Revisions to EPA's Rule on Protections for Subjects in Human Research Involving Pesticides, 5735-5755 [2011-1629]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[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]



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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: https://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 
https://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 https://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 https://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The hours of 
operation of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays. The Docket Facility telephone 
number is (703) 305-5805.

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

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

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

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

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

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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

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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) (https://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

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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 https://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 https://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 https://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 a