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.

02/08/2013
EO12866 Review BILLING CODE 6560-50-P

12P-0881

01/31/2013 – 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-2010-0785; 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 applying to third parties who conduct or support 

research with pesticides involving intentional exposure of human subjects and to persons who 

submit the results of human research with pesticides to EPA. The amendments broaden the 

applicability of the rules to cover human testing with pesticides submitted to EPA under any 

regulatory statute it administers. The amendments also disallow participation in third-party 

pesticide studies by subjects who cannot consent for themselves. Finally, the amendments 

identify specific considerations to be addressed in EPA science and ethics reviews of proposed 

and completed human research with pesticides, drawn from the recommendations of the National 

Academy of Sciences (NAS). The amendments make no changes to the current Federal Policy 

for the Protection of Human Subjects (the “Common Rule”), which governs research with human 

subjects conducted or supported by EPA and many other Federal departments and agencies. 

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

Register].
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ADDRESSES: The docket for this action, identified by docket identification (ID) number EPAHQ-OPP-2010-0785, is available at http://www.regulations.gov or at the OPP Docket in the 

Environmental Protection Agency Docket Center (EPA/DC), located in the EPA West Bldg., 

Rm. 3334, 1301 Constitution Ave., NW., Washington, DC 20460-0001. The Public Reading 

Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. 

The telephone number for the Public Reading Room is (202) 566-1744, and the telephone 

number for the OPP Docket is (703) 305-5805. Please review the visitor instructions and 

additional information about the docket available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Kelly Sherman, Immediate Office of the 

Director (7501P), Office of Pesticide Programs, Environmental Protection Agency, 1200 

Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number: (703) 305-8401; fax 

number: (703) 308-4776; email address: sherman.kelly@epa.gov.

SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Does this Action Apply to Me?

You may be potentially affected by this action if you conduct or sponsor research that 

may be submitted to EPA and which involves intentional exposure of human subjects. The 

following list of North American Industrial Classification System (NAICS) codes is not intended 

to be exhaustive, but rather provides a guide to help readers determine whether this document 

might apply to them. Although EPA has in the past received such third-party research from 

pesticide registrants, other entities could submit such information to EPA.

• Pesticide and other Agricultural Chemical Manufacturing (NAICS code 325320) who 

sponsor or conduct human research with pesticides.

• Other entities (NAICS code 541710) that sponsor or conduct human research with 
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pesticides, and Institutional Review Boards (IRBs) who review human research with pesticides 

to ensure it meets applicable standards of ethical conduct. Under these new provisions, EPA 

must consider the ethical aspects and scientific validity and reliability of research in a manner 

that is consistent with the requirements of the Common Rule as codified in 40 CFR part 26, 

subpart A. The “Common Rule” is the name generally used to refer to the Federal Policy for the 

Protection of Human Subjects, which governs research with human subjects conducted or 

supported by EPA and many other Federal departments and agencies. EPA's codification of the 

Common Rule appears as subpart A in 40 CFR part 26.

B. What Action is the Agency Taking?

The amendments contained in this final rule change the 2006 rule, published in the 

Federal Register issue of February 6, 2006 (71 FR 6138) (FRL-7759-8), subsequently amended 

in the Federal Register issue of June 23, 2006 (71 FR 36171) (FRL-8071-6), and codified at 40 

CFR part 26, in the following substantive respects: 

• By broadening the applicability of 40 CFR part 26, subparts K, L, M, and Q, so these 

subparts would apply not only to research submitted to or considered by EPA under the pesticide 

laws, but also to research involving a “pesticide” (as defined in the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136(u)) which is submitted to or considered 

by EPA under any other regulatory statute it administers.

• By incorporating the definition of “pesticide” from FIFRA, as a substance or mixture of 

substances intended for pesticidal effect.

• By deleting from 40 CFR part 26, subpart K, all references to consent on behalf of a 

subject in research involving intentional exposure to a pesticide by a subject’s “legally 

authorized representative.” 
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• By incorporating into 40 CFR part 26, subparts P and Q, factors to be considered by

EPA and the Human Studies Review Board (HSRB), in their review of proposed and completed 

human research, derived from the recommendations by the National Research Council of NAS in 

its 2004 Report entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes: 

Scientific and Ethical Issues” (hereafter, 2004 NAS Report) to EPA. 

C. What is the Agency's Authority for Taking this Action?

Sections 3(a) and 25(a) of FIFRA (7 U.S.C. 136a(a) and 136w(a)) and section 

408(e)(1)(C) of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 364a(e)(1)(C)),

provide the legal authority for these amendments to the 2006 rule on human research. 

D. What are the Incremental Costs and Benefits of this Action?

The incremental costs of these amendments both to industry and to EPA are expected to 

be negligible. EPA has not, therefore, prepared a new economic analysis for this rule. Because 

no research has been identified that is outside the scope of the 2006 rule but that would be within 

the scope of these amendments, EPA has no basis on which to revise the cost estimates that were 

provided in the economic analysis for the 2006 rule or those most recently provided in the 2008 

renewal of the Information Collection Request (ICR) for the existing regulation at 40 CFR part 

26. The estimates included in the ICR are summarized in Unit VI.B. and a copy of the ICR is 

available in the docket. 

II. Background

A. EPA’s 2006 Rule

As required by section 201 of the Department of the Interior, Environment, and Related 

Agencies Appropriations Act, 2006 (2006 Appropriations Act), Public Law 109-54, 119 Stat. 

531, EPA promulgated a rule in 2006 establishing a set of protections for people participating as 

subjects in third-party human research with pesticides in 40 CFR part 26. (In this context “third-
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party” research is research neither conducted (“first-party”) nor supported (“second-party”) by 

EPA or another Common Rule Federal department or agency.) The 2006 rule prohibits EPA 

from relying on third-party research on pesticides involving intentional exposure of children or 

of pregnant or nursing women, unless relying on the data is crucial to a decision that would 

impose a more stringent regulatory restriction that would improve protection of public health 

than could be justified without relying on the data. It further forbids EPA itself to conduct or 

support any research involving intentional exposure of pregnant or nursing women or of children 

to any substance. 

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

In early 2006, the Natural Resources Defense Council, Inc.; Pesticide Action Network 

North American; Pineros y Campesinos Unido Del Noroeste; Physicians for Social 

Responsibility-San Francisco; Farm Labor Organizing Committee; ALF-CIO; and Migrant 

Clinicians Network petitioned for review of the 2006 rule in the United States Court of Appeals

for the Second Circuit (Second Circuit Court of Appeals) (NRDC v. EPA, No. 06-0820-ag (2d 

Cir.)). The Petitioners argued that the 2006 rule violated the 2006 Appropriations Act because it

did not bar all pesticide research with pregnant women and children, was inconsistent with the 

2004 NAS Report, and was inconsistent with the Nuremburg Code. 

After briefing and argument, but before a decision was rendered by the Second Circuit

Court of Appeals, EPA and Petitioners entered a settlement agreement in which EPA agreed to 

conduct notice-and-comment rulemaking on the issue of whether the 2006 rule should be 

amended. EPA also agreed to propose, at a minimum, amendments to the 2006 rule that were

substantially consistent with language negotiated between the parties and attached to the 

settlement agreement as Exhibit A. This agreement, including Exhibit A, is available in the 

docket for this action as described under ADDRESSES. The settlement agreement makes clear 
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that EPA retained full discretion concerning what amendments were proposed, and what, if any,

amendments are finalized.

C. Proposed Amendments to the 2006 EPA Rule

Consistent with the settlement agreement, on January 18, 2011, EPA Administrator Lisa 

Jackson signed a notice of proposed rulemaking for proposed amendments to the 2006 rule. The 

proposed amendments were substantially consistent with the regulatory language negotiated with 

Petitioners. The notice of proposed rulemaking published in the Federal Register issue of 

February 2, 2011 (76 FR 5735) (FRL-8862-7). 

D. Retrospective Review of the Common Rule

On July 26, 2011, after issuance of EPA’s proposed rule, the Department of Health and 

Human Services (HHS), in coordination with the Office of Science and Technology Policy 

(OSTP), issued an advance notice of proposed rulemaking concerning modernization of the 

Common Rule which governs research with human subjects conducted or supported by EPA and 

many other Federal departments and agencies (76 FR 44512, July 26, 2011). HHS and OSTP 

sought comment on “how to better protect human subjects who are involved in research, while 

facilitating valuable research and reducing burden, delay, and ambiguity for investigators.” Id. 

HHS and OSTP identified seven areas of concern regarding the Common Rule. Most relevant to 

EPA’s proposed amendments to the 2006 rule, was a concern with “the multiple, differing 

regulatory requirements that can apply to a single research study . . . .” These requirements, 

according to HHS and OSTP, “have been criticized as complex, inconsistent, and lacking in 

clarity,” and can result in “unwarranted variability across institutions and their [Institutional 

Review Boards] in how the requirements are interpreted and implemented” (76 FR at 45514). 

HHS and OSTP stressed the importance of clarifying and harmonizing human subject protections 
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across the Federal Government and sought comment on the means by which this could be 

accomplished (76 FR at 44528). 

III. The Final Rule

EPA is finalizing the amendments to the 2006 rule as proposed. This includes changes to 

the scope and consent provisions, and the incorporation of selected individual recommendations 

from the 2004 NAS Report as the specific ethical and scientific factors to be considered by EPA 

and the HSRB in reviewing proposed and completed human research (i.e., proposed §§ 26.1603 

and 26.1703, see 76 FR 5745-5749).

The amendments finalized in this rule are consistent with the recommendations in the 

2004 NAS Report and EPA practice under the 2006 rule. That practice has been modeled 

primarily on EPA’s practice under its Common Rule. Sections 26.109, 26.111, 26.116, and 

26.117 of EPA’s Common Rule explicitly address most of the specific ethical considerations 

included in the amendments to the 2006 rule, including whether risks to subjects are minimized 

(compare § 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 Common 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 provided 
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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 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 § 26.111(a)(1) and the need to take “the importance 

of the knowledge that may reasonably be expected to result” from the study into account, 

mandate that EPA focus on considerations addressing scientific validity such as those included 

in §§ 26.1603 and 26.1703. At a minimum, NAS Recommendations 3-1, 4-1, 5-1, 5-2, 5-3, and 

5-5 are critical to proper consideration of the Common Rule’s ethical requirements and its 

requirement for “sound research design.”

IV. Public Comments on the Proposed Amendments

This unit discusses, in general terms, the public comments on the proposed amendments 

and EPA’s responses to those comments. EPA received a total of 10 public comments on the 

proposed amendments during the 60-day comment period. Comments were submitted by 4

individual citizens and 6 different entities – the Agricultural Handler Exposure Task Force, the 

American Chemistry Council (on behalf of the Antimicrobial Exposure Assessment Task Force 

II), Beyond Pesticides, CropLife America, Natural Resources Defense Council, and SC Johnson 

& Son, Inc. The docket (under docket ID number EPA-HQ-OPP-2010-0785) includes all of the 

comments submitted to EPA on the proposed amendments, as well as EPA’s Response to 

Comments document, which provides detailed responses to all comments received.

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

Two comments addressed the proposed changes to the scope of the 2006 rule. One 

commenter stated that the 2006 Appropriations Act did not permit an expansion of scope beyond 

pesticide studies performed in the FIFRA and FFDCA context, and another argued that the 2006 

Appropriations Act required that the scope of the rule be further expanded beyond studies 

submitted, or intended for submission, to EPA. 

After considering these comments, EPA has decided to finalize the rule text relating to 

scope as it was proposed, i.e., expanding the scope to cover research involving intentional 

exposure of human subjects to pesticides where that research is submitted, or intended to be 

submitted, to EPA under any regulatory statute that EPA administers. As noted in EPA’s 

Response to Comments document, EPA no longer regards the 2006 Appropriations Act as 

authority for this rule. Therefore, EPA believes it is unnecessary to address whether the 2006 

Appropriation Act either requires or does not allow EPA to establish a different scope for this 

rule. 

Nevertheless, EPA regards FIFRA as providing adequate legal authority for the scope of 

research covered by this final rule. Sections 3(a) and 25(a) of FIFRA provide EPA with 

authority to regulate pesticides, including research involving intentional exposure of a human 

subject to a substance, when the substance is being tested as a “pesticide.” That includes research 

intended for submission to EPA, whether under FIFRA, FFDCA, or any of EPA’s other 

regulatory authorities. EPA believes it makes sense to apply the same standards to all human 

studies involving pesticides submitted to EPA. On the other hand, EPA believes that it is not in 

the public interest to extend the prohibition against research involving intentional exposure of 

children or pregnant women to pesticides beyond the scope delineated in the proposed rule

because such a prohibition, if enforceable, could have the unintended effect of prohibiting 
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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 reviewing proposed studies to measure 

exposures experienced by people who mix, load, or apply pesticides. As proposed, EPA would 

have been required to consider whether the proposed research includes representative study 

populations for the endpoint in question and has adequate statistical power to detect appropriate 

effects. These commenters expressed the same concern regarding the proposed regulatory text at 

§ 26.1703(a)(2) and (3), which would require EPA to consider these factors in determining 

whether to rely on the research. As explained in more detail in EPA’s Response to Comments 

document, EPA does not believe that the adoption of the specific ethical and scientific factors 

will impose any additional burden on sponsors of exposure studies or on the types of exposure 

studies referenced by the commenters.

As explained previously, EPA has decided to finalize the proposed text detailing specific 

scientific and ethical aspects of proposed and completed research – including the text proposed at 

§ 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 particular pesticides studies that have been 

approved under the 2006 rule, would also meet the standards reflected in this final rule. 
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C. Other Comments, Including Comments on Narrowing the Scope of the 2006 Rule to Include 

Only Intentional Dosing Studies

The remainder of the public comments addressed issues beyond the scope of the 

proposed amendments. These comments included arguments that the burden of the requirements 

of the 2006 rule (as opposed to any burden connected to this amendment) are unjustified, and 

assertions that EPA’s interpretation in the 2006 rule of the language “research involving 

intentional exposure of a human subject” incorrectly expanded the scope of the rule beyond that 

required in the 2006 Appropriations Act, which addressed only “intentional dosing human 

toxicity studies.” The commenters are referring to § 26.1101(a) of the 2006 rule, which defines 

the scope of the rule as applying to “all research initiated after April 7, 2006 involving 

intentional exposure of a human subject ....” As EPA explained in the preamble to the proposal 

for the 2006 rule, this scope was intended to capture “all intentional dosing human studies 

intended for submission to EPA under the pesticide laws”, i.e., studies involving intentional 

dosing to measure a toxic effect and studies involving intentional dosing to measure other 

scientific endpoints, like exposure (Federal Register issue of September 12, 2005 (70 FR at 

53845) (FRL-7728-2)). Additional discussion in the preambles to the proposal for the 2006 rule

and 2006 rule further explains what studies EPA intended to be included within the scope of the 

2006 rule (70 FR at 53845-53847; 71 FR 6138, 6146, 6149-6150). 

Because these comments were directed at provisions in the 2006 rule that EPA did not

reopen for reconsideration as part of the proposed amendments, these comments are beyond the 

scope of this final rule, and no response to them is required to finalize this rule. Nonetheless, 

EPA appreciates the concerns expressed by the commenters with regard to the burdens imposed 

by the 2006 rule and recognizes that there may be value in considering further amendments to 
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the 2006 rule in a way that reduces the burdens on investigators, e.g., by limiting the types of 

research that are subject to particular requirements of the rule. 

V. Conclusion

EPA received relatively few comments on the proposed rule, and many of the comments 

received did not address the amendments in the proposal. For the reasons noted previously, the 

comments that did address the proposal do not merit any change to the amendments as proposed. 

Accordingly, EPA is finalizing the amendments as proposed for the reasons stated herein and in 

the preamble to the proposed rule. 

VI. Statutory and Executive Order Reviews

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

Improving Regulation and Regulatory Review

Under Executive Order 12866 (58 FR 51735, October 4, 1993), this action is a 

“significant regulatory action,” because the Office of Management and Budget (OMB)

determined that it would raise novel legal or policy issues arising out of legal mandates, the 

President’s priorities, or the principles set forth in the Executive Order. Accordingly, EPA 

submitted this action to OMB for review under Executive Orders 12866 and 13563 (76 FR 3821, 

January 21, 2011). Any changes made in response to OMB recommendations have been 

documented in the docket for this rulemaking as required by the Executive Order.

B. Paperwork Reduction Act (PRA)

This action does not impose any new information collection burden that would require 

additional review or approval by OMB. However, OMB has previously approved the 

information collection requirements contained in the existing regulations at 40 CFR part 26 

under the provisions of PRA (44 U.S.C. 3501 et seq.), and has assigned OMB Control No. 2070-

0169 (EPA ICR No. 2195). The OMB control numbers for EPA’s regulations in 40 CFR are 
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listed in 40 CFR part 9. 

In its 2008 analysis supporting the most recent renewal of this ICR, EPA estimated that 

respondents would submit to the Agency some 34 proposals for or reports of research involving 

intentional exposure of human subjects each year. EPA estimated that preparation of 

information required by the 2006 rule would require about 598 hours per study at a cost of 

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

estimated cost of $1,561,518. In addition, EPA estimated annual submission of 20 reports of 

research requiring only documentation of ethical conduct at a cost of 12 hours/$879 per report, or 

240 hours/$17,580 per year. The total estimate of the annual respondent burden and cost was the 

sum of these two estimates, or 2,572 hours/$1,579,098.

These paperwork burden and cost estimates include activities related to initial rule 

familiarization, as well as activities that researchers would have to perform even without the 

Agency’s rulemaking in this area, such as developing a protocol and maintaining records. 

The average annual burden on EPA for reviewing each of the 34 study submissions was 

estimated to be 178 hours/$16,850 per study, or 6,052 hours/$572,900 per year. The average 

annual burden on EPA for reviewing each of the 20 additional submissions was estimated to be 

44 hours/$3,158 per study, or 880 hours/$63,160 per year. The total estimate of the annual 

burden on EPA was the sum of these two estimates, or 6,932 hours/$636,000 per year.

In no year since promulgation of the 2006 rule have more than 7 protocols been 

submitted to EPA by industry; the average annual rate has been just over 5 for the 5-year period 

of 2006-2010. Somewhat fewer completed reports have been submitted during this period, so 

the average of new protocols and finished studies has been about 11 per year, less than a third of 

the projected 34 per year covered by the ICR. There is no evidence to suggest an upward trend, 

and nothing in these amendments is believed likely to lead to a significant change in the rate of 
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protocol and study submissions.

An agency may not conduct or sponsor, and a person is not required to respond to, a 

collection of information unless it displays a currently valid OMB control number. The OMB 

control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9. 

C. Regulatory Flexibility Act (RFA)

RFA (5 U.S.C. 601 et seq.), generally requires an agency to prepare a regulatory 

flexibility analysis of any rule subject to notice and comment rulemaking requirements under the 

Administrative Procedure Act (5 U.S.C. 551-553) or any other statute unless the agency certifies 

that the rule will not have a significant economic impact on a substantial number of small 

entities. Small entities include small businesses, small organizations, and small governmental 

jurisdictions.

For purposes of assessing the impacts of this rule on small entities, small entity is defined 

as: 

1. A small business as defined by the Small Business Administration’s (SBA) regulations 

at 13 CFR 121.201, which is based on either the maximum number of employees or on the sales 

for small businesses in each industry sector, as defined by a 6-digit NAICS code, and for this 

rule is pesticide and other agricultural chemical manufacturers (NAICS code 325320) who 

sponsor or conduct human research with pesticides, or other entities (NAICS code 541710) that 

sponsor or conduct human research with pesticides, and IRBs who review human research with 

pesticides to ensure it meets applicable standards of ethical conduct; 

2. A small governmental jurisdiction that is a government of a city, county, town, school 

district, or special district with a population of less than 50,000; or 

3. A small organization that is any not-for-profit enterprise which is independently owned 

and operated and is not dominant in its field. 
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After considering the economic impacts of this final rule on small entities, I certify that 

this action will not have a significant economic impact on a substantial number of small entities. 

Because no small entities have been identified that are directly regulated by these amendments, 

EPA has not attempted to reduce the impact of this final rule on small entities. Public comments 

were explicitly invited on all aspects of the proposal and its impacts on small entities, but no 

such comments were received.

D. Unfunded Mandates Reform Act (UMRA)

Title II of UMRA (2 U.S.C. 1531-1538) establishes requirements for Federal agencies to 

assess the effects of their regulatory actions on State, local, and tribal governments and the 

private sector. This rule does not contain a Federal mandate that may result in expenditures of 

$100 million or more for State, local, and tribal governments, in the aggregate, or the private 

sector in any 1 year. Thus, this rule is not subject to the requirements of UMRA sections 202 or 

205. This rule is also not subject to the requirements of UMRA section 203, because it contains 

no regulatory requirements that might significantly or uniquely affect small governments. These 

amendments are unlikely to affect State, local, and tribal governments at all, and are likely to 

affect the private sector only trivially. 

E. Executive Order 13132: Federalism

This action does not have federalism implications because it will not have substantial 

direct effects on the States, on the relationship between the national government and the States, 

or on the distribution of power and responsibilities among the various levels of government, as 

specified in Executive Order 13132 (64 FR 43255, August 10, 1999). It makes marginal changes 

in the scope of an existing rule applying to sponsors and investigators conducting certain kinds 

of research involving human subjects, and refines the standards for EPA oversight of and 

reliance on such research. Thus, Executive Order 13132 does not apply to this action.
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F. Executive Order 13175: Consultation and Coordination with Indian Tribal Governments

This action does not have tribal implications as specified in Executive Order 13175 (65 

FR 67249, November 9, 2000). This action will not have substantial direct effects on Indian 

Tribes, will not significantly or uniquely affect the communities of Indian tribal governments, 

and does not involve or impose any requirements that affect Indian Tribes. Thus, Executive 

Order 13175 does not apply to this action. 

G. Executive Order 13045: Protection of Children from Environmental Health Risks and Safety 

Risks

EPA interprets Executive Order 13045 (62 FR 19885, April 23, 1997), as applying only 

to those regulatory actions that concern health or safety risks, such that the analysis required 

under section 5-501 of the Executive Order has the potential to influence the regulation. This 

action is not subject to Executive Order 13045, because it does not establish an environmental 

standard intended to mitigate health or safety risks, nor is it an “economically significant 

regulatory action” as defined in Executive Order 12866. The 2006 rule applies to the conduct 

and review of research involving intentional exposure of human subjects, and prohibits the 

conduct of or EPA reliance on any such research involving subjects who are children, or 

pregnant or nursing women. These provisions would not be affected by the amendments.

H. Executive Order 13211: Actions Concerning Regulations That Significantly Affect Energy 

Supply, Distribution, or Use

This action is not a “significant regulatory action” as defined in Executive Order 13211 

(66 FR 28355, May 22, 2001), because it is not likely to have a significant adverse effect on the 

supply, distribution, or use of energy.

I. National Technology Transfer and Advancement Act (NTTAA)

Section 12(d) of NTTAA (15 U.S.C. 272 note) directs EPA to use voluntary consensus 

standards in its regulatory activities unless to do so would be inconsistent with applicable law or 
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otherwise impractical. Voluntary consensus standards are technical standards (e.g., materials 

specifications, test methods, sampling procedures, and business practices) that are developed or 

adopted by voluntary consensus standards bodies. NTTAA directs EPA to provide Congress, 

through OMB, explanations when the Agency decides not to use available and applicable 

voluntary consensus standards. This action does not involve any technical standards. Therefore, 

EPA did not consider the use of any voluntary consensus standards.

J. Executive Order 12898: Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations

Executive Order 12898 (59 FR 7629, February 16, 1994) establishes Federal executive 

policy on environmental justice. Its main provision directs Federal agencies, to the greatest 

extent practicable and permitted by law, to make environmental justice part of their mission by 

identifying and addressing, as appropriate, disproportionately high and adverse human health or 

environmental effects of their programs, policies, and activities on minority populations and lowincome populations in the United States.

EPA has determined that this final rule will not have disproportionately high and adverse 

human health or environmental effects on minority or low-income populations, because it does 

not affect the level of protection provided to human health or the environment. This rule does 

not entail special considerations of environmental justice related issues. The strengthened 

protections for human subjects participating in covered research established in the 2006 rule will

not be altered by these amendments. 

VII. Congressional Review Act

The Congressional Review Act (5 U.S.C. 801 et seq.), generally provides that before a 

rule may take effect, the agency promulgating the rule must submit a rule report, which includes 

a copy of the rule, to each House of the Congress and the Comptroller General of the United 
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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 major rule cannot take effect until 60 

days after it is published in the Federal Register. This action is not a “major rule” as defined by 

5 U.S.C. 804(2). 
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List of Subjects in 40 CFR Part 26

Environmental protection, Administrative practice and procedures, Human research,

Pesticides and pests.

Dated: _________________

_________________________________________

Administrator.
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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 amendments read 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 person who 

conducted or supported such research intended either to submit results of the research to EPA for 

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

Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136-136y) or section 408 of the 

Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 346a), or to hold the results of the 

research for later inspection by EPA under FIFRA or section 408 of FFDCA; or

(2) A pesticide if, at any time prior to initiating such research, any person who conducted 

or supported such research intended either to submit results of the research to EPA for 

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

statute administered by EPA other than those statutes designated in paragraph (a)(1) of this 
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section, or to hold the results of the research for later inspection by EPA under any regulatory 

statute administered by EPA other than those statutes designated in paragraph (a)(1) of this 

section.

(b) For purposes of determining a person’s intent under paragraph (a) of this section, 

EPA may consider any available and relevant information. EPA must rebuttably presume the 

existence of intent if:

(1) The person or the person’s agent has submitted or made available for inspection the 

results of such research to EPA; or

(2) The person is a member of a class of people who, or whose products or activities, are 

regulated by EPA and, at the time the research was initiated, the results of such research would 

be relevant to EPA’s exercise of its regulatory authority with respect to that class of people, 

products, or activities.

* * * * *

(d) The EPA Administrator retains final judgment as to whether a particular activity is 

covered by this subpart.

* * * * *

3. In § 26.1102, revise paragraphs (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. 136(u) (Federal Insecticide, Fungicide, and Rodenticide Act, section 2(u)). 

* * * * *
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(k) Common Rule refers to the Federal Policy for the Protection of Human Subjects that 

was established in 1991 by the Office of Science and Technology Policy and codified in 1991 by 

EPA and 14 other Federal departments and agencies (see the Federal Register issue of June 18, 

1991 (56 FR 28003)) and subsequently codified by other Federal departments and agencies. The 

Common Rule contains a widely accepted set of standards for conducting ethical research with 

human subjects, together with a set of procedures designed to ensure that the standards are met. 

Once codified by a Federal department or agency, the requirements of the Common Rule apply 

to research conducted or sponsored by that Federal department or agency. EPA’s codification of 

the Common Rule appears in 40 CFR part 26, subpart A.

§ 26.1111 [Amended]

4. In § 26.1111, remove from paragraph (a)(4) the phrase “or the subject’s legally 

authorized representative.” 

5. In § 26.1116, revise the introductory text of the 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 has obtained the legally effective informed consent of the subject. 

An investigator must seek such consent only under circumstances that provide the prospective 

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

possibility of coercion or undue influence. The information that is given to the subject must be 

in language understandable to the subject. No informed consent, whether oral or written, may 

include any exculpatory language through which the subject is made to waive or appear to waive 

any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the 

institution or its agents from liability for negligence.
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* * * * *

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 subject. When this method is used, there 

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

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

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

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

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

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

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

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

8. Revise § 26.1201 to read as follows:

§ 26.1201 To what does this subpart apply?

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

9. Revise § 26.1301 to read as follows:

§ 26.1301 To what does this subpart apply?

This subpart applies to any person who submits to EPA on or after [insert date 60 days 
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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. 136-136y) or section 408 

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

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

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

statute administered by EPA.

§ 26.1302 [Amended]

10. In § 26.1302, remove the word “shall.” 

§ 26.1502 [Amended]

11. In § 26.1502:

a. Remove in the first sentence of paragraph (a), the period after the phrase “during an 

inspection” and add in its place a comma.

b. Remove in the second sentence of paragraph (a), the phrase “The agency” and add in 

its place “EPA.”

c. Remove in the last sentence of the introductory text of paragraph (b), the phrase “the

Agency” and add in its place “EPA.”

§ 26.1505 [Amended]

12. 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]

13. In § 26.1507, remove from the last sentence, the phrase “The Agency” and add in its 

place “EPA.”

§§ 26.1601 through 26.1603 [Redesignated as §§ 26.1603 through 26.1605]
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14. Redesignate §§ 26.1601 through 26.1603 as §§ 26.1603 through 26.1605.

15. Add new §§ 26.1601 and 26.1602 to subpart P to read as follows:

§26.1601 To what does this subpart apply?

This subpart applies to both of the following:

(a) Reviews by EPA and by the Human Studies Review Board of proposals to conduct 

new research subject to § 26.1125.

(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.

16. In newly redesignated § 26.1603:

a. Remove paragraphs (a) and (e).

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

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

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 validity and 

reliability of the proposed research, including:

(1) Whether the research would be likely to produce data that address an important 

scientific or policy question that cannot be resolved on the basis of animal data or human 
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observational research.

(2) Whether the proposed research is designed in accordance with current scientific 

standards and practices to:

(i) Address the research question.

(ii) Include representative study populations for the endpoint in question.

(iii) Have adequate statistical power to detect appropriate effects.

(3) Whether the investigator proposes to conduct the research in accordance with 

recognized good research practices, including, when appropriate, good clinical practice 

guidelines and monitoring for the safety of subjects.

(c) In reviewing proposals for new research submitted under § 26.1125, the EPA 

Administrator must consider and make determinations regarding ethical aspects of the proposed 

research, including:

(1) Whether adequate information is available from prior animal studies or from other 

sources to assess the potential risks to subjects in the proposed research.

(2) Whether the research proposal adequately identifies anticipated risks to human 

subjects and their likelihood of occurrence, minimizes identified risks to human subjects, and 

identifies likely benefits of the research and their distribution.

(3) Whether the proposed research presents an acceptable balance of risks and benefits. 

In making this determination for research intended to reduce the interspecies uncertainty factor 

in a pesticide risk assessment, the EPA Administrator will also consider the process laid out and 

the attendant discussion for evaluating that type of study as provided in Recommendation 4-1 of

the 2004 Report from the National Research Council of the National Academy of Sciences 

(NAS), entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and 

Ethical Issues.”
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(4) Whether subject selection will be equitable.

(5) Whether subjects’ participation would follow free and fully informed consent.

(6) Whether an appropriately constituted IRB or its foreign equivalent has approved the 

proposed research.

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

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

measures taken to protect such human subjects are adequate.

(8) If any person with a condition that would put them at increased risk for adverse 

effects may become a subject in the proposed research, whether there is a convincing 

justification for selection of such a person, and whether measures taken to protect such human 

subjects are adequate.

(9) Whether any proposed payments to subjects are consistent with the principles of 

justice and respect for persons, and whether they are so high as to constitute undue inducement 

or so low as to be attractive only to individuals who are socioeconomically disadvantaged.

(10) Whether the sponsor or investigator would provide needed medical care for injuries 

incurred in the proposed research, without cost to the human subjects.

(d) With respect to any research or any class of research subject to this subpart, the EPA 

Administrator may recommend additional conditions which, in the judgment of the EPA 

Administrator, are necessary for the protection of human subjects.

* * * * *

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

Studies Review Board reviews.

17. In newly redesignated § 26.1604, revise paragraph (a) to read as follows:

§ 26.1604 EPA review of completed human research.
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(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.

*****

18. Add §§ 26.1606 and 26.1607 to subpart P to read as follows:

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

In commenting on proposals for new research submitted to it by EPA, the Human Studies 

Review Board must consider the scientific merits and ethical aspects of the proposed 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 research submitted to it by EPA, the Human 

Studies Review Board must consider the scientific merits and ethical aspects of the completed 

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

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

Subpart Q—Standards for Assessing Whether to Rely on the Results of Human Research 

in EPA Actions

20. Revise §§ 26.1701through 26.1705 to read as follows:

* * * * *

Sec.

26.1701 To what does this subpart apply?

26.1702 Definitions.

26.1703 Prohibitions applying to all research subject to this subpart.

26.1704 Prohibition of reliance on unethical human research with non-pregnant, non-nursing 

adults.

26.1705 Prohibition of reliance on unethical human research with non-pregnant, non-nursing
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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 human subjects to any 

substance.

(b) For decisions under any regulatory statute administered by EPA other than those 

statutes designated in paragraph (a) of this section, this subpart applies to research involving 

intentional exposure of human subjects to a pesticide.

§ 26.1702 Definitions.

The definitions in § 26.1102 and § 26.1202 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 determines that the data are relevant to a 

scientific or policy question important for EPA decisionmaking, that the data were derived in a 

manner that makes them scientifically valid and reliable, and that it is appropriate to use the data 

for the purpose proposed by EPA. In making such determinations, EPA must consider:

(1) Whether the research was designed and conducted in accordance with appropriate 

scientific standards and practices prevailing at the time the research was conducted.

(2) The extent to which the research subjects are representative of the populations for the 

endpoint or endpoints in question.

(3) The statistical power of the data to support the scientific conclusion EPA intends to 

draw from the data.

(4) In a study that reports only a No Observed Effect Level (NOEL) or a No Observed 
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Adverse Effect Level (NOAEL), whether a dose level in the study gave rise to a biological 

effect, thereby demonstrating that the study had adequate sensitivity to detect an effect of 

interest.

(b) Prohibition of reliance on research subject to this subpart involving intentional 

exposure of human subjects who are pregnant women (and therefore their fetuses), nursing 

women, or children. Except as provided in § 26.1706, EPA must not rely on data from any 

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

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

§ 26.1704 Prohibition of reliance on unethical human research with non-pregnant, nonnursing 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 the time the research was conducted in a way that placed participants at increased risk of harm 

(based on knowledge available at the time the study was conducted) or impaired their informed 

consent. 

(c) The prohibition in this section is in addition to the prohibitions in § 26.1703.

§ 26.1705 Prohibition of reliance on unethical human research with non-pregnant, nonnursing 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,
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or to the codification of the Common Rule by another Federal department or agency.

(b) 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) All applicable provisions of subparts A through L of this part, or the codification of 

the Common Rule by another Federal department or agency; or

(2) If the research was conducted outside the United States, with procedures at least as 

protective of subjects as those in subparts A through L of this part, or the codification of the 

Common Rule by another Federal department or agency.

(c) Except as provided in § 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 the study 

was conducted) or impaired their informed consent.

(d) The prohibition in this section is in addition to the prohibitions in § 26.1703.

§ 26.1706 [Amended]
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21. In § 26.1706, remove in paragraph (d) the word “publishes” and add in its place the 

phrase “has published.” 
Docket ID No.: EPA-HQ-OPP-2010-0785

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

Response to Public Comments

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 Subjects in Human Research Involving Pesticides

that published on February 2, 2011 (76 FR 5735), in which the EPA proposed amending 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-OPP-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 comment on the proposed changes. The Agency received 10 

comments in response to the Notice of Proposed Rulemaking.

1

 In the docket, documents identified with 

Document ID numbers ending in 1 through 6 are supporting documents for the rulemaking; documents 

7-16 are public comments; documents 17-55 are the 28 attachments to NRDC’s comment (see 

discussion 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 scope of the 

proposed amendments. The first issue relates to the proposed expansion of the rule to cover human 

testing 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 relates 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) includes 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-HQ-OPP-2010-0785

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 EPA’s responses to those comments, are discussed below.

Document ID No.: EPA-HQ-OPP-2010-0785-14 (Commenter: SC Johnson)

1. Comment: The 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 and 

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 the 

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, unless 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 the 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 

of EPA’s regulatory statutes. 

Document ID No.: EPA-HQ-OPP-2010-0785-16 (Commenter: Natural Resources Defense Council 

[NRDC])

2. Comment: While 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 has 
Docket ID No.: EPA-HQ-OPP-2010-0785

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 that 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. 

Document ID Nos.: 

EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure Task Force 

[AHETF])

EPA-HQ-OPP-2010-0785-12 (Commenter: CropLife America [CLA])

EPA-HQ-OPP-2010-0785-13 (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 studies. 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 “statistical 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-HQ-OPP-2010-0785-11, 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 appropriate for clinical studies and do not translate directly to occupational 

exposure studies whose purpose is to develop observational exposure data.” (EPA-HQ-OPP-2010-

0785-12, p 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 of 
Docket ID No.: EPA-HQ-OPP-2010-0785

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 impose unwarranted burdens in study 

sponsors and investigators without improving scientific validity or protection of human subjects.” 

(EPA-HQ-OPP-2010-0785-13, 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-HQ-OPP-2010-0785-13, 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 studies. 

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 and ethics reviews of human research involving pesticides. 

76 FR at 5737, 5741, 5749, 5751. 

Under 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 the 2004 NAS Report represents a material change in the way 

a particular pesticide study would have been reviewed. Thus, EPA believes that particular 

pesticides studies that have been approved under the 2006 rule, would also meet the standards 

reflected in this final rule.

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 is 

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 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 

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 study. 

Similarly, statistical power considerations 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 unexposed groups. In some instances, 
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exposed and unexposed 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 exposed and 

unexposed 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 

exposed and unexposed 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 exposure 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 analyses 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 studies. 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

Document ID No.: EPA-HQ-OPP-2010-0785-07 (Commenter: Anonymous)

1. Comment: “It is plausible that several of the current or future-use pesticides might exert transgenerational 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 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 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 rule (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 be 

epidemiological 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 rule. 

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 environmentally disadvantaged 
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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 conventionally grown foods.”

Response: EPA’s 2006 rule and the proposed amended version of the rule have a very clearly 

delineated scope. The rule (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.

Document ID No.: EPA-HQ-OPP-2010-0785-08 (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. 

Document ID No.: EPA-HQ-OPP-2010-0785-09 (Commenter: A. Sow)

4. Comment: “My comment is that protecting 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 difference. 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 environmental practice”

Response: EPA’s mission is to protect human health and the environment. 

Document ID No.: EPA-HQ-OPP-2010-0785- 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 pesticides 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 revisions to its 2006 rule for the protection of 

human subjects in research involving intentional exposure to pesticides. General comments 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, 
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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 Focus 

Document ID Nos.: 

EPA-HQ-OPP-2010-0785-11 (Commenter: AHETF)

EPA-HQ-OPP-2010-0785-12 (Commenter: CLA)

EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF)

EPA-HQ-OPP-2010-0785-14 (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 responses 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 rule 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 study 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 within 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 

changes 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 covered 
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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 previouslypromulgated 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 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 types of research that are 

subject to particular requirements of the rule.

Document ID No.: EPA-HQ-OPP-2010-0785-11 (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 should define “intentional exposure”. (p. 1)

Response: See response to Comment 6, pp. 7-8 of 14. 

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)

Response: 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. 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) 

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 
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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 this 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 regulation 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. Please see response to Comment 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: It is not clear what public comments the commenter is suggesting would be reviewed 

by an expert panel, but the proposal of a “lessons learned” review has merit. EPA will consider 

this option after the revised rule is promulgated. 

Document ID No.: EPA-HQ-OPP-2010-0785-12 (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 

involving intentional dosing of human subjects to study toxicity.” (p. 7)

Response: This comment is not responsive 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 occupational 
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exposure studies should not be covered by the Human Research Rule, please see the response to 

Comment 6, pp. 7-8 of 14. 

Document ID No.: EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF)

14. Comment: The proposed amendments 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 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 the protection of human subjects” is 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 this subpart....” 

Document ID No.: EPA-HQ-OPP-2010-0785-14 (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 rule, Protections for Subjects in 

Human Research (40 CFR 26). The current rulemaking does not reopen consideration of the 

2006 rule generally, but rather makes certain narrowly-targeted revisions to a few specific 

provisions. In the current rulemaking, EPA did not reconsider the underlying basis for the 2006 

rule and comments 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 that human studies involving personal insect repellents should not be 

covered by the rule, please see response to Comment 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 

importance of maintaining the confidentiality of information, it has been extremely difficult to obtain 
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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 been 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 requirements 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-HQ-OPP-2003-0132-0656, pp. 266-267) 

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 requires 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. 

Document ID No.: EPA-HQ-OPP-2010-0785- 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 unproductive, 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-HQ-OPP-2003-0132-0656, p. 143) 
Docket ID No.: EPA-HQ-OPP-2010-0785

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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 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 clearer. 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 

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 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 Human Studies Rule, 

will further strengthen EPA’s process for reviewing these types of studies. 

Document ID No.: EPA-HQ-OPP-2010-0785-16 (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 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 rule 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 scientific 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 
Docket ID No.: EPA-HQ-OPP-2010-0785

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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: “The 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 adding

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 reviews 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: “The 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 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 nonsubstantive 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 (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 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)’s 
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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 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 

importance of the knowledge that may reasonably be expected to result” from the study into 

account, mandate that EPA focus on considerations addressing scientific validity such as those 

included in 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.”
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.

02/08/2013
Docket ID No.: EPA-HQ-OPP-2010-0785

Page 1 of 14

2/6/2013 – Revised Response to Comment Document for Final Rule (Mark-up shows changes 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

Response to Public Comments

Received on the Proposed Rule Entitled:

“Revisions to EPA’s Rule on Protections for Subjects in Human 

Research Involving Pesticides” (RIN 2070-AJ76)

012/31056/2013; 4 p9 am

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 Subjects in Human Research Involving Pesticides

that published on February 2, 2011 (76 FR 5735), in which the EPA proposed amending 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-OPP-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 comment on the proposed changes. The Agency received 10 

comments in response to the Notice of Proposed Rulemaking.

1

 In the docket, documents identified with 

Document ID numbers ending in 1 through 6 are supporting documents for the rulemaking; documents 

7-16 are public comments; documents 17-55 are the 28 attachments to NRDC’s comment (see 

discussion 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 scope of the 

proposed amendments. The first issue relates to the proposed expansion of the rule to cover human 

testing 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 relates 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) includes 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. 
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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 EPA’s responses to those comments, are discussed below.

Document ID No.: EPA-HQ-OPP-2010-0785-14 (Commenter: SC Johnson)

1. Comment: The 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 and 

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 the 

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, unless 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 the 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 

of EPA’s regulatory statutes. 

Document ID No.: EPA-HQ-OPP-2010-0785-16 (Commenter: Natural Resources Defense Council 

[NRDC])

2. Comment: While 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 has 
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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 that 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. 

Document ID Nos.: 

EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure Task Force 

[AHETF])

EPA-HQ-OPP-2010-0785-12 (Commenter: CropLife America [CLA])

EPA-HQ-OPP-2010-0785-13 (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 studies. 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 “statistical 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-HQ-OPP-2010-0785-11, pp. 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 appropriate for clinical studies and do not translate directly to occupational 

exposure studies whose purpose is to develop observational exposure data.” (EPA-HQ-OPP-2010-

0785-12, p. 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 of 
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exposure research being conducted by AEATF and others, are too ambiguous to offer clarity and 

predictability to study sponsors and investigators, and impose unwarranted burdens in study 

sponsors and investigators without improving scientific validity or protection of human subjects.” 

(EPA-HQ-OPP-2010-0785-13, 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-HQ-OPP-2010-0785-13, 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 Report2. EPA thinks thatSome 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 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 and ethics reviews of human research involving pesticides. 

76 FR at 5737, 5741, 5749, 5751. 

Under 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 the 2004 NAS Report represents a material change in the way 

a particular pesticide study would have been reviewed. Thus, EPA believes that particular 

pesticides studies that have been approved under the 2006 rule, would also meet the standards 

reflected in this final rule.

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 is 

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 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 NAS Report).
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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 study. 

Similarly, statistical power considerations 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 unexposed groups. In some instances, 

exposed and unexposed 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 exposed and 

unexposed 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 

exposed and unexposed 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 exposure 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 analyses 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 studies. 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

Document ID No.: EPA-HQ-OPP-2010-0785-07 (Commenter: Anonymous)

1. Comment: “It is plausible that several of the current or future-use pesticides might exert transgenerational 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 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 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 rule (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 be 
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epidemiological 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 rule. 

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 environmentally disadvantaged 

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 conventionally grown foods.”

Response: EPA’s 2006 rule and the proposed amended version of the rule have a very clearly 

delineated scope. The rule (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.

Document ID No.: EPA-HQ-OPP-2010-0785-08 (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. 

Document ID No.: EPA-HQ-OPP-2010-0785-09 (Commenter: A. Sow)

4. Comment: “My comment is that protecting 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 difference. 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 environmental practice”

Response: EPA’s mission is to protect human health and the environment. 

Document ID No.: EPA-HQ-OPP-2010-0785- 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 
Docket ID No.: EPA-HQ-OPP-2010-0785

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everyone. Exposing children to new pesticides 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 revisions to its 2006 rule for the protection of 

human subjects in research involving intentional exposure to pesticides. General comments 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 with Common Focus 

Document ID Nos.: 

EPA-HQ-OPP-2010-0785-11 (Commenter: AHETF)

EPA-HQ-OPP-2010-0785-12 (Commenter: CLA)

EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF)

EPA-HQ-OPP-2010-0785-14 (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 responses 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 rule 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 study 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 within 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.
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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 

changes 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 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 previouslypromulgated 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 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 types 

of research that are subject to particular requirements of the rule.

Document ID No.: EPA-HQ-OPP-2010-0785-11 (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 should define “intentional exposure”. (p. 1).

Response: See response to Comment 6, pp. 7-8 of 14. 

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).

Response: 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. 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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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 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 this 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 regulation 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. Please see response to Comment 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: It is not clear what public comments the commenter is suggesting would be reviewed 

by an expert panel, but the proposal of a “lessons learned” review has merit. EPA will consider 

this option after the revised rule is promulgated. 

Document ID No.: EPA-HQ-OPP-2010-0785-12 (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 
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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 responsive 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 occupational 

exposure studies should not be covered by the Human Research Rule, please see the response to 

Comment 6, pp. 7-8 of 14. 

Document ID No.: EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF)

14. Comment: The proposed amendments 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 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 the protection of human subjects” is 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 this subpart....” 

Document ID No.: EPA-HQ-OPP-2010-0785-14 (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 rule, Protections for Subjects in 

Human Research (40 CFR 26). The current rulemaking does not reopen consideration of the 

2006 rule generally, but rather makes certain narrowly-targeted revisions to a few specific 

provisions. In the current rulemaking, EPA did not reconsider the underlying basis for the 2006 

rule and comments 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).
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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 rule, please see response to Comment 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 

importance 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 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 been 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 requirements 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-HQ-OPP-2003-0132-0656, pp. 266-

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 requires 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. 

Document ID No.: EPA-HQ-OPP-2010-0785- 15 (Nichelle Harriott, Beyond Pesticides)
Docket ID No.: EPA-HQ-OPP-2010-0785

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19. Comment: “[C]onducting experiments on human subjects, intentionally exposing them to 

chemicals that can cause both short and long term adverse effects is unproductive, 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-HQ-OPP-2003-0132-0656, p. 143). 

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 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 clearer. 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 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 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 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 Human Studies Rule, 

will further strengthen EPA’s process for reviewing these types of studies. 

Document ID No.: EPA-HQ-OPP-2010-0785-16 (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 
Docket ID No.: EPA-HQ-OPP-2010-0785

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 rule 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 scientific 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: “The 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 adding

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 reviews 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: “The 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 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 nonsubstantive 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 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 
Docket ID No.: EPA-HQ-OPP-2010-0785

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); 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)’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 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 

importance of the knowledge that may reasonably be expected to result” from the study into 

account, mandate that EPA focus on considerations addressing scientific validity such as those 

included in 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.”