremental costs of these amendments both to industry and to 
EPA are expected to be negligible. EPA has not, therefore, prepared a 
new economic analysis for this rule. Because no research has been 
identified that is outside the scope of the 2006 rule but that would be 
within the scope of these amendments, EPA has no basis on which to 
revise the cost estimates that were provided in the economic analysis 
for the 2006 rule 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 estimates included in the ICR are summarized in 
Unit VI.B. and a copy of the ICR is available in the docket.

II. Background

A. EPA's 2006 Rule

    As required by section 201 of the Department of the Interior, 
Environment, and Related Agencies Appropriations Act, 2006 (2006 
Appropriations Act), Public Law 109-54, 119 Stat. 531, EPA promulgated 
a rule in 2006 establishing a set of protections for people 
participating as subjects in third-party human research with pesticides 
in 40 CFR part 26. (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 prohibits EPA from relying on third-party research on 
pesticides involving intentional exposure of children or of pregnant or 
nursing women, unless relying on the data is crucial to a decision that 
would impose a more stringent regulatory restriction that would improve 
protection of public health than could be justified without relying on 
the data. 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.

B. Petition for Review of the 2006 Rule and Settlement Agreement

    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.
    After briefing and argument, but before a decision was rendered by 
the Second Circuit Court of Appeals, EPA and Petitioners entered a 
settlement agreement in which 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 
were substantially consistent with language negotiated between the 
parties and attached to the settlement agreement as Exhibit A. This 
agreement, including Exhibit A, is available in the docket for this 
action as described under ADDRESSES. The settlement agreement makes 
clear that EPA retained full discretion concerning what amendments were 
proposed, and what, if any, amendments are finalized.

C. Proposed Amendments to the 2006 EPA Rule

    Consistent with the settlement agreement, on January 18, 2011, EPA 
Administrator Lisa Jackson signed a notice of proposed rulemaking for 
proposed amendments to the 2006 rule. The proposed amendments were 
substantially consistent with the regulatory language negotiated with 
Petitioners. The notice of proposed rulemaking published in the Federal 
Register issue of February 2, 2011 (76 FR 5735) (FRL-8862-7).

D. Retrospective Review of the Common Rule

    On July 26, 2011, after issuance of EPA's proposed rule, the 
Department of Health and Human Services (HHS), in coordination with the 
Office of Science and Technology Policy (OSTP), issued an advance 
notice of proposed rulemaking concerning modernization of the Common 
Rule which governs research with human subjects conducted or supported 
by EPA and many other Federal departments and agencies (76 FR 44512, 
July 26, 2011). HHS and OSTP sought comment on ``how to better protect 
human subjects who are involved in research, while facilitating 
valuable research and reducing burden, delay, and ambiguity for 
investigators.'' Id. HHS and OSTP identified seven areas of concern 
regarding the Common Rule. Most relevant to EPA's proposed amendments 
to the 2006 rule, was a concern with ``the multiple, differing 
regulatory requirements that can apply to a single research study * * * 
.'' These requirements, according to HHS and OSTP, ``have been 
criticized as complex, inconsistent, and lacking in clarity,'' and can 
result in ``unwarranted variability across institutions and their 
[Institutional Review Boards] in how the requirements are interpreted 
and implemented'' (76 FR at 45514). HHS and OSTP stressed the 
importance of clarifying and harmonizing human subject protections 
across the Federal Government and sought comment on the means by which 
this could be accomplished (76 FR at 44528).

III. The Final Rule

    EPA is finalizing the amendments to the 2006 rule as proposed. This 
includes changes to the scope and consent provisions, and the 
incorporation of selected individual recommendations from the 2004 NAS 
Report as the specific ethical and scientific factors to be considered 
by EPA and the HSRB in reviewing proposed and completed human research 
(i.e., proposed

[[Page 10540]]

Sec. Sec.  26.1603 and 26.1703, see 76 FR 5745-5749).
    The amendments finalized in this rule are consistent with the 
recommendations in the 2004 NAS Report and EPA practice under the 2006 
rule. That practice has been modeled primarily on EPA's practice under 
its Common Rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA's 
Common Rule explicitly address most of the specific ethical 
considerations included in the amendments to the 2006 rule, including 
whether risks to subjects are minimized (compare Sec.  26.1603(c)(2) 
with existing Sec.  26.111(a)(2)); whether risks are reasonable in 
comparison to benefits (compare Sec.  26.1603(c)(3) with Sec.  
26.111(a)(2)); whether subject selection would be equitable (compare 
Sec.  26.1603(c)(4) with existing Sec.  26.111(a)(3)); whether consent 
will be free and voluntary (compare Sec.  26.1603(c)(5) with existing 
Sec. Sec.  26.116 and 26.117); whether an appropriately constituted 
institutional review board (IRB) has reviewed the proposed research 
(compare Sec.  26.1603(c)(6) with Sec.  26.109); and whether the 
``special problems'' of research involving vulnerable populations are 
taken into account (compare Sec.  26.1603(c)(7) and (8) with existing 
Sec.  26.111(a)(3)). Other considerations are implicitly addressed.
    The Common Rule's requirement to ``minimize risks'' in Sec.  
26.111(a)(1) necessitates consideration of whether adequate animal data 
is available to assess potential risks to subjects (see Sec.  
26.1603(c)(1)). It would involve consideration of whether medical care 
is to be provided for injuries incurred in the proposed research (see 
Sec.  26.1603(c)(10)). Section 26.111(b)'s requirement that additional 
safeguards be in place to protect against undue influence of 
``economically'' disadvantaged persons ensures that consideration of 
whether any proposed payments are so high as to constitute undue 
inducement or so low as to be attractive only to individuals who are 
socioeconomically disadvantaged (see Sec.  26.1603(c)(9)). Although 
scientific considerations are not addressed in similar detail in the 
Common Rule requirements, nonetheless, the requirement to consider 
scientific validity and reliability and the Common Rule's emphasis on 
the need for ``sound research design'' in Sec.  26.111(a)(1) and the 
need to take ``the importance of the knowledge that may reasonably be 
expected to result'' from the study into account, mandate that EPA 
focus on considerations addressing scientific validity such as those 
included in Sec. Sec.  26.1603 and 26.1703. At a minimum, NAS 
Recommendations 3-1, 4-1, 5-1, 5-2, 5-3, and 5-5 are critical to proper 
consideration of the Common Rule's ethical requirements and its 
requirement for ``sound research design.''

IV. Public Comments on the Proposed Amendments

    This unit discusses, in general terms, the public comments on the 
proposed amendments and EPA's responses to those comments. EPA received 
a total of 10 public comments on the proposed amendments during the 60-
day comment period. Comments were submitted by 4 individual citizens 
and 6 different entities--the Agricultural Handler Exposure Task Force, 
the American Chemistry Council (on behalf of the Antimicrobial Exposure 
Assessment Task Force II), Beyond Pesticides, CropLife America, Natural 
Resources Defense Council, and SC Johnson & Son, Inc. The docket (under 
docket ID number EPA-HQ-OPP-2010-0785) includes all of the comments 
submitted to EPA on the proposed amendments, as well as EPA's Response 
to Comments document, which provides detailed responses to all comments 
received.

A. Comments on Proposal To Expand Scope To Include Research Submitted 
to EPA Under Any Regulatory Statute EPA Administers

    Two comments addressed the proposed changes to the scope of the 
2006 rule. One commenter stated that the 2006 Appropriations Act did 
not permit an expansion of scope beyond pesticide studies performed in 
the FIFRA and FFDCA context, and another argued that the 2006 
Appropriations Act required that the scope of the rule be further 
expanded beyond studies submitted, or intended for submission, to EPA.
    After considering these comments, EPA has decided to finalize the 
rule text relating to scope as it was proposed, i.e., expanding the 
scope to cover research involving intentional exposure of human 
subjects to pesticides where that research is submitted, or intended to 
be submitted, to EPA under any regulatory statute that EPA administers. 
As noted in EPA's Response to Comments document, EPA no longer regards 
the 2006 Appropriations Act as authority for this rule. Therefore, EPA 
believes it is unnecessary to address whether the 2006 Appropriation 
Act either requires or does not allow EPA to establish a different 
scope for this rule.
    Nevertheless, EPA regards FIFRA as providing adequate legal 
authority for the scope of research covered by this final rule. 
Sections 3(a) and 25(a) of FIFRA provide EPA with authority to regulate 
pesticides, including research involving intentional exposure of a 
human subject to a substance, when the substance is being tested as a 
``pesticide.'' That includes research intended for submission to EPA, 
whether under FIFRA, FFDCA, or any of EPA's other regulatory 
authorities. EPA believes it makes sense to apply the same standards to 
all human studies involving pesticides submitted to EPA. On the other 
hand, EPA believes that it is not in the public interest to extend the 
prohibition against research involving intentional exposure of children 
or pregnant women to pesticides beyond the scope delineated in the 
proposed rule because such a prohibition, if enforceable, could have 
the unintended effect of prohibiting valuable research.

B. Comments on Inclusion of NAS-Derived Considerations

    Two commenters questioned whether new regulatory text proposed at 
Sec.  26.1603(b)(2)(ii) and (iii) would change the ways in which EPA 
has been reviewing proposed studies to measure exposures experienced by 
people who mix, load, or apply pesticides. As proposed, EPA would have 
been required to consider whether the proposed research includes 
representative study populations for the endpoint in question and has 
adequate statistical power to detect appropriate effects. These 
commenters expressed the same concern regarding the proposed regulatory 
text at Sec.  26.1703(a)(2) and (3), which would require EPA to 
consider these factors in determining whether to rely on the research. 
As explained in more detail in EPA's Response to Comments document, EPA 
does not believe that the adoption of the specific ethical and 
scientific factors will impose any additional burden on sponsors of 
exposure studies or on the types of exposure studies referenced by the 
commenters.
    As explained previously, EPA has decided to finalize the proposed 
text detailing specific scientific and ethical aspects of proposed and 
completed research--including the text proposed at Sec.  
26.1603(b)(2)(ii) and (iii) and at Sec.  26.1703(a)(2) and (3)--that 
EPA and the HSRB must consider when reviewing such research. EPA also 
notes that, under the 2006 rule as amended through this final rule, EPA 
does not intend to change the way in which it reviews exposure research 
with respect to the inclusion of representative populations or the 
statistical power of the study, although EPA will consider whether 
further guidance on this issue

[[Page 10541]]

is needed. In addition, EPA does not believe the codification of the 
specific ethical and scientific factors derived from the 2004 NAS 
Report represents a material change in the way a particular pesticide 
study would have been reviewed. Thus, EPA believes that particular 
pesticides studies that have been approved under the 2006 rule, would 
also meet the standards reflected in this final rule.

C. Other Comments, Including Comments on Narrowing the Scope of the 
2006 Rule To Include Only Intentional Dosing Studies

    The remainder of the public comments addressed issues beyond the 
scope of the proposed amendments. These comments included arguments 
that the burden of the requirements of the 2006 rule (as opposed to any 
burden connected to this amendment) are unjustified, and assertions 
that EPA's interpretation in the 2006 rule of the language ``research 
involving intentional exposure of a human subject'' incorrectly 
expanded the scope of the rule beyond that required in the 2006 
Appropriations Act, which addressed only ``intentional dosing human 
toxicity studies.'' The commenters are referring to Sec.  26.1101(a) of 
the 2006 rule, which defines the scope of the rule as applying to ``all 
research initiated after April 7, 2006 involving intentional exposure 
of a human subject * * *.'' As EPA explained in the preamble to the 
proposal for the 2006 rule, this scope was intended to capture ``all 
intentional dosing human studies intended for submission to EPA under 
the pesticide laws'', i.e., studies involving intentional dosing to 
measure a toxic effect and studies involving intentional dosing to 
measure other scientific endpoints, like exposure (Federal Register 
issue of September 12, 2005 (70 FR at 53845) (FRL-7728-2)). Additional 
discussion in the preambles to the proposal for the 2006 rule and 2006 
rule further explains what studies EPA intended to be included within 
the scope of the 2006 rule (70 FR at 53845-53847; 71 FR 6138, 6146, 
6149-6150).
    Because these comments were directed at provisions in the 2006 rule 
that EPA did not reopen for reconsideration as part of the proposed 
amendments, these comments are beyond the scope of this final rule, and 
no response to them is required to finalize this rule. Nonetheless, EPA 
appreciates the concerns expressed by the commenters with regard to the 
burdens imposed by the 2006 rule and recognizes that there may be value 
in considering further amendments to the 2006 rule in a way that 
reduces the burdens on investigators, e.g., by limiting the types of 
research that are subject to particular requirements of the rule.

V. Conclusion

    EPA received relatively few comments on the proposed rule, and many 
of the comments received did not address the amendments in the 
proposal. For the reasons noted previously, the comments that did 
address the proposal do not merit any change to the amendments as 
proposed. Accordingly, EPA is finalizing the amendments as proposed for 
the reasons stated herein and in the preamble to the proposed rule.

VI. Statutory and Executive Order Reviews

A. Executive Order 12866: Regulatory Planning and Review and Executive 
Order 13563: Improving Regulation and Regulatory Review

    Under Executive Order 12866 (58 FR 51735, October 4, 1993), this 
action is a ``significant regulatory action,'' because the Office of 
Management and Budget (OMB) determined that it would raise novel legal 
or policy issues arising out of legal mandates, the President's 
priorities, or the principles set forth in the Executive Order. 
Accordingly, EPA submitted this action to OMB for review under 
Executive Orders 12866 and 13563 (76 FR 3821, January 21, 2011). Any 
changes made in response to OMB recommendations have been documented in 
the docket for this rulemaking as required by the Executive Order.

B. Paperwork Reduction Act (PRA)

    This action does not impose any new information collection burden 
that would require additional review or approval by OMB. However, OMB 
has previously approved the information collection requirements 
contained in the existing regulations at 40 CFR part 26 under the 
provisions of PRA (44 U.S.C. 3501 et seq.), and has assigned OMB 
Control No. 2070-0169 (EPA ICR No. 2195). The OMB control numbers for 
EPA's regulations in 40 CFR are listed in 40 CFR part 9.
    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 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. Regulatory Flexibility Act (RFA)

    RFA (5 U.S.C. 601 et seq.), generally requires an agency to prepare 
a regulatory flexibility analysis of any rule subject to notice and 
comment rulemaking requirements under the Administrative Procedure Act 
(5 U.S.C. 551-553) or any other statute unless the agency certifies 
that the rule will not have a significant economic impact on a 
substantial number of small entities. Small entities include small 
businesses,

[[Page 10542]]

small organizations, and small governmental jurisdictions.
    For purposes of assessing the impacts of this rule on small 
entities, small entity is defined as:
    1. A small business as defined by the Small Business 
Administration's (SBA) regulations at 13 CFR 121.201, which is based on 
either the maximum number of employees or on the sales for small 
businesses in each industry sector, as defined by a 6-digit NAICS code, 
and for this rule is pesticide and other agricultural chemical 
manufacturers (NAICS code 325320) who sponsor or conduct human research 
with pesticides, or other entities (NAICS code 541710) that sponsor or 
conduct human research with pesticides, and IRBs who review human 
research with pesticides to ensure it meets applicable standards of 
ethical conduct;
    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; or
    3. A small organization that is any not-for-profit enterprise which 
is independently owned and operated and is not dominant in its field.
    After considering the economic impacts of this final rule on small 
entities, I certify that this action will not have a significant 
economic impact on a substantial number of small entities. Because no 
small entities have been identified that are directly regulated by 
these amendments, EPA has not attempted to reduce the impact of this 
final rule on small entities. Public comments were explicitly invited 
on all aspects of the proposal and its impacts on small entities, but 
no such comments were received.

D. Unfunded Mandates Reform Act (UMRA)

    Title II of UMRA (2 U.S.C. 1531-1538) establishes requirements for 
Federal agencies to assess the effects of their regulatory actions on 
State, local, and tribal governments and the private sector. This rule 
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. Thus, this rule is not 
subject to the requirements of UMRA sections 202 or 205. This rule is 
also not subject to the requirements of UMRA section 203, because it 
contains no regulatory requirements that might significantly or 
uniquely affect small governments. These amendments are unlikely to 
affect State, local, and tribal governments at all, and are likely to 
affect the private sector only trivially.

E. Executive Order 13132: Federalism

    This action does not have federalism implications because it will 
not have substantial direct effects on the States, on the relationship 
between the national government and the States, or on the distribution 
of power and responsibilities among the various levels of government, 
as specified in Executive Order 13132 (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. Thus, Executive Order 13132 does not 
apply to this action.

F. Executive Order 13175: Consultation and Coordination With Indian 
Tribal Governments

    This action does not have tribal implications as specified in 
Executive Order 13175 (65 FR 67249, November 9, 2000). This action will 
not 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. Executive Order 13045: Protection of Children From Environmental 
Health Risks and Safety Risks

    EPA interprets Executive Order 13045 (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 
amendments.

H. Executive Order 13211: Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use

    This action is not a ``significant regulatory action'' as defined 
in Executive Order 13211 (66 FR 28355, May 22, 2001), because it is not 
likely to have a significant adverse effect on the supply, 
distribution, or use of energy.

I. National Technology Transfer and Advancement Act (NTTAA)

    Section 12(d) of NTTAA (15 U.S.C. 272 note) directs EPA to use 
voluntary consensus standards in its regulatory activities unless to do 
so would be inconsistent with applicable law or otherwise impractical. 
Voluntary consensus standards are technical standards (e.g., materials 
specifications, test methods, sampling procedures, and business 
practices) that are developed or adopted by voluntary consensus 
standards bodies. NTTAA directs EPA to provide Congress, through OMB, 
explanations when the Agency decides not to use available and 
applicable voluntary consensus standards. This action does not involve 
any technical standards. Therefore, EPA did not consider the use of any 
voluntary consensus standards.

J. Executive Order 12898: Federal Actions To Address Environmental 
Justice in Minority Populations and Low-Income Populations

    Executive Order 12898 (59 FR 7629, February 16, 1994) establishes 
Federal executive policy on environmental justice. Its main provision 
directs Federal agencies, to the greatest extent practicable and 
permitted by law, to make environmental justice part of their mission 
by identifying and addressing, as appropriate, disproportionately high 
and adverse human health or environmental effects of their programs, 
policies, and activities on minority populations and low-income 
populations in the United States.
    EPA has determined that this final rule will not have 
disproportionately high and adverse human health or environmental 
effects on minority or low-income populations, because it does not 
affect the level of protection provided to human health or the 
environment. This rule does not entail special considerations of 
environmental justice related issues. The strengthened protections for 
human subjects participating in covered research established in the 
2006 rule will not be altered by these amendments.

VII. Congressional Review Act

    The Congressional Review Act (5 U.S.C. 801 et seq.), generally 
provides that before a rule may take effect, the agency promulgating 
the rule must submit a rule report, which includes a copy of the rule, 
to each House of the Congress and the Comptroller General of the United 
States. EPA will submit a

[[Page 10543]]

report containing this rule and other required information to the U.S. 
Senate, the U.S. House of Representatives, and the Comptroller General 
of the United States prior to publication of the rule in the Federal 
Register. A major rule cannot take effect until 60 days after it is 
published in the Federal Register. This action is not a ``major rule'' 
as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 26

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

    Dated: February 8, 2013.
Lisa P. Jackson,
Administrator.

    Therefore, 40 CFR chapter I is amended as follows:

PART 26--[AMENDED]

0
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).

0
2. In Sec.  26.1101:
0
a. Remove paragraphs (a), (c), and (g).
0
b. Redesignate paragraph (b) as (c), (f) as (g), (e) as (f), and (d) as 
(e).
0
c. Add new paragraphs (a), (b), and (d).
    The amendments 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 April 15, 2013 
involving intentional exposure of a human subject to:
    (1) Any substance if, at any time prior to initiating such 
research, any person who conducted or supported such research intended 
either to submit results of the research to EPA for consideration in 
connection with any action that may be performed by EPA under the 
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 
136-136y) or section 408 of the Federal Food, Drug, and Cosmetic Act 
(FFDCA) (21 U.S.C. 346a), or to hold the results of the research for 
later inspection by EPA under FIFRA or section 408 of FFDCA; 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 EPA Administrator retains final judgment as to whether a 
particular activity is covered by this subpart.
* * * * *

0
3. In Sec.  26.1102, revise paragraphs (a) and (c) and add new 
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 the Federal Register issue of June 18, 
1991 (56 FR 28003)) 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 appears in 40 CFR part 26, subpart A.

Sec.  26.1111  [Amended]

0
4. In Sec.  26.1111, remove from paragraph (a)(4) the phrase ``or the 
subject's legally authorized representative.''

0
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.
* * * * *

0
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

[[Page 10544]]

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

0
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

0
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.

0
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 on or after 
April 15, 2013 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]

0
10. In Sec.  26.1302, remove the word ``shall.''

Sec.  26.1502  [Amended]

0
11. In Sec.  26.1502:
0
a. Remove in the first sentence of paragraph (a), the period after the 
phrase ``during an inspection'' and add in its place a comma.
0
b. Remove in the second sentence of paragraph (a), the phrase ``The 
agency'' and add in its place ``EPA.''
0
c. Remove in the last sentence of the introductory text of paragraph 
(b), the phrase ``the Agency'' and add in its place ``EPA.''

Sec.  26.1505  [Amended]

0
12. In Sec.  26.1505, remove from the last sentence, the citation 
``Sec.  26.1502(c)'' and add in its place ``Sec.  26.1502(b)(4).''

Sec.  26.1507  [Amended]

0
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]

0
14. Redesignate Sec. Sec.  26.1601 through 26.1603 as Sec. Sec.  
26.1603 through 26.1605.

0
15. Add new Sec. Sec.  26.1601 and 26.1602 to subpart P 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 Sec.  26.1125.
    (b) Reviews by EPA on or after April 15, 2013 and, to the extent 
required by Sec.  26.1604, by the Human Studies Review Board of reports 
of completed research subject to Sec.  26.1701.

Sec.  26.1602   Definitions.

    The definitions in Sec.  26.1102 also apply to this subpart.

0
16. In newly redesignated Sec.  26.1603:
0
a. Remove paragraphs (a) and (e).
0
b. Redesignate paragraphs (b) through (d) as (e) through (g).
0
c. Add new paragraphs (a), (b), (c), (d), and (h).
    The amendments 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 scientific validity and reliability of 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 EPA Administrator will also consider the process laid 
out and the attendant discussion for evaluating that type of study as 
provided in Recommendation 4-1 of 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 subject 
to this subpart, the EPA Administrator may recommend additional 
conditions which, in the judgment of the EPA

[[Page 10545]]

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.

0
17. In newly redesignated Sec.  26.1604, revise 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.
* * * * *

0
18. Add Sec. Sec.  26.1606 and 26.1607 to subpart P 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 
required 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.

0
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

0
20. Revise Sec. Sec.  26.1701 through 26.1705 to read as follows:
* * * * *
Sec.
26.1701 To what does this subpart apply?
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.
26.1705 Prohibition of reliance on unethical human research with 
non-pregnant, non-nursing adults initiated after April 7, 2006.
* * * * *

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 also apply to 
this subpart.

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.

    (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.

    (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

[[Page 10546]]

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]

0
21. In Sec.  26.1706, remove in paragraph (d) the word ``publishes'' 
and add in its place the phrase ``has published.''

[FR Doc. 2013-03456 Filed 2-13-13; 8:45 am]
BILLING CODE 6560-50-P