Attachment #B – Review Period: 11/07/11 – 06/08/12

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 #B – Review Period: 11/07/11 – 06/08/12

(1) A copy of the information that was submitted to OIRA for 

review under the Executive Order.

02/08/2013
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1 EO 12866_HumanSubjectsRevisions_RIN 2070-AJ76_FRM_2011-09-15.docx

2 BILLING CODE 6560–50–P

3 ENVIRONMENTAL PROTECTION AGENCY

4 40 CFR Part 26

5 [EPA–HQ–OPP–2010–0785; FRL–XXXX–X]

6 RIN 2070–AJ76

7 Protections for Subjects in Human Research Involving Pesticides

8 AGENCY: Environmental Protection Agency (EPA).

9 ACTION: Final rule.

10 SUMMARY: EPA is finalizing narrowly-tailored amendments to the portions of its rules for the 

11 protection of human subjects of research applying to third parties who conduct or support 

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

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

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

15 regulatory statute it administers. They also disallow participation in third-party pesticide studies 

16 by subjects who cannot consent for themselves. Finally, the amendments identify specific 

17 considerations to be addressed in EPA science and ethics reviews of proposed and completed 

18 human research with pesticides, drawn from the recommendations of the National Academy of 

19 Sciences (NAS). The amendments make no changes to the Common Rule or EPA’s codification 

20 of the Common Rule. 

21 DATES: This rule is effective on [60 days after publication]

22 ADDRESSES: EPA has established a docket for this action under docket identification (ID) 

23 number EPA–HQ–OPP–2010–0785. All documents in the docket are listed in the docket index 

24 available at http://www.regulations.gov. Although listed in the index, some information is not 
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25 publicly available, e.g., CBI or other information whose disclosure is restricted by statute. 

26 Certain other material, such as copyrighted material, is not placed on the Internet and will be 

27 publicly available only in hard copy form. Publicly available docket materials are available 

28 either in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at 

29 the OPP Regulatory Public Docket in Rm. S–4400, One Potomac Yard (South Bldg.), 2777 S. 

30 Crystal Dr., Arlington, VA. The hours of operation of this Docket Facility are from 8:30 a.m. to 

31 4 p.m., Monday through Friday, excluding legal holidays. The Docket Facility telephone 

32 number is (703) 305-5805.

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

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

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

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

37 SUPPLEMENTARY INFORMATION:

38 I. Does this Action Apply to Me?

39 You may be potentially affected by this action if you conduct human research on 

40 substances regulated by EPA. Potentially affected entities may include, but are not limited to,

41 entities that conduct or sponsor research involving intentional exposure of human subjects that 

42 may be submitted to EPA. Although EPA has in the past received such third-party research from 

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

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

45 sponsor or conduct human research with pesticides.

46 • Other entities (NAICS code 541710) that sponsor or conduct human research with 

47 pesticides, and Institutional Review Boards who review human research with pesticides to ensure 
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48 it meets applicable standards of ethical conduct.

49 This listing is not intended to be exhaustive, but rather provides a guide for readers 

50 regarding entities likely to be affected by this action. Other types of entities not listed in this unit 

51 could also be affected. The North American Industrial Classification System (NAICS) codes 

52 have been provided to assist you and others in determining whether this action might apply to 

53 certain entities. If you have any questions regarding the applicability of this action to a particular 

54 entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.

55 II. General Information

56 A. What Action is the Agency Taking?

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

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

59 on June 23, 2006 (71 FR 36171) (FRL-8071-6), and codified at 40 CFR part 26, in the following 

60 substantive respects: 

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

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

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

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

65 by EPA under any other regulatory statute it administers.

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

67 substances intended for pesticidal effect.

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

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

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

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

73 research, derived from the recommendations of NAS in its 2004 Report to EPA, and from the 

74 Nuremberg Code.

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

76 The legal authority for these amendments to the 2006 rule on human research is set forth 

77 in detail in the preamble to the proposed rule. 76 FR 5735, 5736-5755 (February 2, 2011) . In 

78 brief, the authority for these amendments is provided by section 201 of the Department of the 

79 Interior, Environment, and Related Agencies Appropriations Act, 2006, Public Law 109-54 

80 (2006 Appropriations Act), and sections 3(a)( and 25(a) of FIFRA.

81 III. Background

82 As required by section 201 of the 2006 Appropriations Act, EPA promulgated a rule 

83 establishing a set of protections for people participating as subjects in third-party human research 

84 with pesticides. (In this context “third-party” research is research neither conducted (“first85 party”) nor supported (“second-party”) by EPA or another Common Rule Federal department or 

86 agency.) The 2006 rule prohibits EPA from relying on third-party research on pesticides 

87 involving intentional exposure of children or of pregnant or nursing women, unless relying on 

88 the data is crucial to a decision that would impose a more stringent regulatory restriction that 

89 would improve protection of public health than could be justified without relying on the data. It 

90 further forbids EPA itself to conduct or support any research involving intentional exposure of 

91 pregnant or nursing women or of children to any substance. 

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

93 North American, Pineros y Campesinos Unido Del Noroeste, Physicians for Social 
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94 Responsibility-San Francisco, Farm Labor Organizing Committee, ALF-CIO, and Migrant 

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

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

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

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

99 2004 NAS Report, and was inconsistent with the Nuremburg Code. 

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

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

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

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

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

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

106 docket for this action as described under ADDRESSES. The settlement agreement makes clear 

107 that EPA retained full discretion concerning what amendments were proposed, and what, if any,

108 amendments are finalized.

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

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

111 The proposed amendments were substantially consistent with the regulatory language negotiated 

112 with Petitioners. The notice of proposed rulemaking was published in the Federal Register on 

113 February 2, 2011. 

114 IV. Public Comments on the Notice of Proposed Rulemaking

115 A. Summary

116 This unit discusses, in general terms, the public comments on the proposed rulemaking 
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117 and EPA’s responses to those comments. For additional details, please refer to the docket for 

118 this action (EPA–HQ–OPP–2010–0785). The docket includes all of the comments submitted to 

119 EPA on this action, as well as a separate document that provides EPA’s detailed responses to the 

120 comments.

121 EPA received a total of 10 public comments on the proposed rulemaking during the 60-

122 day comment period. Comments were submitted by four individual citizens and six different 

123 entities – the Agricultural Handler Exposure Task Force, the American Chemistry Council (on 

124 behalf of the Antimicrobial Exposure Assessment Task Force II), Beyond Pesticides, CropLife 

125 America, Natural Resources Defense Council, and SC Johnson & Son, Inc.

126 B. Comments within the scope of the proposed rulemaking

127 EPA has identified only two issues raised by the commenters that are within the scope of 

128 the proposed rulemaking. The first issue relates to the proposed expansion of the scope of the 

129 rule to cover human testing with pesticides submitted to EPA under any regulatory statute it 

130 administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. 

131 One commenter argued that EPA was without authority to expand the scope of the rule and 

132 another requested that the scope be even broader. The second issue relates to new regulatory text 

133 at §26.1603(b)(2)(ii and iii) and § 26.1703(a)(2 and 3) which would require EPA to consider 

134 whether proposed and completed research includes representative study populations for the 

135 endpoint in question and has adequate statistical power to detect appropriate effects. Several 

136 commenters addressed this issue.

137 1. Comments about proposed scope changes

138 Comment: SC Johnson & Son commented that the proposed scope expansion exceeds 

139 EPA’s statutory authority.
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140 Response: EPA’s authority for this proposed revision to the rule can be found in the 

141 Appropriations Act and in FIFRA. Section 201 of the Appropriations Act gives EPA the 

142 authority to issue a rule covering research involving the intentional dosing toxicity studies for 

143 pesticides. The Appropriations Act does not expressly limit EPA’s authority to studies 

144 conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. 

145 FIFRA provides additional authority to issue rules covering the use of both unregistered and 

146 registered pesticides, regardless of whether that research is conducted for submission under 

147 FIFRA. Section 3(a) of FIFRA permits EPA to regulate the distribution, sale, or use of any 

148 unregistered pesticide in any State “[t]o the extent necessary to prevent unreasonable adverse 

149 effects on the environment.” Section 25(a) authorizes EPA to “prescribe regulations to carry out 

150 the provisions of [FIFRA].” EPA has determined that this rule ensures that registered pesticides 

151 are not used in a manner that would cause unreasonable adverse effects on the environment, 

152 including humans. 

153 Comment: Natural Resources Defense Council commented that the scope should be 

154 further expanded, asserting that Section 201 of the 2006 Appropriations Act requires a “clear ban 

155 on intentional dosing toxicity stud[ies] on pregnant women or children.” Natural Resources 

156 Defense Council believes the “intent to submit” requirement in the scope provisions creates a 

157 loophole that could allow third parties to conduct intentional dosing toxicity studies with 

158 pregnant women or children. 

159 Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in 

160 FIFRA, EPA does not believe that the 2006 Appropriations Act compels the broad ban 

161 advocated by NRDC. The human studies that Congress was primarily concerned about during 

162 the debates leading up to the passage of the 2006 Appropriations Act were those that involved 
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163 intentional testing of pesticides on human subjects and EPA’s consideration or reliance on those 

164 studies. EPA was prohibited from relying on any human studies until it issued a rule in 

165 accordance with the requirements of the 2006 Appropriations Act. This context implies that a 

166 reasonable interpretation of what Congress was requiring EPA to do was to issue a rule covering 

167 human studies involving exposure to pesticides when those studies were submitted to EPA. 

168 Nothing in the legislative history indicates that Congress intended EPA’s rule to apply to studies 

169 that were outside of EPA’s purview. As mentioned above, EPA has authority, and believes it is 

170 reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides 

171 that are submitted to EPA under other laws that it administers. This rule covers studies that are

172 within EPA’s purview. However, to expand the 2006 rule to impose prohibitions or conditions 

173 on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies 

174 involving unregistered pesticides that are conducted outside the United States) is clearly outside 

175 EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect 

176 of prohibiting valuable research.

177 2. Comments about revised rule language on representative subjects and statistical 

178 analysis

179 Comment: The American Chemistry Council (for the Antimicrobial Exposure 

180 Assessment Task Force II), the Agricultural Handler Exposure Task Force, and CropLife 

181 America commented on the new regulatory text at §26.1603(b)(2)(ii and iii) which would require 

182 EPA to consider whether the proposed research includes representative study populations for the 

183 endpoint in question and has adequate statistical power to detect appropriate effects, and the new 

184 regulatory text at §26.1703(a)(2 and 3) which would require EPA to consider these factors in 

185 determining whether to rely on the research. The American Chemistry Council argues that these 
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186 criteria are “inapposite to the types of exposure research being conducted by AEATF and 

187 others...” The Agricultural Handler Exposure Task Force and CropLife America claim that the 

188 criteria are “more appropriate for clinical studies and do not translate directly to occupational 

189 exposure studies...” All three commenters sought clarification on how the criteria would apply 

190 to exposure studies. They expressed concern that adding these criteria to the rule would impose 

191 additional burdens on sponsors of exposure studies. Specifically, they asked that EPA confirm 

192 that it does not expect any effect from the adoption of these criteria on the continued approval of 

193 the worker exposure studies.

194 Response: As discussed in the preamble to the proposed rule, this language is a 

195 combination of recommendations 3-1(b) and 5-1(c) from the 2004 Report by the National 

196 Research Council of the National Academies of Science (NAS) titled Intentional Human Dosing 

197 Studies for EPA Regulatory Purposes (hereafter, NAS Report). EPA disagrees with the assertion 

198 that the criteria on representative populations and statistical power are not applicable to exposure 

199 studies. Although the NAS recommendations on which these criteria are based were drafted 

200 with an eye toward toxicological testing, the scientific concepts embodied have broad 

201 applicability to scientific testing. Further, the language used by EPA in this rule is generic in 

202 nature and not limited to toxicological testing. Terms such as “effect” or “endpoint,” when used 

203 without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA 

204 believes the criteria are potentially applicable to all types of intentional exposure human studies 

205 covered by this rule. 

206 Nonetheless, EPA does not believe that adoption of these criteria will impose additional 

207 burdens on sponsors of the type of exposure studies referenced by the commenters. Even though 

208 the NAS’ recommendations about representative study populations and adequate statistical 
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209 power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied 

210 the principles underlying these recommendations, as well as the general NAS directive that 

211 studies should be designed and conducted in accordance with appropriate scientific standards and 

212 practices, in its consideration of human research since the promulgation of the rule in 2006. 

213 Thus, EPA does not anticipate any effect from adding these NAS recommendations to the 2006 

214 rule on the Agency’s consideration of ongoing or future worker occupational exposure studies, 

215 except that EPA’s consideration of these issues will be even more transparent. As EPA 

216 repeatedly noted in the preamble to the proposed rule, the proposed amendments essentially 

217 codify the scope and approach used under the 2006 rule in EPA’s science and ethics reviews of 

218 human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this 

219 comment response, EPA further clarifies the applicability of the criteria at issue to exposure 

220 studies.

221 The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is 

222 relevant to any scientific endeavor in which less than the full population is examined or tested 

223 and for which valid extrapolation to a larger population is desired. EPA does not agree that the 

224 language could be construed as not applying to exposure studies, given that the 

225 representativeness of the sample is a relevant consideration in evaluating, for proposed and 

226 completed research, whether the observed effects of the completed study would predict the 

227 responses of a larger population. 

228 In evaluating what is a representative population for a study, the NAS emphasized that 

229 EPA should focus on the “objectives of the study” (NAS Report, p. 77). For a study intended to 

230 measure worker exposure, representation of the general workforce would be evaluated with 

231 respect to, among other characteristics, types of equipment used, the monitored subjects’ work 
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232 experience, and work situations that could be defined by factors such as geographic location or 

233 crop. The exposure studies to date have been representative of the workforce studied in this 

234 manner. As discussed below, EPA considers explicit adoption of the representative population 

235 criterion as a codification of existing practice and does not believe that adoption of this criterion 

236 will impose any additional burden on sponsors of exposure studies.

237 The commenters appear to be concerned that the representative population consideration 

238 will require that a study use a fully statistically random sample imposing additional burdens on 

239 sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular 

240 method for demonstrating representativeness; rather, the rule only requires that EPA, in 

241 determining the scientific validity and reliability of proposed and completed studies, “consider” 

242 representativeness. Moreover, as noted above, the NAS Report stressed that representativeness 

243 was a study-specific determination based on the objectives of the study. For exposure studies, a 

244 fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate 

245 sampling strategies can produce a sample which represents a broader range of conditions than 

246 would be present in a random sample of similar limited size and thus may produce results that 

247 reasonably approximate real world exposures with respect to the overall magnitude and “spread.” 

248 For example, the Agricultural Handler Exposure Task Force (AHETF) and the Antimicrobial 

249 Exposure Assessment Task Force II (AEATF-II) are using a “purposive diversity selection” 

250 sampling procedure in their exposure research. This procedure attempts to produce a sample 

251 which incorporates some random elements (where feasible); the resulting sample can be more 

252 useful from a regulatory perspective in that it more likely represents the range of conditions and 

253 situations under which exposure occurs. This approach meets the objectives of the study and is 

254 consistent with the representative population consideration requirement. The Agency recognizes 
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255 that random sampling, in many cases, may be considered to be the “gold-standard” for 

256 demonstrating representativeness in a statistical sense. Nonetheless, for the reasons stated above, 

257 the use of alternate sampling strategies can, under certain circumstances, produce a sample 

258 which is sufficiently representative given the study objectives. 

259 The statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a 

260 relevant concept for both toxicology and exposure studies. Statistical power evaluates how 

261 accurately a study can measure the effect being studied. For example, a toxicity study typically 

262 evaluates whether a chemical causes an effect by comparing the responses of the treated and 

263 untreated groups. In some instances, treated and untreated groups will not show different 

264 (statistically significant) responses, even though the chemical actually does cause the effect. 

265 The statistical “power” of a toxicological study can be thought of as the ability of the study to 

266 detect a difference between treated and untreated groups given that a difference of a defined 

267 magnitude does exist. Statistical power can be an important concept in evaluating the design of 

268 toxicity studies since it helps in ascertaining the degree to which the study will be able to find a 

269 significant difference between treated and untreated groups, when a difference of defined 

270 magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical 

271 power of the study is an irrelevant consideration if the study found a statistically significant 

272 relationship between exposure and an effect. Conversely, when a completed toxicity study finds 

273 no such relationship, evaluating the statistical power of the study design becomes relevant 

274 because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of 

275 the result. As to exposure studies, statistical power could have applicability to an exposure study 

276 design if, for example, that study attempted to evaluate the relationship between dermal or 

277 inhalation exposure and an exposure variable. The statistical power of such an exposure study 
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278 would also be a consideration if that study was interpreted as showing that there is no 

279 relationship between the tested variables. 

280 EPA has required various statistical analyses of exposure studies under the 2006 rule 

281 other than statistical power analyses. For example, EPA has relied upon standard regression 

282 analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the 

283 merit of worker exposure studies. EPA expects that those or similar analyses will, in all 

284 probability, suffice going forward under the requirement in the revised rule that researchers have 

285 a general obligation to ensure that their research is “designed and conducted in accordance with 

286 appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 

287 26.1703(a) (EPA must determine that “data were derived in a manner that makes them 

288 scientifically valid and reliable”). Therefore, EPA does not believe that the revised rule will 

289 impose any additional burden on sponsors of exposure studies with regard to statistical analyses 

290 generally.

291 Finally, even if either or both of these criteria turn out to be inapplicable to some studies 

292 covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, 

293 or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in 

294 reviewing a study, EPA or the HSRB determines that either or both of the criteria are not 

295 applicable to that particular study, a notation by EPA or the HSRB of the reason for such 

296 determination would constitute appropriate consideration of the criteria in accordance with the 

297 rule. Similarly, for a person submitting a study design or a completed study to EPA and the 

298 HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted 

299 may satisfy the rule’s requirements.

300 B. Comments outside of the scope of the proposed rulemaking
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301 The remainder of the public comments addressed issues beyond the scope of the 

302 proposed rulemaking. These comments included arguments that the burden of the requirements 

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

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

305 intentional exposure of a human subject” from the 2006 Appropriations act was incorrect. 

306 Because these comments were directed at a prior rulemaking and EPA has not reopened these 

307 issues for reconsideration in this rulemaking, they are beyond the scope of this rulemaking and 

308 no response to them is appropriate at this time. EPA’s Response to Comments document, 

309 available in the docket for this action, explains in more detail why these comments are outside 

310 the scope of the current rulemaking. 

311 V. Final Rule

312 As noted above, EPA received relatively few comments on the proposed rule, and most 

313 of the comments received did not even address the amendments in the proposal. For the reasons 

314 noted above, the comments that did address the proposal do not merit any change to the 

315 amendments, as proposed. As explained in the preamble to the proposed rule, EPA proposed 

316 these amendments because they further the 2006 rule’s goal of ensuring that EPA does not rely 

317 on research involving intentional exposure of human subjects to pesticides that is not ethically 

318 conducted or that is not scientifically sound and they are consistent with the language and 

319 purposes of the 2006 Appropriations Act. Many of the amendments are codifications of the 

320 manner in which EPA and HSRB have interpreted and implemented the 2006 rule. For these 

321 reasons, EPA is finalizing the rule as proposed in 76 FR 5735, 5736-5755 (February 2, 2011). A 

322 detailed explanation of the amendments is provided in the preamble of the proposed rule.

323 VI. Statutory and Executive Order Reviews
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324 A. Executive Order 12866: Regulatory Planning and Review and Executive Order 13563: 

325 Improving Regulation and Regulatory Review

326

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

328 “significant regulatory action,” because OMB determined that it would raise novel legal or 

329 policy issues arising out of legal mandates, the President’s priorities, or the principles set forth in 

330 the Executive Order. Accordingly, EPA submitted this action to the Office of Management and 

331 Budget (OMB) for review under Executive Orders 12866 and 13563 (76 FR 3821, January 21, 

332 2011). Any changes made in response to OMB recommendations have been documented in the 

333 docket for this rulemaking as required by the Executive Order.

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

335 be negligible. EPA has not, therefore, prepared a new economic analysis for this rulemaking. 

336 Because no research has been identified that is outside the scope of the 2006 rule but that would 

337 be within the scope of these amendments, EPA has no basis on which to revise the cost estimates 

338 that were provided in the economic analysis for the 2006 rulemaking or those most recently 

339 provided in the 2008 renewal of the Information Collection Request (ICR) for the existing 

340 regulation at 40 CFR part 26. The recent estimates included in the ICR are summarized in Unit 

341 VI.B and a copy of the ICR is available in the docket. 

342 B. Paperwork Reduction Act

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

344 additional review or approval by OMB. However, the Office of Management and Budget 

345 (OMB) has previously approved the information collection requirements contained in the 

346 existing regulations at 40 CFR part 26 under the provisions of the Paperwork Reduction Act

347 (PRA), 44 U.S.C. 3501 et. seq. and has assigned OMB Control No. 2070-0169 (EPA ICR No. 

348 2195). The OMB control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9. 
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349 In its 2008 analysis supporting the most recent renewal of this ICR, EPA estimated that 

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

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

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

353 $45,927 per study, for a total estimated annual burden for affected entities of 20,332 hours at an 

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

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

356 240 hours/$17,580 per year. The total estimate of the annual respondent burden and cost was the 

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

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

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

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

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

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

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

364 44 hours/$3,158 per study, or 880 hours/$63,160 per year. The total estimate of the annual 

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

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

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

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

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

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

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

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

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

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

376 C. Regulatory Flexibility Act 

377 The Regulatory Flexibility Act generally requires an Agency to prepare a regulatory 

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

379 Administrative Procedure Act or any other statute unless the agency certifies that the rule will 

380 not have a significant economic impact on a substantial number of small entities. Small entities 

381 include small businesses, small organizations and small governmental jurisdictions.

382 For purposes of assessing the impacts of today’s rule on small entities, small entity is 

383 defined as: (1) a small business as defined by the Small Business Administration’s (SBA) 

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

385 on the sales for small businesses in each industry sector, as defined by a 6-digit NAICS code, 

386 and for this rule is pesticide and other agricultural chemical manufacturers (NAICS code 

387 325320) who sponsor or conduct human research with pesticides, or other entities (NAICS code 

388 541710) that sponsor or conduct human research with pesticides, and Institutional Review 

389 Boards who review human research with pesticides to ensure it meets applicable standards of 

390 ethical conduct; (2) a small governmental jurisdiction that is a government of a city, county, 

391 town, school district or special district with a population of less than 50,000; or (3) a small 

392 organization that is any not-for-profit enterprise which is independently owned and operated and 

393 is not dominant in its field. 

394 After considering the economic impacts of this final rule on small entities, I certify that 
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395 this action will not have a significant adverse economic impact on a substantial number of small 

396 entities. Because no small entities have been identified that are directly regulated by these 

397 amendments, EPA has not attempted to reduce the impact of this final rule on small entities. 

398 Public comments were explicitly invited on all aspects of the proposal and its impacts on small 

399 entities, but no such comments were received.

400 D. Unfunded Mandates Reform Act

401 This rule does not contain a Federal mandate that may result in expenditures of $100 

402 million or more for State, local, and tribal governments, in the aggregate, or the private sector in 

403 any 1 year. Thus, this rule is not subject to the requirements of sections 202 or 205 of UMRA.

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

405 contains no regulatory requirements that might significantly or uniquely affect small 

406 governments. These amendments are unlikely to affect State, local, and tribal governments at 

407 all, and are likely to affect the private sector only trivially. 

408 E. Executive Order 13132 (Federalism)

409 This action does not have federalism implications. It will not have substantial direct 

410 effects on the States, on the relationship between the national government and the States, or on 

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

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

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

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

415 reliance on such research. Thus, Executive Order 13132 does not apply to this action.

416 In the spirit of Executive Order 13132, and consistent with EPA policy to promote 

417 communications between EPA and State and local governments, EPA specifically requested
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418 comments on the proposed action from State and local officials. EPA did not receive any such 

419 comments. 

420 F. Executive Order 13175 

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

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

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

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

425 Order 13175 does not apply to this action. 

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

427 Risks

428 EPA interprets EO 13045 (62 FR 19885, April 23, 1997), as applying only to those 

429 regulatory actions that concern health or safety risks, such that the analysis required under

430 section 5-501 of the Order has the potential to influence the regulation. This action is not subject 

431 to EO 13045, because it does not establish an environmental standard intended to mitigate health 

432 or safety risks, nor is it an “economically significant regulatory action” as defined in Executive 

433 Order 12866. The 2006 rule applies to the conduct and review of research involving intentional 

434 exposure of human subjects, and prohibits the conduct of or EPA reliance on any such research 

435 involving subjects who are children, or pregnant or nursing women. These provisions would not 

436 be affected by the amendments.

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

438 Supply, Distribution, or Use

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

440 (66 FR 28355, May 22, 2001), because it is not likely to have a significant adverse effect on the 
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441 supply, distribution, or use of energy.

442 I. National Technology Transfer and Advancement Act

443 Section 12(d) of the National Technology Transfer and Advancement Act of 1995 

444 (“NTAA”), Public Law No. 104-113, 12(d) (15 U.S.C. 272 note) directs EPA to use voluntary 

445 consensus standards in its regulatory activities unless to do so would be inconsistent with 

446 applicable law or otherwise impractical. Voluntary consensus standards are technical standards 

447 (e.g., materials specifications, test methods, sampling procedures, and business practices) that are 

448 developed or adopted by voluntary consensus standards bodies. NTTAA directs EPA to provide 

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

450 applicable voluntary consensus standards. This action does not involve any technical standards. 

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

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

453 Populations and Low-Income Populations

454 Executive Order (EO) 12898 (59 FR 7629, February 16, 1994) establishes federal 

455 executive policy on environmental justice. Its main provision directs federal agencies, to the 

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

457 mission by identifying and addressing, as appropriate, disproportionately high and adverse 

458 human health or environmental effects of their programs, policies, and activities on minority 

459 populations and low-income populations in the United States.

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

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

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

463 not entail special considerations of environmental justice related issues. The strengthened 
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464 protections for human subjects participating in covered research established in the 2006 rule will

465 not be altered by these amendments. 

466 VI. Congressional Review Act

467

468 The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the Small Business 

469 Regulatory Fairness Act of 1996, generally provides that before a rule may take effect, the 

470 agency promulgating the rule must submit a rule report, which includes a copy of the rule, to 

471 each House of the Congress and the Comptroller General of the United States. EPA will submit 

472 a report containing this rule and other required information to the U.S. Senate, the U.S. House of 

473 Representatives, and the Comptroller General of the United States prior to publication of the rule 

474 in the Federal Register. A Major rule cannot take effect until 60 days after it is published in the 

475 Federal Register. This action is a not “major rule” as defined by 5 U.S.C. 804(2). 

476 List of Subjects in 40 CFR Part 26

477 Environmental protection, Administrative practice and procedures, Human research, 

478 Pesticides and pests.

479

480

481 Dated: _________________

482

483

484

485

486 ____________________________________

487 Administrator.

488

489

490

491
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492 Therefore, 40 CFR chapter I will be amended as follows:

493

494 PART 26—[AMENDED]

495

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

497 Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21 U.S.C. 346a(e)(1)(C); 

498 sec. 201, Pub. L. 109–54, 119 Stat. 531; and 42 U.S.C. 300v–1(b).

499 2. Amend § 26.1101 as follows:

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

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

502 c. Add new paragraphs (a), (b), and (d) to read as follows.

503 § 26.1101 To what does this subpart apply?

504 (a) Except as provided in paragraph (c) of this section, this subpart applies to all research 

505 initiated after [effective date of final rule] involving intentional exposure of a human subject to:

506 (1) Any substance if, at any time prior to initiating such research, any person who 

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

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

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

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

511 research for later inspection by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 of 

512 FFDCA (21 U.S.C. 346a); or

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

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

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

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

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

519 section.

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

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

522 existence of intent if:

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

524 results of such research to EPA; or

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

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

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

528 products, or activities.

529 * * * * *

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

531 by this subpart.

532 * * * * *

533 3. In § 26.1102, revise paragraphs (a) and (c) to read as follows:

534 § 26.1102 Definitions.

535 (a) Administrator means the Administrator of the Environmental Protection Agency 

536 (EPA) and any other officer or employee of EPA to whom authority has been delegated.

537 * * * * *

538 (c) Pesticide means any substance or mixture of substances meeting the definition in 7 

539 U.S.C. 136(u) [Federal Insecticide, Fungicide, and Rodenticide Act, section 2(u)]. 

540 § 26.1111 [AMENDED]
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541 4. In § 26.1111 remove from paragraph (a)(4) the phrase “or the subject’s legally 

542 authorized representative”. 

543 5. In § 26.1116 revise the introductory text of the section to read as follows: 

544 § 26.1116 General requirements for informed consent.

545

546 No investigator may involve a human being as a subject in research covered by this 

547 subpart unless the investigator has obtained the legally effective informed consent of the subject. 

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

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

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

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

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

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

554 institution or its agents from liability for negligence.

555 6. Revise § 26.1117 to read as follows:

556 § 26.1117 Documentation of informed consent.

557 (a) Informed consent must be documented by the use of a written consent form approved 

558 by the IRB and signed by the subject. A copy shall be given to the subject.

559 (b) The consent form may be either of the following:

560 (1) A written consent document that embodies the elements of informed consent required 

561 by § 26.1116. This form may be read to the subject, but in any event, the investigator must give 

562 the subject adequate opportunity to read it before it is signed; or

563 (2) A short form written consent document stating that the elements of informed consent 

564 required by § 26.1116 have been presented orally to the subject. When this method is used, there 

565 must be a witness to the oral presentation. Also, the IRB shall approve a written summary of 
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566 what is to be said to the subject. Only the short form itself is to be signed by the subject. 

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

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

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

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

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

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

573 8. Revise § 26.1201 to read as follows:

574 § 26.1201 To what does this subpart apply?

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

576

577 9. Revise § 26.1301 to read as follows:

578 § 26.1301 To what does this subpart apply?

579 This subpart applies to any person who submits to EPA after [effective date of final rule] 

580 either of the following:

581 (a) A report containing the results of any human research for consideration in connection 

582 with an action that may be performed by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 

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

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

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

586 statute administered by EPA.

587 § 26.1302 [AMENDED]

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

589 § 26.1502 [AMENDED]

590 11. Amend § 26.1502 as follows:
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591 a. In the first sentence of paragraph (a) remove the period after the phrase “during an 

592 inspection” and add in its place a comma; and

593 b. In the second sentence of paragraph (a) remove the phrase “The Agency” and add in 

594 its place “EPA.”

595 c. In the last sentence of the introductory text of paragraph (b) remove the phrase “The 

596 Agency” and add in its place “EPA.”

597 § 26.1505 [AMENDED]

598 12. In § 26.1505 remove from the last sentence, the phrase “§ 26.1502(c)” and add in its 

599 place “§ 26.1502(b)(4).”

600 § 26.1507 [AMENDED]

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

602 place “EPA”.

603 § 26.1601-26.1603 [REDESIGNATED]

604 14. Amend subpart P of this part by redesignating §§ 26.1601 through 26.1603 as §§ 

605 26.1603 through 26.1605.

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

607 §26.1601 To what does this subpart apply?

608 This subpart applies to both of the following:

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

610 new research subject to 40 CFR 26.1125.

611 (b) Reviews by EPA after [effective date of the final rule] and, to the extent required by 

612 § 26.1604, by the Human Studies Review Board of reports of completed research subject to 40 

613 CFR 26.1701.
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614 § 26.1602 Definitions.

615 The definitions in § 26.1102 apply to this subpart as well.

616 16. Amend newly redesignated § 26.1603 as follows:

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

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

619 c. Add new paragraphs (a), (b), (c), (d), and (h) to read as follows.

620 § 26.1603 EPA review of proposed human research.

621 (a) EPA must review all proposals for new human research submitted under § 26.1125 in 

622 a timely manner.

623 (b) In reviewing proposals for new human research submitted under § 26.1125, the EPA 

624 Administrator must consider and make determinations regarding the proposed research, 

625 including:

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

627 scientific or policy question that cannot be resolved on the basis of animal data or human 

628 observational research.

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

630 standards and practices to:

631 (i) Address the research question.

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

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

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

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

636 guidelines and monitoring for the safety of subjects.

637 (c) In reviewing proposals for new research submitted under § 26.1125, the EPA 
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638 Administrator must consider and make determinations regarding ethical aspects of the proposed 

639 research, including:

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

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

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

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

644 identifies likely benefits of the research and their distribution.

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

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

647 in a pesticide risk assessment, the Administrator must consider Recommendation 4-1 in the 2004 

648 Report from the National Research Council of the National Academy of Sciences (NAS), entitled 

649 “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues.”

650 (4) Whether subject selection will be equitable.

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

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

653 proposed research.

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

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

656 measures taken to protect such human subjects are adequate.

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

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

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

660 subjects are adequate.
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661 (9) Whether any proposed payments to subjects are consistent with the principles of 

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

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

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

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

666 (d) With respect to any research or any class of research, the EPA Administrator may 

667 recommend additional conditions which, in the judgment of the EPA Administrator, are 

668 necessary for the protection of human subjects.

669 * * * * *

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

671 Studies Review Board reviews.

672 17. Amend newly redesignated § 26.1604 by revising paragraph (a) to read as follows:

673 § 26.1604 EPA review of completed human research.

674 (a) When considering, under any regulatory statute it administers, data from completed 

675 research involving intentional exposure of humans to a pesticide, EPA must thoroughly review 

676 the material submitted under § 26.1303, if any, and other available, relevant information and 

677 document its conclusions regarding the scientific and ethical conduct of the research.

678 *****

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

680 § 26.1606 Human Studies Review Board review of proposed human research.

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

682 Review Board must consider the scientific merits and ethical aspects of the proposed research, 

683 including all elements listed in § 26.1603(b) and (c) and any additional conditions recommended 
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684 pursuant to § 26.1603(d).

685 § 26.1607 Human Studies Review Board review of completed human research.

686 In commenting on reports of completed research submitted to it by EPA, the Human 

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

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

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

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

691 in EPA Actions

692 20. Revise §§ 26.1701-26.1705 to read as follows:

693 § 26.1701 To what does this subpart apply?

694 (a) For decisions under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C. 

695 346a), this subpart applies to research involving intentional exposure of human subjects to any 

696 substance.

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

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

699 intentional exposure of human subjects to a pesticide.

700 § 26.1702 Definitions.

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

702 § 26.1703 Prohibitions applying to all research subject to this subpart.

703 (a) Prohibition of reliance on scientifically invalid research. EPA must not rely on data 

704 from research subject to this subpart unless EPA determines that the data are relevant to a 

705 scientific or policy question important for EPA decision-making, that the data were derived in a 

706 manner that makes them scientifically valid and reliable, and that it is appropriate to use the data 
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707 for the purpose proposed by EPA. In making such determinations, EPA must consider:

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

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

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

711 endpoint or endpoints in question.

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

713 draw from the data.

714 (4) In a study that reports only a No Observed Effect Level (NOEL) or a No Observed 

715 Adverse Effect Level (NOAEL), whether a dose level in the study gave rise to a biological 

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

717 interest.

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

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

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

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

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

723 § 26.1704 Prohibition of reliance on unethical human research with non-pregnant, non724 nursing adults which is not subject to § 26.1705.

725 (a) This section applies to research subject to this subpart that is not subject to § 26.1705.

726 (b) Except as provided in § 26.1706, EPA must not rely on data from any research subject 

727 to this section if there is clear and convincing evidence that:

728 (1) The conduct of the research was fundamentally unethical (e.g., the research was 

729 intended to seriously harm participants or failed to obtain informed consent); or 
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730 (2) The conduct of the research was deficient relative to the ethical standards prevailing 

731 at the time the research was conducted in a way that placed participants at increased risk of harm 

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

733 consent. 

734 (c) This prohibition is in addition to the prohibitions in § 26.1703.

735 § 26.1705 Prohibition of reliance on unethical human research with non-pregnant, non736 nursing adults initiated after April 7, 2006, and subject to subparts A through L of this 

737 part or codification of the Common Rule by another Federal department or agency.

738 (a) This section applies to research subject to this subpart, that:

739 (1) Was initiated after April 7, 2006. 

740 (2) Was subject, at the time it was conducted, either to subparts A through L of this part 

741 or to another codification of the Federal Policy for the Protection of Human Subjects, generally 

742 referred to as the “Common Rule.”

743 (b) Except as provided in § 26.1706, EPA must not rely on data from any research subject 

744 to this section unless EPA determines that the research was conducted in substantial compliance 

745 with either:

746 (1) All applicable provisions of subparts A through L of this part or codification of the 

747 Common Rule by another Federal department or agency; or

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

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

750 Common Rule by another Federal department or agency.

751 (c) Except as provided in § 26.1706, EPA must not rely on data from any research subject 

752 to this section unless EPA determines that the research was conducted in substantial compliance 
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753 with either:

754 (1) A proposal that was found to be acceptable under § 26.1603(c), and no amendments 

755 to or deviations from that proposal placed participants at increased risk of harm (based on 

756 knowledge available at the time the study was conducted) or impaired their informed consent. If 

757 EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted 

758 information that would have altered the outcome of EPA’s evaluation of the proposal under § 

759 26.1603(c), EPA must not rely on that data.

760 (2) A proposal that would have been found to be acceptable under § 26.1603(c), if it had 

761 been subject to review under that section, and no amendments to or deviations from that proposal 

762 placed participants at increased risk of harm (based on knowledge available at the time the study 

763 was conducted) or impaired their informed consent.

764 (d) This prohibition is in addition to the prohibitions in § 26.1703.

765 21. In paragraph (d) of § 26.1706, remove the phrase “publishes” and add in its place 

766 “has published.” 

767 [FR Doc. ??–????? Filed ??–??–??; 8:45 am]
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EO 12866_HumanSubjectsRevisions_RIN 2070-AJ76_FRM_RtC_2011-09-15.docx

EPA Response to Public Comments

Action: Proposed Rule; Revisions to EPA’s Rule on Protections for Subjects in Human 

Research Involving Pesticides

(Tier 3; SAN 5448; RIN 2070-AJ76)

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 EPA’s Rule on Protections for Subjects in Human Research 

Involving Pesticides, published on February 2, 2011 (76 FR 5735). EPA is proposing amending 

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. All 

comments appear in their entirety in the public docket for this rulemaking, identified as “EPAHQ-OPP-2010-0785” and accessible at 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 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 Rulemaking

EPA has identified only two issues raised by commenters that are within the scope of the 

proposed rulemaking. 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 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.

 1 One comment from the Natural Resources Defense Council included 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 NRDC resubmitted them because they wanted all of the documents located in a single 

docket. 
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Document # 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. “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’s authority for this proposed revision to the rule can be found in the 

2006 Appropriations Act and in FIFRA. Section 201 of the 2006 Appropriations Act 

gives EPA the authority to issue a rule covering research involving the intentional dosing 

toxicity studies for pesticides. The 2006 Appropriations Act does not expressly limit 

EPA’s authority to studies conducted with pesticides that are intended to be submitted 

under only FIFRA and the FFDCA. FIFRA provides additional authority to issue rules 

covering the use of both unregistered and registered pesticides, regardless of whether that 

research is conducted for submission under FIFRA. Section 3(a) of FIFRA permits EPA 

to regulate the distribution, sale, or use of any unregistered pesticide in any State “[t]o the 

extent necessary to prevent unreasonable adverse effects on the environment”. Section 

25(a) authorizes EPA to “prescribe regulations to carry out the provisions of [FIFRA].” 

EPA has determined that this rule ensures that registered and unregistered pesticides are 

not used in a manner that would cause unreasonable adverse effects on the environment, 

including humans. 

Document # 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: Notwithstanding the authority provided in the 2006 Appropriations Act and 

in FIFRA, EPA does not believe that the 2006 Appropriations Act compels the broad ban 

advocated by NRDC. The human studies that Congress was primarily concerned about 

during the debates leading up to the passage of the 2006 Appropriations Act were those 

that involved intentional testing of pesticides on human subjects and EPA’s consideration 

or reliance on those studies. EPA was prohibited from relying on any human studies until 

it issued a rule in accordance with the requirements of the 2006 Appropriations Act. This 

context implies that a reasonable interpretation of what Congress was requiring EPA to 

do was to issue a rule covering human studies involving exposure to pesticides when 

those studies were submitted to EPA. Nothing in the legislative history indicates that 

Congress intended EPA’s rule to apply to studies that were outside of EPA’s purview. 

As mentioned above, EPA has 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 
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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.

Document # EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure 

Task Force [AHETF])

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

Document # 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 (iiii) 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 caseby-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 
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the types of 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 discussed in the preamble to the proposed rule, this language is a 

combination of recommendations 3-1(b) and 5-1(c) from 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, NAS Report). EPA disagrees 

with the assertion that the criteria on representative populations and statistical power are 

not applicable to exposure studies. Although the NAS recommendations on which these 

criteria are based were drafted with an eye toward toxicological testing, the scientific 

concepts embodied have broad applicability to scientific testing. Further, the language 

used by EPA in this rule is generic in nature and not limited to toxicological testing. 

Terms such as “effect” or “endpoint,” when used without a modifier, can refer to any 

result to be examined in a scientific study. Thus, EPA believes the criteria are potentially 

applicable to all types of intentional exposure human studies covered by this rule. 

Nonetheless, EPA does not believe that adoption of these criteria will impose additional 

burdens on sponsors of the type of exposure studies referenced by the commenters. 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. Thus, EPA does not anticipate any effect 

from adding these NAS recommendations to the 2006 rule on the Agency’s consideration 

of ongoing or future worker occupational exposure studies, except that EPA’s 

consideration of these issues will be even more transparent. As EPA repeatedly noted in 

the preamble to the proposed rule, the proposed amendments essentially codify the scope 

and approach used under the 2006 rule in EPA’s science and ethics reviews of human 

research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this 

comment response, EPA further clarifies the applicability of the criteria at issue to 

exposure studies.

The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is 

relevant to any scientific endeavor in which less than the full population is examined or 

tested and for which valid extrapolation to a larger population is desired. EPA does not 

agree that the language could be construed as not applying to exposure studies, given that 

the representativeness of the sample is a relevant consideration in evaluating, for 

proposed and completed research, whether the observed effects of the completed study 

would predict the responses of a larger population. 
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In evaluating what is a representative population for a study, the NAS emphasized that 

EPA should focus on the “objectives of the study” (NAS Report, p. 77). For a study 

intended to measure worker exposure, representation of the general workforce would be 

evaluated with respect to, among other characteristics, types of equipment used, the 

monitored subjects’ work experience, and work situations that could be defined by 

factors such as geographic location or crop. The exposure studies to date have been 

representative of the workforce studied in this manner. As discussed below, EPA 

considers explicit adoption of the representative population criterion as a codification of 

existing practice and does not believe that adoption of this criterion will impose any 

additional burden on sponsors of exposure studies.

The commenters appear to be concerned that the representative population consideration 

will require that a study use a fully statistically random sample imposing additional 

burdens on sponsors of exposure studies. EPA disagrees. The rule language does not 

mandate a particular method for demonstrating representativeness; rather, the rule only 

requires that EPA, in determining the scientific validity and reliability of proposed and 

completed studies, “consider” representativeness. Moreover, as noted above, the NAS 

Report stressed that representativeness was 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 and is consistent with the 

representative population consideration requirement. The Agency recognizes that 

random sampling, in many cases, may be considered to be the “gold-standard” for 

demonstrating representativeness in a statistical sense. Nonetheless, for the reasons 

stated above, the use of alternate sampling strategies can, under certain circumstances, 

produce a sample which is sufficiently representative given the study objectives. 

The statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a 

relevant concept for both toxicology and exposure studies. Statistical power evaluates 

how accurately a study 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 treated and untreated groups. In some instances, treated and untreated 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 treated and untreated 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 
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between treated and untreated 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 researchers have a general obligation to ensure that their research is 

“designed and conducted in accordance with appropriate scientific standards and 

practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 26.1703(a) (EPA must determine 

that “data were derived in a manner that makes them scientifically valid and reliable”). 

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.

Finally, even if either or both of these criteria turn out to be inapplicable to some studies 

covered by the rule, that fact should not result in a significant burden for either EPA, the 

HSRB, or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 

26.1703, if in reviewing a study, EPA or the HSRB determines that either or both of the 

criteria are not applicable to that particular study, a notation by EPA or the HSRB of the 

reason for such determination would constitute appropriate consideration of the criteria in 

accordance with the rule. Similarly, for a person submitting a study design or a 

completed study to EPA and the HSRB for review, an explanation of why certain criteria 

are inapplicable to the study submitted may satisfy the rule’s requirements.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking

Document # EPA-HQ-OPP-2010-0785-07 (Commenter: Anonymous)

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

trans-generational epigenetic effects that have not been studied yet. Families of applicators 

may be at highest risk for these kinds of effects. It is hard to imagine a 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.”
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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 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 # 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 # 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”
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Response: EPA’s mission is to protect human health and the environment. 

Document # 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 rules 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 # EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure 

Task Force [AHETF])

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

Document # EPA-HQ-OPP-2010-0785-13 (Commenter: American Chemistry 

Council/Antimicrobial Exposure Assessment Task Force II [AEATF])

Document # 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 
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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 by this definition. Accordingly, 

no response to this comment is warranted. The proposed changes to the 2006 rule do 

not reopen the question of the applicability of the rule to worker exposure studies and 

the commenters cannot reopen consideration of that previously-promulgated provision 

by filing comments on the issue in a rulemaking that does not address the issue.

Document # EPA-HQ-OPP-2010-0785-11 (Commenter: Richard Collier, Agricultural 

Handler Exposure Task Force)

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)
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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, databased 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 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.

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
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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 # EPA-HQ-OPP-2010-0785-12 (Commenter: Wendelyn Jones, Crop Life 

America)

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 exposure studies should not be covered by the Human 

Research Rule, please see the response to Comment 6, pp. 7-8 of 14. 

Document # EPA-HQ-OPP-2010-0785-13 (Commenter: Has Shah, American Chemistry 

Council, for the Antimicrobial Exposure Assessment Task Force II)

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)). But there will not be any changes

in the meaning or application of this provision. As a result, this comment is not 
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responsive to the current rulemaking. In simply re-ordering the text of the rule with 

regard to this language, EPA did reconsider the need for this language or invite 

reconsideration by commenters. 

Document # EPA-HQ-OPP-2010-0785-14 (Commenter: Charles Boyd, SC Johnson & Co.)

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 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 
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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 thirdparty 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 under 

Executive Order 13563. The revisions to EPA’s 2006 rule proposed in this action are not 

part of that effort. 

Document # 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) 

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 
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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 reworded 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.” EPA has 

explicitly added these factors in the proposed rule to ensure that they are considered in 

evaluating the appropriateness of payments to study subjects. 

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 # EPA-HQ-OPP-2010-0785-16 (Commenter: Jennifer Sass, Natural Resources 

Defense Council (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 decisions. 
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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: The Agency is pleased that NRDC supports this proposed change. 
Attachment #B – Review Period: 11/07/11 – 06/08/12

(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
11P-1492

EO 12866_HumanSubjectsRevisions_RIN 2070-AJ76_FRM_2011-09-15.docx

BILLING CODE 6560–50–P

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 26

[EPA–HQ–OPP–2010–0785; FRL–XXXX–X9325-5]

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. They 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 EPArequire 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 EPA’s codification of the Common Rule.supported by EPA and many 

other Federal departments and agencies, 

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

Register].

ADDRESSES: EPA has established a The docket for this action is available at 

http://www.regulations.gov under docket identification (ID) number EPA–HQ–OPP–2010–0785. 

All documents in the docket are listed in the docket index available at . Although listed in the 

index, some information is not publicly available, e.g., CBI or other information whose 

disclosure is restricted by statute. Certain other material, such as copyrighted material, is not 

placed on the Internet and will be publicly available only in hard copy form. Publicly available 

docket materials are available either in the electronic docket at ,, or, if only available in hard 

copy, at the OPP Regulatory Public Docket in Rm. S–4400, One Potomac Yard (South Bldg.), 

2777 S. Crystal Dr., Arlington, VA. The the EPA Docket Center (EPA/DC), located in EPA 

West, Room 3334, 1301 Constitution Ave. NW., Washington, DC 20460. The EPA/DC hours of 

operation of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through Friday, excluding 

legal holidays. The Docket Facility telephone number of the EPA/DC Public Reading Room is 

(202) 566-1744, and for the OPP Docket it is (703) 305-5805. For more information about the 

docket and instructions about visiting the EPA/DC, go to 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; e-mail address: sherman.kelly@epa.gov.

SUPPLEMENTARY INFORMATION:

I. Does this Action Apply to Me?Executive Summary

A. Does this Action Apply to Me?

You may be potentially affected by this action if you conduct human research on 

substances regulated by EPA. Potentially affected entities may include, but are not limited to,
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entities that conduct or sponsor research involvingthat may be submitted to EPA and which 

involves intentional exposure of human subjects that may be submitted to EPA. . The following 

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

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

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

registrants, other entities could submit such information to EPA.

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

sponsor or conduct human research with pesticides.

• Other entities (NAICS code 541710) that sponsor or conduct human research with 

pesticides, and Institutional Review Boards who review human research with pesticides to ensure 

it meets applicable standards of ethical conduct.

This listing is not intended to be exhaustive, but rather provides a guide for readers 

regarding entities likely to be affected by this action. Other types of entities not listed in this unit 

could also be affected. The North American Industrial Classification System (NAICS) codes 

have been provided to assist you and others in determining whether this action might apply to 

certain entities. If you have any questions regarding the applicability of this action to a particular 

entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.

II. General Information

AB. 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 

on June 23, 2006 (71 FR 36171) (FRL-8071-6), and codified at 40 CFR part 26, in the following 

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

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

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

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

by EPA under any other regulatory statute it administers.

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

substances intended for pesticidal effect.

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

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

authorized representative.” 

• By incorporating into 40 CFR part 26, subparts P and Q, factors to be considered byan 

explicit requirement that EPA and the Human Studies Review Board (HSRB)), in their review 

of proposed and completed human research, derived frommust consider the recommendations of 

NAS in its 2004 Report to EPA,ethical aspects and fromscientific validity and reliability of 

research under the Nuremberg Coderequirements 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.

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

The Sections 3(a) and 25(a) of FIFRA 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?
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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 rulemaking. 

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

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

that were provided in the economic analysis for the 2006 rulemaking or those most recently 

provided in the 2008 renewal of the Information Collection Request (ICR) for the existing 

regulation at 40 CFR part 26. The recent estimates included in the ICR are summarized in Unit 

is set forth in detail in the preamble to the proposed rule. 76 FR 5735, 5736-5755 (February 2, 

2011) . In brief, the authority for these amendments is providedV.B. and a copy of the ICR is 

available in the docket. 

II. Background

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

Agencies Appropriations Act, 2006, Public Law 109-54 (2006 Appropriations Act), and sections 

3(a)( and 25(a) of FIFRA.

III. Background

As required by section 201 of the 2006 Appropriations Act, EPA promulgated a rule in 

2006 establishing a set of protections for people participating as subjects in third-party human 

research with pesticides. in 40 CFR part 26. (In this context “third-party” research is research 

neither conducted (“first-party”) nor supported (“second-party”) by EPA or another Common 

Rule Federal department or agency.) The 2006 rule prohibits EPA from relying on third-party 

research on pesticides involving intentional exposure of children or of pregnant or nursing 

women, unless relying on the data is crucial to a decision that would impose a more stringent 

regulatory restriction that would improve protection of public health than could be justified 
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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. 

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,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), and was inconsistent with the Nuremburg Code. 

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

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

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

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

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

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

docket for this action as described under ADDRESSES. The settlement agreement makes clear 

that EPA retained full discretion concerning what amendments were proposed, and what, if any,

amendments are finalized.

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

February 2, 2011. 

III. The Final Rule

EPA is finalizing the proposed changes to the scope and consent provisions of the 2006 

rule as proposed. EPA has decided to modify the form in which EPA articulates the requirement 

for consideration of ethical and scientific factors when reviewing proposed and completed 

human research. Specifically, instead of codifying selected individual recommendations from the 

2004 NAS Report as the specific ethical and scientific factors to be considered in reviewing 

proposed and completed human research (i.e., proposed sections 26.1603 and 26.1703), see 76 

FR 5735, 5745-5749, February 2, 2011, EPA has included broader language requiring EPA and 

the Human Studies Review Board to “consider the ethical aspects and scientific validity and 

reliability of the proposed research under the requirements of the Common Rule as codified in 40 

CFR part 26, Subpart A, except as modified in 40 CFR 26.1116 and 26.1117.” See 40 CFR 

26.1603 as promulgated in this final rule (review of proposed research). As indicated in the 

following discussion, EPA considers that the substituted language regarding the Common Rule 

either explicitly or implicitly addresses the individual 2004 NAS recommendations originally 

proposed for inclusion. As such, EPA’s revised approach maximizes consistency across the 

Federal Government with regard to requirements pertaining to the review of human studies and

allows EPA to continue to consider the individual recommendations of the 2004 NAS Report in 

its review of human research involving pesticides. This approach is consistent with existing 

Agency practice and goals of section 201 of the 2006 Appropriations Act.

EPA’s decision not to include the specific text from the 2004 NAS report in the final

revisions is driven by two factors. First, on July 26, 2011, after issuance of the proposed rule, 

the Department of Health and Human Services (HHS), in coordination with the Office of Science 
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and Technology Policy (OSTP), issued an advance notice of proposed rulemaking concerning 

modernization of the Common Rule which governs research with human subjects conducted or 

supported by EPA and many other Federal departments and agencies. (76 FR 44512, July 26, 

2011). HHS and OSTP sought comment on “how to better protect human subjects who are 

involved in research, while facilitating valuable research and reducing burden, delay, and 

ambiguity for investigators.” Id. HHS and OSTP identified seven areas of concern regarding the 

Common Rule. Most relevant to EPA’s proposed amendments to the 2006 rule, was a concern 

with “the multiple, differing regulatory requirements that can apply to a single research study . . . 

.” These requirements, according to HHS and OSTP, “have been criticized as complex, 

inconsistent, and lacking in clarity,” and can result in “unwarranted variability across institutions 

and their [Institutional Review Boards] in how the requirements are interpreted and 

implemented.” (76 FR at 45514.) HHS and OSTP stressed the importance of clarifying and 

harmonizing human subject protections across the federal government and sought comment on 

the means by which this could be accomplished. (76 FR at 44528.) EPA believes that including 

the specific NAS-derived considerations in the 2006 rule, which otherwise closely mirrors the 

Common Rule, will make the federal government’s goal of harmonization of rules governing 

human research more difficult. 

A second factor influencing EPA’s decision is that EPA did receive several comments 

noting that as to some of the NAS-derived considerations, it was unclear as to how these specific 

criteria would apply to human exposure, as opposed to human toxicity, studies. EPA believes 

these types of issues can be more appropriately addressed through a guidance document rather 

than through rule text.

Despite the decision not to include the NAS-derived factors for consideration in the final 

rule, the rule will be consistent with the recommendations in the 2004 NAS Report and EPA 
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practice under the 2006 rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA’s Common 

Rule explicitly address most of the specific ethical considerations proposed for inclusion in the 

2006 rule including whether risks to subjects are minimized (compare proposed §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 proposed §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately 

constituted IRB has reviewed the proposed research (compare proposed §26.1603(c)(6) with 

§26.109); and whether the “special problems” of research involving vulnerable populations are 

taken into account (compare proposed §26.1603(c)(7) and (8) with existing §26.111(a)(3)). 

Other proposed 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 proposed §26.1603(c)(1)). It would 

involve consideration of whether medical care is to be provided for injuries incurred in the 

proposed research (see proposed §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 proposed §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 
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proposed for inclusion 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.”

IV. Public Comments on the Notice of Proposed Rulemaking

A. Summary

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

and EPA’s responses to those comments. For additional details, please refer to the docket for 

this action (EPA–HQ–OPP–2010–0785). The docket includes all of the comments submitted to 

EPA on this action, as well as a separate document that provides EPA’s detailed responses to the 

comments.

EPA received a total of 10 public comments on the proposed rulemaking during the 60-

day comment period. Comments were submitted by four individual citizens and six 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 No. EPA–HQ–OPP–2010–0785) includes all of the comments submitted to EPA on 

the proposed rule, as well as EPA’s Response to Comments document, which provides detailed 

responses to all comments received.

B. A. Comments within on Proposal to Expand Scope to Include Research Submitted to 

EPA Under Any Regulatory Statute EPA Administers

Two comments addressed the proposed changes to the scope of the proposed 

rulemaking2006 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 
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expanded beyond studies submitted, or intended for submission, to EPA. 

EPA has identified only two issues raised by the commenters that are within the scope of 

the proposed rulemaking. The first issue relates to the proposed expansion of the scope 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. 

One commenter argued that EPA was without authority to expand the scope of the rule and 

another requested that the scope be even broader. The second issue relates to new regulatory text 

at §26.1603(b)(2)(ii and iii) and § 26.1703(a)(2 and 3) which would require EPA to consider 

whether proposed and completed research includes representative study populations for the 

endpoint in question and has adequate statistical power to detect appropriate effects. Several 

commenters addressed this issue.

1. Comments about proposed scope changes

Comment: SC Johnson & Son commented that the proposed scope expansion exceeds 

EPA’s statutory authority.

Response: EPA’s authority for this proposed revision to the rule can be found in the 

Appropriations Act and in FIFRA. Section 201 of the Appropriations Act gives EPA the 

authority to issue a rule covering research involving the intentional dosing toxicity studies for 

pesticides. The Appropriations Act does not expressly limit EPA’s authority to studies 

conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. 

FIFRA provides additional authority to issue rules covering the use of both unregistered and 

registered pesticides, regardless of whether that research is conducted for submission under 

FIFRA. Section 3(a) of FIFRA permits EPA to regulate the distribution, sale, or use of any 

unregistered pesticide in any State “[t]o the extent necessary to prevent unreasonable adverse 

effects on the environment.” Section 25(a) authorizes EPA to “prescribe regulations to carry out 
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the provisions of [FIFRA].” EPA has determined that this rule ensures that registered pesticides 

are not used in a manner that would cause unreasonable adverse effects on the environment, 

including humans. 

Comment: Natural Resources Defense Council commented that the scope should be 

further expanded, asserting that Section 201 of the 2006 Appropriations Act requires a “clear ban 

on intentional dosing toxicity stud[ies] on pregnant women or children.” Natural Resources 

Defense Council believes the “intent to submit” requirement in the scope provisions creates a 

loophole that could allow third parties to conduct intentional dosing toxicity studies with 

pregnant women or children. 

Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in 

FIFRA, EPA does not believe that the 2006 Appropriations Act compels the broad ban 

advocated by NRDC. The human studies that Congress was primarily concerned about during 

the debates leading up to the passage of the 2006 Appropriations Act were those that involved 

intentional testing of pesticides on human subjects and EPA’s consideration or reliance on those 

studies. EPA was prohibited from relying on any human studies until it issued a rule in 

accordance with the requirements of the 2006 Appropriations Act. This context implies that a 

reasonable interpretation of what Congress was requiring EPA to do was to issue a rule covering 

human studies involving exposure to pesticides when those studies were submitted to EPA. 

Nothing in the legislative history indicates that Congress intended EPA’s rule to apply to studies 

that were outside of EPA’s purview. As mentioned above, EPA has 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 
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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.

2. Comments about revised rule language on representative subjects and statistical 

analysis

Comment: The American Chemistry Council (for the Antimicrobial 

Exposure Assessment Task Force II), the Agricultural Handler Exposure Task Force, and 

CropLife America commented on the new regulatory text at §26.1603(b)(2)(ii and iii) which 

would require EPAAfter 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. FIFRA sections 3(a) and 25(a) 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 
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children or pregnant women to pesticides beyond the scope delineated in the proposed rule

because such a prohibition, if enforceable, could have the unintended effect of prohibiting 

valuable research..

B. Comments on Inclusion of NAS-Derived Considerations

Two commenters questioned whether new regulatory text proposed at §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, and the new . 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. The American Chemistry Council argues that these 

criteria are “inapposite to the types of exposure research being conducted by AEATF and 

others...” The Agricultural Handler Exposure Task Force and CropLife America claim that the 

criteria are “more appropriate for clinical studies and do not translate directly to occupational 

exposure studies...” All three commenters sought clarification on how the criteria would apply 

to exposure studies. They expressed concern that adding these criteria to the rule would impose 

additional burdens on sponsors of exposure studies. Specifically, they asked that EPA confirm 

that it does not expect any effect from the adoption of these criteria on the continued approval of 

the worker exposure studies.

Response: As discussed in the preamble to the proposed rule, this language is a 

combination of recommendations 3-1(b) and 5-1(c) from 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, NAS Report). EPA disagrees with the assertion 
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that the criteria on representative populations and statistical power are not applicable to exposure 

studies. Although the NAS recommendations on which these criteria are based were drafted 

with an eye toward toxicological testing, the scientific concepts embodied have broad 

applicability to scientific testing. Further, the language used by EPA in this rule is generic in 

nature and not limited to toxicological testing. Terms such as “effect” or “endpoint,” when used 

without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA 

believes the criteria are potentially applicable to all types of intentional exposure human studies 

covered by this rule. 

Nonetheless, EPA does not believe that adoption of these criteria will impose additional 

burdens on sponsors of the type of exposure studies referenced by the commenters. 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. 

Thus, EPA does not anticipate any effect from adding these NAS recommendations to the 2006 

rule on the Agency’s consideration of ongoing or future worker occupational exposure studies, 

except that EPA’s consideration of these issues will be even more transparent. As EPA 

repeatedly noted in the preamble to the proposed rule, the proposed amendments essentially 

codify the scope and approach used under the 2006 rule in EPA’s science and ethics reviews of 

human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this 

comment response, EPA further clarifies the applicability of the criteria at issue to exposure 

studies.

The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is 
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relevant to any scientific endeavor in which less than the full population is examined or tested 

and for which valid extrapolation to a larger population is desired. EPA does not agree that the 

language could be construed as not applying to exposure studies, given that the 

representativeness of the sample is a relevant consideration in evaluating, for proposed and 

completed research, whether the observed effects of the completed study would predict the 

responses of a larger population. 

In evaluating what is a representative population for a study, the NAS emphasized that 

EPA should focus on the “objectives of the study” (NAS Report, p. 77). For a study intended to 

measure worker exposure, representation of the general workforce would be evaluated with 

respect to, among other characteristics, types of equipment used, the monitored subjects’ work 

experience, and work situations that could be defined by factors such as geographic location or 

crop. The exposure studies to date have been representative of the workforce studied in this 

manner. As discussed below, EPA considers explicit adoption of the representative population 

criterion as a codification of existing practice and does not believe that adoption of this criterion 

will impose any additional burden on sponsors of exposure studies.

The commenters appear to be concerned that the representative population consideration 

will require that a study use a fully statistically random sample imposing additional burdens on 

sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular 

method for demonstrating representativeness; rather, the rule only requires that EPA, in 

determining the scientific validity and reliability of proposed and completed studies, “consider” 

representativeness. Moreover, as noted above, the NAS Report stressed that representativeness 

was 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 
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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 and is 

consistent with the representative population consideration requirement. The Agency recognizes 

that random sampling, in many cases, may be considered to be the “gold-standard” for 

demonstrating representativeness in a statistical sense. Nonetheless, for the reasons stated above, 

the use of alternate sampling strategies can, under certain circumstances, produce a sample 

which is sufficiently representative given the study objectives. 

The statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a 

relevant concept for both toxicology and exposure studies. Statistical power evaluates how 

accurately a study 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 treated and 

untreated groups. In some instances, treated and untreated 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 treated and untreated 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 treated and untreated groups, when a difference of defined 
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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 researchers have 

a general obligation to ensure that their research is “designed and conducted in accordance with 

appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 

26.1703(a) (EPA must determine that “data were derived in a manner that makes them 

scientifically valid and reliable”). 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.

Finally, even if either or both of these criteria turn out to be inapplicable to some studies 

covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, 

or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in 
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reviewing a study, EPA or the HSRB determines that either or both of the criteria are not 

applicable to that particular study, a notation by EPA or the HSRB of the reason for such 

determination would constitute appropriate consideration of the criteria in accordance with the 

rule. Similarly, for a person submitting a study design or a completed study to EPA and the 

HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted 

may satisfy the rule’s requirements.

B. Comments outside of the scope of the proposed rulemaking

As explained previously, EPA has decided not 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 

would have been required to consider. Although not finalizing the proposed text makes the 

comments moot, EPA notes that, 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. 

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 rulemaking. These comments included arguments that the burden of the requirements 

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

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

intentional exposure of a human subject” from the 2006 Appropriations act was incorrect. 

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 
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Appropriations Act, which addressed only “intentional dosing human toxicity studies.” The 

commenters are referring to section 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. 70 

FR 53838 at 53845 (September 12, 2005). Additional discussion in the preambles to the 

proposed and final rules further explains what studies EPA intended to be included within the 

scope of the 2006 rule. 70 FR at 53845-47; 71 FR 6138, 6146, 6149-50 (February 6, 2006). 

Because these comments were directed at a prior rulemaking and EPA has not reopened 

these issues for reconsideration in this rulemaking, they are beyond the scope of this rulemaking

and no response to them is appropriate at this time. EPA’s Response to Comments document, 

available in the docket for this action, explains in more detail why these comments are outside 

the scope of the current rulemaking, and no response to them is required to finalize this rule. 

Nonetheless, EPA appreciates the concerns expressed by the commenters with regard to the 

burdens imposed by the 2006 rule and recognizes that there may be value in considering further 

amendments to the 2006 rule in a way that reduces the burdens on investigators, e.g., by limiting 

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

V. Final Rule

As noted above, IV. Conclusion

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

comments received did not even address the amendments in the proposal. For the reasons noted 

abovepreviously, the comments that did address the proposal do not, for the most part, merit any 
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change to the amendments, as proposed. As explained in the preamble to the proposed rule, EPA 

proposed these amendments because they further Accordingly, with the exception of the 2006 

rule’s goal of ensuring that EPA does not rely on research involving intentional 

exposureinclusion of human subjects to pesticides that is not ethically conducted or that is not 

scientifically soundthe NAS-derived considerations in proposed sections 26.1603 and they are 

consistent with the language and purposes of the 2006 Appropriations Act. Many of the 

amendments are codifications of the manner in which EPA and HSRB have interpreted and 

implemented the 2006 rule. For these reasons26.1703, EPA is finalizing the rule in the same 

form as proposed in 76 FR 5735, 5736-5755 (February 2, 2011). A detailed explanation offor 

the reasons stated herein and in the preamble to the proposed rule. Given the amendments is 

providedreasons discussed in the preamble ofUnit III., EPA is not including the proposed 

rule.NAS-derived considerations and substituting more general language requiring consideration 

of ethical and scientific requirements in the Common Rule in reviewing proposed and final 

human research. This approach allows EPA to continue to review such research consistent with 

the 2004 NAS Report recommendations while not interfering with HHS’ and OSTP’s initiative 

to harmonize the federal government’s standards on human research. 

VIV. 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 OMBthe 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 the Office of Management and Budget (OMB) for review under 
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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.

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 rulemaking. 

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

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

that were provided in the economic analysis for the 2006 rulemaking or those most recently 

provided in the 2008 renewal of the Information Collection Request (ICR) for the existing 

regulation at 40 CFR part 26. The recent estimates included in the ICR are summarized in Unit 

VI.B and a copy of the ICR is available in the docket. 

B. Paperwork Reduction Act (PRA)

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

additional review or approval by OMB. However, the Office of Management and Budget 

(OMB) has previously approved the information collection requirements contained in the 

existing regulations at 40 CFR part 26 under the provisions of the Paperwork Reduction Act

(PRA),, 44 U.S.C. 3501 et. seq.., and has assigned OMB Control No. 2070-0169 (EPA ICR No. 

2195). The OMB control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9. 

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

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

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

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

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

estimated cost of $1,561,518. In addition, EPA estimated annual submission of 20 reports of 
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research requiring only documentation of ethical conduct at a cost of 12 hours/$879 per report, or 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

protocol and study submissions.

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

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

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

C. Regulatory Flexibility Act (RFA)

The Regulatory Flexibility ActRFA, 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 
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requirements under the Administrative Procedure Act 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 today’s rule on small entities, small entity is 

defined as: (1) a small business as defined by the Small Business Administration’s (SBA) 

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

on the sales for small 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 Institutional Review 

Boards who review human research with pesticides to ensure it meets applicable standards of 

ethical conduct; (2) a small governmental jurisdiction that is a government of a city, county, 

town, school district or special district with a population of less than 50,000; or (3) a small 

organization that is any not-for-profit enterprise which is independently owned and operated and 

is not dominant in its field. 

After considering the economic impacts of this final rule on small entities, I certify that 

this action will not have a significant adverse 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 
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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 sections 202 or 205 of 

UMRA. This rule is also not subject to the requirements of section 203 of UMRA, 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. It 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.

In the spirit of Executive Order 13132, and consistent with EPA policy to promote 

communications between EPA and State and local governments, EPA specifically requested

comments on the proposed action from State and local officials. EPA did not receive any such 

comments. 

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 wouldwill not have substantial direct effects on 

Indian Tribes, will not significantly or uniquely affect the communities of Indian Tribal 
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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 EOExecutive 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 Order has the potential to influence the regulation. This action is not 

subject to EOExecutive 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 the National Technology Transfer and Advancement Act of 1995 

(“NTAA”), Public Law No. 104-113, 12(d) (NTTAA, 15 U.S.C. 272 note), directs EPA to use 

voluntary consensus standards in its regulatory activities unless to do so would be inconsistent 

with applicable law or otherwise impractical. Voluntary consensus standards are technical 

standards (e.g., materials specifications, test methods, sampling procedures, and business
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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 (EO) 12898 (59 FR 7629, February 16, 1994) establishes federal 

executive policy on environmental justice. Its main provision directs federal agencies, to the 

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

mission by identifying and addressing, as appropriate, disproportionately high and adverse 

human health or environmental effects of their programs, policies, and activities on minority 

populations and low-income populations in the United States.

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

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

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

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

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

not be altered by these amendments. 

VI. Congressional Review Act

The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the Small Business 

Regulatory Fairness Act of 1996, generally provides that before a rule may take effect, the 

agency promulgating the rule must submit a rule report, which includes a copy of the rule, to 

each House of the Congress and the Comptroller General of the United States. Pursuant to the
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Congressional Review Act, 5 U.S.C. 801 et seq., 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 a not a “major rule” as defined by 5 U.S.C. 804(2). 

List of Subjects in 40 CFR Part 26

Environmental protection, Administrative practice and procedures, Human research, 

Pesticides and pests.

Dated: _________________

____________________________________

Administrator.
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Therefore, 40 CFR chapter I will be amended as follows:

PART 26—[AMENDED]

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

Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21 U.S.C. 346a(e)(1)(C); 

sec. 201, Pub. L. 109–54, 119 Stat. 531; and 42 U.S.C. 300v–1(b).

2. Amend § 26.1101 as follows:

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

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

c. Add new paragraphs (a), (b), and (d) to read as follows.

§ 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 after [effective date of final rule] involving intentional exposure of a human subject to:

(1) Any substance if, at any time prior to initiating such research, any person who 

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

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

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

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

research for later inspection by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 of 

FFDCA (21 U.S.C. 346a); or

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

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

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

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

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

section.

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

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

existence of intent if:

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

results of such research to EPA; or

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

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

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

products, or activities.

* * * * *

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

by this subpart.

* * * * *

3. In § 26.1102, revise paragraphs (a) and (c) 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)]. 

§ 26.1111 [AMENDED]

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

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. 
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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 after [effective date of final rule] 

either of the following:

(a) A report containing the results of any human research for consideration in connection 

with an action that may be performed by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 

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

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

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

statute administered by EPA.

§ 26.1302 [AMENDED]

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

§ 26.1502 [AMENDED]

11. Amend § 26.1502 as follows:

a. In the first sentence of paragraph (a) remove the period after the phrase “during an 
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inspection” and add in its place a comma; and

b. In the second sentence of paragraph (a) remove the phrase “The Agency” and add in 

its place “EPA.”

c. In the last sentence of the introductory text of paragraph (b) remove the phrase “The 

Agency” and add in its place “EPA.”

§ 26.1505 [AMENDED]

12. In § 26.1505 remove from the last sentence, the phrase “§ 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”.

§ 26.1601-26.1603 [REDESIGNATED]

14. Amend subpart P of this part by redesignating §§ 26.1601 through 26.1603 as §§ 

26.1603 through 26.1605.

15. Add new §§ 26.1601 and 26.1602 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 40 CFR 26.1125.

(b) Reviews by EPA after [effective date of the final rule] and, to the extent required by 

§ 26.1604, by the Human Studies Review Board of reports of completed research subject to 40 

CFR 26.1701.

§ 26.1602 Definitions.

The definitions in § 26.1102 apply to this subpart as well.
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16. Amend newly redesignated § 26.1603 as follows:

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

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

c. Add new paragraphs (a), (b), (c), (d), and (h) to read as follows.

§ 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 proposed research, 

including:the ethical aspects and scientific validity and reliability of the proposed research under 

the requirements of the Common Rule as codified in 40 CFR Part 26, Subpart A, except as 

modified in 40 CFR §§ 26.1116 and 26.1117. 

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

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

observational research.

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

standards and practices to:

(i) Address the research question.

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

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

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

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

guidelines and monitoring for the safety of subjects.

(c) In reviewing proposals for new research submitted under § 26.1125, the EPA 
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Administrator must consider and make determinations regarding ethical aspects of the proposed 

research, including:

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

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

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

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

identifies likely benefits of the research and their distribution.

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

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

in a pesticide risk assessment, the Administrator must consider Recommendation 4-1 in the 2004 

Report from the National Research Council of the National Academy of Sciences (NAS), entitled 

“Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues.”

(4) Whether subject selection will be equitable.

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

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

proposed research.

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

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

measures taken to protect such human subjects are adequate.

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

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

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

subjects are adequate.

(9) Whether any proposed payments to subjects are consistent with the principles of 
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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 (c) 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. Amend newly redesignated § 26.1604 by revising paragraph (a) to read as follows:

§ 26.1604 EPA review of completed human research.

(a) When considering, under any regulatory statute it administers, data from completed 

research involving intentional exposure of humans to a pesticide, EPA must thoroughly review 

the material submitted under § 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 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 listedrequired in § 26.1603(b) and (c) and any additional conditions 

recommended pursuant to § 26.1603(dc).

§ 26.1607 Human Studies Review Board review of completed human research.
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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 §§ 26.1701-26.1705 to read as follows:

§ 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 apply to this subpart as well.

§ 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 decision-making, that the data were derived in a 

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

for the purpose proposed by EPA. In making 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.
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(2) The extent to which the research subjects are representative of the populations for the 

endpoint or endpoints in question.

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

draw from the data.

(4) In a study that reports only a No Observed Effect Level (NOEL) or a No Observed 

Adverse Effect Level (NOAEL), whether a dose level in the study gave rise to a biological 

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

interest.

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

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

women, or children. Except as provided in § 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 which is not subject to § 26.1705.

(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. 
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(c) This prohibition 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, and subject to subparts A through L of this 

part or codification of the Common Rule by another Federal department or agency.

(a) This section applies to research subject to this subpart, that:

(1) Was initiated after April 7, 2006. 

(2) Was subject, at the time it was conducted, either to subparts A through L of this part 

or to another codification of the Federal Policy for the Protection of Human Subjects, generally 

referred to as the “Common Rule.”

(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 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 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 
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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) This prohibition is in addition to the prohibitions in § 26.1703.

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

“has published.” 

[FR Doc. ??–????? Filed ??–??–??; 8:45 am]##
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EO12866_HumanSubjectsRevisions_RIN2070-AJ76_FRM_RtC_2012-06-07.docxEO 

12866_HumanSubjectsRevisions_RIN 2070-AJ76_FRM_RtC_2011-09-15.docx

EO 12866 Review Draft – As revised by EPA on 6/6/2012; 6:23 pm.

EPA Response to Public Comments on the

Action: Proposed Rule; Revisions to EPA’s Rule on Protections for Subjects in 

Human Research Involving Pesticides

(Tier 3; SAN 5448; (RIN 2070-AJ76)

Comment Period: 2/2/2011 - 4/4/2011

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

I. Summary

This document addresses comments received in response to the Notice of Proposed

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

Involving Pesticides, which published on February 2, 2011 (76 FR 5735). EPA is proposing 

amendingproposed to amend 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 EPA. All comments appear in their entirety in the public docket for this 

rulemaking is accessible at http://www.regulations.gov, identified as “EPA-HQ-OPP-2010-

0785” and accessible at under Docket ID No. EPA-HQ-OPP-2010-0785.

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

 InAs listed 

in the index for Docket ID No. EPA-HQ-OPP-2010-0785docket, Documents 1, the individual 

documents identified by document identification numbers that end in -0001 through 6-0006 are 

supporting documents for the rulemaking. Documents 7-16identified by document ID Nos. that 

end in -0007 through -0016 are public comments. Documents 17-55identified by document ID 

Nos. that end in -0017 through -0055 are the 28 attachments to NRDC’ssubmitted with the

comment identified by the document ID No. that ends in -0016 (see discussion in Footnote 1, 

below). 

II. Comments on Issues within the Scope of the Proposed Rulemaking

EPA has identified only two significant issues raised by commenters that are within the 

scope of the proposed rulemaking. The first issue relates to the proposed expansion of the rule to 

 1 OneThe comment from the Natural Resources Defense Council (NRDC) included 28 attachments. Although 

these attachments wereare posted to the docket as individual comments, they are actually supportingthe

documents for NRDC’sprovided by NRDC in support of their comments on this proposed rulemaking. The 28 

documents also appear in other EPA dockets, but NRDC resubmitted them because they wanted all of the 

documents located in a single docketas part of their comments on this proposed rulemaking. 
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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 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 # 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). 

See Document No. EPA-HQ-OPP-2010-0785-0014Response: EPA’s authority for this 

proposed revision to the rule can be found in the 2006 Appropriations Act and in FIFRA. 

Section 201 of the 2006 Appropriations Act gives EPA the authority to issue a rule 

covering research involving the intentional dosing toxicity studies for pesticides. The 

2006 Appropriations Act does not expressly limit EPA’s authority to studies conducted 

with pesticides that are intended to be submitted under only FIFRA and the FFDCA. 

FIFRA provides additional authority to issue rules covering the use of both unregistered 

and registered pesticides, regardless of whether that research is conducted for submission 

under FIFRA. Section 3(a) of FIFRA permits EPA to regulate the distribution, sale, or 

use of any unregistered pesticide in any State “[t]o the extent necessary to prevent 

unreasonable adverse effects on the environment”. Section 25(a) authorizes EPA to 

“prescribe regulations to carry out the provisions of [FIFRA].” EPA has determined that 

this rule ensures that registered and unregistered pesticides are not used in a manner that 

would cause unreasonable adverse effects on the environment, including humans. 

Document # EPA-HQ-OPP-2010-0785-16 (Commenter: Natural Resources Defense 

Council [NRDC])

(Commenter: SC Johnson).

EPA 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 
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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. 

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)).

See Document No. EPA-HQ-OPP-2010-0785-0016Response: Notwithstanding the 

authority provided in the 2006 Appropriations Act and in FIFRA, EPA does not believe that 

the 2006 Appropriations Act compels the broad ban advocated by NRDC. The human studies 

that Congress was primarily concerned about during the debates leading up to the passage of 

the 2006 Appropriations Act were those that involved intentional testing of pesticides on 

human subjects and EPA’s consideration or reliance on those studies. EPA was prohibited 

from relying on any human studies until it issued a rule in accordance with the requirements 

of the 2006 Appropriations Act. This context implies that a reasonable interpretation of what 

Congress was requiring EPA to do was to issue a rule covering human studies involving 

exposure to pesticides when those studies were submitted to EPA. Nothing in the legislative 

history indicates that Congress intended EPA’s rule to apply to studies that were outside of 

EPA’s purview. (Commenter: Natural Resources Defense Council [NRDC])2.

EPA 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 

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. 

 2 See footnote 1, and use docket index to access individual attachments to this comment.
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Document # EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure 

Task Force [AHETF])

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

Document # 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 (iiii) 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.

See comments: Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Agricultural 

Handler Exposure Task Force [AHETF]); Document No. EPA-HQ-OPP-2010-0785-0012

(Commenter: CropLife America [CLA]); Document No. EPA-HQ-OPP-2010-0785-0013

(Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force 

II [AEATF]).

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 caseby-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-2010-0785-0011(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-2010-0785-0012(EPA-HQ-OPP2010-0785-12,, p 6)
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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 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-2010-0785-0013(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” (EPA-HQ-OPP-2010-0785-

0013(AEATF, EPA-HQ-OPP-2010-0785-13,, p 5).

EPA Response: As discussed in the preambleThis comment is moot to the extent it refers to the 

NAS-derived considerations included in proposed rule, thissections 26.1603 and 26.1703 

because EPA has removed that specific language is a combination of recommendations 3-1(b) 

and 5-1(c) from the 2004 Reportfinal rule. However, the comments remain relevant because 

EPA will be guided in implementing the amended 2006 rule (as it has since its initial 

promulgation) by the National Research Council of the National Academies of Science (NAS) 

titled Intentional Human Dosing Studies for EPA Regulatory Purposes (hereafter, 

recommendations of the NAS Report). EPA . Accordingly, EPA believes a detailed response to 

these comments is appropriate.

EPA disagrees with the assertion that the criteriaNAS recommendations on representative 

populations and statistical power are not applicable to exposure studies. Although the 

NAS recommendations on which these criteria are based were drafted with an eye toward 

toxicological testing, the scientific concepts embodied have broad applicability to 

scientific testing. Further, the language used by EPA in this rule is generic in nature and 

not limited to toxicological testing. Terms such as “effect” or “endpoint,” when used 

without a modifier, can refer to any result to be examined in a scientific study. Thus, 

EPA believes the criteria are potentially applicable to all types of intentional exposure 

human studies covered by this rule. 

Nonetheless, EPA does not believe that adoption of these criteria will impose additional burdens 

on sponsors of the type of exposure studies referenced by the commenters. 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. 

Thus, EPA does not anticipate any effect from adding these NAS recommendations to the 2006 

rule on the Agency’s consideration of ongoing or future worker occupational exposure studies, 

except that EPA’s consideration of these issues will be even more transparent. As EPA 

repeatedly noted in the preamble to the proposed rule, the proposed amendments essentially 

codify the scope and approach used under the 2006 rule and used in EPA’s science and ethics 

reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the 

remainder of this comment response, EPA further clarifies the applicability of the criteria at issue 

to exposure studies.
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The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is 

relevant to any scientific endeavor in which less than the full population is examined or 

tested and for which valid extrapolation to a larger population is desired. EPA does not 

agreenotes that the language could be construed as not applying to exposure studies, 

given that the representativeness of the sample is a relevant consideration in evaluating, 

for proposed and completed research, whether the observed effects of the completed study 

would predict the responses of a larger population. 

In evaluating what is a representative population for a study, the NAS emphasized that 

EPA should focus on the “objectives of the study” in determining what is a representative 

population (NAS Report, p. 77). For a study intended to measure worker exposure, 

representation of the general workforce would be evaluated with respect to, among other 

characteristics, types of equipment used, the monitored subjects’ work experience, and 

work situations that could be defined by factors such as geographic location or crop. The 

exposure studies to date have been representative of the workforce studied in this manner. 

As discussed below, EPA considers explicit adoption of the representative population 

criterion as a codification of existing practice and does not believe that adoption of this 

criterion will impose any additional burden on sponsors of exposure studies.

The commenters appear to be concerned that the representative population consideration will 

require that a study use a fully statistically random sample imposing additional burdens on 

sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular 

method for demonstrating representativeness; rather, the rule only requires that EPA, in 

determining the scientific validity and reliability of proposed and completed studies, “consider” 

representativeness. Moreover, as noted above, the NAS Report stressed that representativeness 

was 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 and is consistent with the representative population 

consideration requirement. The Agency recognizes that random sampling, in many cases, may 

be considered to be the “gold-standard” for demonstrating representativeness in a statistical 

sense. Nonetheless, for the reasons stated above, the use of alternate sampling strategies can, 

under certain circumstances, produce a sample which is sufficiently representative given the 

study objectivesThis approach meets the objectives of the study. 

TheSimilarly, statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) 

isconsiderations are also a relevant concept for both toxicology and exposure studies. Statistical 

power evaluates how accuratelythe 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 treatedexposed and untreatedunexposed groups. In some 
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instances, treatedexposed and untreatedunexposed 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 treatedexposed and untreatedunexposed 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 treatedexposed and untreatedunexposed 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 researchers have a general 

obligation to ensure that their research is “designed and conducted in accordance with 

appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 

26.1703(a) (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.

Finally, even if either or both of these criteria turn out to be inapplicable to some studies 

covered by the rule, that fact should not result in a significant burden for either EPA, the 

HSRB, or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 

26.1703, if in reviewing a study, EPA or the HSRB determines that either or both of the 

criteria are not applicable to that particular study, a notation by EPA or the HSRB of the 

reason for such determination would constitute appropriate consideration of the criteria in 

accordance with the rule. Similarly, for a person submitting a study design or a 

completed study to EPA and the HSRB for review, an explanation of why certain criteria 

are inapplicable to the study submitted may satisfy the rule’s requirements.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking

Document # EPA-HQ-OPP-2010-0785-07 (Commenter: Anonymous)

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

trans-generational epigenetic effects that have not been studied yet. Families of applicators 

may be at highest risk for these kinds of effects. It is hard to imagine a scientifically valid 
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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.”

See Document No. EPA-HQ-OPP-2010-0785-0007 (Commenter: Anonymous).

EPA 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 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.”

See Document No. EPA-HQ-OPP-2010-0785-0007 (Commenter: Anonymous).

EPA 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 # 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.” 

See Document No. EPA-HQ-OPP-2010-0785-08 (Commenter: Chris (no surname 

provided)).

EPA Response: Comments concerning research with animals are beyond the scope of these 

revisions. 

Document # 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 
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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”

See Document No. EPA-HQ-OPP-2010-0785-0009 (Commenter: A. Sow).

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

Document # 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.”

See Document No. EPA-HQ-OPP-2010-0785-0010 (Commenter: Anonymous).

EPA Response: EPA is proposing narrowly-targeted revisions to its rules 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 # EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure 

Task Force [AHETF])

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

Document # EPA-HQ-OPP-2010-0785-13 (Commenter: American Chemistry 

Council/Antimicrobial Exposure Assessment Task Force II [AEATF])

Document # 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. 
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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.

Since these major points of the following commenters are similar in content, and EPA’s 

responses to those points are discussed together:

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Agricultural Handler 

Exposure Task Force [AHETF]); Document No. EPA-HQ-OPP-2010-0785-0012

(Commenter: CropLife America [CLA]); Document No. EPA-HQ-OPP-2010-0785-0013

(Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force 

II [AEATF]); Document No. EPA-HQ-OPP-2010-0785-0014 (Commenter: SC Johnson).

EPA 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 

by this definition. Accordingly, no response to this comment is warranted. The proposed 

changes to the 2006 rule do not reopen the question of the applicability of the rule to worker 

exposure studies and the commenters cannot reopen consideration of that previously-
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promulgated provision by filing comments on the issue in a rulemaking that does not address the 

issue.

Document # EPA-HQ-OPP-2010-0785-11 (Commenter: Richard Collier, Agricultural 

Handler Exposure Task Force)

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.

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)).

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).

EPA Response: See the EPA response to Ccomment #6, pp. 7-8 of 14 in this unit. 

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)

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).

EPA 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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See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).

EPA 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) ).

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).

EPA 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.

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).

EPA 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 the EPA response to comment #6 in this unit. 

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)).

See Document No. EPA-HQ-OPP-2010-0785-0011 (Commenter: Richard Collier, 

Agricultural Handler Exposure Task Force).
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EPA 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 # EPA-HQ-OPP-2010-0785-12 (Commenter: Wendelyn Jones, Crop Life 

America)

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)).

See Document No. EPA-HQ-OPP-2010-0785-0012 (Commenter: Wendelyn Jones, Crop 

Life America).

EPA 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 EPA response to Ccomment #6, pp. 7-8 of 14 in this unit. 

Document # EPA-HQ-OPP-2010-0785-13 (Commenter: Has Shah, American Chemistry 

Council, for the Antimicrobial Exposure Assessment Task Force II)

1. 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)). But there will not be any changes

in the meaning or application of this provision. As a result, this comment is not 

responsive to the current rulemaking. In simply re-ordering the text of the rule with 
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regard to this language, EPA did reconsider the need for this language or invite 

reconsideration by commenters. 

Document # EPA-HQ-OPP-2010-0785-14 (Commenter: Charles Boyd, SC Johnson & Co.)

14. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0014 (Commenter: Charles Boyd, SC 

Johnson & Co.).

EPA 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.

15. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0014 (Commenter: Charles Boyd, SC 

Johnson & Co.).

EPA 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 the EPA response to Ccomment #6, pp. 7-8 of 14 in this 

unit. 

16. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0014 (Commenter: Charles Boyd, SC 

Johnson & Co.).
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EPA 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 thirdparty 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.” (Dockument ID No. EPA-HQ-OPP-2003-0132-0656EPA-HQ-OPP2003-0132-0656,, pp. 266-267) 

1. 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 under 

Executive Order 13563. The revisions to EPA’s 2006 rule proposed in this action are not 

part of that effort. 

Document # EPA-HQ-OPP-2010-0785- 15 (Nichelle Harriott, Beyond Pesticides)

17. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0015 (Nichelle Harriott, Beyond Pesticides).

EPA 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 
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research.” (Dockument ID No. EPA-HQ-OPP-2003-0132-0656EPA-HQ-OPP-2003-0132-0656,,

p. 143) ). 

18. 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) ).

See Document No. EPA-HQ-OPP-2010-0785-0015 (Nichelle Harriott, Beyond Pesticides).

EPA 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.” 

EPA has explicitly added these factorsAlthough this specific language is not being included in 

the final rule, EPA will be guided by the NAS recommendations in implementing the rule. 

IV. Other Comments 

1. Comment: The proposed ruleamendments also authorize the EPA Administrator to ensure 

that they"recommend additional conditions which, in the judgment of the EPA Administrator,

are considered in evaluating the appropriateness of paymentsnecessary 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).

Document No. EPA-HQ-OPP-2010-0785-0013 (Commenter: Has Shah, American Chemistry 

Council, for the Antimicrobial Exposure Assessment Task Force II).

EPA 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)). subjects.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....” 
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2. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0015 (Nichelle Harriott, Beyond Pesticides).

EPA 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. 

3. 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.

See Document # EPA-HQ-OPP-2010-0785-16No. EPA-HQ-OPP-2010-0785-0014

(Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC))Charles Boyd, 

SC Johnson & Co.).

EPA Response: EPA is continuing to carefully consider all existing regulations under 

Executive Order 13563. The revisions to EPA’s 2006 rule proposed in this action are not part of 

that effort. 

V. Comments Substantially Agreeing with the Proposed Rulemaking

1. 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) ).

See Document No. EPA-HQ-OPP-2010-0785-0016 (Commenter: Jennifer Sass, Natural 

Resources Defense Council (NRDC)).

EPA 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. 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. 
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2. 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) ).

See Document No. EPA-HQ-OPP-2010-0785-0016 (Commenter: Jennifer Sass, Natural 

Resources Defense Council (NRDC)).

EPA 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. 

3. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0016 (Commenter: Jennifer Sass, Natural 

Resources Defense Council (NRDC)).

EPA Response: The Agency is pleased that NRDC is satisfied with the proposed change. 

4. 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)).

See Document No. EPA-HQ-OPP-2010-0785-0016Response: The Agency is pleased that 

NRDC supports this proposed change. (Commenter: Jennifer Sass, Natural Resources 

Defense Council (NRDC)).

EPA Response: As discussed in comment response #1, it has been determined that there is no 

longer a legal obligation to include the NAS-derived recommendations because section 201 of 

the Appropriations Act does not continue to impose any obligations on EPA. For policy reasons, 

EPA has decided to modify the form in which EPA articulates the requirement for consideration 

of ethical and scientific factors when reviewing proposed and completed human research. 

Specifically, instead of codifying selected individual recommendations from the 2004 NAS 

Report as the specific ethical and scientific factors to be considered in reviewing proposed and 

completed human research (i.e., proposed sections 26.1603 and 26.1703), see 76 FR 5735, 5745-

5749, February 2, 2011, EPA has included broader language requiring EPA and the Human 

Studies Review Board to “consider the ethical aspects and scientific validity and reliability of the 

proposed research under the requirements of the Common Rule as codified in 40 CFR part 26, 

Subpart A, except as modified in 40 CFR 26.1116 and 26.1117.” See 40 CFR 26.1603 as 

promulgated in this final rule (review of proposed research). As indicated in the following 

discussion, EPA considers that the substituted language regarding the Common Rule either 
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explicitly or implicitly addresses the individual 2004 NAS recommendations originally proposed 

for inclusion. As such, EPA’s revised approach maximizes consistency across the Federal 

Government with regard to requirements pertaining to the review of human studies and allows 

EPA to continue to consider the individual recommendations of the 2004 NAS Report in its 

review of human research involving pesticides. This approach is consistent with existing Agency 

practice and goals of section 201 of the 2006 Appropriations Act.

EPA’s decision not to include the specific text from the 2004 NAS report in the final revisions is 

driven by two factors. First, on July 26, 2011, after issuance of the proposed rule, the 

Department of Health and Human Services (HHS), in coordination with the Office of Science 

and Technology Policy (OSTP), issued an advance notice of proposed rulemaking concerning 

modernization of the Common Rule which governs research with human subjects conducted or 

supported by EPA and many other Federal departments and agencies. (76 FR 44512, July 26, 

2011). HHS and OSTP sought comment on “how to better protect human subjects who are 

involved in research, while facilitating valuable research and reducing burden, delay, and 

ambiguity for investigators.” Id. HHS and OSTP identified seven areas of concern regarding the 

Common Rule. Most relevant to EPA’s proposed amendments to the 2006 rule, was a concern 

with “the multiple, differing regulatory requirements that can apply to a single research study . . . 

.” These requirements, according to HHS and OSTP, “have been criticized as complex, 

inconsistent, and lacking in clarity,” and can result in “unwarranted variability across institutions 

and their [Institutional Review Boards] in how the requirements are interpreted and 

implemented.” (76 FR at 45514.) HHS and OSTP stressed the importance of clarifying and 

harmonizing human subject protections across the federal government and sought comment on 

the means by which this could be accomplished. (76 FR at 44528.) EPA believes that including 

the specific NAS-derived considerations in the 2006 rule, which otherwise closely mirrors the 

Common Rule, will make the federal government’s goal of harmonization of rules governing 

human research more difficult. 

A second factor influencing EPA’s decision is that EPA did receive several comments noting 

that as to some of the NAS-derived considerations, it was unclear as to how these specific 

criteria would apply to human exposure, as opposed to human toxicity, studies. EPA believes 

these types of issues can be more appropriately addressed through a guidance document rather 

than through rule text.

Despite the decision not to include the NAS-derived factors for consideration in the final rule, 

the rule will be consistent with the recommendations in the 2004 NAS Report and EPA practice 

under the 2006 rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA’s Common Rule 

explicitly address most of the specific ethical considerations proposed for inclusion in the 2006 

rule including whether risks to subjects are minimized (compare proposed §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 proposed §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately 

constituted IRB has reviewed the proposed research (compare proposed §26.1603(c)(6) with 

§26.109); and whether the “special problems” of research involving vulnerable populations are 

taken into account (compare proposed §26.1603(c)(7) and (8) with existing §26.111(a)(3)). 

Other proposed considerations are implicitly addressed. The Common Rule’s requirement to 

“minimize risks” in section 26.111(a)(1) necessitates consideration of whether adequate animal 
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data is available to assess potential risks to subjects (see proposed §26.1603(c)(1)). It would 

involve consideration of whether medical care is to be provided for injuries incurred in the 

proposed research (see proposed §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 proposed §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 

proposed for inclusion 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.”