## Attachment # A
– Review Period: 02/01/13
– 02/08/13

EO 12866 Documentation related to the following action:

Final Rule: EPA's Rule on Protections for Subjects in Human Research Involving Pesticides (RIN 2070

- AJ76; FRL

- 9353

- 4; EPA Docket ID #: EPA

- HQ

- OPP

- 2010

- 0785)

NOTE : Under Executive Order 12866 (58 FR 51735, October 4, 1993), EPA submitted this action to OMB for review under Executive Orders 12866 and 13563 (76 FR 3821, January 21, 2011) on two occasions. As such, the documentation for each review is represented as two separate attachments. See docket entry for the full documentation

. 02/08/2013

## Attachment # A
– Review Period: 02/01/13
– 02/08/13

(1) A copy of the information that was submitted to OIRA for review under the Executive Order.

02/08/2013E O1 28 66 R ev ie w BILLING CODE 6560

- 50

- P

12P

- 0881 01/ 3 1 /2013

– Revised Final Rule ( NO Mark

- up). Filename : RIN2070

- AJ76_EO12866_HumanSubjectsRevisions_FRM_2013

- 01

- 31_4pm.docx

ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 26 [ EPA
- HQ
- OPP
- 20 10
- 0785 ; FRL
- 9353
- 4 ] RIN 2070
- AJ76 Protections for Subjects in Human Research Involving Pesticides AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule. SUMMARY: EPA is finalizing narrowly tailored amendments to the portions of its rules for the protection of human subjects of research apply ing to third parties who conduct or support research with pesticides involving intentional exposure of human subjects and to person s who submit the results of human research wi th 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 b y 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 conduc ted or supported by EPA and many other Federal departments and agencies

. DATES : This rule is effective [ insert date 60 days after date of publication in the Federal Register ]

.Page 2 of 32

E O1 28 66 R ev ie w 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 revie w 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 in formation 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 withPage 3 of 32

E O1 28 66 R ev ie w pesticides, and Instit utional 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 huma n 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 amendm ents 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 p art 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 invol ving 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 “pestici de” 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 o n behalf of a subject in research involving intentional exposure to a pesticide by a subject’s “legally authorized representative.”Page 4 of 32

E O1 28 66 R ev ie w • 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 the se 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 fo r 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 V I .B. and a copy of the ICR is availabl e 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 promulg at ed 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

-Page 5 of 32

E O1 28 66 R ev ie w 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 in volving 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 Amer ican; 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 r ule violated the 200 6 Appropriations Act because it d id not bar all pesticide research with pregnant women and children , w as inconsistent with the
2004 NAS Report , and w as inconsistent with the Nuremburg Code

. After briefing and argument , but before a decision was rendered by the Second Circuit Court of Appeals , EPA and P etitioners entered a settlement agreement in which E PA agree d to conduct notice

- and

- comment rulemaking on the issue of whether the 2006 r ule should be amended

. EPA also agree d to propose, at a minimum, amendments to the 2006 rule that were substantially consistent with language negotiated between the parti es 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 make s clearPage 6 of 32

E O1 28 66 R ev ie w that EPA retain ed full discretion concerning what amendments wer e 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 fo r proposed amendments to the 2006 rule . The proposed amendments were substantially consistent with the regulatory language negotiated with Petitioners. The notice of proposed rule making 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 a n 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 im portance of clarifying and harmonizing human subject protectionsPage 7 of 32

E O1 28 66 R ev ie w across the Federal Government and sought comment on the means by which this could be accomplished (76 FR at 44528).
I II . 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 §§ 26.1603 and 26.170 3, s ee 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 includ ed in the amendments to the 2006 rule, including whether risks to subjects are minimized (compare § 26.1603(c)(2) with existing § 26.111(a)(2)); whether risks are reasonable in comparison to benefits (compare § 26.1603(c)(3) with § 26.111(a)(2)); whether subject selection would be equitable (compare § 26.1603(c )(4) with existing § 26.111(a)(3)); whether consent will be free and voluntary (compare § 26.1603(c)(5) with existing §§ 26.116 and 26.117); whether an appropriately constituted institutional review board (IRB) has reviewed the proposed research (compare § 26.1603(c)(6) with § 26.109); and whether the “special problems” of research involving vulnerable populations are taken into account (compare § 26.1603(c)(7) and (8) with existing § 26.111(a)(3)). Other considerations are implicitly addressed. The Com mon Rule’s requirement to “minimize risks” in § 26.111(a)(1) necessitates consideration of whether adequate animal data is available to assess potential risks to subjects (see § 26.1603(c)(1)). It would involve consideration of whether medical care is to be providedPage 8 of 32

E O1 28 66 R ev ie w for injuries incurred in the proposed research (see § 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 § 26.1603(c)(9)). Although scientific considerations are not addressed in simila r 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 § 26.111(a)(1) and the need to take “the importance of the know ledge 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 §§ 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.”
I V. 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 Agricultura l 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 d ocket ID number EPA

- HQ

- OPP

- 20 10

- 0785) includes all of the comments submitted to EPA on th e 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 S cope to Include Research Submitted to EPA under AnyPage 9 of 32

E O1 28 66 R ev ie w 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, o r 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. S ections 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 i s 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 u nintended effect of prohibitingPage 1 0 of 32

E O1 28 66 R ev ie w valuable research. B. Comments on Inclusion of NAS

- Derived Considerations Two commenters questioned whether new regulatory text proposed at § 26.1603(b)(2)(ii ) and ( iii) would change the ways in which EPA has been reviewin g 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 § 26.1703(a)(2 ) and ( 3) , which w ould 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 final ize the proposed text detailing specific scientific and ethical aspects of proposed a nd completed research

– including the text proposed at § 26.1603(b)(2)(ii ) and ( iii) and at § 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 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 par ticular pesticides studies that have been approved under the 2006 rule, would also meet the standards reflected in this final rule.Page 11 of 32

E O1 28 66 R ev ie w 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 i nterpretation 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 § 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 h uman 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 dosi ng 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 (7 0 FR at 53845

- 538 47; 71 FR 6138, 6146, 6149

- 61 50). Because these comments were directed at provisions in the 2006 rule that EPA did not reopen for reconsideration as part of the proposed amen d ments , the se 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 commen ters with regard to the burdens imposed by the 2006 rule and recognizes that there may be value in considering further amend ments toPage 12 of 32

E O1 28 66 R ev ie w 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.
V I . Statutory and E xecutive Order Reviews
A. Executive Order 12866: Regulatory Planning and Review and Executive Order 13563: I

mproving 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 submitt ed this action to OMB for review under Executive Order s 12866 and 13563 (76 FR 3821, January 21, 2011). A ny changes made in response to OMB recommendations have been documented in the docket for this rulemaking as required by the Executive Order.
B

. Pape rwork 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 arePage 13 of 32

E O1 28 66 R ev ie w 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 es timated 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 re viewing 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 sin ce 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 ofPage 14 of 32

E O1 28 66 R ev ie w 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 number s 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 a gency 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, small organizations , and small governmental jurisdictions

. For purposes of assessing the impacts of t hi s 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 bus inesses in each industry sector, as defined by a 6

- digit NAICS code, and for this rule is p esticide and other agricultural chemical manufac turers (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

.Page 15 of 32

E O1 28 66 R ev ie w 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 nu mber 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 c omments were explicitly invited on all aspect s of the proposal and its impacts on small entities , but no such comments were received

. D

. Unfunded Mandate s 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 ma ndate 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 se ction 203, b ecause 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 federalis m implications because i t 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 apply ing 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.Page 16 of 32

E O1 28 66 R ev ie w F

. Executive Order 1 3175 : 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 t ribal 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 t o 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 t he 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 E nergy 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 e ffect on the supply, distribution, or use of energy.
I

. National Technology Transfer and Advancement Act (NTTAA) Section 12(d) of NT T AA ( 15 U.S.C. 272 n ote ) directs EPA to use voluntary consensus standards in its regulatory activities unless to do so would be inconsistent with applicable law orPage 17 of 32

E O1 28 66 R ev ie w 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 direc ts EPA to provide Congress, through OMB, explanations when the Agency decides not to use available and applicable voluntary consensus standards. T his action does not involve any technical standards . Therefore, EPA did not consider the use of any voluntar y consensus standards.
J

. E xecutive O rder 12898: Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations Executive Order 12898 ( 59 FR 7629, February 16, 1994) establishes F ederal executive policy on environmental justice. Its main provision directs F ederal agencies , to the greatest extent practicable and permitted by law, to make environmental justice part of their mission by identifying and addressing, as appropriate, disp roportionately 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 t his final rule will not have disproportiona tely 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 o f environm ental 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

. VI I . Congressional Review Act The Congressional Review Act ( 5 U.S. C. 801 et seq
. ) , generally provides that before a rule may take ef fect, the a gency 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 UnitedPage 18 of 32

E O1 28 66 R ev ie w States. EPA will submit a 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 m ajor rule cann ot 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).Page 19 of 32

E O1 28 66 R ev ie w List of Subjects in 40 CFR P art 26 Environmental protection, Administrative practice and procedure s , Human r esearch, Pesticides and pests.

Dated:

_________________

_________________________________________

Administrator.Page 20 of 32

E O1 28 66 R ev ie w Therefore, 40 CFR chapter I is amended as follows: PART 26
-- [AMENDED]
1

. The authority citation for part 26 is revised to read as follows: Authority: 5 U.S.C

. 301; 7 U.S.C

. 136a(a) and 136w(a)(1); 21 U.S.C

. 346a(e)(1)(C);

sec . 201 , Pub

. L . 109

- 54, 119 Stat. 531; and 42 U.S.C

. 300v

- 1(b).
2

. In § 26.1101 :

a . Remove paragraphs (a), (c), and (g)

. b

. Redesignate paragraphs (b) as (c), ( f ) as ( g ), (e) as (f), and ( d ) as ( e ).

c . Add new paragraphs (a), (b), and (d)

. The amendment s rea d as follows : § 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 [ insert date 60 days after date of publication in the Federal Register ] involving intentional exposure of a human subject to: (1) Any substance if, at any time prior to initiating such research, any pe rson 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 und er any regulatory
statute administered by EPA other than those statutes designated in paragraph (a)(1) of thisPage 21 of 32

E O1 28 66 R ev ie w section , or to hold the results of the research for later inspection by EPA under any regulatory
statute administered by EPA other than those sta tutes desi gnated 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 re search 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 pa rticular activity is covered by this subpart

. * * * * * 3

. In § 26.1102 , r evise paragraph s (a) and (c) and a new paragraph (k) to read as follows: § 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

. 13 6(u) ( Federal Insecticide, Fungicide , and Rodenticide Act , section 2(u) )

.
* * * * *Page 22 of 32

E O1 28 66 R ev ie w (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 spons ored by that Federal department or agency. EPA’s codification of the Common Rule appears in 40 CFR part 26, subpart A.
§ 26. 1111 [ Amended ] 4

. In § 26.1111 , r emove from paragraph (a)(4) the phrase “or the subject’s legally authorized representative

. ” 5

. In § 26.1116 , revis e the introductory text of th e section to read as follows: § 26.1116 General requirements for informed consent. No investigator may involve a human being as a subject in research covered by this subpart unless the investigator ha s 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
p ossibility 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 institu tion or its agents from liability for negligence.Page 23 of 32

E O1 28 66 R ev ie w * * * * *
6

. Revise § 26.1117 to read as follows: § 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 § 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 § 26.1116 have been presented orally to the subjec t

. 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

. H owever, the witness must sign both the short form and a copy of the summary, and the person actually obtaining consent must sign a copy of the summary

. A copy of the summary must be given to the subject, in addition to a copy of the short form.
7

. Revise the heading for subpart L t o read as follows: Subpart L

— Prohibition of Third
- Party Research Involving Intentional Exposure to a Pesticide of Human Subjects W ho are Children or Pregnant or Nursing Women
8

. Revise § 26.1201 to read as follows: § 26.1201 To what does this subpart apply? This s ubpart applies to any research subject to subpart K of this part.
9

. Revise § 26.1301 to read as follows: § 26.1301 To what does this subpart apply? This subpart applies to any person who submits to EPA on or after [ insert date 60 daysPage 24 of 32

E O1 28 66 R ev ie w after date of publication in the Federal Register ] 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

. 1 36

- 136y) or section 408 of FFDCA (21 U.S.C

. 346a). (b) A report containing the results of any human research on or with a pesticide for consideration in connection with any action that may be performed by EPA under any regulatory
statute administered by EPA. § 26.1302 [ Amended ] 1 0

. In § 26.1302 , remov e the word “shall

. ” § 26.1502 [ Amended ] 1 1

. In § 26.1502:

a . Remove i n the first sentence of p aragraph (a) , the period after the phrase “during an inspection” and add in its place a comma . b

. Remove i n the second sentence of paragraph (a) , the phrase “ The a gency ” and add in its place “EPA.”

c. Remove i n the last sentence of the introductory text of paragraph (b) , the phrase “ t he
A gency” and add in its place “EPA.” § 26.1505 [ Amended ] 1 2

. In § 26.1505 , remove from the last sentence , the citation “§ 26.1502(c)” and add in its place “§ 26.1502(b)(4).” § 26.1507 [ Amended ] 1 3

. In § 26.1507 , re mov e from the last sentence, the phrase “The A gency” and add in its place “EPA

. ” §§ 26.1601 through 26. 1603 [ Redesignated as §§ 26.1603 through 26.1605 ]Page 25 of 32

E O1 28 66 R ev ie w 1 4

. R edesignat e §§ 26.1601 through 26.1603 as §§ 26.1603 through 26.1605.
1 5

. A dd new §§ 26.1601 and 26.1602 to su b part P to read as follows: §26.1601 To what does this subpart apply? This subpart applies t o both of the following: (a) Reviews by EPA and by the Human Studies Review Board of proposals to conduct new research subject to § 2 6.1125

. (b) Reviews by EPA on or after [ insert date 60 days after date of publication in the Federal Register ] and, to the extent required by § 26.1604, by the Human Studies Review Board of reports of completed research subject to § 26.1701

. § 26.1602 Definitions. The definitions in § 26.1102 also apply to this subpart. 1 6

. In n ewly redesignated § 26.1603:

a . Re move p aragraphs (a) and (e). b

. Redesignate paragraphs (b) thr ough (d) as ( e ) through ( g ).

c . Add new paragraphs (a), (b), (c), (d), and ( h )

. The amendments read as follows : § 26.1603 EPA review of proposed human research. (a) EPA must review all proposals for new human research submitted under § 26.1125 in a timely manner. (b) In reviewing proposals for new human research submitted under § 26.1125, the EPA Administrator must consider and make determinations regarding the scientific va lidity 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 humanPage 26 of 32

E O1 28 66 R ev ie w observational researc h. (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 saf ety of subjects. (c) In reviewing proposals for new research submitted under § 26.1125, the EPA Administrator must consider and make determinations regarding ethical aspects of the proposed research , including: (1) Whether adequate information is availab le 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, minimize s 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 red uce 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 t he National Research Council of the National Academy of Sciences (NAS) , entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues.”Page 27 of 32

E O1 28 66 R ev ie w (4) Whether subject selection will be equitable. (5) Whether subjects’ partici pation 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 s ubject 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 prin ciples 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 nee ded 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 Administrator, are necessary for the protection of human subjects.
* * * * * (h) EP A must provide the submitter of the proposal copies of the EPA and Human Studies Review Board reviews.
1 7

. In newly redesignated § 26.1604 , revise paragraph (a) to read as follows: § 26.1604 EPA review of completed human research.Page 28 of 32

E O1 28 66 R ev ie w (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 § 26.1303, if any, and other available, relevant information and document its conclusions regarding the scientific and ethical conduct of the research.

*****
1 8

. A dd §§ 26.1606 and 26.1607 to subpart P to r ead as follows: § 26.1606 Human Studies Review Board review of proposed human research. In commenting on proposals for new research submitted to it by EPA, the Human Studies Review Board must consider the scientific merits and ethical aspects of the propo sed research, including all elements required in § 26.1603 (b) and (c) and any additional conditions recommended pursuant to § 26.1603(d). § 26.1607 Human Studies Review Board review of completed human research. In commenting on reports of completed resear ch 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 s ubpart Q of this part. 19

. Revise the heading for subpart Q to read as follows: Subpart Q

— Standards for Assessing Whether to Rely on the Results of Human Research in EPA Actions
2 0

. Revise §§ 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

- nursingPage 29 of 32

E O1 28 66 R ev ie w adults initiated after April 7, 2006.
* * * * * § 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 h uman subjects to any substance. (b) For decisions under any regulatory statute administered by EPA other than those statutes designated in paragraph (a) of this section, this subpart applies to research involving intentional exposure of human subjects to a pesticide. § 26.1702 Definitions. The definitions in § 26.1102 and § 26. 1202 also apply to this subpart. § 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 determine s 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 th e research subjects are representative of the populations for the end point or endpoints in question. (3) The statistical power of the data to support the scientific conclusion EPA in tends to draw from the data. (4) In a study that reports only a No Obser ved Effect Level (NOEL) or a No ObservedPage 30 of 32

E O1 28 66 R ev ie w 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 re liance on research subject to this subpart involving intentional exposure of human subjects who are pregnant women (and therefore their fetuses), nursing women, or children

. Except as provided in § 26.1706, EPA must not rely on data from any research subj ect to this subpart involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child. § 26.1704 Prohibition of reliance on unethical human research with non
- pregnant, non nursing adults . ( a) This section applies to research subject to this subpart that is not subject to § 26.1705. (b) Except as provided in § 26.1706, EPA 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 t he 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) Th e prohibition in this section is in addition to the prohibitions in § 26.1703. § 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 ,Page 31 of 32

E O1 28 66 R ev ie w or to the codification of the Common Rule by another Federal department or agency. (b) Except as provided in § 26.1706, EP A 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 C ommon 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 § 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 § 26.1603(c), and no amendments to or deviations from that proposal placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed consent

. If EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted information that would have altered the outcome of EPA’s evaluation of the proposal under § 26.1603(c), EPA must not rely on that data. (2) A proposal that would have been found to be acceptable under § 26.1603(c), if it had been subject to review under that section, and no amendments to or deviations from that proposal placed participants at increased risk of harm (based on knowledge available at the time t he study was conducted) or impaired their informed consent. (d) Th e prohibition in this section is in addition to the prohibitions in § 26.1703. § 26.1706 [Amended]Page 32 of 32

E O1 28 66 R ev ie w 21

. In § 26.1706 , remove in paragraph (d) the word “publishes” and add in its place the phrase “has published

. ”Docket ID No.: EPA
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Page 1 of 14 01/ 31 /2013

– Revised Response to Comment Document for Final Rule (NO Mark

- up). Filename: RIN2070

- AJ76_EO12866_HumanSubjectsRevisions_FRM_Response2Comments_2013

- 01

- 31_4pm.docx 

### U.S. Environmental Protection Agency (EPA) Office of Chemical Safety and Pollution Prevention R esponse to Public Comment s Received on the Proposed Rule Entitled:
“ Revisions to EPA’s Rule on Protections for Subjects in Human Research Involving Pesticides ” (RIN 2070
- AJ76) 01/ 31 /2013 ; 4 pm
Public Comment Period : 2/2/2011
- 4/4/2011
I. Summary This document addresses comments received in response to the Notice of Proposed Rulemaking for Revisions to the EPA’s Rule on Protections for Subje cts in Human Research Involving Pesticides that published o n February 2, 2011 (76 FR 5735) , in which the EPA propos ed amend ing the portions of its 2006 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 the EPA. All comments appear in their entirety in the public docket for this rulemaking, identified as EPA Docket ID No. EPA

- HQ

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- 2010

- 0785 and accessible at http:// www.regulations.gov

. EPA proposed several narrowly

- targeted changes to regulatory text as a result of a settlement agreement and specifically requested com ment on the proposed changes. The Agency received 10 comments in response to the N otice of P roposed Rulemaking

. 1 In the d ocket , d ocuments identified with Document ID numbers ending in 1 through 6 are supporting documents for the rulemaking ; d ocuments 7

- 16 are public comments ; d ocuments 17

- 55 are the 28 attachments to NRDC ’s comment ( see discuss ion in Footnote 1 , below )

. II. Comments on Issues within the Scope of the Proposed Amendments EPA has identified only two issues raised by commenters that are within the sc ope of the proposed amendments

. The first issue relate s to the proposed expansion of the rule to cover human testi ng with pesticides submitted to EPA under any regulatory statute it administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. The second issue relate s to proposed revisions to § 26.1603(b)(2)(ii ) and ( iii ) and § 26.1703(a)(2 ) and ( 3) to require EPA to

1 The comment from the Natural Resources Defense Council (NRDC) include s 28 attachments. Although these attachments were posted to the docket as individual comments, they are actually supporting documents for NRDC’s comments on this proposed rulemaking. The 2 8 documents also appear in other EPA dockets, but were resubmitted so that all of the documents were included in this docket.Docket ID No.: EPA
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Page 2 of 14 consider whether proposed and completed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. The specific comments, and EP A’s responses to those comments, are discussed below.
Document ID No.: EPA
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- 14 (Commenter: SC Johnson)
1. Comment: T he 2006 Appropriations Act does not require or authorize EPA to issue a rule that applies to studies performed outside of the FFDCA / FIFRA context

. “ Nothing in the Appropriations Act language required or authorized EPA to issue a rule that applies to studies performed outside of the FIFRA/FFDCA context. Thus, the Appropriations Act does not expand EPA’s rulemaking authority under FIFRA or the FFDCA such that EPA can issue a rule that regulates studies performed for submission under other statutes. EPA’s proposed revision exceeds the Agency’s statutory authority by attempting to regulate human testing under statutes beyond FIFRA a nd FFDCA. We therefore urge EPA not to adopt this proposed revision to the Rule.” (p 10). Response: EPA originally promulgated this rule under the authority of the 2006 Appropriations Act and FIFRA. Although the proposal cites the 2006 Appropriations Act as authority for th e proposed rule, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA. “ A federal appropriations act applies only for the fiscal year in which it is passed, unles s it expressly provides otherwise.” Building & Constr. Trades Dep't v. Martin , 961 F.2d 269 (D.C. Cir.), cert. denied , 506 U.S. 915 (1992). Because section 201 contains no language providing for the continuing effect of its requirements, these requirements expired with FY 2006. Accordingly, EPA is not citing the 2006 Appropriations Act as authority for th e final rule. Because the 2006 Appropriations Act is no longer in effect, this expansion of the scope of the 2006 rule is being promulgated on the authority of FIFRA alone. FIFRA gives EPA broad authority to regulate the sale, distribution, and use of pesticides . This authority encompasses regulation of the sale, distribution, and use of pesticides in human testing. The commenter is wrong to suggest that EPA interpreted the 2006 Appropriations Act as expanding its authority under FIFRA. The commenter is also incorrect to argue that EPA is asserting the authority under FIFRA to regulate testing under other EPA regulatory statutes. EPA is not in this rule generally regulating testing under all of its regulatory statutes; rather, it is regulating the use of pesticides in human testing, regardless of under what EPA regulatory regime that testing is done. FIFRA authority easily extends to cover such a sale, distribution, and use of pesticides. EPA believes this expansion of the scope of the 2006 rule is warranted to assure that research involving intentional exposure of human subjects to pesticides will be treated in a similar manner under all o f EPA’s regulatory statutes.
Document ID No.: EPA
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- 16 (Commenter: Natural Resources Defense Council [NRDC])
2. Comment: W hile the expanded scope of the proposed rule “would narrow the loophole created by the ‘intention’ [to submit to EPA] standard, we would prefer that the loophole be closed by including a clear ban on the conduct of any intentional dosing toxicity study on pregnant women or children. Section 201 [of the 2006 Appropriations Act] requires such a ban...” (p 6) Response : Because NRDC’s argument is based on a statutory provision no longer in force (i.e., section 201 of the Appropriations Act), it is without me rit

. As mentioned above, EPA hasDocket ID No.: EPA
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Page 3 of 14 authority, and believes it is reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides that are submitted to EPA under other laws that it administers. This rule covers studies tha t are within EPA’s purview. However, to expand the 2006 rule to impose prohibitions or conditions on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies involving unregistered pesticides that are conducted outside t he United States) is clearly outside EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research, for example, by preventing researchers from studying whether repellent impregnated bed n ets reduced the incidence of malaria in African villages.
Document ID No s .: EPA
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- 11 (Commenter : Agricultural Handler Exposure Task Force [AHETF]) EPA
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- 12 (Commenter: CropLife America [CLA]) EPA
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF])
3. Comment: The AHETF, CLA , and AEATF cite concerns with the proposed new regulatory text at § 26.1603(b)(2)(ii ) and ( iii) that would require EPA to consider whether the proposed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. AEATF, AHETF, and CLA are similarly concerned with the proposed new regulatory text at § 26.1703(a)(2 ) and ( 3) that would require EPA to consider these factors in determining whether to rely on completed research . The commenters’ argue that while these factors are pertinent to clinical studies they have little or no relevance to exposure st udies. The specific comments from each commenter are quoted below.
AHETF : “Another problem area for the proposed amendments to the Rule concerns issues that require case

- by

- case consideration of the EPA and HSRB. In these situations, the proposed Rule cannot address the specificity needed for a given proposed study because of the contextual information and interpretation required. Specifically, the proposed amendments (see Exhibit A, Subpart K, Section 26.1703), present an itemized list regarding EPA ‟ s consideration of reliance on data from research involving “intentional exposure” of human subjects... These criteria require interpretation by subject matter experts on a case

- by

- case basis and ... more specific definition of the terms “representative” and “s tatistical power” are necessary because these are protocol/study design

- specific aspects...Further, these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies...” (EPA

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- 11, p 15

- 16)
C LA : “CLA notes and agrees that these considerations play an important role in some human testing and we argue that subject matter experts need to provide input on a case

- by

- case basis. The study design aspects require specific considerations to be made by EPA (and the HSRB, as well as other federal advisors, i.e., the EPA FIFRA Scientific Advisory Panel). However, there appears to be unnecessary complexity added to the evaluation of occupational exposure studies. Many of these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies whose purpose is to develop observational exposure data.” (EPA

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- 12, p 6)
AEATF : “AEATF is concerned, however, that proposed changes to 40 CFR Part 26, requ iring representative study populations and ‘ adequate statistical power ’ are inapposite to the types ofDocket ID No.: EPA
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Page 4 of 14 exposure research being conducted by AEATF and others, are too ambiguous to offer clarity and predictability to study sponsors and investigators, and imp ose unwarranted burdens in study sponsors and investigators without improving scientific validity or protection of human subjects.” (EPA

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- 13, p 3)

. Further on the topic of “representative study populations” and “adequate statistical power” , the commenters request that EPA “confirm that EPA does not expect any effect on the continued approval of the worker exposure studies” (AEATF, EPA

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- 13, p 5). Response: As it has since its initial promulgation, the EPA will be guided in implementing the amended 2006 rule by the recommendations of the 2004 NAS Report. EPA disagrees with the assertion that the NAS recommendations on representative populations and statistical power are not applicable to exposure studi es. Even though the NAS’ recommendations about representative study populations and adequate statistical power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied the principles underlying these recommendations, as well as the general NAS directive that studies should be designed and conducted in accordance with appropriate scientific standards and practices, in its consideration of human research since the promulgation of the rule in 2006 and used in EPA’s science a nd ethics reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751.
U nder the 2006 rule as amended through this rulemaking, 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 is needed. EPA does not believe the codification of the specific ethical and scientific factors derived from t he 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. EPA notes that the NAS emphasized that EPA should focus on the “objectives of the study” in determining what is a representative population (NAS Report, p. 77). Thus, representativeness i s a study

- specific determination based on the objectives of the study. For exposure studies, a fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate sampling strategies can produce a sample which represents a broader range of conditions than would be present in a random sample of similar limited size and thus may produce results that reasonably approximate real world exposures with respect to the overall magnitude and “spread.” For example, the Agricultural H andler Exposure Task Force (AHETF) and the Antimicrobial Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” sampling procedure in their exposure research. This procedure attempts to produce a sample which incorporates some random elements (where feasible); the resulting sample can be more useful from a regulatory perspective in that it more likely represents the range of conditions and situations under which exposure occurs. This approach meets the objectives of the s tudy. Similarly, statistical power consideration s are also a relevant concept for both toxicology and exposure studies. Statistical power evaluates the extent to which a study design can measure the effect being studied. For example, a toxicity study typically evaluates whether a chemical causes an effect by comparing the responses of the exposed and un exposed groups. In some instances ,Docket ID No.: EPA
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Page 5 of 14 expos ed and un expos ed groups will not show different (statistically significant) responses, even though the chemical actually does cause the effect. The statistical “power” of a toxicological study can be thought of as the ability of the study to detect a difference between expos ed and un expos ed groups given that a difference of a defined magnitude does exist. Statistical power can be an important concept in evaluating the design of toxicity studies since it helps in ascertaining the degree to which the study will be able to find a significant difference between expos ed and un expos ed groups , when a difference of defined magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical power of the study is an irrelevant consideration if the study found a statistically significant relationship between exposure and an effect. Conversely , when a completed toxicity study finds no such relationship, evaluating the statistical power of the study design becomes relevant because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of the result. As to expos ure studies, statistical power could have applicability to an exposure study design if, for example, that study attempted to evaluate the relationship between dermal or inhalation exposure and an exposure variable. The statistical power of such an exposur e study would also be a consideration if that study was interpreted as showing that there is no relationship between the tested variables. EPA has required various statistical analyses of exposure studies under the 2006 rule other than statistical powe r analyses. For example, EPA has relied upon standard regression analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the merit of worker exposure studies. EPA expects that those or similar analyses will, in all pro bability, suffice going forward under the requirement in the revised rule that EPA must determine that “data were derived in a manner that makes them scientifically valid and reliable”. 40 CFR 26.1703(a). Therefore, EPA does not believe that the revised rule will impose any additional burden on sponsors of exposure studies with regard to statistical analyses generally.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking
Document ID No.: EPA
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- 07 ( Commenter: Anonymous ) 1. Comment: “ It is plausible that several of the current or future

- use pesticides might exert trans

generational epigenetic effects that have not been studied yet. Families of applicators may be at highest risk for these kinds of effects. It is hard to imagin e a scientifically valid study of these effects that would not require inclusion of children (but these children need not be exposed). A finer distinction should be made in the regulation between assent of children to participate in studies where they wil l be exposed to a pesticide, and assent of children to participate in studies where someone else will be exposed to a pesticide.” Response: EPA’s 2006 r ule (currently, and as it is proposed to be amended) covers intentional exposure studies, not epidemiol ogical or observational studies. The type of study that the commenter has described (studying pesticide applicator families) would likely be epidemiological or observational and would not be covered by the rule. If, however, a protocol proposed intention al exposure research involving families with children or pregnant women, that research would not be permitted under EPA’s 2006 r ule. 2. Comment: “On another note, the phrasing of this proposed regulation is very broad and I worry could have a negative impact on research intended to intervene against the childhood obesity and diabetes epidemics, which disproportionately affect socially and environ mentally disadvantagedDocket ID No.: EPA
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Page 6 of 14 communities. Is consumption of a conventional apple in an obesity study considered an intentional exposure to pesticide? EPA should clarify in its final regulation that this statute does not limit assent of minors for studies involvi ng conventionally grown foods.” Response: EPA’s 2006 r ule and the proposed amended version of the r ule have a very clearly delineated scope. The r ule (currently, and as it is proposed to be amended) applies to intentional exposure studies intended for submission to EPA. It does not apply to dietary studies even if those studies involve consumption of a food item containing a pesticide residue, because such a study would not be considered an intentional exposure study.
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- 08 ( Commenter: Chris (no surname provided) )
3. Comment: Commenter objects “to the requirement and reliance on animal research that continue to be present in research procedures required by the EPA.” Response: Comments concerning research with animals are beyond the scope of these revisions.
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- 09 ( Commenter: A. Sow )
4. Comment : “ My comment is that p rotecting the environment will be great for our safety and our wellbeing. I am confident that by improving this regulation we will save the world. People will feel much healthier and have a longer life expectancy. We should educate people how not to use things that harm the environment and fine those who do not respect it. There are many social issues that are harming our environment right now and we can fix them if we all pitch in and do our part, we can change things all around us and in the world and make a differen ce. As Theodore Roosevelt said “ To waste and destroy our natural re sources, to skin and exhaust the land instead of using it so as to increase its usefulness, will result in undermining in the days of our children the very prosperity which we ought by right to hand down to them. ” EPA's main role would be to protect and i mprove the environment. By doing so EPA will make sure that businesses and industries understand their environment responsibilities, enabling them to comply with legislation and good practice and to realize the great economic benefits for a good environmen tal practice ” Response: EPA’s mission is to protect human health and the environment.
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- 10 ( Commenter: Anonymous )
5. Comment: “ Human testing is never a safe or smart way to decide whether or not a product is safe. In the predicament that pesticides or other products that were being tested on human was unsafe; human beings being used as test subject would suffer unjustly. Products such as pesticides need to be made and created with all knowledge of being safe for use and tested on animals and not humans. There needs to be defined regulations on new products and how to go about make them safe for everyone. Exposing children to new p esticides with the intentions to see if they are safe or not makes absolutely no sense; doing this puts children in harm’s way. ” Response: EPA is proposing narrowly

- targeted revision s to its 2006 rule for the protection of human subjects in research involving intentional exposure to pesticides

. General c omments on the scientific merit of conducting pesticide research with human subjects are beyond the scope of the proposed rulemaking . However, co nsistent with the commenter’s concern for children,Docket ID No.: EPA
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Page 7 of 14 the proposed rule does strengthen the provisions in EPA’s 2006 rule ensuring that children are not used as test subjects in research involving intentional exposure to pesticides. Comments with Common Focu s Document ID No s .:

EPA
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- 11 (Commenter: AHETF ) EPA
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- 12 (Commenter: CLA ) EPA
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- 13 (Commenter: AEATF) EPA
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- 14 (Commenter: SC Johnson)
Documents

- 11,

- 12,

- 13 and

- 14 , from the AHETF, CLA , AEATF, and SC Johnson, are similar in content , so their major points and EPA’s resp onses to those points are discussed together.
6. Comment: EPA should reconsider its interpretation of the definition of research involving intentional exposure of a human subject. Studies monitoring the occupational exposure of workers while they mix , load, and/or apply registered pesticide products in a manner that is consistent with normal work activities should not be considered intentional exposure studies. All four commenters present essentially the same arguments in favor of this change to the rule:
• Occupational exposure studies were not intended to be covered by 40 CFR 26. In the 2006 Appropriations Act, Congress intended to require EPA to promulgate a r ule concerning

“ third

- party intentional dosing human toxicity studies for pesticides. ” EPA’s current practice of considering occupational exposure studies that alter a worker ’s exposure to be intentional exposure studies goes beyond the legal mandate requir ed by the 2006 Appropriations Act.
• A s tud y measuring a worker’s exposure during normal agricultural activities is not the same as a human toxicity study.
• EPA needs better occupational exposure data. Considering these studies to be intentional exposure studies requiring Human Studies Review Board (HSRB) review has caused delays and greater expense.
• Very little additional worker protection has resulted from the additional HSRB oversight. Response: This topic is not withi n the scope of the current rulemaking. The 2006 rule provides the definition for “research involving intentional exposure of a human subject” : § 26.1102(i) Research involving intentional exposure of a human subject means 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. Since promulgation of the rule in 2006, EPA has interpreted this definition, consistent with its discussion in the preamble to the final rule (71 FR 6138) , as covering scripted worker exposure studies because the scripting alters the level and/or timing of the worker’s exposure. The proposed rulemaking on which the Agency is currently accepting comment does not propose change s to the definition of “research involving intentional exposure of a human subject ” in section 26.1102(i) . Further , the Agency has not invited comment on its application of that definition , or, in any other way, indicated it intended to reconsider the scope of research coveredDocket ID No.: EPA
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Page 8 of 14 by this definition . Accordingly, no response to this comment is warranted. The proposed changes to the 2006 rule do not reopen the qu estion of the applicability of the rule to worker exposure studies and the commenters cannot reopen consideration of that previously

promulgated provision by filing comments on the issue in a rulemaking that does not address the issue. Nonetheless, EPA app reciates the concerns expressed by the commenters with regard to the burdens imposed by the 2006 rule and recognizes that there may be value in further amending the rule in a way that reduces the regulatory burdens on investigators , e.g., by limiting the t ypes of research that are subject to particular requirements of the rule

. Document ID No.: EPA
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- 1 1 ( Commenter: AHETF )
7. Comment : “[T] he AHETF supports EPA’s ongoing efforts to ensure protection of the health and safety of human subjects participating in research studies. However, the occupational exposure monitoring studies conducted by AHETF should not be subject to this regulatory program. The Final Rule went far beyond the legal mandate required by the Appropriations Act of 2006 which concerned “third party intentional dosing human toxicity studies for pesticides”. The Rule also is at odds with the 2004 NRC report as to how intentional human dosing should be defined. ” Classifying studies that monitor exposure to individuals who would be exposed in the course of their normal activities in the same manner as studies that measure the toxic effects of pesticides in human subjects is disingenuous. Therefore, the proposed amendments are neither adequate nor appropriate to clarify how EPA shoul d define “intentional exposure”. (p

. 1) Response : See response to Comment 6 , p p . 7

- 8 of 1 4

. 8. Comment: “ EPA's anticipated revision of its Human Subjects Rule presents an opportunity for the Agency to clarify the definition of “research involving intentional exposure of a human subject.” (p

. 7)
R esponse : EPA did not take the opportunity presented by the proposed revisions to the Human Research Rule to reconsider, or invite reconsideration of, the definition of “research involving intentional exposure of a human subject.” Having not taken that opportunity in the proposed rule, it would be inappropriate to address the issue here.
9. Comment: “ EPA claims to need the data in a timely fashion in order to make accurate, data

- based decisions on the safety of pesticide use. T he current impact of these delays will be that a program consisting of 33 study types that should have been completed by 2011 is now probably an additional 10 years from completion.” (p. 12) Response: EPA agrees that the occupational exposure data currently being generated by the AHETF is useful for risk assessment purposes. However, the requirement for HSRB review of this type of human study was not raised in the proposed rule, and, thus, it would be inappropriate to address the issue here.
10. Com ment: The HSRB has changed the underlying objectives of the AHETF program “...from a diversity capturing approach toward more of a population sampling approach. Instead of allowing the selection of workers and other monitoring unit (MU) conditions that wi ll achieve the originalDocket ID No.: EPA
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Page 9 of 14 diversity objectives, AHETF was forced to modify its approach by adopting the overly extensive recruitment plan that ensures that virtually every worker in a selected monitoring area has the potential of being monitored.” (p

. 15) Response: Comments on particular HSRB recommendations that are not relevant to the proposed changes to 40 CFR 26 are beyond the scope of this rulemaking and it would be inappropriate to comment on them in the context of th is rulemaking.
11. Comment: EPA says that they want to reduce regulatory burden, but there is no evidence of that desire in the revision to the rule. These revisions implement by regul a tion what EPA was already doing. Response : The burden

- reducing steps sought by this commenter relate to matters not addressed by this rulemaking. As such, it would be inappropriate to comment on them in the context of the rulemaking. P lease see response to C omment 6 , pp. 7

- 8 of 14

. 12. Comment: “ AHETF recommends that EPA consider utilizing an expert panel to review public comments, regarding the “lessons learned” from the EPA and HSRB process and options for continued improvements. Such a forum could address various aspects of the process involved in vetting occupational exposure studies which have substantive impact on time and cost. These include: 1) determining the documentation necessary for proposed research (using examples); 2) the format of the documentation needed for efficient electronic submission and subsequent review; and 3) ways to optimize and expedite the process (web based meetings; internet and intranet sites that could facilitate review by EPA and the HSRB). ” (p

. 16) Response: I t is not clear what public comments the commenter is suggesting would be reviewed by an expert panel , b ut th e proposal of a “lessons learned” review has merit. EPA will consider this option after the revised rule is promulgated.
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- 12 (Commenter: CLA )
13. Comment: Occupational monitoring studies, as is the case with all human studies, must meet at least four stringent conditions: 1. The knowledge gained from the study is expected to promote human health. 2. The knowledge cannot be reasonably obtained by other means. 3. The study is not expected to cause serious or irreversible harm to the subjects. 4. Appropriate safeguards are in place to minimize harm to the subjects. All AHETF occupational exposure studies are in compliance with the EPA approved label involving application rates, methods of application, and crops treated. Therefore, such design and study conduct is observational in nature. This type of study is in distinct contrast to clinical investigations in volving intentional dosing of human subjects to study toxicity. ” (p

. 7) Response : This comment is not responsi ve to the proposed rulemaking. EPA agrees that these four conditions , among others, are necessary for occupational exposure monitoring studies to be considered ethical , and that these are not clinical investigations involving intentional dosing to study toxicity. To the extent the commenter is arguing that this distinction means occupationalDocket ID No.: EPA
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Page 10 of 14 exposure studies should not be covered by the Human R esearch Rule, please see the response to Comment 6 , pp. 7

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. Document ID No.: EPA
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14. C omment: The p roposed a mendments also authorize the EPA Administrator to "recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects." Proposed 40 CFR 26.1603(d). This provision does not provide any boundaries for s uch conditions and therefore does not provide sufficient opportunity for stakeholders to comment. Such a provision does not provide adequate certainty or predictability to study sponsors or investigators and therefore should not be adopted in a final rule. (p

. 5) Response: The language “ recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for t he protection of human subjects” i s already present in 40 CFR part 26, at § 26.1601(a). The Agency is re - ordering the text (the language is moving from § 26.1601(a) to 26.1603(d)). In addition, EPA is clarifying in the final rule that § 26.1603(d) is applicable only to “any research or class of research that is subject to th is subpart ....”
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- 14 (Commenter: SC Johnson)
15. Comment: “Continuing to impose these burdens simply cannot be justified where there is already an adequate review process in place. The Common Rule and comparable consensus standards apply regardless of the type of human subjects ’ research being conducted....” (p

. 2) Response : This comment questions the need for EPA’s 2006 r ule , Protections for Subjects in Human Research (40 CFR 26) . Th e current rulemaking does not reopen consideration of the 2006 r ule generally , but rather makes certain narrowly

- targeted revisions to a few specific provisions. In th e current rulemaking , EPA did not reconsider the underlying basis for the 2006 r ule and co mments raising such issues are beyond the scope of this rulemaking.
16. Comment: “The burdens of the HSRB process disproportionately impact personal insect repellent products. New products using existing active ingredient personal insect repellents are taking over two years to get through the HSRB process, even though these are well characterized active ingredients with complete and fully understood toxicological profiles, decades of consumer use, and very low incidence of adverse effects. The impact on new actives is also problematic. We understand that no new insect repellent active ingredients have gone through the HSRB review process since the implementation of the 2006 Rule. We believe the burdens and uncertainties involved with the HSRB review process are directly impeding the development of new repellent products

. ” (p

. 6) Response: This comment is not responsive to the current proposed rulemaking. To the extent this comment is implying t hat human studies involving personal insect repellents should not be covered by the r ule, please see response to C omment 6 , pp. 7

- 8 of 14

. 17. Comment: HSRB should be more like FDA’s advisory committees which are not FACA committees and do not have to have public meetings. “... the ‘openness’ requirements of FACA have created significant obstacles for registrants. In studies of repellent products, much of the information submitted for HSRB review is proprietary and confidential.... Notwithstanding the imp ortance of maintaining the confidentiality of information , it has been extremely difficult to obtainDocket ID No.: EPA
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Page 11 of 14 adequate assurance that proprietary information will be protected from disclosure by the HSRB.” (p

. 7) Response: This comment is not responsive to the amendments under consideration in this rulemaking. The HSRB’s formation under the Federal Advisory Committee Act is not an issue involved in this rulemaking, and, thus, comment on that decision is inappropriate here

. Similar comments were made on the 2006 Rule , to which the Agency responded,

“ Specifically, (1) FACA committees are required to be unbiased and independent. (2) The HSRB is not simply an “ethics committee”; it will provide formal external peer review of both scientific and ethical aspects of human research; as such it will be entirely consistent with other FACA committees established by EPA. (3) The FDA review process does not involve an independent review committee as required by the Appropriations Act. (4) The NAS recommended an HSRB, and noted that there were various models elsewhere in the government. The FDA model was identified as one extreme, in that neither the proceedings nor the reports of the internal committee were public. At the other extreme the NAS committee noted the NIH recombinant DNA oversight committee, which does all its business in the public eye. (5) EPA acknowledges that different procedures apply to EPA research and to covered third

- party research, but notes as well that this has b een true for many years, and that under this final rule, for the first time the substantive standards for approving and conducting first

- second

- and third

- party research will be the same. (6) EPA agrees that regulatory ethics review for pesticides should be independent, apolitical, and consistent with the Common Rule. (7) EPA does not agree that consistency with FDA is more important than compliance with the Appropriations Act. An internal review group, such as FDA’s, would not satisfy the clear requiremen ts of that Act.

... FACA committees are able to protect confidential business information. There are established procedures for this, and none need to be defined in this rule. ” ( Docket ID EPA

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18. Comment: Executive Order #13563 requires federal agencies to review the necessity and effectiveness of existing regulations and consider principles to use the b est and “least burdensome” tools for achieving regulatory ends. It also r equires inter

- agency coordination to simplify and harmonize redundant or inconsistent regulations. Response: EPA is continuing to carefully consider all existing regulations consistent with Executive Order 13563

. The proposed revisions to EPA’s 2006 rule that are part of this action are not part of that effort.
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- 15 (Nichelle Harriott, Beyond Pesticides) 19. Comment: “ [C] onducting experiments on human subjects, intentionally exposing them to chemicals that can cause both short and long term adverse effects is un productive, unethical and lacking in scientific integrity. ” (p

. 1) Response: Comments regarding the validity of any research with human subjects are beyond the scope of this rulemaking. Similar comments were made on EPA’s 2006 Human Research Rule , to which the Agency responded, “ Nevertheless , the Agency believes that there is stil l a place in its regulatory decision

- making for scientifically sound, ethically conducted human research.” ( Docket ID EPA

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Page 12 of 14 20. Comment : Beyond Pesticides is concerned that paying subjects to participate in studies will lead to coercion based on financial compensation. “The agency must seriously address the issue of remuneration so as to protect those who may be recruited to becoming a sub ject for human dosing studies . The agency must also define what constitutes payments as being considered too high or too low. Nevertheless low

- income and other financially disadvantaged populations will be disproportionately affected, especially since pay ment for research participation can be perceived as a potential income source among participants

. Thus, financial remuneration for participating in human studies should be reconsidered, and be done on a strictly voluntary basis with non monetary incentives.” (p

. 3) Response: EPA specifically sought comment on whether the exact language regarding remuneration from NAS Recommendation 5

- 3 or EPA’s proposed language (slightly re

- worded from NAS Recommendation 5

- 3 ) is clear er . The commenter is not addressing that issue, but is instead objecting to the overall notion of remuneration , arguing that financial remuneration is not appropriate for human subjects in pesticide studies . EPA continues to agree with the NAS report that remuneration is appropriate to provide an incentive for participation and to reimburse subjects for the time and inconvenience of participating in such research. The question of what amount of remuneration is appropriate is more difficult , but EPA agrees with the NAS be nchmarks that such payments should be neither “so high as to constitute undue inducement” nor “so low as to be attractive only to individuals who are socioeconomically disadvantaged.” Although this specific language is not being included in the final rule , EPA will be guided by the NAS recommendations in implementing the rule.
21. Comment: “It is inevitable that although this proposal theoretically sets a higher standard for the review of human studies, EPA’s lax oversight and review process would lead to the unconditional approval of many questionable human studies.” (p

. 3 ) Response: EPA has engaged in a rigorous scientific and ethical review of all intentional exposure human studies submitted for consideration under FIFRA and the FFDCA. Since the promulgation of the 2006 rule, this review has involved consultation with science and ethics experts on the Human Studies Review Board about all intentional exposure studies

. The present rulemaking , which proposes narrowly

- targeted changes to the EPA’s 2006 H uman S tudies R ule, will further strengthen EPA’s process for reviewing these types of studies.
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- 16 ( NRDC )
22. Comment: “The proposed rule would amend the 2006 final rule to partially or fully address many of the 2006 final rule ’ s deficiencies, including inconsistencies with Section 201, and would reduce the likelihood that unethical or unscientific research being conduct ed and/or relied upon by EPA.” (p

. 6) Response: The Agency is pleased that NRDC supports the proposed changes to the rule, although EPA does not concede that the 2006 final rule contained any deficiencies that compelled the proposed changes to that rul e. EPA also disagrees that there is a likelihood, in the absence of the proposed changes, that EPA would rely on unethical or unscientific human research. EPA performs rigorous scientific and ethical reviews and submits those reviews to, and consults wit h , the Human Studies Review Board before determining whether to approve intentional exposure human study protocols or to rely on completed research in regulatoryDocket ID No.: EPA
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Page 13 of 14 decisions

. In addition, as noted in comment response #1, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA. 23. Comment: “T he issue of significantly deficient is adequately addressed by deleting the word “significantly”, as recommended by the Human Studies Review Board (HSRB) (FR at 5750)... We are satisfied with this amendment to delete the word.” (p

. 6) Response: The Agency is pleased that NRDC is satisfied with the proposed change , although EPA notes that this change was not recommended by the HSRB as suggested by NRDC

. EPA notes that in addition to deleting the word “significantly” from §26.1704, the Agency is add ing language that explicitly characterizes the kinds of deficiencies that would make a study unacceptable. The language is based on the HSRB’s application of the standard of §26.1704 in its review s since 2006

. 24. Comment : “ The issue of consent by a surrogate is addressed by EPA ’ s proposal to delete all references permitting consent by a subject ’s legal representative (FR at 5745). We are satisfied with this amendment to delete the reference.” (p

. 7) Response: The Agency is pleased that NRDC is satisfied with the proposed change.
25. Comment: “ T he proposed rule would also add substantive standards for assessing scientific validity. While EPA may believe that such standards are unnecessary, because it had discretion under the 2006 final rule to reject studies it considered unscientific, there is a substantial policy an d legal need for incorporating such standards into the rule....We support EPA ’ s incorporation, through the proposed rule, of stronger, more specific scientific standards.” (p 7) Response: As discussed in comment response #1 in this document , EPA believes there is no longer a legal obligation because section 201 of the Appropriations Act does not continue to impose any obligations on EPA

. For policy reasons, EPA has decided to include the specific text from the 2004 NAS Report in the final revis ions with only a few non

substantive wording changes. EPA believes that the revisions in the final 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 §26.1603(c)(2) with existing §26.111(a)(2)); whether risks are reasonable in comparison to benefits (compare §26.1603(c)(3) with §26.111(a)(2)); whether subject selection would be equitable (compa re §26.1603(c)(4) with existing §26.111(a)(3)); whether consent will be free and voluntary (compare §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately constituted IRB has reviewed the proposed research (compare §26.1603(c)(6) with §26.109); and whether the “special problems” of research involving vulnerable populations are taken into account (compare §26.1603(c)(7) and (8) with existing §26.111(a)(3)). Other considerations are implicitly addressed. The Common Rule’s requirement to “minimize risks” in section 26.111(a)(1) necessitates consideration of whether adequate animal data is available to assess potential risks to subjects (see §26.1603(c)(1)). It would involve consideration of whether medical care is to be provided for injuries incurred in the proposed research (see §26.1603(c)(10)). Section 26.111(b)’sDocket ID No.: EPA
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Page 14 of 14 requirement that additional safeguards be in place to protect against undue influence of “economically” disadvantaged persons ensures that co nsideration 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 §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 section 26.111(a)(1) and the need to take “the import ance 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 sections 26.1603 and 26.1703. At a minimum, NAS Recommendation s 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.”

## Attachment # A
– Review Period: 02/01/13
– 02/08/13

(2) Documentation of any substantive changes that were made to the draft document that was submitted to OIRA/OMB for review, when compared with what completed review, using

... (a) A copy of the draft document submitted, with redline and strikeout to show all the substantive changes that were made during the review. 02/08/2013Docket ID No.: EPA
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Page 1 of 14 2/ 6 /2013

– Revised Response to Comment Document for Final Rule ( Mark
- up s hows c hanges made during EO 12866 Review ). Filename: RIN2070

- AJ76_EO12866_HumanSubjectsRevisions_FRM_Response2Comments_2013

- 02

- 05_pm.docx 

### U.S. Environmental Protection Agency (EPA) Office of Chemical Safety and Pollution Prevention R esponse to Public Comment s Received on the Proposed Rule Entitled:
“ Revisions to EPA’s Rule on Protections for Subjects in Human Research Involving Pesticides ” (RIN 2070
- AJ76) 0 1 2 / 31 0 5 6 /2013 ; 4 p 9 a m Public Comment Period : 2/2/2011
- 4/4/2011
I. Summary This document addresses comments received in response to the Notice of Proposed Rulemaking for Revisions to the EPA’s Rule on Protections for Subje cts in Human Research Involving Pesticides that published o n February 2, 2011 (76 FR 5735) , in which the EPA propos ed amend ing the portions of its 2006 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 the EPA. All comments appear in their entirety in the public docket for this rulemaking, identified as EPA Docket ID No. EPA

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. EPA proposed several narrowly

- targeted changes to regulatory text as a result of a settlement agreement and specifically requested com ment on the proposed changes. The Agency received 10 comments in response to the N otice of P roposed Rulemaking

. 1 In the d ocket , d ocuments identified with Document ID numbers ending in 1 through 6 are supporting documents for the rulemaking ; d ocuments 7

- 16 are public comments ; d ocuments 17

- 55 are the 28 attachments to NRDC ’s comment ( see discuss ion in Footnote 1 , below )

. II. Comments on Issues within the Scope of the Proposed Amendments EPA has identified only two issues raised by commenters that are within the sc ope of the proposed amendments

. The first issue relate s to the proposed expansion of the rule to cover human testi ng with pesticides submitted to EPA under any regulatory statute it administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. The second issue relate s to proposed revisions to § 26.1603(b)(2)(ii ) and ( iii ) and § 26.1703(a)(2 ) and ( 3) to require EPA to

1 The comment from the Natural Resources Defense Council (NRDC) include s 28 attachments. Although these attachments were posted to the docket as individual comments, they are actually supporting documents for NRDC’s comments on this proposed rulemaking. The 28 documents also appear in other EPA dockets, but were resubmitted so that all of the documents were included in this docket.Docket ID No.: EPA
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Page 2 of 14 consider whether proposed and completed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. The specific comments, and EP A’s responses to those comments, are discussed below.
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- 14 (Commenter: SC Johnson)
1. Comment: T he 2006 Appropriations Act does not require or authorize EPA to issue a rule that applies to studies performed outside of the FFDCA / FIFRA context

. “ Nothing in the Appropriations Act language required or authorized EPA to issue a rule that applies to studies performed outside of the FIFRA/FFDCA context. Thus, the Appropriations Act does not expand EPA’s rulemaking authority under FIFRA or the FFDCA such that EPA can issue a rule that regulates studies performed for submission under other statutes. EPA’s proposed revision exceeds the Agency’s statutory authority by attempting to regulate human testing under statutes beyond FIFRA a nd FFDCA. We therefore urge EPA not to adopt this proposed revision to the Rule.” (p

. 10). Response: EPA originally promulgated this rule under the authority of the 2006 Appropriations Act and FIFRA. Although the proposal cites the 2006 Appropriations Act as authority for th e proposed rule, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA. “ A federal appropriations act applies only for the fiscal year in which it is passed, unle ss it expressly provides otherwise.” Building & Constr. Trades Dep't v. Martin , 961 F.2d 269 (D.C. Cir.), cert. denied , 506 U.S. 915 (1992). Because section 201 contains no language providing for the continuing effect of its requirements, these requirements expired with FY 2006. Accordingly, EPA is not citing the 2006 Appropriations Act as authority for th e final rule. Because the 2006 Appropriations Act is no longer in effect, this expansion of the scope of the 2006 rule is being promulgated on the authority of FIFRA alone. FIFRA gives EPA broad authority to regulate the sale, distribution, and use of pesticides . This authority encompasses regulation of the sale, distribution, and use of pesticides in human testing. The commenter is wrong to suggest that EPA interpreted the 2006 Appropriations Act as expanding its authority under FIFRA. The commenter is also incorrect to argue that EPA is asserting the authority under FIFRA to regulate testing under other EPA regulatory statutes. EPA is not in this rule generally regulating testing under all of its regulatory statutes; rather, it is regulating the use of pesticides in human testing, regardless of under what EPA regulatory regime that testing is done. FIFRA authority easily extends to cover such a sale, distribution, and use of pesticides. EPA believes this expansion of the scope of the 2006 rule is warranted to assure that research involving intentional exposure of human subjects to pesticides will be treated in a similar manner under all o f EPA’s regulatory statutes.
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- 16 (Commenter: Natural Resources Defense Council [NRDC])
2. Comment: W hile the expanded scope of the proposed rule “would narrow the loophole created by the ‘intention’ [to submit to EPA] standard, we would prefer that the loophole be closed by including a clear ban on the conduct of any intentional dosing toxicity study on pregnant women or children. Section 201 [of the 2006 Appropriations Act] requires such a ban...” (p

. 6)

. Response : Because NRDC’s argument is based on a statutory provision no longer in force (i.e., section 201 of the Appropriations Act), it is without merit

. As mentioned above, EPA hasDocket ID No.: EPA
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Page 3 of 14 authority, and believes it is reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides that are submitted to EPA under other laws that it administers. This rule covers studies t hat are within EPA’s purview. However, to expand the 2006 rule to impose prohibitions or conditions on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies involving unregistered pesticides that are conducted outside the United States) is clearly outside EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research, for example, by preventing researchers from studying whether repellent impregnated bed nets reduced the incidence of malaria in African villages.
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- 11 (Commenter : Agricultural Handler Exposure Task Force [AHETF]) EPA
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- 12 (Commenter: CropLife America [CLA]) EPA
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF])
3. Comment: The AHETF, CLA , and AEATF cite concerns with the proposed new regulatory text at § 26.1603(b)(2)(ii ) and ( iii) that would require EPA to consider whether the proposed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. AEATF, AHETF, and CLA are similarly concerned with the proposed new regulatory text at § 26.1703(a)(2 ) and ( 3) that would require EPA to consider these factors in determining whether to rely on completed research . The commenters’ argue that while these factors are pertinent to clinical studies they have little or no relevance to exposure stu dies. The specific comments from each commenter are quoted below.
AHETF : “Another problem area for the proposed amendments to the Rule concerns issues that require case

- by

- case consideration of the EPA and HSRB. In these situations, the proposed Rule cannot address the specificity needed for a given proposed study because of the contextual information and interpretation required. Specifically, the proposed amendments (see Exhibit A, Subpart K, Section 26.1703), present an itemized list regarding EPA ‟ s consideration of reliance on data from research involving “intentional exposure” of human subjects... These criteria require interpretation by subject matter experts on a case

- by

- case basis and ... more specific definition of the terms “representative” and “s tatistical power” are necessary because these are protocol/study design

- specific aspects...Further, these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies...” (EPA

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- 11, p p. 15

- 16)

. CLA : “CLA notes and agrees that these considerations play an important role in some human testing and we argue that subject matter experts need to provide input on a case

- by

- case basis. The study design aspects require specific considerations to be made by EPA (and the HSRB, as well as other federal advisors, i.e., the EPA FIFRA Scientific Advisory Panel). However, there appears to be unnecessary complexity added to the evaluation of occupational exposure studies. Many of these criteria are more appropria te for clinical studies and do not translate directly to occupational exposure studies whose purpose is to develop observational exposure data.” (EPA

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. 6)

. AEATF : “AEATF is concerned, however, that proposed changes to 40 CFR Part 26, requiring representative study populations and ‘ adequate statistical power ’ are inapposite to the types ofDocket ID No.: EPA
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Page 4 of 14 exposure research being conducted by AEATF and others, are too ambiguous to offer clarity and predictability to study sponsors and investigators, an d impose unwarranted burdens in study sponsors and investigators without improving scientific validity or protection of human subjects.” (EPA

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. 3)

. Further on the topic of “representative study populations” and “adequate statistical power”, the commenters request that EPA “confirm that EPA does not expect any effect on the continued approval of the worker exposure studies” (AEATF, EPA

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. 5). Response: As it has since its initial promulgation, the EPA will be guided in implementing the amended 2006 rule by the recommendations of the 2004 NAS Report 2

. EPA thinks that Some of the commenters may have misinterpreted the NAS recommendation to be required characteristics of all studies covered by this rule ; rather , as further explained below, the NAS recommends that these concepts be considered in reviewing these studies. As such, EPA disagrees with the assertion that the NAS recommendations on representative populations and statistical power are not applicable to exposure studies. Even though the NAS’ recommendations about representative study populations and adequate statistical power were not specifically articulated in EPA’s 2006 Fin al Rule (40 CFR 26), EPA has applied the principles underlying these recommendations, as well as the general NAS directive that studies should be designed and conducted in accordance with appropriate scientific standards and practices, in its consideration of human research since the promulgation of the rule in 2006 and used in EPA’s science and ethics reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751.
U nder the 2006 rule as amended through this rulemaking, EPA does not in tend 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 is needed. EPA does not belie ve 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 ha ve been approved under the 2006 rule, would also meet the standards reflected in this final rule. EPA notes that the NAS emphasized that EPA should focus on the “objectives of the study” in determining what is a representative population (NAS Report, p. 77). Thus, representativeness i s a study

- specific determination based on the objectives of the study. For exposure studies, a fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate sampling st rategies can produce a sample which represents a broader range of conditions than would be present in a random sample of similar limited size and thus may produce results that reasonably approximate real world exposures with respect to the overall magnitud e and “spread.” For example, the Agricultural Handler Exposure Task Force (AHETF) and the Antimicrobial Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” sampling procedure in their exposure research. This procedure attempts to produce a sample which incorporates some random elements (where feasible); the resulting sample can be more

2 The 2004 Report by the National Research Council of the National Academies of Science (NAS) titled “ Intentional Human Dosing Studies for EPA Regulatory Purposes” (hereafter, 2004 NA S Report)

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Page 5 of 14 useful from a regulatory perspective in that it more likely represents the range of conditions and situations under which exposure occu rs. This approach meets the objectives of the study. Similarly, statistical power consideration s are also a relevant concept for both toxicology and exposure studies. Statistical power evaluates the extent to which a study design can measure the effect being studied. For example, a toxicity study typically evaluates whether a chemical causes an effect by comparing the responses of the exposed and un exposed groups. In some instances , expos ed and un expos ed groups will not show different (statisti cally significant) responses, even though the chemical actually does cause the effect. The statistical “power” of a toxicological study can be thought of as the ability of the study to detect a difference between expos ed and un expos ed groups given that a difference of a defined magnitude does exist. Statistical power can be an important concept in evaluating the design of toxicity studies since it helps in ascertaining the degree to which the study will be able to find a significant difference between expos ed and un expos ed groups , when a difference of defined magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical power of the study is an irrelevant consideration if the study found a statistically significant relationship between exposure and an effect. Conversely, when a completed toxicity study finds no such relationship, evaluating the statistical power of the study design becomes relevant because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of the result. As to exposure studies, statistical power could have applicability to an exposure study design if, for example, that study attempted to evaluate the relationship between dermal or inhalation exposur e and an exposure variable. The statistical power of such an exposure study would also be a consideration if that study was interpreted as showing that there is no relationship between the tested variables. EPA has required various statistical analyse s of exposure studies under the 2006 rule other than statistical power analyses. For example, EPA has relied upon standard regression analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the merit of worker exposure s tudies. EPA expects that those or similar analyses will, in all probability, suffice going forward under the requirement in the revised rule that EPA must determine that “data were derived in a manner that makes them scientifically valid and reliable”. 40 CFR 26.1703(a). Therefore, EPA does not believe that the revised rule will impose any additional burden on sponsors of exposure studies with regard to statistical analyses generally.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking
D ocument ID No.: EPA
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- 07 ( Commenter: Anonymous )
1. Comment: “ It is plausible that several of the current or future

- use pesticides might exert trans

generational epigenetic effects that have not been studied yet. Families of applicators may be at highest risk for these kinds of effects. It is hard to imagine a scientif ically valid study of these effects that would not require inclusion of children (but these children need not be exposed). A finer distinction should be made in the regulation between assent of children to participate in studies where they will be exposed to a pesticide, and assent of children to participate in studies where someone else will be exposed to a pesticide.” Response: EPA’s 2006 r ule (currently, and as it is proposed to be amended) covers intentional exposure studies, not epidemiological or observational studies. The type of study that the commenter has described (studying pesticide applicator families) would likely beDocket ID No.: EPA
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Page 6 of 14 epidemiolog ical or observational and would not be covered by the rule. If, however, a protocol proposed intentional exposure research involving families with children or pregnant women, that research would not be permitted under EPA’s 2006 r ule.
2. Comment: “On anot her note, the phrasing of this proposed regulation is very broad and I worry could have a negative impact on research intended to intervene against the childhood obesity and diabetes epidemics, which disproportionately affect socially and environmentally d isadvantaged communities. Is consumption of a conventional apple in an obesity study considered an intentional exposure to pesticide? EPA should clarify in its final regulation that this statute does not limit assent of minors for studies involving convent ionally grown foods.” Response: EPA’s 2006 r ule and the proposed amended version of the r ule have a very clearly delineated scope. The r ule (currently, and as it is proposed to be amended) applies to intentional exposure studies intended for submission to EPA. It does not apply to dietary studies even if those studies involve consumption of a food item containing a pesticide residue, because such a study would not be considered an intentional exposure study.
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- 08 ( Co mmenter: Chris (no surname provided) )
3. Comment: Commenter objects “to the requirement and reliance on animal research that continue to be present in research procedures required by the EPA.” Response: Comments concerning research with animals are beyond the scope of these revisions.
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- 09 ( Commenter: A. Sow )
4. Comment : “ My comment is that p rotecting the environment will be great for our safety and our wellbeing. I am confident that by improving this regulation we will save the world. People will feel much healthier and have a longer life expectancy. We should educate people how not to use things that harm the environment and fine those who do not respect it. There are many social issues that are harming our environment right now and we can fix them if we all pitch in and do our part, we can change things all around us and in the world and make a differen ce. As Theodore Roosevelt said “ To waste and destroy our natural resources, to skin and exhaust the land instead of using it so as to increase its usefulness, will result in undermining in the days of our children the very prosperity which we ought by right to hand down to them. ” EPA's main role would be to protect and improve the environment. By doing so EPA will make sure that businesses and industries understand their environment responsibilities, enabling them to comply with legislation and good practice and to realize the great economic benefits for a good environm ental practice ” Response: EPA’s mission is to protect human health and the environment.
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- 10 ( Commenter: Anonymous )
5. Comment: “ Human testing is never a safe or smart way to decide whether or not a product is safe. In the predicament that pesticides or other products that were being tested on human was unsafe; human beings being used as test subject would suffer unjustly. Products such as pesticides need to be made and created with all knowledge of being safe for use and tested on animals and not humans. There needs to be defined regulations on new products and how to go about make them safe forDocket ID No.: EPA
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Page 7 of 14 everyone. Exposing children to new p esticides with the intentions to see if they are safe or not makes absolutely no sense; doing this puts children in harm’s way. ” Response: EPA is proposing narrowly

- targeted revision s to its 2006 rule for the protection of human subjects in research invo lving intentional exposure to pesticides

. General c omments on the scientific merit of conducting pesticide research with human subjects are beyond the scope of the proposed rulemaking . However, consistent with the commenter’s concern for children, the proposed rule does strengthen the provisions in EPA’s 2006 rule ensuring that children are not used as test subjects in research involving intentional exposure to pesticides. Comments wi th Common Focus
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EPA
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- 11 (Commenter: AHETF ) EPA
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- 12 (Commenter: CLA ) EPA
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- 13 (Commenter: AEATF) EPA
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Documents

- 11,

- 12,

- 13 and

- 14 , from the AHETF, CLA , AEATF, and SC Johnson, are similar in content , so their major points and EPA’s resp onses to those points are discussed together.
6. Comment: EPA should reconsider its interpretation of the definition of research involving intentional exposure of a human subject. Studies monitoring the occupational exposure of workers while they mix , load, and/or apply registered pesticide products in a manner that is consistent with normal work activities should not be considered intentional exposure studies. All four commenters present essentially the same arguments in favor of this change to the rule:
• Occupational exposure studies were not intended to be cov ered by 40 CFR 26. In the 2006 Appropriations Act, Congress intended to require EPA to promulgate a r ule concerning

“ third

- party intentional dosing human toxicity studies for pesticides. ” EPA’s current practice of considering occupational exposure studies that alter a worker ’s exposure to be intentional exposure studies goes beyond the legal mandate required by the 2006 Appropriations Act.
• A s tud y measuring a worker’s exposure during norm al agricultural activities is not the same as a human toxicity study.
• EPA needs better occupational exposure data. Considering these studies to be intentional exposure studies requiring Human Studies Review Board (HSRB) review has caused delays and greate r expense. • Very little additional worker protection has resulted from the additional HSRB oversight. Response: This topic is not withi n the scope of the current rulemaking. The 2006 rule provides the definition for “research involving intentional exposure of a human subject” : § 26.1102(i) Research involving intentional exposure of a human subject means a study of a substance in which the exposure to the substance experienced by a human subject participating i n the study would not have occurred but for the human subject's participation in the study.Docket ID No.: EPA
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Page 8 of 14 Since promulgation of the rule in 2006, EPA has interpreted this definition, consistent with its discussion in the preamble to the final rule (71 FR 6138) , as cover ing scripted worker exposure studies because the scripting alters the level and/or timing of the worker’s exposure. The proposed rulemaking on which the Agency is currently accepting comment does not propose change s to the definition of “research involving intentional exposure of a human subject ” in section 26.1102(i) . Further , the Agency has not invited comment on its application of that definition , or, in any other way, indicated it intended to reconsider the scop e of research covered by this definition . Accordingly, no response to this comment is warranted. The proposed changes to the 2006 rule do not reopen the question of the applicability of the rule to worker exposure studies and the commenters cannot reopen consideration of that previously

promulgated provision by filing comments on the issue in a rulemaking that does not address the issue. Nonetheless, EPA appreciates the concerns expressed by the commenters with regard to the burdens imposed by the 2006 ru le and recognizes that there may be value in further amending the rule in a way that reduces the regulatory burdens on investigators , e.g., by limiting the types of research that are subject to particular requirements of the rule

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- 1 1 ( Commenter: AHETF )
7. Comment : “[T] he AHETF supports EPA’s ongoing efforts to ensure protection of the health and safety of human subjects participating in research studies. However, the occupational exposure monitoring studies conducted by AHETF should not be subject to this regulatory program. The Final Rule went far beyond the legal mandate required by the Appropriations Act of 2006 which concerned “third party intentional dosing human toxicity studies for pesticides”. The Rul e also is at odds with the 2004 NRC report as to how intentional human dosing should be defined. ” Classifying studies that monitor exposure to individuals who would be exposed in the course of their normal activities in the same manner as studies that meas ure the toxic effects of pesticides in human subjects is disingenuous. Therefore, the proposed amendments are neither adequate nor appropriate to clarify how EPA should define “intentional exposure”. (p

. 1)

. Response : See response to Comment 6 , p p . 7

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. 8. Comment: “ EPA's anticipated revision of its Human Subjects Rule presents an opportunity for the Agency to clarify the definition of “research involving intentional e xposure of a human subject.” (p

. 7)

. R esponse : EPA did not take the opportunity presented by the proposed revisions to the Human Research Rule to reconsider, or invite reconsideration of, the definition of “research involving intentional exposure of a human subject.” Having not taken that opportunity in the proposed rule, it would be inappropriate to address the issue here.
9. Comment: “ EPA claims to need the data i n a timely fashion in order to make accurate, data

- based decisions on the safety of pesticide use. The current impact of these delays will be that a program consisting of 33 study types that should have been completed by 2011 is now probably an additional 10 years from completion.” (p. 12)

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Page 9 of 14 Response: EPA agrees that the occupational exposure data currently being generated by the AHETF is useful for risk assessment purposes. However, the requirement for HSRB review of this type of human study was not raised in the proposed rule, and, thus, it would be inappropriate to address the issue here.
10. Comment: The HSRB has changed the underlying objectives of the AHETF program “...from a diversity capturing approach toward more of a population sampling approach. Instead of allowing the selection of workers and other monitoring unit (MU) conditions that will achieve the original diversity objectives, AHETF was forced to modify its approach by adopting the ove rly extensive recruitment plan that ensures that virtually every worker in a selected monitoring area has the potential of being monitored.” (p

. 15)

. Response: Comments on particular HSRB recommendations that are not relevant to the proposed changes to 40 CFR 26 are beyond the scope of this rulemaking and it would be inappropriate to comment on them in the context of th is rulemaking.
11. Comment: EPA says that they want to reduce regulatory burden, but there is no evidence of that desire in the revision to the rule. These revisions implement by regula tion what EPA was already doing. Response : The burden

- reducing steps sought by this commenter relate to matters not addressed by this rulemaking. As such, it would be inappropriate to comment on them in the context of the rulemaking. P lease see response to C omment 6 , pp. 7

- 8 of 14

. 12. Comment: “ AHETF recommends that EPA consider utilizing an expert panel to review public comments, regarding the “lessons learned” from the EPA and HSRB process and options for continued improvements. Such a forum could address various aspects of the process involved in vetting occupational exposure studies which have substantive impact on time and cost. These include: 1) determining the documentation necessary for proposed research (using examples); 2) the format of the documentation needed for efficient electronic submission and subsequent review; and 3) ways to optimize and expedite t he process (web based meetings; internet and intranet sites that could facilitate review by EPA and the HSRB). ” (p

. 16)

. Response: It is not clear what public comments the commenter is suggesting would be reviewed by an expert panel , b ut th e proposal of a “lessons learned” review has merit. EPA will consider this option after the revised rule is promulgated.
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- 12 (Commenter: CLA )
13. Comment: Occupational monitoring studies, as is the case with all human studies, must meet at least four stringent conditions: 1. The knowledge gained from the study is expected to promote human health. 2. The knowledge cannot be reasonably obtained by other means. 3. The study is not expected to cause serious or irreversible harm to the subjects. 4. Appropriate safeguards are in place to minimize harm to the subjects. All AHETF occupational exposure studies are in compliance with the EPA approved label involving application rates, methods of application, and crops treated. Therefore, such design and studyDocket ID No.: EPA
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Page 10 of 14 conduct is observational in nature. This type of study is in distinct contrast to clinical investigations involving intentional dosing of human subjects to study toxicity. ” (p

. 7)

. Response : This comment is not responsi ve to the proposed rulemaking. EPA agrees that these four conditions , among others, are necessary for occupational exposure monitoring studies to be considered ethical , and that these are not clinical investigations involving intentional dosing to study t oxicity. To the extent the commenter is arguing that this distinction means occupational exposure studies should not be covered by the Human Research Rule, please see the response to Comment 6 , pp. 7

- 8 of 1 4

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14. C omment: The p roposed a mendments also authorize the EPA Administrator to "recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects." Proposed 40 CFR 26.1603(d). This provision does not provide any boundaries for such conditions and therefore does not provide sufficient opport unity for stakeholders to comment. Such a provision does not provide adequate certainty or predictability to study sponsors or investigators and therefore should not be adopted in a final rule. (p

. 5)

. Response: The language “ recommend additional conditio ns which, in the judgment of the EPA Administrator, are necessary for t he protection of human subjects” i s already present in 40 CFR part 26, at § 26.1601(a). The Agency is re - ordering the text (the language is moving from § 26.1601(a) to 26.1603(d)). In addition, EPA is clarifying in the final rule that § 26.1603(d) is applicable only to “any research or class of research that is subject to th is subpart ....”
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15. Comment: “Continuing to impose these burdens simply cannot be justified where there is already an adequate review process in place. The Common Rule and comparable consensus standards apply regardless of the type of human subjects ’ research being conducted....” (p

. 2)

. Response : This comment questions the need for EPA’s 2006 r ule , Protections for Subjects in Human Research (40 CFR 26) . Th e current rulemaking does not reopen consideration of the 2006 r ule generally , but rather makes certain narrowly

- targeted revisions to a few specific provisions. In th e current rulemaking , EPA did not reconsider the underlying basis for the 2006 r ule and comments raising such issues are beyond the scope of t his rulemaking.
16. Comment: “The burdens of the HSRB process disproportionately impact personal insect repellent products. New products using existing active ingredient personal insect repellents are taking over two years to get through the HSRB process, even though these are well characterized active ingredients with complete and fully understood toxicological profiles, decades of consumer use, and very low incidence of adverse effects. The impact on new actives is also problematic. We understand that no new insect repellent active ingredients have gone through the HSRB review process since the implementation of the 2006 Rule. We believe the burdens and uncertainties involved with the HSRB review process are directly impeding the development of new repellent products

. ” (p

. 6)

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Page 11 of 14 Response: This comment is not responsive to the current proposed rulemaking. To the extent this comment is implying that human studies involving personal insect repellents should not be covered by the r ule, please see response to C omment 6 , pp. 7

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. 17. Comment: HSRB should be more like FDA’s advisory committees which are not FACA committees and do not have to have public meetings. “... the ‘openness’ requirements of FACA have created significant obstacles for registrants. In studies of repellent products, much of the information submitted for HSRB review is proprietary and confidential.... Notwithstanding the imp ortance of maintaining the confidentiality of information , it has been extremely difficult to obtain adequate assurance that proprietary information will be protected from disclosure by the HSRB.” (p

. 7)

. Response: This comment is not responsive to the amendments under consideration in this rulemaking. The HSRB’s formation under the Federal Advisory Committee Act (FACA) is not an issue involved in this rulemaking, and, thus, comment on that decision is inappropria te here. Similar comments were made on the 2006 Rule , to which the Agency responded,

“ Specifically, (1) FACA committees are required to be unbiased and independent. (2) The HSRB is not simply an “ethics committee”; it will provide formal external peer review of both scientific and ethical aspects of human research; as such it will be entire ly consistent with other FACA committees established by EPA. (3) The FDA review process does not involve an independent review committee as required by the Appropriations Act. (4) The NAS recommended an HSRB, and noted that there were various models elsewh ere in the government. The FDA model was identified as one extreme, in that neither the proceedings nor the reports of the internal committee were public. At the other extreme the NAS committee noted the NIH recombinant DNA oversight committee, which does all its business in the public eye. (5) EPA acknowledges that different procedures apply to EPA research and to covered third

- party research, but notes as well that this has been true for many years, and that under this final rule, for the first time the s ubstantive standards for approving and conducting first

- second

- and third

- party research will be the same. (6) EPA agrees that regulatory ethics review for pesticides should be independent, apolitical, and consistent with the Common Rule. (7) EPA does not agree that consistency with FDA is more important than compliance with the Appropriations Act. An internal review group, such as FDA’s, would not satisfy the clear requirements of that Act.

... FACA committees are able to protect confidential business inform ation. There are established procedures for this, and none need to be defined in this rule. ” ( Docket ID EPA

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- 267) EPA is not commenting on whether the commenter’s characterization of FDA’s committee is accurate.
18. Comment: Executive Order # 13563 requires federal agencies to review the necessity and effectiveness of existing regulations and consider principles to use the best and “least burdensome” tools for achieving regulatory ends. It also r equires inter

- agency coordination to simplify and harmonize redundant or inconsistent regulations. Response: EPA is continuing to carefully consider all existing regulations consistent with Executive Order 13563

. The proposed revisions to EPA’s 2006 rule that are part of this action are not part of that effort.
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Page 12 of 14 19. Comment: “ [C] onducting experiments on human subjects, intentionally exposing them to chemicals that can cause both short and long term adverse effects is un productive, unethical and lacking in scientific integrity. ” (p

. 1)

. Response: Comments regarding the validity of any research with human subjects are beyond the scope of this rulemaking. Similar comments were made on EPA’s 2006 Human Research Rule , to which the Agency responded, “ Nevertheless , the Agency believes that there is still a place in its regulatory decision

- making for scientifically sound, ethically conducted human research.” ( Docket ID EPA

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. 20. Comment : Beyond P esticides is concerned that paying subjects to participate in studies will lead to coercion based on financial compensation. “The agency must seriously address the issue of remuneration so as to protect those who may be recruited to becoming a subject for human dosing studies . The agency must also define what constitutes payments as being considered too high or too low. Nevertheless low

- income and other financially disadvantaged populations will be disproportionately affected, especially since payment for research participation can be perceived as a potential income source among participants

. Thus, financial remuneration for participating in human studies should be reconsidered, and be done on a strictly voluntary basis with non monetary incentives.” (p

. 3)

. Response: EPA specifically sought comment on whether the exact language regarding remuneration from NAS Recommendation 5

- 3 or EPA’s proposed language (slightly re

- worded from NAS Recommendation 5

- 3 ) is clear er . The commenter is not addressing that issue, but is instead objecting to the overall notion of remuneration , arguing that financial remuneration is not appropriate for human subjects in pesticide studies . EPA continues to agree with the 2004 NAS report R eport that rem uneration is appropriate to provide an incentive for participation and to reimburse subjects for the time and inconvenience of participating in such research. The question of what amount of remuneration is appropriate is more difficult , but EPA agrees with the NAS benchmarks that such payments should be neither “so high as to constitute undue inducement” nor “so low as to be attractive only to individuals who are socioeconomically disadvantaged.” Although this specific language is not being included in the final rule, EPA will be guided by the NAS recommendations in implementing the rule.
21. Comment: “It is inevitable that although this proposal theo retically sets a higher standard for the review of human studies, EPA’s lax oversight and review process would lead to the unconditional approval of many questionable human studies.” (p

. 3 )

. Response: EPA has engaged in a rigorous scientific and ethical review of all intentional exposure human studies submitted for consideration under FIFRA and the FFDCA. Since the promulgation of the 2006 rule, this review has involved consultation with science and et hics experts on the Human Studies Review Board about all intentional exposure studies . The present rulemaking , which proposes narrowly

- targeted changes to the EPA’s 2006 H uman S tudies R ule, will further strengthen EPA’s process for reviewing these types o f studies.
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- 16 ( NRDC )
22. Comment: “The proposed rule would amend the 2006 final rule to partially or fully address many of the 2006 final rule ’ s deficiencies, including inconsistencies with Section 201, and would reduceDocket ID No.: EPA
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Page 13 of 14 the likelihood that unethical or unscientific research being conducted and/or relied upon by EPA.” (p

. 6)

. Response: The Agency is pleased that NRDC supports the proposed changes to the rule, although EPA does not concede that the 2006 final rul e contained any deficiencies that compelled the proposed changes to that rule. EPA also disagrees that there is a likelihood, in the absence of the proposed changes, that EPA would rely on unethical or unscientific human research. EPA performs rigorous s cientific and ethical reviews and submits those reviews to, and consults with , the Human Studies Review Board before determining whether to approve intentional exposure human study protocols or to rely on completed research in regulatory decisions

. In addition, as noted in comment response #1, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA. 23. Comment: “T he issue of significantly deficient is adequately addressed by deleting t he word “significantly”, as recommended by the Human Studies Review Board (HSRB) (FR at 5750)... We are satisfied with this amendment to delete the word.” (p

. 6)

. Response: The Agency is pleased that NRDC is satisfied with the proposed change , although EPA notes that this change was not recommended by the HSRB as suggested by NRDC

. EPA notes that in addition to deleting the word “significantly” from §26.1704, the Agency is add ing language that explicitly characterizes the kinds of deficiencies that woul d make a study unacceptable. The language is based on the HSRB’s application of the standard of §26.1704 in its review s since 2006

. 24. Comment : “ The issue of consent by a surrogate is addressed by EPA ’ s proposal to delete all references permitting consent by a subject ’s legal representative (FR at 5745). We are satisfied with this amendment to delete the reference.” (p

. 7)

. Response: The Agency is pleased that NRDC is satisfied with the proposed change.
25. Comment: “ T he proposed rule would also add substantive standards for assessing scientific validity. While EPA may believe that such standards are unnecessary, because it had discretion under the 2006 final rul e to reject studies it considered unscientific, there is a substantial policy and legal need for incorporating such standards into the rule....We support EPA ’ s incorporation, through the proposed rule, of stronger, more specific scientific standards.” (p

. 7)

. Response: As discussed in comment response #1 in this document , EPA believes there is no longer a legal obligation because section 201 of the Appropriations Act does not continue to impose any obligations on EPA

. For policy reasons, EPA has decided to include the specific text from the 2004 NAS Report in the final revisions with only a few non substantive wording changes. EPA believes that the revisions in the final rule are consistent with the recommendations in the 2004 NAS Report (entitled “ Intentional Human Dosing Studies for EPA Regulatory Purposes” ) 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 explici tly address most of the specific ethical considerations included in the amendments to the 2006 rule , including whether risks to subjects are minimized (compare §26.1603(c)(2) with existing §26.111(a)(2)); whether risks are reasonable in comparison to benef its (compare §26.1603(c)(3) with §26.111(a)(2)); whether subject selectionDocket ID No.: EPA
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Page 14 of 14 would be equitable (compare §26.1603(c)(4) with existing §26.111(a)(3)); whether consent will be free and voluntary (compare §26.1603(c)(5) with existing §§26.116 and 26.117); wheth er an appropriately constituted IRB has reviewed the proposed research (compare §26.1603(c)(6) with §26.109); and whether the “special problems” of research involving vulnerable populations are taken into account (compare §26.1603(c)(7) and (8) with existi ng §26.111(a)(3)). Other considerations are implicitly addressed. The Common Rule’s requirement to “minimize risks” in section 26.111(a)(1) necessitates consideration of whether adequate animal data is available to assess potential risks to subjects (se e §26.1603(c)(1)). It would involve consideration of whether medical care is to be provided for injuries incurred in the proposed research (see §26.1603(c)(10)). Section 26.111(b)’s requirement that additional safeguards be in place to protect against un due 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 § 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 rese arch design” in section 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 include d in sections 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.”