54402 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

§ 86.1105–87 Emission standards for 

which nonconformance penalties are 

available. 

* * * * * 

(e) The values of COC50, COC90, and 

MC50 in paragraphs (a) and (b) of this 

section are expressed in December 1984 

dollars. The values of COC50, COC90, 

and MC50 in paragraphs (c) and (d) of 

this section are expressed in December 

1989 dollars. The values of COC50, 

COC90, and MC50 in paragraph (f) of this 

section are expressed in December 1991 

dollars. The values of COC50, COC90, 

and MC50 in paragraphs (g) and (h) of 

this section are expressed in December 

1994 dollars. The values of COC50, 

COC90, and MC50 in paragraph (i) of this 

section are expressed in December 2001 

dollars. The values of COC50, COC90, 

and MC50 in paragraph (j) of this section 

are expressed in December 2011 dollars. 

These values shall be adjusted for 

inflation to dollars as of January of the 

calendar year preceding the model year 

in which the NCP is first available by 

using the change in the overall 

Consumer Price Index, and rounded to 

the nearest whole dollar in accordance 

with ASTM E29–67 (reapproved 1980), 

Standard Recommended Practice for 

Indicating Which Places of Figures Are 

To Be Considered Significant in 

Specified Limiting Values. This method 

was approved by the Director of the 

Federal Register in accordance with 5 

U.S.C. 552(a) and 1 CFR part 51. This 

document is available from ASTM 

International, 100 Barr Harbor Drive, 

P.O. Box C700, West Conshohocken, PA 

19428–2959, and is also available for 

inspection as part of Docket A–91–06, 

located at the U.S. EPA, Air and 

Radiation Docket and Information 

Center, 1301 Constitution Ave. NW., 

Room 3334, EPA West Building, 

Washington, DC 20004, (202) 202–1744 

or at the National Archives and Records 

Administration (NARA). For 

information on the availability of this 

material at NARA, call 202–741–6030, 

or go to: http://www.archives.gov/ 

federal-register/cfr/ibr-locations.html. 

This incorporation by reference was 

approved by the Director of the Federal 

Register on January 13, 1992. These 

materials are incorporated as they exist 

on the date of the approval and a notice 

of any change in these materials will be 

published in the Federal Register. 

* * * * * 

(j) Effective in the 2012 and later 

model years, NCPs will be available for 

the following emission standard: 

(1) Diesel heavy-duty engine oxides of 

nitrogen standard of 0.20 grams per 

brake horsepower-hour in § 86.007– 

11(a)(1)(i). 

(i) [Reserved]. 

(ii) For heavy heavy-duty diesel 

engines: 

(A) The following values shall be used 

to calculate an NCP in accordance with 

§ 86.1113–87(a): 

(1) COC50: $3,219. 

(2) COC90: $3,775. 

(3) MC50: $10,729 per gram per brake 

horsepower-hour NOX. 

(4) F: 1.173. 

(5) UL: 0.50 grams per brake 

horsepower-hour NOX. 

(B) The following factor shall be used 

to calculate the engineering and 

development component of the NCP for 

the standard set forth in § 86.007– 

11(a)(1)(i) in accordance with 

§ 86.1113–87(h): 0.005. 

(2) Manufacturers may not generate 

emission credits for any pollutant from 

engines for which the manufacturer 

pays an NCP for the NOX standard 

identified in paragraph (j)(1) of this 

section. 

(3) The penalty shall be adjusted 

annually as specified in § 86.1113–87 

with 2012 as the first year. Note that this 

means AAF2012 is equal to 1. 

■ 5. Section 86.1113–87 is amended by 

revising paragraph (g)(1) to read as 

follows: 

§ 86.1113–87 Calculation and payment of 

penalty. 

* * * * * 

(g)(1) Except as provided in paragraph 

(g)(2) of this section, the 

nonconformance penalty or penalties 

assessed under this subpart must be 

paid as follows: 

(i) By the quarterly due dates, i.e., 

within 30 days of the end of each 

calendar quarter (March 31, June 30, 

September 30 and December 31), or 

according to such other payment 

schedule as the Administrator may 

approve pursuant to a manufacturer’s 

request, for all nonconforming engines 

or vehicles produced by a manufacturer 

in accordance with paragraph (b) of this 

section and distributed into commerce 

for that quarter. 

(ii) The penalty shall be payable to 

U.S. Environmental Protection Agency, 

NCP Fund, Motor Vehicle and Engine 

Compliance Program, P.O. Box 

979032St. Louis, MO 63197–9000. Note 

on the check and supporting 

information that this is an NCP 

payment. 

* * * * * 

[FR Doc. 2012–21967 Filed 9–4–12; 8:45 am] 

BILLING CODE P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 180 

[EPA–HQ–OPP–2002–0302; FRL–9359–9] 

Dichlorvos (DDVP); Order Denying 

NRDC’s Objections on Remand 

AGENCY: Environmental Protection 

Agency (EPA) 

ACTION: Final Order. 

SUMMARY: In this order, EPA denies an 

objection to a prior order denying a 

petition requesting that EPA revoke all 

pesticide tolerances for dichlorvos 

under section 408(d) of the Federal 

Food, Drug, and Cosmetic Act. The 

objection was filed on February 1, 2008, 

by the Natural Resources Defense 

Council (NRDC). The original petition 

was also filed by NRDC. Previously, in 

July 2008, EPA denied this same 

objection but the United States Court of 

Appeals for the Second Circuit vacated 

that decision, in part, and remanded the 

matter to EPA. This order is being 

issued in response to the court’s 

remand. 

DATES: This order is effective September 

5, 2012. 

ADDRESSES: The docket for this action, 

identified by docket identification (ID) 

number EPA–HQ–OPP–2002–0302, is 

available either electronically through 

http://www.regulations.gov or in hard 

copy at the OPP Docket in the 

Environmental Protection Agency 

Docket Center (EPA/DC), located in EPA 

West, Rm. 3334, 1301 Constitution Ave. 

NW., Washington, DC 20460–0001. The 

Public Reading Room is open from 8:30 

a.m. to 4:30 p.m., Monday through 

Friday, excluding legal holidays. The 

telephone number for the Public 

Reading Room is (202) 566–1744, and 

the telephone number for the OPP 

Docket is (703) 305–5805. Please review 

the visitor instructions and additional 

information about the docket available 

at http://www.epa.gov/dockets. 

FOR FURTHER INFORMATION CONTACT: 

Melanie Biscoe, Pesticide Re-evaluation 

Division (7508P), Office of Pesticide 

Programs, Environmental Protection 

Agency, 1200 Pennsylvania Ave. NW., 

Washington, DC 20460–0001; telephone 

number: (703) 305–7106; email address: 

biscoe.melanie@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

In this document EPA denies an 

objection by the Natural Resources 

Defense Council (NRDC) concerning 

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Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 54403 

EPA’s denial of NRDC’s petition to 

revoke pesticide tolerances. This action 

may also be of interest to agricultural 

producers, food manufacturers, or 

pesticide manufacturers. Potentially 

affected entities may include, but are 

not limited to those engaged in the 

following activities: 

• Crop production (North American 

Industrial Classification System 

(NAICS) code 111), e.g., agricultural 

workers; greenhouse, nursery, and 

floriculture workers; farmers. 

• Animal production (NAICS code 

112), e.g., cattle ranchers and farmers, 

dairy cattle farmers, livestock farmers. 

• Food manufacturing (NAICS code 

311), e.g., agricultural workers; farmers; 

greenhouse, nursery, and floriculture 

workers; ranchers; pesticide applicators. 

• Pesticide manufacturing (NAICS 

code 32532), e.g., agricultural workers; 

commercial applicators; farmers; 

greenhouse, nursery, and floriculture 

workers; residential users. 

B. How can I get electronic access to 

other related information? 

You may access a frequently updated 

electronic version of EPA’s tolerance 

regulations at 40 CFR part 180 through 

the Government Printing Office’s e-CFR 

site at http://ecfr.gpoaccess.gov/cgi/t/ 

text/text-idx?&c=ecfr&tpl=/ecfrbrowse/ 

Title40/40tab_02.tpl. 

II. Introduction 

A. What action is the agency taking? 

In this order, EPA is issuing a revised 

denial of an objection to an earlier EPA 

order, (72 FR 68662, December 5, 2007), 

denying a petition to revoke all 

tolerances established for the pesticide 

dichlorvos (DDVP) under the Federal 

Food, Drug, and Cosmetic Act (FFDCA), 

21 U.S.C. 346a. Both the objection as 

well as the petition was filed with EPA 

by NRDC. (Refs. 1 and 2). EPA had 

previously denied this objection, (73 FR 

42683, July 23, 2008), but that order was 

vacated, in part, by the United States 

Court of Appeals for the Second Circuit. 

(NRDC v. US EPA, 658 F.3d 200 (2d Cir. 

2011)). 

NRDC’s petition, filed on June 2, 

2006, pursuant to FFDCA section 

408(d)(1), asserted numerous grounds as 

to why the dichlorvos tolerances 

allegedly fail to meet the FFDCA’s safety 

standard. This petition was filed as EPA 

was completing its reassessment of the 

safety of the dichlorvos tolerances 

pursuant to FFDCA section 408(q). (Ref. 

3). In response to the petition, EPA 

undertook an extensive review of its 

dichlorvos safety evaluation in the 

tolerance reassessment decision. Based 

on this extensive review, EPA 

concluded that dichlorvos met the 

FFDCA safety standard and, therefore, 

denied the petition. (72 FR 68695). 

NRDC then filed objections with EPA to 

the petition denial order and requested 

a hearing on its objections. The 

objections narrowed NRDC’s claims to 

two main assertions—that, in assessing 

the risk to dichlorvos, EPA unlawfully 

reduced the statutory tenfold (10X) 

additional safety factor for the 

protection of infants and children and 

EPA unlawfully relied on a human 

toxicity study (the Gledhill study). After 

carefully reviewing the objections and 

hearing requests, EPA determined that 

NRDC’s hearing requests did not satisfy 

the regulatory requirements for such 

requests and that its substantive 

objections were without merit. (73 FR 

42709–42711). NRDC sought review of 

EPA’s decision in the United States 

Court of Appeal for the Second Circuit. 

As noted, the Second Circuit court 

vacated a portion of EPA’s order finding 

that ‘‘[b]ecause EPA failed to explain 

why it did not use a 10X children’s 

safety factor for dichlorvos risk 

assessments that relied on the Gledhill 

study, EPA acted in an arbitrary and 

capricious manner.’’ (658 F.3d at 218). 

Specifically, the court vacated ‘‘those 

portions of EPA’s July 23, 2008 order 

assessing the risk of dichlorvos based on 

the Gledhill study * * * ’’ (Id.). The 

court remanded the matter to EPA. (Id. 

at 219). 

On remand, EPA has carefully 

examined the court’s opinion and has 

reconsidered that portion of its prior 

decision that relied on the Gledhill 

study in assessing dichlorvos risk. 

Because the court found this portion of 

EPA’s order to be arbitrary and 

capricious due to its absence of an 

adequate explanation on the additional 

safety factor for the protection of infants 

and children, EPA focused on a 

reexamination of what additional safety 

factor for the protection of infants and 

children should be applied for the 

assessments based on the Gledhill 

study. EPA concludes, like it did in the 

July 23, 2008 order, that a threefold (3X) 

additional safety factor will protect the 

safety of infants and children. 

Accordingly, EPA again denies NRDC’s 

objections as to those portions of the 

July 23, 2008 order that were vacated. 

Although EPA reaches the same 

conclusion on remand on the additional 

safety factor for the protection of infants 

and children, EPA has provided a 

revised, more extensive explanation for 

its position. Because this revised 

explanation addresses the court’s reason 

for finding portions of the July 23, 2008 

order to be arbitrary and capricious, 

EPA has not otherwise reopened or 

reconsidered that prior order. 

B. What is the agency’s authority for 

taking this action? 

NRDC petitioned to revoke the 

dichlorvos tolerances pursuant to the 

petition procedures in FFDCA section 

408(d)(1). (21 U.S.C. 346a(d)(1)). Under 

section 408(d), EPA may respond to 

such a petition by either issuing a final 

or proposed rule modifying or revoking 

the tolerances or issuing an order 

denying the petition. (21 U.S.C. 

346a(d)(4)). Here, EPA responded by 

issuing an order under section 

408(d)(4)(iii) denying the petition. (72 

FR 68622, December 5, 2007). 

Orders issued under section 

408(d)(4)(iii) are subject to a statutorilycreated administrative review process. 

(21 U.S.C. 346a(g)(2)). Any person may 

file objections to a section 408(d)(4)(iii) 

order with EPA and request a hearing on 

those objections. (Id.). EPA is required 

by section 408(g)(2)(C) to issue a final 

order resolving the objections to the 

section 408(d)(4)(iii) order. (21 U.S.C. 

346a(g)(2)(C)). NRDC filed objections to 

EPA’s denial of its dichlorvos petition 

and EPA issued a section 408(g)(2)(C) 

order denying NRDC’s objections. (73 

FR 42683, July 23, 2008). EPA’s order 

denying NRDC’s objections was vacated, 

in part, and remanded to EPA. This 

revised order on remand is also being 

issued under section 408(g)(2)(C). 

III. Statutory and Regulatory 

Background 

In this Unit, EPA provides 

background on the relevant statutes and 

regulations governing the matter on 

remand as well as a much-abbreviated 

discussion on pertinent Agency risk 

assessment policies. A full discussion of 

EPA’s approach to pesticide risk 

assessment is included in EPA’s prior 

order on NRDC’s objections. (73 FR 

42685–42688). Because the court’s 

decision focused on the explanation 

offered by EPA for its use of safety 

factors, this Unit includes an expanded 

discussion on use of safety or 

uncertainty factors, including the 

additional safety factor required by the 

FQPA for the protection of infants and 

children. Further, because Benchmark 

Dose Methods analysis is discussed for 

the first time in this revised order, a 

short section explaining that concept is 

included. 

A. FFDCA/FIFRA and Applicable 

Regulations 

1. In general. EPA establishes 

maximum residue limits, or 

‘‘tolerances,’’ for pesticide residues in 

food and feed commodities under 

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54404 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

section 408 of the FFDCA. (21 U.S.C. 

346a). Without such a tolerance or an 

exemption from the requirement of a 

tolerance, a food containing a pesticide 

residue is ‘‘adulterated’’ under section 

402 of the FFDCA and may not be 

legally moved in interstate commerce. 

(21 U.S.C. 331, 342). Monitoring and 

enforcement of pesticide tolerances are 

carried out by the U.S. Food and Drug 

Administration (FDA) and the U.S. 

Department of Agriculture (USDA). 

Section 408 was substantially rewritten 

by the Food Quality Protection Act of 

1996 (FQPA), which added the 

provisions discussed below establishing 

a detailed safety standard for pesticides, 

additional protections for infants and 

children, and the endocrine disrupting 

substances screening program. (Pub. L. 

104–170, 110 Stat. 1489 (1996)). 

EPA also regulates pesticides under 

the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA), (7 U.S.C. 136 

et seq). While the FFDCA authorizes the 

establishment of legal limits for 

pesticide residues in food, FIFRA 

requires the approval of pesticides prior 

to their sale and distribution, (7 U.S.C. 

136a(a)), and establishes a registration 

regime for regulating the use of 

pesticides. FIFRA regulates pesticide 

use in conjunction with its registration 

scheme by requiring EPA review and 

approval of pesticide labels and 

specifying that use of a pesticide 

inconsistent with its label is a violation 

of Federal law. (7 U.S.C. 136j(a)(2)(G)). 

2. Safety standard for pesticide 

tolerances. A pesticide tolerance may be 

promulgated or left in effect by EPA 

only if the tolerance is ‘‘safe.’’ (21 U.S.C. 

346a(b)(2)(A)(i)). This standard applies 

when responding both to petitions to 

establish and petitions to revoke 

tolerances. ‘‘Safe’’ is defined by the 

statute to mean that ‘‘there is a 

reasonable certainty that no harm will 

result from aggregate exposure to the 

pesticide chemical residue, including 

all anticipated dietary exposures and all 

other exposures for which there is 

reliable information.’’ (21 U.S.C. 

346a(b)(2)(A)(ii)). 

Risks to infants and children are given 

special consideration. Providing 

additional protection to infants and 

children was a particular focus of the 

FQPA. Section 408(b)(2)(C) requires 

EPA to make a specific determination 

regarding the safety of tolerances to 

infants and children and to consider, 

among other things, information 

‘‘concerning the special susceptibility of 

infants and children to the pesticide 

chemical residues * * *.’’ (21 U.S.C. 

346a(b)(2)(C)(i)(II) and (ii)(II)). This 

provision also creates a presumptive 

additional safety factor for the 

protection of infants and children. 

Specifically, it directs that ‘‘[i]n the case 

of threshold effects, * * * an additional 

tenfold margin of safety for the pesticide 

chemical residue and other sources of 

exposure shall be applied for infants 

and children to take into account 

potential pre- and post-natal toxicity 

and completeness of the data with 

respect to exposure and toxicity to 

infants and children.’’ (21 U.S.C. 

346a(b)(2)(C)). EPA is permitted to ‘‘use 

a different margin of safety for the 

pesticide chemical residue only if, on 

the basis of reliable data, such margin 

will be safe for infants and children.’’ 

(Id.). For convenience’s sake, the legal 

requirements regarding the additional 

safety margin for infants and children in 

section 408(b)(2)(C) are referred to 

throughout this Order as the ‘‘FQPA 

safety factor for the protection of infants 

and children’’ or simply the ‘‘FQPA 

safety factor.’’ 

3. Procedures for establishing, 

amending, or revoking tolerances. 

Tolerances are established, amended, or 

revoked by rulemaking under the 

unique procedural framework set forth 

in the FFDCA. Generally, a tolerance 

rulemaking is initiated by the party 

seeking to establish, amend, or revoke a 

tolerance by means of filing a petition 

with EPA. (See 21 U.S.C. 346a(d)(1)). 

EPA publishes in the Federal Register a 

notice of the petition filing and requests 

public comment. (21 U.S.C. 346a(d)(3)). 

After reviewing the petition, and any 

comments received on it, EPA may issue 

a final rule establishing, amending, or 

revoking the tolerance, issue a proposed 

rule to do the same, or deny the 

petition. (21 U.S.C. 346a(d)(4)). 

Once EPA takes final action on the 

petition by establishing, amending, or 

revoking the tolerance or denying the 

petition, any party may file objections 

with EPA to EPA’s decision on the 

petition and seek an evidentiary hearing 

on those objections. (21 U.S.C. 

346a(g)(2)). Objections and hearing 

requests must be filed within 60 days. 

(Id.). The statute provides that EPA shall 

‘‘hold a public evidentiary hearing if 

and to the extent the Administrator 

determines that such a public hearing is 

necessary to receive factual evidence 

relevant to material issues of fact raised 

by the objections.’’ (21 U.S.C. 

346a(g)(2)(B)). EPA regulations make 

clear that hearings will only be granted 

where it is shown that there is ‘‘a 

genuine and substantial issue of fact,’’ 

the requestor has identified evidence 

that ‘‘would, if established, resolve one 

or more of such issues in favor of the 

requestor,’’ and the issue is 

‘‘determinative’’ with regard to the relief 

requested. (40 CFR 178.32(b)). Further, 

a party may not raise issues in 

objections unless they were part of the 

petition and an objecting party must 

state objections to the EPA decision and 

not just repeat the allegations in its 

petition. Corn Growers v. EPA, 613 F.2d 

266 (D.C. Cir. 2010), cert. denied, 131 S. 

Ct. 2931 (2011). EPA’s final order on the 

objections is subject to judicial review. 

(21 U.S.C. 346a(h)(1)). 

B. EPA Risk Assessment for 

Tolerances—Policy and Practice 

1. The safety determination—risk 

assessment. To assess risk of a pesticide 

tolerance, EPA combines information on 

pesticide toxicity with information 

regarding the route, magnitude, and 

duration of exposure to the pesticide. 

The risk assessment process involves 

four distinct steps: (1) Identification of 

the toxicological hazards posed by a 

pesticide; (2) determination of the ‘‘level 

of concern’’ with respect to human 

exposure to the pesticide; (3) estimation 

of human exposure to the pesticide; and 

(4) characterization of risk posed to 

humans by the pesticide based on 

comparison of human exposure to the 

level of concern. 

Toxicological hazards posed by a 

pesticide are identified through use of 

testing in laboratory animals or humans. 

Generally, EPA will use the lowest ‘‘no 

observed adverse affect level’’ (NOAEL) 

or ‘‘lowest observed adverse effect 

level’’ (LOAEL) from the available 

studies or a calculated value called a 

Benchmark Dose as a starting point 

(called ‘‘the Point of Departure’’) in 

estimating the ‘‘level of concern’’ for 

human exposure to the pesticide. Points 

of Departure and levels of concern will 

be identified for all exposure routes to 

the pesticide (oral, dermal, and 

inhalation) and durations of exposure 

(acute, short-term, intermediate-term, 

and chronic). Another critical aspect of 

the ‘‘level of concern’’ determination 

involves the use of safety or uncertainty 

factors to compensate for the limitations 

of toxicology testing. Safety and 

uncertainty factors are discussed in 

detail in Unit III.B.2. below. Having 

identified a pesticide’s hazards, the 

Point(s) of Departure, and level(s) of 

concern, EPA then estimates exposure 

to the pesticide taking into account the 

various routes of exposure, how 

exposures vary over time, and the 

differences in exposure to different 

subpopulations. Finally, EPA combines 

information on hazard, level of concern, 

and exposure to produce a 

characterization of the risk posed by the 

pesticide. Risks are calculated for all of 

the various routes and durations of 

exposure scenarios associated with a 

pesticide. These risk assessment 

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Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 54405 

scenarios may be calculated separately 

for different age-based population 

groups (e.g., non-nursing infants) or 

applied to all population groups, 

including infants and children, 

depending on information on the 

potential for exposure and data on 

differential sensitivity. A more 

comprehensive discussion of this risk 

assessment process is presented in 

EPA’s previous order denying 

objections. (73 FR 42685–42689). 

Before turning to a detailed 

discussion of safety and uncertainty 

factors, EPA’s risk characterization 

process is briefly summarized because it 

is frequently referred to in this order. 

For pesticides that pose a risk over a 

certain threshold of exposure, EPA’s 

characterization of risk is presented in 

one of two ways: Either using the 

Reference Dose (RfD) approach or the 

Margin of Exposure (MOE) approach. 

Importantly, these different approaches 

do not render substantively different 

results. Both approaches use the same 

data—the Point of Departure, the 

applicable safety/uncertainty factors, 

and human exposure to the pesticide; 

they just express the characterization of 

risk in a different metric. Under the RfD 

approach, EPA directly extrapolates a 

dose from an animal or human study to 

an overall safe dose for humans. An RfD 

is calculated by dividing all applicable 

safety/uncertainty factors into the level 

of exposure from animal or human 

studies determined appropriate for 

assessing risk (i.e., the ‘‘Point of 

Departure’’). Estimated human exposure 

to the pesticide is then compared to the 

RfD to determine if it is excessive. 

Under the Margin of Exposure (MOE) 

approach, EPA does not calculate a safe 

dose in humans but rather focuses on 

the margin of exposure between a dose 

from an animal or human study and 

human exposure to the pesticide. A 

MOE is calculated by dividing human 

exposure to the pesticide into the Point 

of Departure. To determine whether that 

MOE is considered sufficiently 

protective of humans, EPA compares it 

to the product of all applicable safety/ 

uncertainty factors, referred to as the 

target MOE. MOEs that are less than the 

target MOE indicate a risk of concern. 

At bottom, both approaches extrapolate 

a safe measure of human exposure from 

animal or human studies using a 

mixture of uncertainty/safety factors. 

2. Safety and uncertainty factors. 

i. History. It has long been a standard 

risk assessment practice to use 

numerical factors in conjunction with 

experimental toxicity data in assessing 

risk to humans from exposure to 

chemical substances. (Ref. 4). These 

numerical factors are designed to 

provide an additional margin of safety 

so that risks to the populations covered 

by an assessment are not understated. 

The practice was first developed by the 

Food and Drug Administration (FDA) in 

the middle part of the last century. (Ref. 

5). An influential 1954 paper by two 

FDA scientists called for a hundredfold 

margin of safety when extrapolating 

from long-term animal experiments to 

calculate safe doses in humans. (Ref. 6). 

The paper justified this safety factor on 

the basis of, among other things, 

potential differences in sensitivity 

between humans and laboratory animals 

as well as potential variations in 

sensitivity within humans. Accordingly, 

the paper recognized that a smaller 

factor would be appropriate where 

adequate human data are available. An 

explicit recommendation for a factor ‘‘as 

low as 10’’ was made by the Joint Food 

and Agricultural Organization/World 

Health Organization (FAO/WHO) 

Meeting on Pesticide Residues in 1965 

for circumstances where human data 

was relied upon. (Ref. 7 at 12). 

Eventually, it became common 

regulatory practice to treat the 

hundredfold margin of safety as 

comprised of two tenfold factors: The 

first addressing the potential difference 

in sensitivity between humans and 

experimental animals (i.e., interspecies 

sensitivity) and the second addressing 

variation within the human population 

(i.e., intraspecies sensitivity). The 

rationale for these two factors is 

concisely summarized in a recent 

publication from the International 

Programme on Chemical Safety: 

The interspecies uncertainty factor can be 

considered to convert the NOAEL/NOAEC 

[No observed adverse effect concentration] 

for animals (derived from a small group of 

relatively homogeneous test animals) into the 

NOAEL/NOAEC anticipated for an average 

representative healthy human. The 

uncertainty factor for human variability 

converts the NOAEL/NOAEC for the average 

human into a NOAEL/NOAEC for susceptible 

humans. Although adverse effect data in 

humans can be used directly without the 

need for an interspecies factor, the paucity of 

such data means that the vast majority of risk 

assessments are based on studies in 

experimental animals. 

(Ref. 8 at 15). 

EPA, as well as other Federal and 

international regulatory bodies, also 

will, where appropriate, apply 

additional numerical factors to take into 

account chemical-specific 

considerations affecting the risk 

assessment. (Ref. 9) Use of these 

additional factors is further explained in 

Unit III.B.2.v., vi, and vii. 

ii. Terminology. Different terminology 

has been used to label numerical factors 

used in calculating safe doses of 

chemical substances. As noted, they 

were first referred to as ‘‘safety’’ factors. 

The terminology has evolved over the 

decades, however, such that what was 

once generally called a safety factor has 

come to be generally referred to as an 

uncertainty factor. (Ref. 10 at A–3). The 

rationale for the change was that, 

although the use of such factors does 

promote safety, there was a concern that 

the use of the term ‘‘safety’’ implied that 

these factors provided absolute safety. 

(Ref. 11). The FQPA reintroduced the 

term ‘‘safety’’ factors with its reference 

to a ‘‘margin of safety.’’ 21 U.S.C. 

346a(b)(2)(C). Subsequent to the passage 

of FQPA, EPA’s Office of Pesticide 

Programs (OPP) has used the terms 

safety factor and uncertainty factor 

interchangeably. Both terms have been 

criticized by the National Academy of 

Sciences (NAS). The NAS explained 

that the terms safety and uncertainty 

imply that factors ‘‘are simply added on 

for safety or because of a lack of 

knowledge or confidence in the 

process.’’ (Ref. 12 at 132). To the 

contrary, according to the NAS, these 

factors are scientifically-based and used 

‘‘to adjust for differences in individual 

human sensitivities, for humans’ 

generally greater sensitivity than test 

animals’ on a milligram-per-kilogram 

basis, for the fact that chemicals 

typically induce harm at lower doses 

with longer exposures, and so on.’’ (Id.). 

iii. Scientific basis for inter- and 

intraspecies factors. Only limited 

scientific data, involving differing 

sensitivity of humans and animals, are 

cited in the 1954 article in justification 

of the recommendation for a 

hundredfold safety factor. Subsequent 

investigations of both animal and 

human toxicity data, however, have 

provided general support for the 

protectiveness of the tenfold factors for 

interspecies and intraspecies sensitivity 

differences if an adequate toxicity 

database is available. (Refs. 9, 13, 14, 

and 15). The interspecies factor has 

been investigated through comparisons 

of toxicity testing in laboratory animals 

and humans. (Refs. 15 and 16). The 

protectiveness of the human 

intraspecies factor has been assessed 

through examining sub-population 

differences both among various human 

age groups (the young, adults, and 

elderly) as revealed in pharmaceutical 

trials and between juvenile and adult 

laboratory animals identified in toxicity 

testing. (Ref. 13 at 211 (‘‘For substances 

other than pharmaceuticals, age-related 

differences in toxicity have been 

primarily investigated in rodent 

studies.’’); Ref. 17 at 462–463 

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(describing pharmaceutical trials 

involving humans and comparative 

studies in juvenile and adult laboratory 

animals)). For example, the NAS, in its 

report ‘‘Pesticides in the Diets of Infants 

and Children,’’ looked to both human 

data and animal data in evaluating the 

potential for increased sensitivity in 

infants and children to pesticides. (Ref. 

18 at 344–345). 

iv. Adjustment of inter- and 

intraspecies factors. In addition to 

evaluating the protectiveness of the 

intra- and interspecies uncertainty 

factors, scientists have also examined 

both generic biological as well as 

chemical-specific factors that may affect 

intra- and interspecies variability with 

the aim of deriving more accurate 

uncertainty factor values than the 

default tenfold values. 

One reason humans are considered to 

be potentially more sensitive to toxic 

agents than laboratory animals is that 

otherwise equivalent external doses of 

such agents for humans and animals on 

a milligram-per-kilogram of body weight 

basis may result in a greater internal 

dose for humans. This is due to species 

differences in general metabolic 

processes—commonly referred to as 

toxicokinetics—and ‘‘is thought to be 

related to species differences in 

exchange surfaces and distribution 

networks that constrain concentration 

and flux of metabolic reactants.’’ (Ref. 

19 at 4–35; see Ref. 15 at 228). 

In addition to toxicokinetic effects on 

internal dose, differences between 

humans and laboratory animals are also 

driven by toxicodynamic factors. 

Toxicodynamics refers to the manner in 

which the target tissue and body 

respond to the toxic agent. Thus, 

interspecies differences are a factor of 

both differences in the internal dose 

received by humans and animals and 

differences in how humans and animals 

react to the internal dose received. 

Similarly, sensitivity differences 

between juveniles and adults, whether 

humans or animals, are also considered 

to be tied to toxicokinetic and 

toxicodynamic factors. Accordingly, 

both the inter- and intraspecies 

uncertainty factors are considered to 

have toxicokinetic and toxicodynamic 

components. EPA typically has 

considered both the tenfold (10X) interand intraspecies factors to be roughly 

equally divided on a logarithmic basis 

(i.e., 100.5 or roughly a 3X factor) 

between toxicokinetics and 

toxicodynamics. (Ref. 19 at 4–29; see 

also Ref. 19 at 4–40 (explaining why two 

3X factors [technically, 3.16X] would be 

equivalent to a 10X factor)). Other 

organizations have recommended that, 

while toxicokinetics and 

toxicodynamics play an equal role in 

intra-human variability, toxicokinetics 

has a greater effect on interspecies 

differences and thus recommend that 

the tenfold interspecies factor be 

divided into a fourfold factor for 

toxicokinetics and 2.5-fold factor for 

toxicodynamics. (Ref. 8 at 17; see Ref. 

14). 

Of the toxicokinetic and 

toxicodynamic differences between 

humans and animals and among various 

human subgroups, the most is known 

about the toxicokinetic differences 

between humans and animals. For 

inhalation exposures, EPA has used 

toxicokinetic information on humans 

and animals to create generic dosimetric 

adjustment factors that replace that 

portion of the interspecies factor tied to 

toxicokinetic differences. (Refs. 19 at 4– 

29; 20). Where such dosimetric 

adjustment factor is used, the 

interspecies factor is reduced to 3X. 

EPA guidance entitled ‘‘A Review of 

the Reference Dose and Reference 

Concentration Processes’’ (‘‘RfD 

Guidance’’) also urges that data be 

developed to support substitution of 

chemical-specific adjustment factors 

(sometimes referred to as data-derived 

factors) for the default 10X uncertainty 

factors for inter- and intraspecies 

variability. (Ref. 19 at xviii –xix, 4–47). 

This guidance recognizes that chemicalspecific data from both humans and 

animals has been relied upon by EPA to 

adjust the human intraspecies 

uncertainty factor citing an article by 

Dourson et al. That article collects 

instances in which EPA has adjusted 

uncertainty factors on a chemicalspecific basis. (Ref. 9). For example, 

Dourson et al. point to a 1996 EPA 

assessment of Aroclor that reduced the 

human intraspecies factor to 3X given 

that the Point of Departure came from a 

sensitive animal population—there, 

infant rhesus monkeys. In discussing 

the Dourson et al. article, the RfD 

Guidance notes that: 

In those cases where developmental effects 

were the most sensitive endpoint (0 RfCs, 6 

RfDs), reduction of the intraspecies 

[uncertainty factor] from 10 to 3 was based 

on data derived either from human data 

showing which age groups or time periods 

were most susceptible (e.g., methyl mercury 

exposure to the developing fetus) or from an 

animal study with support from strong 

human or other data (e.g., Aroclor 1016 in 

utero exposure in monkeys, strontiuminduced rachitic bones in young rats). 

(Ref. 19 at 4–43). The RfD Guidance 

endorsed a view similar to that 

expressed in an agency-wide paper 

prepared in development of EPA’s 

Children’s Safety Factor Policy. That 

paper also noted that there were 

circumstances where data from human 

studies or from animal studies might 

support reduction of the human 

intraspecies uncertainty factor: ‘‘The 

Toxicology Working Group recommends 

that reduction of the intraspecies 

uncertainty factor from a default of 10 

be considered only if data are complete 

and the age group or window of 

vulnerability during development has 

been clearly delineated, preferably 

based on human data or on animal data 

with supporting human data.’’ (Ref. 21 

at 28). On the other hand, the RfD 

guidance also recognized that a 10X 

intraspecies factor ‘‘may sometimes be 

too small because of factors that can 

influence large differences in 

susceptibility, such as genetic 

polymorphisms.’’ (Ref. 19 at 4–44). 

In sum, the 10X inter- and 

intraspecies factors are default values. 

Although there is substantial scientific 

support for these default values, 

chemical-specific human and animal 

data may be relied upon in reducing, 

confirming, or increasing these default 

values. 

v. Additional Safety/Uncertainty 

Factors. In addition to the inter- and 

intraspecies factors, risk assessors from 

EPA as well as other Federal and 

international regulatory agencies also 

apply ‘‘additional’’ or ‘‘modifying’’ 

safety/uncertainty factors based on 

specific circumstances related to the 

toxicity data, particularly with regard to 

deficiencies in that data. Like the interand intra-species factors, these 

additional factors help to ensure that 

risks to populations covered by an 

assessment are not understated. 

Additional factors are applied to 

address: (1) An absence of critical 

toxicity data; (2) the failure of a study 

to identify a NOAEL; (3) the necessity 

of using sub-chronic data to choose a 

Point of Departure for estimating 

chronic risk; and (4) results in a study 

that suggest the inter- or intraspecies 

factors may not be sufficient (sometimes 

referred to as a ‘‘modifying factor’’). 

(Ref. 10 at 9). Generally, a safety factor 

value of 10X or 3X (which is considered 

to be one-half of 10X on the logarithmic 

scale) is used to address these concerns. 

The protectiveness of these default 

values has also been the subject of 

scientific examination. Studies have 

been done on the variations in the levels 

of NOAELs in the databases for various 

pesticides. They confirm the need for an 

additional factor when core data are 

lacking. (Ref. 22). Examination of the 

completeness of the animal database 

remains important even when human 

data are used as the Point of Departure 

for calculating the RfD. The latest EPA 

guidance on RfDs emphasizes that in 

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these circumstances ‘‘[i]nformation on 

life stages and organ systems may come 

from either animal or human studies.’’ 

(Ref. 19 at 4–45). The guidance notes 

that ‘‘the lack of a two-generation 

animal reproduction study might be 

considered a deficiency even if the 

reference value is based on human 

data.’’ (Id.). Similarly, research has been 

conducted on existing databases to 

determine the adequacy of uncertainty 

factors used to address reliance on a 

LOAEL instead of a NOAEL, or 

subchronic data to estimate chronic risk. 

(Refs. 9 and 15). 

Selection of particular values for these 

additional uncertainty values depends 

on what is known from the full body of 

information about the chemical, 

including both data from testing with 

animals and humans, about the 

chemical. For example, as EPA’s RfD 

Guidance advises: ‘‘the size of the 

database factor to be applied will 

depend on other information in the 

database and on how much impact the 

missing data may have on determining 

the toxicity of a chemical and, 

consequently, the POD [Point of 

Departure].’’ (Ref. 19 at 4–45). With 

regard to an additional factor for 

extrapolation of a NOAEL from a 

LOAEL, Dourson et al. report that 

‘‘[a]nalysis of several data bases suggest 

that a factor of 10 or lower is adequate 

and that use of data does support a 

lower factor with certain chemicals.’’ 

(Ref. 9 at 112). The critical 

consideration, according to Dourson et 

al., is the severity of the effect at the 

LOAEL: ‘‘The data indicate that when 

faced with a LOAEL and not a NOAEL, 

the choice of uncertainty factor should 

generally depend on the severity of the 

effect at the LOAEL.’’ (Id.). Specifically, 

Dourson et al. note that ‘‘[l]ess severe 

effects would not require a large factor, 

because, presumably, the LOAEL is 

closer to the unknown NOAEL.’’ (Id.). 

vi. FQPA safety factor—integration 

with traditional uncertainty factors. 

EPA’s safety/uncertainty factor practice 

with regard to pesticides was altered to 

a degree by the Food Quality Protection 

Act (FQPA). (Ref. 10). That Act 

established a presumptive additional 

‘‘safety’’ factor of 10X to protect infants 

and children. The additional factor was 

designed to account for the 

completeness of the toxicity and 

exposure databases and the potential for 

pre- and post-natal toxicity. EPA has 

interpreted this legislation as both a 

‘‘codification and expansion’’ of prior 

EPA practice with regard to additional 

safety/uncertainty factors. (Ref. 10 at A– 

3—A–5). It codified EPA’s prior practice 

by requiring the additional presumptive 

factor to address toxicity data 

completeness issues (i.e., absence of a 

particular study, lack of a NOAEL in a 

completed study, or absence of chronic 

data). These traditional additional 

uncertainty factors became FQPA safety 

factors for the protection of infants and 

children. This accords greater protection 

to infants and children because for 

FQPA safety factors, unlike pre-FQPA 

additional factors, there is a 

presumption, which can only be 

overcome by reliable data, that they will 

be applied. At the same time, EPA 

concluded that Congress had not 

intended EPA to double-up on safety 

factors by, for example, applying an 

additional uncertainty factor due to 

missing data, and applying an FQPA 

additional safety factor as well to 

address the same missing data. (Ref. 10 

at A–4). Congress expanded EPA’s prior 

practice by providing that the additional 

FQPA safety factor for the protection of 

infants and children was designed to 

address not just toxicity data 

deficiencies but exposure data 

deficiencies as well and by its emphasis 

on protecting against potential pre- and 

post-natal toxicity. In theory, EPA could 

have, prior to the enactment of the 

FQPA, used an ‘‘additional’’ or 

‘‘modifying’’ factor to address health 

risks to children not otherwise protected 

by the interspecies, intraspecies, or data 

deficiency safety factors, but use of such 

a factor was not common. The FQPA 

also modified the status quo by making 

the additional safety factor for infants 

and children presumptive in nature. 

The narrowly-focused and highlyprescriptive nature of the FQPA safety 

factor provision has required careful 

integration with pesticide risk 

assessment approaches under other 

statutes and, more generally, with 

Agency risk assessment practices. As 

noted above, the FQPA, with regard to 

the assessment of risks to infants and 

children, essentially codified EPA’s 

prior risk assessment practice as to 

additional uncertainty factors and it 

expanded the use of additional 

uncertainty factors into new areas. The 

FQPA, however, did not speak to use of 

traditional (non-additional) uncertainty 

factors (i.e., the inter- and intraspecies 

factors). Thus, the end result was that 

some uncertainty factors for FFDCA 

pesticides remained unaffected by the 

new statutory requirements (the interand intraspecies factors), some 

uncertainty factors became FQPA safety 

factors (additional uncertainty factors 

that addressed toxicity data 

deficiencies), and some safety factors 

that either had previously never existed 

or were at least extremely rare were 

created as a statutory phenomenon (a 

factor to address exposure data base 

deficiencies and a factor to address 

potential pre- and post-natal toxicity). 

This selective inter-weaving of statutory 

requirements with Agency science 

policy made FFDCA risk assessments 

for pesticides unique compared to 

general Agency risk assessment practice. 

Pesticide risk, however, is not 

regulated under a single statute. Risks to 

workers or the environment from 

pesticide use are regulated by EPA 

under FIFRA, not the FFDCA. Further, 

EPA may address risks posed by 

pesticide contamination of the 

environment under several other 

statutes, including the Safe Drinking 

Water Act, 42 U.S.C. 300f et seq., the 

Resource Conservation and Recovery 

Act, 42 U.S.C. 6901 et seq., and the 

Comprehensive Environmental 

Response, Compensation, and Liability 

Act, 42 U.S.C. 9601 et seq. Prior to 

enactment of the FQPA’s specific 

provisions on pesticide risk assessment, 

a pesticide risk assessment performed 

by EPA’s Office of Pesticide Programs 

under the aegis of FFDCA section 408 

could generally be easily translated for 

use by the Office of Pesticide Programs 

under FIFRA, or by the other media 

offices within EPA for use under other 

statutes. However, once pesticide risk 

assessment under the FQPA became not 

simply a matter of good scientific 

practice but was channeled by explicit 

statutory requirements, it became 

incumbent upon the Office of Pesticide 

Programs to prepare its FFDCA 

pesticide risk assessments in a manner 

that clearly delineated what aspects of 

the assessment were driven solely by 

science and what aspects primarily by 

FQPA statutory requirements. 

Specifically, the Office of Pesticide 

Programs had to be transparent with 

regard to whether it was relying on 

FQPA safety factors based on unique 

FQPA requirements (exposure database 

deficiencies and potential pre- and postnatal toxicity) or FQPA safety factors 

that are essentially a codification of 

prior general EPA ‘‘additional’’ safety/ 

uncertainty factor practice. 

EPA addressed these transparency 

issues at length in its 2002 policy 

statement on the FQPA safety factor. To 

clarify how the FQPA safety factor 

provision left a portion of prior safety/ 

uncertainty practice unchanged, 

codified another portion, and also 

expanded the use of safety factors, EPA 

explained the overlap between the 

FQPA safety factor and additional safety 

factors in depth and included the 

following figure to graphically illustrate 

the issue: 

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54408 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

With regard to providing transparency 

on the FQPA safety factor decisions, 

EPA took two steps. First, it adopted a 

new term, the ‘‘special’’ FQPA safety 

factor, for children safety factors that 

were based solely on the new FQPA 

requirements. Second, it adopted the 

approach of calculating two different 

safe doses for a pesticide: one that 

excluded any ‘‘special’’ FQPA safety 

factors and one that included them. The 

former was referred to, in line with 

standard EPA policy, as a Reference 

Dose (RfD), and the latter as a 

Population Adjusted Dose (PAD). 

Introducing the new terminology on 

FQPA safety factors into longestablished safety factor practice has 

proved challenging. EPA staff on 

occasion drafted documents that (1) 

claimed no FQPA safety factor was 

needed but applied an additional 

uncertainty factor to address the 

completeness of the toxicity data base or 

reliance on a LOAEL; or (2) treated the 

‘‘special’’ FQPA safety factor as the only 

type of FQPA safety factor. However, as 

EPA’s policy made clear, EPA 

interpreted FFDCA section 408(b)(2)(C) 

as codifying prior practice as to 

additional uncertainty factors such that 

these factors became FQPA factors. The 

mislabeling of uncertainty factors did 

not substantively change risk 

assessment outcomes but it did raise the 

confusion level on an already complex 

topic. Eventually, EPA determined that 

the term ‘‘special’’ FQPA safety factor 

caused more problems than it solved 

and abandoned it. However, EPA has 

retained the approach of continuing to 

calculate both a safe dose with, and 

without, what was once referred to as 

‘‘special’’ FQPA safety factors. 

vii. FQPA safety factor—decisionmaking guidance. In 2002, EPA issued 

detailed policy guidance for Agency risk 

assessors on decision-making under the 

FQPA safety factor provision. The 

purpose of this guidance was concisely 

set forth by EPA: ‘‘[T]his guidance 

explains how OPP intends to ‘take 

intoaccount * * * potential pre- and 

post-natal toxicity and completeness of 

the data with respect to exposure and 

toxicity to infants and children’’ as 

directed by FFDCA section 

408(b)(2)(C)(i).’ ’’ (Ref. 10 at ii). 

Although the guidance is structured 

around these statutory considerations, 

EPA also emphasizes throughout that 

the FQPA safety factor decision is a 

weight-of-the-evidence decision that 

must consider all available data. Thus, 

the policy specifies that ‘‘[b]efore any 

decisions are made on the appropriate 

FQPA safety factor applied to ensure the 

safety of infants and children from the 

use of a particular pesticide, all of the 

relevant submitted data for the pesticide 

should be assembled and reviewed by 

Agency scientists.’’ (Id. at 8). 

This emphasis on the broadness of the 

inquiry is repeated in the discussion of 

the statutory consideration related to the 

completeness of the toxicity database. 

According to EPA, this consideration 

should not be narrowly focused on 

EPA’s existing database requirements. 

Rather, ‘‘the ‘completeness’ inquiry 

should be a broad one that takes into 

account all data deficiencies.’’ (Ref. 10 

at 23). At the same time, the guidance 

stresses that ‘‘a determination of the 

possible need for and size of the 

database uncertainty factor will 

necessarily involve an assessment that 


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considers the overall weight-of-evidence 

to evaluate the significance of the data 

deficiency.’’ (Id. at 26). 

With regard to potential pre- and postnatal toxicity, the policy emphasizes 

that evaluation of this consideration 

cannot be divorced from the existing 

process for choosing levels of concern 

(i.e., RfDs, PADs, and target MOEs). 

Thus, EPA instructs risk assessors to 

evaluate the concern with data showing 

pre- and post-natal toxicity by 

considering, among other things, ‘‘the 

degree to which protection for infants 

and children is provided by the 

standard approach for deriving RfDs 

through the application of traditional 

uncertainty factors.’’ (Id. at 29). The 

guidance stresses that ‘‘[i]n particular, 

the risk assessor should consider the 

protection accorded infants and 

children by the intraspecies uncertainty 

factor.’’ (Id.). EPA notes that the 

scientific literature as well as the 

National Academy of Sciences has 

concluded that the intraspecies factor is 

generally adequate to protect infants 

and children; however, the policy 

points out that certain chemicals may 

display greater than 10X age-related 

variability. For this reason, EPA 

reiterates that ‘‘[t]he adequacy of the 

standard intraspecies factor to address 

the potential for greater sensitivity or 

susceptibility of children should be 

considered in the context of evidence on 

potential pre- and post-natal toxicity as 

discussed below.’’ (Id.; see also Id. at 

51–52). The policy paper went on to 

provide numerous examples of weightof-the-evidence considerations relevant 

to evaluation of human and animal data 

on pre- and post-natal toxicity. (Id. at 

30–33). 

The discussion on the completeness 

of the exposure database focuses on 

whether the various approaches EPA 

uses to assess exposure are likely to 

understate it. Risk assessors are to 

evaluate whether their assessments 

‘‘have addressed all significant exposure 

routes’’ and whether ‘‘there may be 

uncertainty about whether OPP’s 

approach to estimating exposure for a 

particular use pattern, pathway, or 

aggregate exposure is sufficiently health 

protective.’’ (Id. at 48). 

3. Benchmark dose approach. As 

indicated above, EPA has traditionally 

used a NOAEL or LOAEL as a Point of 

Departure in estimating an exposure 

level of concern for a pesticide or other 

substance. Increasingly, however, EPA 

uses a more sophisticated modeling tool 

known as the Benchmark Dose approach 

as an alternative to using NOAELs or 

LOAELs for Point of Departure 

selection. (Refs. 23). A benchmark dose, 

or BMD, is a point estimate along a 

dose-response curve that corresponds to 

a specific response level. For example, 

a BMD10 represents a 10% change from 

the background level (the background 

level is typically derived from the 

control group). In addition to a BMD, a 

confidence limit may also be calculated. 

Confidence limits express the 

uncertainty in a BMD that may be due 

to sampling and/or experimental error. 

The lower confidence limit on the BMD 

is termed the benchmark dose limit 

(BMDL). Use of a BMD or BMDL for 

deriving the Point of Departure allows 

more precise estimates of the Point of 

Departure, resulting in tighter 

confidence intervals. Use of the BMDL 

also helps ensure with high confidence 

(e.g., 95% confidence) that the selected 

percentage of change from background 

is not exceeded. Numerous scientific 

peer review panels over the last decade 

have supported the Agency’s 

application of the BMD approach as a 

scientifically supportable method for 

deriving Point of Departures in human 

health risk assessment, and as an 

improvement over the historically 

applied approach of using NOAELs or 

LOAELs. (Refs. 24, 25, and 26). The 

NOAEL/LOAEL approach can look at 

the dose response at only the few doses 

used in a study, and is therefore limited 

by the characteristics of the study 

design, such as dose selection, dose 

spacing, and sample size. (Ref. 23 at 3– 

5). With the BMD approach, all the dose 

response data are used to derive a dose 

response curve. For all of these reasons, 

BMD analysis is preferred by EPA to the 

NOAEL/LOAEL approach of selecting a 

Point of Departure from studies when 

the available data are amenable to BMD 

modeling consistent with the biological 

processes relevant to the study in 

question. 

IV. Dichlorvos 

Dichlorvos is a chlorinated 

organophosphate pesticide that inhibits 

plasma, red blood cell (RBC), and brain 

cholinesterase in a variety of species. 

(Ref. 3 at 122–123). Cholinesterase 

inhibition is a disruption of the normal 

process in the body by which the 

nervous system chemically 

communicates with muscles and glands. 

Although cholinesterase inhibition in 

the nervous system is not itself regarded 

as a direct adverse effect, it is ‘‘generally 

accepted as a key component of the 

mechanism of toxicity leading to 

adverse cholinergic effects.’’ (Ref. 27 at 

25; see 73 FR 42688–42689). Inhibition 

of blood cholinesterase ‘‘is not an 

adverse effect, but may indicate a 

potential for adverse effects on the 

nervous system’’ and thus serves as a 

‘‘surrogate’’ for cholinesterase inhibition 

in the nervous system (Ref. 27 at 28). 

Subchronic and chronic oral dichlorvos 

exposures to rats and dogs as well as 

chronic inhalation dichlorvos exposure 

to rats resulted in significant decreases 

in plasma, RBC, and/or brain 

cholinesterase activity. Repeated, oral 

subchronic dichlorvos exposures in 

male humans were associated with 

statistically and biologically significant 

decreases in RBC cholinesterase 

inhibition. These cholinesterase effects 

occurred at dose levels below levels at 

which any other adverse effect was 

seen. Generally, there was no evidence 

of increased sensitivity to young 

animals following exposure to 

dichlorvos. No evidence of increased 

sensitivity to young animals was seen 

following in utero dichlorvos exposure 

to rat and rabbit fetuses as well as pre/ 

post natal dichlorvos exposure to rats in 

developmental, reproduction, and 

comparative cholinesterase studies. The 

only evidence of sensitivity in the 

young was seen in one parameter, 

auditory startle amplitude, in a 

developmental neurotoxicity study; 

however, the effects in the rat pups in 

that study were at levels well above 

levels that result in RBC cholinesterase 

inhibition. 

Because inhibition of cholinesterase 

activity was identified as the most 

sensitive effect, it was selected as the 

toxicity endpoint for assessment of risks 

for all acute and chronic dietary 

exposures, as well as short-, 

intermediate-, and long-term (chronic) 

dermal, inhalation, and incidental oral 

residential exposures. For each risk 

assessment scenario, EPA selected a 

Point of Departure based on either an 

animal or human study taking into 

account the duration of the study and 

the route of exposure used in the study. 

(Ref. 3 at 130–135). These Points of 

Departure were used in calculating RfD/ 

PADs and acceptable MOEs. Due to the 

lack of sensitivity differences between 

adults and juveniles, the resulting RfD/ 

PADs and acceptable MOEs were 

designated as applicable to all 

population subgroups, including infants 

and children. Animal studies were used 

in choosing levels of concern for 

evaluating risk from acute and chronic 

dietary exposure; acute dermal 

exposure; and acute and chronic 

inhalation exposure. A human study 

(the Gledhill study) was used in 

evaluating risk from short-term 

incidental oral exposure; short-, 

intermediate-, and long-term dermal 

exposure; and short- and intermediateterm inhalation exposure. All of the 

studies from which a Point of Departure 

was selected were conducted in adults 

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54410 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

(adult humans or adult animals). (See 

Table 1). 

Safety factor determinations used in 

determining the level of concern for 

each risk assessment scenario differed 

based on whether EPA relied on one of 

several different animal studies or a 

human study for the Point of Departure 

for that scenario. For levels of concerns 

derived from a Point of Departure from 

an animal study, EPA generally applied 

a 100X safety factor (10X for 

interspecies variability and 10X for 

intraspecies variability). Based on a 

weight-of-the-evidence evaluation, EPA 

removed the 10X FQPA safety factor for 

risk assessments based on an animal 

study. (See Table 1). EPA’s weight-ofthe-evidence evaluation concluded that 

(1) the toxicity database was complete; 

(2) most of the data indicated no 

increased sensitivity in the young and 

the only evidence of increased 

sensitivity occurred at levels well above 

the Points of Departure used for 

establishing the levels of concern; and 

(3) its estimate of human exposure to 

dichlorvos was not understated. 

For levels of concerns derived from a 

Point of Departure from the human 

study, EPA applied a 10X safety factor 

for intraspecies variability and a 3X 

FQPA safety factor. (72 FR 68694– 

68695). No interspecies factor was 

applied because EPA was not 

extrapolating a level of concern in 

humans from a dose in an animal study. 

The weight-of-the-evidence balance for 

the FQPA safety factor was slightly 

different for risk assessments relying on 

the Gledhill human study for the Point 

of Departure. In addition to all of the 

considerations pertaining to the 

assessments with an animal-derived 

Point of Departure, the Gledhill-based 

risk assessments introduced another 

factor to consider—namely, that the 

Gledhill study raised a data 

completeness issue due to the fact that 

it only identified a LOAEL. This latter 

factor convinced EPA to retain a portion 

of the FQPA safety factor when relying 

on the human study for the Point of 

Departure. EPA concluded, however, 

that reliable data supported reduction of 

the 10X factor to 3X because the effect 

seen at the LOAEL in that study was so 

marginal (16 percent RBC cholinesterase 

inhibition) that a lower dose would 

have been unlikely to detect any adverse 

effect. (72 FR 68694–68695; see Table 

1). 

TABLE 1—SUMMARY OF RISK ASSESSMENT SCENARIOS, POPULATION GROUPS, AND UNCERTAINTY/SAFETY FACTORS FOR

DICHLORVOS

Scenario Study from which point 

of departure taken 

Age and species of 

study subjects 

Population groups covered 

by risk assessment Uncertainty/safety factors 

Acute Dietary ................ Rat acute oral cholinesterase study.Adult rats ..................... All population groups, including infants and children.Interspecies—10X; Intraspecies— 

10X; FQPA—1X. 

Chronic Dietary ............ 1-year dog study .......... Adult dogs .................... All population groups, including infants and children.Interspecies—10X; Intraspecies— 

10X; FQPA—1X. 

Short-term Incidental 

Oral.

Human 21-day oral 

study.

Adult humans ............... All population groups, including infants and children.Interspecies—1X; Intraspecies— 

10X; FQPA—3X. 

Acute Dermal and 

Acute Incidental Oral.

Rat acute oral cholinesterase study.Adult rats ..................... All population groups, including infants and children.Interspecies—10X; Intraspecies— 

10X; FQPA—1X. 

Short-, Intermediateand Long-term Dermal.Human 21-day oral 

study.

Adult humans ............... All population groups, including infants and children.Interspecies—1X; Intraspecies— 

10X; FQPA—3X. 

Acute Inhalation ........... Rat acute oral cholinesterase study.Adult rats ..................... All population groups, including infants and children.Interspecies—10X; Intraspecies— 

10X; FQPA—1X. 

Short- and Intermediate-term Inhalation.Human 21-day oral 

study.

Adult humans ............... All population groups, including infants and children.Interspecies—1X; Intraspecies— 

10X; FQPA—3X. 

Long-term Inhalation .... 2-year rat inhalation 

study.

Adult rats ..................... All population groups, including infants and children.Interspecies—10X; Intraspecies— 

3X; FQPA—1X. 

V. NRDC’s Petition to Revoke 

Dichlorvos Tolerances and the 

Administrative Proceedings on the 

Petition 

A. NRDC’s Petition and EPA’s Denial of 

the Petition 

On June 2, 2006, the NRDC filed a 

petition with EPA which, among other 

things, requested that EPA conclude the 

dichlorvos tolerance reassessment 

process by August 3, 2006, with a 

finding that the dichlorvos tolerances do 

not meet the FFDCA safety standard and 

issue a final rule by August 3, 2006, 

revoking all dichlorvos tolerances. 

NRDC’s petition contained dozens of 

claims as to why dichlorvos’ FFDCA 

tolerances should be revoked. After 

carefully considering all of NRDC’s 

claims, the public comment received on 

the petition, and a revised risk 

assessment EPA conducted in response 

to the petition, EPA issued an order 

pursuant to FFDCA section 408(d)(4)(iii) 

denying the request to revoke 

dichlorvos’ FFDCA tolerances. (72 FR 

68662, December 5, 2007). 

B. NRDC’s Objections and EPA’s Denial 

of the Objections 

On February 1, 2008, NRDC filed, 

pursuant to FFDCA section 408(g)(2), 

objections to EPA’s denial of its 

tolerance revocation petition and 

requested a hearing on those objections. 

NRDC’s objections and requests for 

hearing included two main claims: (1) 

That EPA has unlawfully failed to retain 

the full 10X safety factor for the 

protection of infants and children; and 

(2) that it was unlawful for EPA to rely 

on a toxicity study for dichlorvos (the 

Gledhill study) that was conducted with 

humans. Because NRDC did not seek 

judicial review on EPA’s substantive 

conclusions on the latter issue but only 

challenged EPA’s denial of a hearing on 

the issue, and because the Second 

Circuit court on review did not reach 

the hearing issue, the Gledhill study is 

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further discussed only to the extent it 

bears on the FQPA safety factor 

decision. 

NRDC cited several grounds for its 

assertion that EPA unlawfully lowered 

the 10X children’s safety factor. 

However, only two of its arguments 

were later raised in NRDC’s judicial 

challenge to EPA’s decision. First, 

NRDC claimed that EPA lacked 

adequate data on dichlorvos’ potential 

effects on the endocrine system because 

EPA had not received data on endocrine 

effects through the Endocrine Disruptor 

Screening Program. Second, NRDC 

argued that EPA’s choice of a 3X 

additional safety factor was based on 

generic data and ‘‘not [ ] on any data 

specific to DDVP.’’ (Ref. 1 at 5). 

EPA denied both of NRDC’s reasons 

for its objection to the choice of a 3X 

FQPA factor. EPA rejected NRDC’s 

endocrine data argument on both legal 

and factual grounds. EPA concluded 

that the statute gave it broad discretion 

to determine what data are needed in 

making a determination on the FQPA 

safety factor and that nothing in section 

408(p), creating the Endocrine Disruptor 

Screening Program, overrode that broad 

discretion. As a factual matter, EPA 

found that it had adequate data on 

endocrine effects from the existing 

dichlorvos database. (73 FR 42697– 

42698). 

EPA also rejected NRDC’s claim that 

it relied on wholly generic data, rather 

than dichlorvos-specific data, in 

choosing a 3X FQPA factor. NRDC’s 

argument here was that EPA chose 3X 

because EPA considers 3X to be a halfvalue of a 10X factor rather than on data 

pertaining to dichlorvos. In response, 

EPA noted that its petition denial order 

had comprehensively restated its basis 

for its FQPA safety factor decision, and 

that restatement focused in great detail 

on the toxicology data for dichlorvos, 

particularly, the data on the sensitivity 

of the young. (73 FR 42695). EPA further 

pointed out that although the statutory 

considerations underlying the FQPA 

safety factor generally supported 

removal of the 10X additional factor, the 

reason EPA chose to retain a 3X FQPA 

safety factor for some assessments was 

directly tied to a deficiency in a 

dichlorvos study (the Gledhill study) 

that is critical to those assessments. 

(Id.). Thus, there was no basis for 

NRDC’s claim that EPA had not relied 

on dichlorvos-specific data in making 

its FQPA safety factor decision. 

VI. Judicial Review of EPA’s Denial 

Order 

A. NRDC’s Petition for Judicial Review 

and the Matters Presented on Review 

NRDC petitioned the Second Circuit 

court for review of EPA’s denial of 

certain of its objections and hearing 

requests. As to its hearing requests, 

NRDC argued that EPA improperly 

denied its request for a hearing on 

statistical and informed consent issues 

presented by the Gledhill study. As to 

its objections, NRDC asserted (1) that, as 

a legal matter, EPA was required to 

retain the 10X FQPA factor if it did not 

have data from the Endocrine Disruptor 

Screening Program; and (2) that EPA’s 

choice of a 3X FQPA factor was 

arbitrary and capricious because EPA 

had relied upon ‘‘generic assertions that 

unlawfully fail to take into account any 

dichlorvos-specific information for 

infants and children.’’ (Ref. 28 at 37). 

NRDC supported the latter argument in 

the following fashion. First, it argued 

that EPA chose 3X solely because it was 

half of 10X. Second, NRDC asserted that 

EPA’s consideration of the Gledhill 

study did not constitute ‘‘dichlorvosspecific information for infants and 

children’’ because the Gledhill study 

was conducted with adults. Third, 

NRDC dismissed EPA’s reliance on 

dichlorvos developmental studies in 

animals on the ground that a prior case 

had held that EPA had not, in that 

particular case, offered an adequate 

explanation of how the data on 

developing animals supported the 

FQPA factor chosen. 

In response, EPA explained that 

NRDC’s focus on EPA’s discussion of 

why 3X is considered half of 10X 

ignored the central part of EPA’s 

analysis: An assessment of whether the 

dichlorvos data showed 3X would be 

safe. EPA responded to the claim of a 

failure to consider ‘‘dichlorvos-specific 

information for infants and children’’ by 

noting that the Gledhill study had not 

been considered in isolation in the 

decision on the FQPA safety factor but 

in the context of ‘‘the animal data 

showing no difference in adult-young 

sensitivity’’ because it was ‘‘that very 

data that shows why the Gledhill study 

is appropriate for the entire population 

* * *’’ (Ref. 29 at 63). Further, EPA 

noted that NRDC’s argument that EPA 

reliance on animal sensitivity data does 

not justify a choice of 3X contradicted 

the core of NRDC’s claim—that EPA had 

not considered ‘‘dichlorvos-specific 

information for infants and children.’’ 

(Id. at 62). 

B. The Second Circuit Court’s Decision 

on Review 

On review, the Second Circuit court 

addressed three issues: (1) Was EPA 

legally compelled to retain the 10X 

FQPA safety factor in the absence of 

obtaining data from the Endocrine 

Disruptor Screening Program; (2) did 

EPA adequately explain its decision on 

the FQPA safety factor; and (3) was 

NRDC entitled to an evidentiary hearing 

with regard to its claims regarding the 

alleged statistical and informed consent 

deficiencies in the Gledhill study. 

1. Endocrine data. The court held that 

EPA was not statutorily required to 

retain the 10X FQPA factor in 

circumstances where it has not obtained 

the data required under the Endocrine 

Disruptor Screening Program. (658 F.3d 

at 219). The court found ‘‘no indication 

in the statute or legislative history that 

Congress * * * intended the children’s 

safety factor to be mandatory in 

assessing the risks of all pesticides until 

EPA completed the estrogen disruptor 

screening program * * *’’ (Id.). 

According to the court, ‘‘Congress 

allowed EPA to determine, based on all 

available data, whether there was 

‘reliable data’ supporting a reduced or 

waived children’s safety factor * * *’’ 

(Id.). 

2. FQPA safety factor. Contrary to the 

narrow FQPA safety factor issue 

presented to EPA in NRDC’s 

objections—did EPA’s decision on the 

FQPA safety factor rely on ‘‘a generic 

assertion [instead of being] based on any 

data specific to DDVP’’?—the court 

framed the issue on the FQPA factor 

more broadly: ‘‘NRDC now seeks review 

of that EPA order, arguing in part that 

EPA failed to explain why, when 

assessing the safety of dichlorvos for 

certain exposure scenarios, EPA did not 

apply an additional tenfold children’s 

safety factor, to account for potential 

pre- and post-natal toxicity and 

completeness of data with respect to 

exposure and toxicity to infants and 

children.’’ (Id. at 201). 

The court found that, for risk 

assessments relying on the Gledhill 

study in deriving the Point of Departure, 

EPA had provided essentially no 

explanation with regard to the FQPA 

safety factor. The court noted that EPA 

had retained an additional 3X safety 

factor for these risk assessments but the 

court concluded that it was EPA’s 

express position that this factor was not 

based on any evaluation of the risks to 

infants and children but rather was 

intended to address the lack of NOAEL 

in the Gledhill study only. According to 

the court, ‘‘[i]n EPA’s IRED and two 

published orders, EPA consistently 

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reiterated this position and declined to 

claim that the 3X factor was based on 

any evaluation of the risk to infants and 

children.’’ (Id. at 216). Further, the court 

concluded that, unlike the risk 

assessments that were not based on the 

Gledhill study, EPA did not rely on the 

developmental animal studies showing 

no differential sensitivity between adult 

and juvenile animals. According to the 

court, ‘‘EPA explicitly stated that it did 

not rely on any animal studies.’’ (Id. at 

217). The court thought this abnegation 

of reliance of animal studies was 

confirmed by EPA’s decision not to 

apply an interspecies factor to the 

Gledhill-based assessments. (Id.). 

Although the court noted that EPA 

called the 3X factor a FQPA factor, the 

court found that label to be insufficient 

absent an explanation ‘‘[i]n []either its 

IRED []or its two orders [of] how the 3X 

factor was designed ‘to take into account 

potential pre- and post-natal toxicity 

and completeness of the data with 

respect to infants and children.’ ’’ (Id.). 

The court held that EPA’s reasoning 

concerning the marginal effects seen at 

the LOAEL in the Gledhill study did not 

constitute a sufficient explanation 

because EPA did not relate that 

reasoning ‘‘to ‘potential pre- and postnatal toxicity and completeness of the 

data with respect to infants and 

children.’ ’’ (Id.). Finally, the court 

questioned EPA’s analysis that the 

effects at the LOAEL were marginal 

suggesting that EPA had not done a 

proper statistical analysis. (Id. at 218). 

Accordingly, the court concluded 

that, as to risk assessments that used the 

Gledhill study to derive the Point of 

Departure, EPA’s order was arbitrary 

and capricious due to EPA’s failure to 

provide an adequate explanation with 

regard to its decision on the FQPA 

safety factor. (Id.). Given this 

conclusion, the court vacated the aspect 

of EPA’s order pertaining to risk 

assessments based on the Gledhill study 

and remanded the matter to EPA. (Id. at 

220). 

3. Evidentiary hearing. With regard to 

NRDC’s request for an evidentiary 

hearing on issues it raised concerning 

the Gledhill study, the court determined 

that it did not need to resolve this 

question given its disposition of the 

FQPA safety factor issue. As the court 

pointed out, ‘‘EPA may decide, on 

remand, not to rely on the Gledhill 

study or to rely on the study in a 

different manner or for different 

reasons.’’ (Id. at 219). 

VII. FQPA Safety Factor Determination 

for Gledhill-based Assessments 

A. Introduction 

FFDCA section 408(b)(2)(C) expressly 

requires EPA to apply a default 

additional 10X safety factor for the 

protection of infants and children 

unless EPA determines, based on 

reliable data, that a different factor 

would be safe. Under the terms of the 

statute, this additional safety factor is 

imposed ‘‘to take into account potential 

pre- and post-natal toxicity and 

completeness of the data with respect to 

exposure and toxicity to infants and 

children.’’ (21 U.S.C. 346a(b)(2)(C)). To 

implement these statutory commands, 

EPA has released detailed guidance that 

advises EPA risk assessors in making 

decisions on the FQPA safety factor to 

focus on potential pre- and post-natal 

toxicity and the completeness of the 

toxicity and exposure databases. In the 

dichlorvos IRED and the two orders 

responding to NRDC’S dichlorvos 

petition, EPA devoted several pages to 

explaining how its decision to apply a 

3X FQPA safety factor complied with 

the statutory directives on the FQPA 

safety factor and was consistent with its 

policy guidance document. (See Ref. 3 

at 128–132; 72 FR 68694–68695; 73 FR 

42695–42696). From start to finish this 

discussion centered on the issues of 

completeness of the toxicity and 

exposure databases for dichlorvos and 

the potential increased sensitivity of 

infants and children to dichlorvos from 

pre- and post-natal toxicity. 

Nevertheless, in vacating, in part, 

EPA’s dichlorvos order, the Second 

Circuit court held that there was a 

complete absence of an explanation 

from EPA as to how EPA’s choice of a 

safety factor protected infants and 

children. As the court repeatedly stated, 

‘‘EPA did not explain why a children’s 

safety factor less than 10X would ‘take 

into account potential pre- and postnatal toxicity and completeness of the 

data with respect to infants and 

children.’ ’’ (658 F.3d at 217). In fact, the 

court rejected EPA’s claim to have 

applied any FQPA safety factor at all. 

According to the court, the additional 

safety factor applied by EPA could not 

be considered a FQPA safety factor 

given what the court viewed as EPA’s 

denial that the additional safety factor 

had anything to do with infants and 

children. (Id. at 211, 216). 

Following a close review of EPA’s 

prior explanations and the court’s 

opinion, EPA now recognizes that the 

discussion of the FQPA safety factor in 

its dichlorvos IRED and orders was less 

than transparent. EPA’s explanation for 

its position on the FQPA safety factor 

used, at times, a form of short-hand that 

hid rather than elucidated its reasoning. 

In particular, EPA’s short-hand appears 

to have led the court to the following 

two misunderstandings: (1) That EPA’s 

use of a 3X safety factor to address the 

lack of a NOAEL in the Gledhill study 

had nothing to do with the safety of 

infants and children; and (2) that EPA 

did not consider the animal 

developmental data in making a 

determination on the FQPA safety factor 

for assessments relying on the Gledhill 

study. Clarification of EPA’s position on 

these two issues is critical to an 

understanding of EPA’s FQPA safety 

factor decision. Accordingly, on 

remand, EPA has first addressed how 

the Gledhill-based assessments relate to 

protection of infants and children and 

how EPA used animal developmental 

data in these assessments. Only then 

does EPA offer its explanation as to 

how, in light of the court’s opinion, its 

choice of a FQPA safety factor for the 

Gledhill-based risk assessment is 

protective of the safety of infants and 

children, as required by FFDCA section 

408(b)(2)(C). 

B. Clarifications 

1. Applying a FQPA safety factor to 

address the lack of a NOAEL in the 

Gledhill Study. Numerous times in the 

IRED as well as its dichlorvos orders, 

EPA stated that an additional 3X safety 

factor was applied in risk assessments 

using the LOAEL in the Gledhill study 

as the Point of Departure due to a ‘‘lack 

of a NOAEL’’ in the study. (Ref. 3 at 133; 

658 F.3d at 217 (collecting cites)). EPA 

explained that the safety factor was used 

to project a NOAEL for the study. The 

court interpreted these statements as 

meaning the 3X factor had nothing to do 

with the protection to infants and 

children. According to the court, ‘‘EPA 

explained that the 3X factor [used in 

conjunction with the Gledhill study] 

was not based on any risk to children 

or infants, but accounted for EPA’s 

‘failure to identify a NOAEL in the 

[Gledhill] study.’ ’’ (Id. at 214). 

Certainly, the narrow issue addressed by 

the use of the 3X factor was the lack of 

a NOAEL in the Gledhill study. 

However, extrapolating a NOAEL 

through use of a safety factor is not an 

end in itself. Rather, the safety factor 

was used to ensure that dichlorvos risk 

assessments relying on the LOAEL in 

the Gledhill study adequately protect 

the population groups covered by those 

assessments. Importantly, the 

population groups covered by the 

Gledhill-based assessments include 

infants and children. Thus, the 3X factor 

to account for the lack of a NOAEL in 

the Gledhill study was critical to 

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protecting infants and children. 

However, EPA’s orders and IRED failed 

to make this linkage between the 3X 

factor and the safety of infants and 

children clear. That linkage is fleshed 

out in detail below. 

As discussed in Unit III.B.2.v., prior 

to the passage of FQPA, EPA had 

applied an additional uncertainty factor 

to address a data deficiency such as 

when adverse effects were seen in the 

lowest dose of a toxicological study (i.e., 

when the study did not provide a 

NOAEL). Such a factor is used to 

essentially extrapolate a NOAEL for the 

study. Without an additional safety 

factor, there is uncertainty as to whether 

reliance on the LOAEL as a Point of 

Departure in calculating a RfD/PAD or 

MOE is adequately protective of the 

populations covered by the risk 

assessment scenario relying on that RfD/ 

PAD or MOE. 

EPA has interpreted the FQPA as 

codifying this LOAEL-to-NOAEL 

uncertainty factor as a FQPA safety 

factor when the factor is used in a 

portion of a risk assessment (i.e., in a 

particular exposure scenario) that 

assesses, at least in part, the risk to 

infants and children. (Ref. 10 at 11–16, 

A–3—A–4). The logic here is 

straightforward. A study that fails to 

produce a NOAEL is considered to be a 

data deficiency that affects the 

completeness of the toxicity database. 

The statute specifically references 

completeness of the toxicity database as 

a reason for requiring an additional 

safety factor for the protection of infants 

and children. Thus, when the LOAEL 

from a study that lacks a NOAEL is 

chosen for the Point of Departure for a 

risk assessment applying to infants, 

children, or women of child-bearing age 

(for the purpose of protecting fetuses), 

the safety factor used to address this 

data deficiency is a FQPA safety factor 

for the protection of infants and 

children. This is the case whether or not 

the Point of Departure is used for 

infants, children, or women of childbearing age only or for both adults and 

all other population groups, including 

infants and children. Many risk 

assessments for particular exposure 

scenarios use the same Point of 

Departure for both adults and infants 

and children because frequently the 

relevant toxicity data show a lack of 

differential sensitivity between adults 

and the young. However, use in a risk 

assessment of the same Point of 

Departure for both adults and the young 

does not make the FQPA safety factor 

provision inapposite. EPA’s position is 

that any assessment of risk for a 

particular exposure scenario that 

includes, at least in part, an assessment 

of risks to infants and children triggers 

the FQPA safety factor provision. 

Nothing in section 408(b)(2)(C) limits 

the safety factor provision only to 

situations where infants or children are 

more sensitive than adults. For similar 

reasons, it is also irrelevant to 

application of the FQPA safety factor 

provision whether the Point of 

Departure is from a study involving 

juveniles or adults. Points of Departure 

for assessing risks to infants and 

children are based on the studies 

showing the most sensitive effects, 

whether the studies are conducted in 

adults or juveniles. (See Ref. 17 at 452 

(‘‘[C]hronic and subchronic tests in 

[adult animals] have value in assessing 

potential risks to children by, for 

example, identifying target sites for 

toxicity and providing dose-response 

information that may be useful for 

human safety assessment, irrespective of 

life stage.’’). The critical factor for the 

FQPA safety factor provision is whether 

the study is being used for a Point of 

Departure for assessing risk to infants 

and children. 

With this background, the connection 

between the use of a 3X safety factor to 

address the Gledhill study LOAEL and 

the protection of the infants and 

children can now be explicated. 

Because the Gledhill study produced 

cholinesterase effects at the lowest level 

in the subchronic studies in the 

dichlorvos database and the database 

showed no age-related sensitivity, (see 

discussion in Unit VII.C.), EPA chose 

the Gledhill LOAEL as the Point of 

Departure for assessing risks for shortand intermediate-term exposure 

scenarios to all population groups, 

including infants and children. In other 

words, the Gledhill LOAEL was selected 

as the Point of Departure for all 

population groups for these exposure 

scenarios because the dichlorvos 

database demonstrated that the Gledhill 

study not only provided the best 

measure of cholinesterase inhibition for 

protecting adults but that it was the best 

measure for protecting infants and 

children. Nonetheless, EPA also 

recognized that the data deficiency in 

the Gledhill study—the failure of the 

Gledhill study to identify a NOAEL— 

raises uncertainty as to what that study 

indicates regarding the threshold below 

which exposure to dichlorvos will not 

result in cholinesterase inhibition. To 

address this uncertainty and thus 

protect the safety of all population 

groups covered by the risk assessments, 

including infants and children, EPA 

chose to apply an additional safety 

factor of 3X. This choice of a safety 

factor was made under the rubric of the 

FQPA safety factor provision because 

the uncertainty raised by reliance on a 

LOAEL both (1) affected the assessment 

of the risk to infants and children; and 

(2) was driven by a data deficiency 

affecting the completeness of the 

toxicity database. (73 FR 42695; 72 FR 

68694–68695; Ref. 3 at 133, 134). Thus, 

the additional 3X safety factor used in 

assessments relying on the Gledhill 

study was not simply to address the lack 

of a NOAEL in that study but rather to 

ensure the protection of infants and 

children (among others) given that a 

LOAEL was used as the Point of 

Departure for assessing risk to infants 

and children for several exposure 

scenarios. Regrettably, the connection 

between a safety factor used to address 

the lack of a NOAEL in a study in adults 

and the protection of infants and 

children was not transparent in EPA’s 

IRED or its denial of NRDC’s petition 

and objections. That linkage should now 

be clear. 

2. Reliance on animal developmental 

data. EPA’s FQPA safety factor policy 

emphasizes the importance of 

considering the ‘‘weight-of-evidence 

analyses for the completeness of the 

toxicity database, the degree of concern 

for pre- and postnatal toxicity, and 

results of the exposure assessments’’ in 

making a safety factor determination. 

(Ref. 10 at 50). In particular, the policy 

stresses ‘‘taking into account all 

pertinent information in evaluating 

potential pre- and postnatal toxicity.’’ 

(Id. at 29). The policy recognizes that 

human data on pre- and postnatal 

toxicity is ‘‘difficult to obtain’’ and for 

that reason discusses, in detail, how 

animal developmental data should be 

considered in evaluating the potential 

for pre- and post-natal toxicity in 

humans. (Id. at 28–31). Although EPA 

did discuss the animal data on juvenile 

sensitivity in its FQPA safety factor 

determination, (72 FR 68694–68695), 

the court concluded that EPA had not 

considered that data in making a 

determination on the FQPA safety factor 

for assessments relying on the Gledhill 

study for the Point of Departure. 

To support this conclusion, the court 

opined that EPA’s orders specifically 

referenced the animal developmental 

studies in conjunction with the safety 

factor determination for the nonGledhill-based assessments but had not 

done so as to the Gledhill-based 

assessments. The court is correct that 

EPA did not clearly explain that its 

discussion of the animal developmental 

data related both to the assessments 

based on a Point of Departure from 

animal data as well as the assessments 

relying on the Gledhill study for the 

Point of Departure. EPA’s discussion of 

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54414 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

1The one human study that was not used for 

selection of a Point of Departure was conducted 

with the pesticide oxamyl. The oxamyl human 

study was submitted for the purpose of justifying 

a reduction of the 10X interspecies factor despite 

use of an animal study for the Point of Departure. 

The Human Studies Review Board concluded that 

the ‘‘intentional human dosing study of oxamyl was 

sufficiently robust to be used for reducing the 10x 

inter-species (i.e. animal to human) uncertainty 

factor in the cumulative risk assessment for the Nmethyl carbamates.’’ (Ref. 36 at 28). Thus, it is not 

even a given that a full interspecies factor will be 

applied when an animal study is relied upon to 

extrapolate a dose in humans. 

the Gledhill study, and the data 

deficiency therein, followed the analysis 

of the animal developmental data but 

did not directly reference that data or 

the statutory considerations bearing on 

the FQPA safety factor decision. (Id.). 

To avoid this error in its revised safety 

factor finding below, EPA has included 

a discussion of the data deficiency in 

the Gledhill study under the topic of 

‘‘completeness of the data with respect 

to * * * toxicity’’ and also explicitly 

discussed how the statutory 

consideration pertaining to the potential 

for pre- or post-natal toxicity, and the 

animal data bearing on this issue, was 

considered in the context of the 

Gledhill-based assessments. 

The court also concluded that ‘‘EPA 

explicitly stated that it did not rely on 

any animal studies’’ in connection with 

the Gledhill-based assessments, (658 

F.3d at 217), citing to language in the 

IRED that specified that where the Point 

of Departure was chosen from the 

Gledhill study ‘‘there was no need to 

account for interspecies extrapolation 

* * * [s]ince the study was conducted 

in human subjects.’’ (Ref. 3 at 133, 134). 

According to the court, ‘‘[w]hen EPA 

did rely on the animal studies * * * [it] 

properly applied a safety factor of ‘10X 

for interspecies differences.’ ’’ (658 

F.23d at 217). The court appears to have 

drawn the conclusion that the 

interspecies factor should be applied 

whenever EPA considers animal studies 

in any aspect of the risk assessment. 

Thus, the court reasoned that because 

EPA did not apply an interspecies factor 

for the Gledhill-based assessments, it 

could not have considered the animal 

developmental data in the FQPA safety 

factor determination for dichlorvos. 

The court has misapprehended the 

reason EPA uses an interspecies factor 

in risk assessments. The factor is not 

automatically applied whenever animal 

data are considered in any aspect of a 

risk assessment. Rather, as explained in 

Unit III.B.2., the interspecies factor is 

used when extrapolating from a dose in 

an animal study (generally a NOAEL or 

LOAEL) on a milligram-per-kilogram of 

body weight basis to a dose in humans. 

(See Ref. 10 at 10 (an interspecies factor 

is used ‘‘if animal data have been used 

as the basis for deriving the hazard 

values’’). The interspecies factor is 

designed to account for possible 

toxicokinetic and toxicodynamic 

differences in humans and laboratory 

animals that may result in differences in 

internal dose and organ sensitivity 

between humans and animals. Thus, in 

the dichlorvos animal assessments in 

which EPA relied on animal data for the 

Point of Departure, EPA did apply an 

interspecies factor. For those 

assessments, EPA was either 

extrapolating a RfD for humans from 

animal data or comparing the margin 

between human exposure and the dose 

in animals that was judged to be a 

NOAEL. No interspecies factor was 

necessary in assessments based on the 

LOAEL from the Gledhill study because 

EPA was not extrapolating from a 

NOAEL or LOAEL in laboratory animals 

to humans or comparing human 

exposure to a dose from an animal 

study. Rather, EPA had data in 

humans—the Gledhill study—and was 

relying on that data for the Point of 

Departure. There was no need to 

account for the toxicokinetic and 

toxicodynamics differences between 

humans and animals when deriving a 

safe dose for humans from a study 

conducted with humans. 

EPA, however, did rely on the animal 

developmental data in the FQPA safety 

factor determination for the Gledhillbased assessments. But that reliance was 

for a purpose distinct and separate from 

use of the data for extrapolating a dose 

from animals to humans. In accordance 

with Agency FQPA safety factor policy, 

EPA considered the dichlorvos animal 

developmental data with regard to the 

important information it provides on 

whether the 10X intraspecies factor for 

dichlorvos is protective of infants and 

children. (Ref. 10 at 29). A primary 

focus of the animal developmental data 

(the rat and rabbit developmental 

studies, the rat reproduction study, the 

rat developmental neurotoxicity study, 

and comparative cholinesterase studies) 

is on the relative sensitivity of adult and 

juvenile animals. Because EPA would 

rarely have data on the relative 

sensitivity among different age groups of 

humans to a pesticide, these animal data 

help inform, as EPA policy makes clear, 

whether the 10X intraspecies factor is 

sufficiently protective of infants and 

children. (Id.). 

Considering animal developmental 

data in evaluating the intraspecies factor 

is a standard part of EPA’s risk 

assessment process. As discussed in 

Unit III.B.2 and above, animal 

developmental data are central both to 

establishing the justification for the 10X 

default value for the intraspecies factor 

and for evaluating the protectiveness of 

this default value for specific chemicals. 

Although broad-based surveys of data 

on adult/juvenile sensitivity in both 

humans and animals generally support 

the use of a 10X default value for the 

intraspecies factor, there is wide 

recognition that the possibility of 

heightened sensitivity in infants and 

children warrants obtaining 

particularized data on juvenile/adult 

animal sensitivity for individual 

chemical risk assessments. When these 

data are available, they may indicate 

that there is no heightened concern 

warranting an additional safety factor or 

that an additional factor is necessary 

above and beyond the default 10X value 

for the intraspecies factor. In a few 

cases, EPA has even relied, at least in 

part, on animal data as supporting a 

reduction in the default 10X 

intraspecies factor. 

Yet, despite the centrality of animal 

data to the justification for and selection 

of the intraspecies factor, EPA is not 

aware of any instance where an 

interspecies factor has been applied 

solely for reliance on animal data on 

adult-juvenile sensitivity to evaluate the 

protectiveness of the human 

intraspecies factor. For example, EPA’s 

long-established and consistent practice 

is not to apply an interspecies factor 

when relying on a human study for the 

Point of Departure even though a 

decision on the intraspecies factor is 

still an essential part of such 

assessments. Dourson et al. collected a 

summary of all EPA’s RfDs on EPA’s 

Integrated Risk Information System 

(IRIS) as of May 2000 that used human 

data for the Point of Departure. (Ref. 17). 

All 24 such assessments identified used 

an interspecies factor of 1X (i.e., no 

factor). EPA has identified 9 additional 

such risk assessments on IRIS postdating May 2000, and each one of those 

also does not apply an interspecies 

factor. (Ref. 30). Even more on point are 

EPA pesticide risk assessments relying 

on human data. Since the promulgation 

of the 2006 Human Research Rule, EPA 

has accepted 10 human studies for use 

in pesticide risk assessments other than 

the Gledhill study. (Id.). A Point of 

Departure was selected from 9 of those 

10 studies.1 Yet, in none of those 

assessments did EPA apply an 

interspecies factor in conjunction with a 

Point of Departure from a human study 

even though the assessments do not 

focus on the human data exclusively. 

Animal developmental data play a 

critical part in these assessments, 

particularly where a FQPA safety factor 

analysis is required. 

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The FQPA safety factor analysis in the 

tolerance reassessment document for the 

pesticide ethephon provides a good 

example of this. With ethephon, ‘‘[t]he 

conventional UF of 10X for interspecies 

extrapolation was not applied because 

the endpoint selected for the risk 

assessment was from a human study.’’ 

(Ref. 31 at 6). At the same time, EPA 

noted that: 

The Agency concluded that no FQPA 

Safety Factor is necessary to protect the 

safety of infants and children in assessing 

ethephon exposure and risks because the 

toxicology database for ethephon contains 

acceptable guideline developmental and 

reproductive studies as well as acute and 

subchronic neurotoxicity studies. [Guideline 

studies are conducted in animals. (40 CFR 

158.500)]. The Agency also concluded that 

there is no quantitative or qualitative 

evidence of increased susceptibility 

following in utero or postnatal exposure in 

any of the developmental or reproductive 

studies. The RfDs and toxicity endpoints 

established are protective of pre/postnatal 

toxicity following acute and chronic 

exposures. 

(Id.). A variation on the approach in 

ethephon is the safety/uncertainty 

factors chosen in assessing the risk of 

the pesticide methomyl. (Ref. 32 at 5). 

For the methomyl risk assessments that 

relied on a human study for the Point 

of Departure, the Agency applied a 10X 

intraspecies, a 1X interspecies factor (no 

extrapolation from a dose in animals to 

humans), and a 2X (data-derived) FQPA 

safety factor. The 2X FQPA factor was 

chosen because, unlike dichlorvos, the 

adult/juvenile comparative 

cholinesterase data in rats showed that 

juveniles were approximately twice as 

sensitive to methomyl as adults. Thus, 

a 2X FQPA safety factor was applied to 

ensure that the 10X intraspecies factor 

was sufficiently protective. However, 

just as with dichlorvos and ethephon, 

no interspecies factor (1X) was used 

because the Point of Departure was 

derived from a human, not animal, 

study. A final example illustrating that 

consideration of animal data in 

conjunction with choice of a Point of 

Departure from a human study does not 

result in use of a 10X interspecies factor 

is the assessment of the pesticide 

chloropicrin. With chloropicrin, EPA 

relied upon a human study for the Point 

of Departure and thus no interspecies 

factor (1X) was applied. However, EPA’s 

consideration of the data from humans 

and animals also led EPA to conclude 

that no intraspecies factor (1X) was 

needed either. (Ref. 33). No interspecies 

factor was applied as a result of 

consideration of animal data in 

evaluating the need for an intraspecies 

factor. 

Use of a 10X interspecies factor for 

reliance on animal developmental data 

to evaluate the protectiveness of the 

intraspecies factor would also lead to 

illogical results. For example, animal 

developmental data are now considered 

so critical to evaluating pre- and postnatal toxicity that the FQPA imposes a 

presumptive 10X safety factor in their 

absence. Yet, once the data are 

submitted, it does not make sense to 

replace the 10X safety factor that 

addressed their absence with a safety 

factor of equivalent value to address 

their mere use for evaluation of pre- and 

post-natal toxicity. Leaving aside what 

the animal developmental data show, 

there cannot be equal need for safety 

factors both in the absence and presence 

of adequate animal developmental data. 

In sum, it would not only be 

unprecedented, but inconsistent with 

well-established safety factor practice, 

to suggest that the mere consideration of 

animal data in evaluating the 

protectiveness of the intraspecies factor 

triggers application of an interspecies 

factor. Importantly, under the FFDCA 

section 408, EPA is only authorized to 

consider ‘‘safety factors which in the 

opinion of experts qualified by scientific 

training and experience to evaluate the 

safety of food additives are generally 

recognized as appropriate for the use of 

animal experimentation data.’’ 21 U.S.C. 

346a(b)(2)(D)(ix). 

Unfortunately, EPA’s short-hand 

description of its FQPA determination 

misled the court regarding EPA’s 

consideration of the animal 

developmental data. Further, EPA’s 

brief explanation for why it did not 

apply an interspecies factor did not 

clarify the situation. This, in turn, 

resulted in confusion regarding the role 

of the interspecies factor. EPA’s revised 

FQPA safety factor explanation attempts 

to avoid such pitfalls. 

C. Revised FQPA Safety Factor Decision 

1. Introduction and background. The 

Second Circuit court has vacated that 

portion of EPA’s order on NRDC’s 

objections ‘‘assessing the risk of 

dichlorvos based on the Gledhill study 

* * * .’’ (658 F.3d at 220). The court 

found that EPA had ‘‘failed to explain 

why it did not use a 10X children’s 

safety factor’’ for those assessments. 

(Id.). 

In the IRED, EPA relied on the 

Gledhill human study for selection of 

the Point of Departure for assessing 

dermal (short-, intermediate-, and longterm), incidental oral (short-term), and 

inhalation (short- and intermediateterm) risk for all population subgroups, 

including infants and children. Agencywide guidance on Reference Dose 

selection emphasizes that human data 

provides the best source for assessing 

human risk: ‘‘Adequate human data are 

the most relevant for assessing risks to 

humans. When sufficient human data 

are available to describe the exposureresponse relationship for an adverse 

outcome(s) that is judged to be the most 

sensitive effect(s), reference values 

should be based on human data.’’ (Ref. 

19 at 4–12; see Ref. 10 at 33 (‘‘human 

data are the most relevant data for 

assessing health risks’’)). EPA chose the 

Gledhill study, in particular, for 

determination of the Point of Departure 

because it evaluated cholinesterase 

inhibition, the most sensitive effect for 

dichlorvos as shown by animals studies, 

and because the Gledhill study has ‘‘the 

lowest LOAEL established for RBC 

cholinesterase inhibition in a repeated 

oral exposure to dichlorvos.’’ (Ref. 3 at 

133). Specifically, it was the lowest 

LOAEL considering both the human and 

animal studies and cholinesterase 

effects in adults and juveniles. EPA’s 

determination that the Gledhill study 

‘‘is sufficiently robust for developing a 

Point of Departure for estimating 

dermal, incidental oral, and inhalation 

risk from exposure to DDVP,’’ was 

concurred in by the Human Studies 

Review Board, an independent expert 

panel of scientists. (72 FR 68675). 

The level of concern for the risk 

assessments relying on the Gledhill 

study for the Point of Departure was 

expressed in terms of a target MOE of 

30. That value was based on an 

intraspecies uncertainty factor of 10X 

and a FQPA safety factor of 3X. 

Although EPA concluded that neither 

the data on pre- or postnatal toxicity or 

on exposure to dichlorvos showed a 

need for a FQPA safety factor, EPA 

found that the data deficiency with 

regard to the Gledhill study—namely, 

its lack of a NOAEL—justified the 

retention of a 3X FQPA safety factor. 

2. FQPA safety factor decision. In 

making a FQPA safety factor 

determination, EPA follows a weight-ofthe-evidence approach that focuses on 

the three considerations explicitly noted 

in FFDCA section 408(b)(2)(C): the 

completeness of the toxicity database; 

the potential for pre- and post-natal 

toxicity; and the completeness of the 

exposure database. (Ref. 10 at iv). Each 

of those considerations is discussed 

below. 

i. Completeness of the toxicity 

database. In ruling on NRDC’s petition, 

EPA concluded that it had a complete 

toxicity database under the pesticide 

data requirements in 40 CFR part 158. 

This included all required data 

specifically pertaining to effects on the 

young—developmental studies in two 

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2Statistical significance is a term used to describe 

observed data that differ from the overall 

distribution of values by a level that is unlikely to 

be due to random error. Statistical significance is 

examined in terms of the probability of the 

observed differences occurring. By convention, 

observed values that have a 5 or 1 percent chance 

of occurring are treated as statistically significant, 

with 1 percent being the more rigorous standard. 

(Ref. 43). 

species (rat and rabbit); a two-generation 

reproduction study in rats; and a 

developmental neurotoxicity study in 

rats. EPA also had comparative 

cholinesterase inhibition data in adult 

and juvenile rats. EPA did not have data 

submitted pursuant to the Endocrine 

Disruptor Screening Program, but for the 

reasons explained in its order denying 

NRDC’s petition, EPA has concluded 

that it has adequate data on dichlorvos’ 

endocrine effects for the purposes of its 

FQPA safety factor decision. (73 FR 

42697–42698). 

In addition to these standard animal 

toxicity studies, the dichlorvos 

registrant had submitted one toxicity 

study in humans, the Gledhill study, 

that EPA had determined was in 

compliance with its Human Research 

Rule. (40 CFR part 26). As discussed 

below, there is a data deficiency issue 

with this study that is pertinent to the 

completeness of the toxicity database 

consideration. Although this study was 

conducted in adults, it is highly relevant 

to the protection of infants and children 

because EPA has, for the reasons 

explained in Units VII.B.1. and VII.C.1, 

selected the Gledhill study for 

identifying a Point of Departure for as to 

several risk assessment scenarios for all 

population groups, including infants 

and children. Thus, how EPA addresses 

the data deficiency in the Gledhill study 

will directly affect how it assesses risks 

to infants and children. 

The Gledhill study was a repeat dose 

study measuring RBC cholinesterase 

inhibition in control and dichlorvostreated human subjects. Only a single 

dose level (7 mg) was used in the study. 

Cholinesterase inhibition in the treated 

subjects reached a level of 16 percent by 

day 18 of treatment (i.e., cholinesterase 

activity levels declined to 84 percent of 

the pre-dose mean by day 18). As shown 

in Table 2 below (reprinted from EPA’s 

Data Evaluation Record of the Gledhill 

study and the Gledhill study report), the 

statistical analysis of the results of the 

Gledhill study shows a high level of 

statistical significance (at the 1 percent 

level) 2 for cholinesterase activity levels 

both between controls and treated 

subjects and between pre- and postdosing cholinesterase levels for treated 

subjects for most days post-dosing. 

TABLE 2—RESULTS OF THE GLEDHILL STUDY

Timepoint 

Placebo (n = 3) Dosed (n = 6) 

Mean SD % pre-dose 

mean Mean SD % pre-dose mean 

Pre-dose ........... 18483 .52 1346 .91 100 17738.33 1713.50 100 

Day 1 ................ 17930 .00 1404 .24 97 17628.33 1914.45 99 

Day 2 ................ 18180 .00 1564 .7 98 16816.67* 1546.63 95 

Day 4 ................ 18740 .00 1771 .13 101 16933.33** 1597.33 95 

Day 7 ................ 18530 .00 1888 .36 100 16181.67** †† 1759.48 91 

Day 9 ................ 18460 1007 .03 100 16708.33 2504.97 94 

Day 11 .............. 19210 .00 1035 .95 104 16036.67** †† 1654.38 90 

Day 14 .............. 18490 .00 1642 .35 100 15333.33** †† 1250.34 86 

Day 16 .............. 17706 .67 2470 .15 96 15191.67** †† 1062.59 86 

Day 18 .............. 18260 .00 2298 .87 99 14855.00** †† 1198.51 84 

* Statistically significant difference from pre-dose at the 5% level (paired t-test). 

** Statistically significant difference from pre-dose at the 1% level (paired t-test). 

††Statistically significant difference between placebo and dose groups at the 1% level (t-test, based on repeated measures of analysis of 

covariance). 

(Refs. 34 and 35). 

EPA found these statistical results to 

be sufficiently ‘‘robust’’ to support use 

of the Gledhill study as the Point of 

Departure. This judgment was 

concurred on by the Human Studies 

Review Board. (Ref. 36). The Board 

relied upon the following aspects of the 

study: The repeated dose approach 

which allowed examination of the 

sustained nature of RBC cholinesterase 

inhibition; robust analysis of RBC 

cholinesterase inhibition both in terms 

of identifying pre-treatment levels and 

consistency of response within and 

between subjects; and the observation of 

a low, but statistically significant RBC 

cholinesterase inhibition response. (Id. 

at 39). The HSRB concluded that 

‘‘[a]lthough a study using a single dose 

level is not ideal for establishing a 

LOAEL, there was general consensus 

that RBC cholinesterase is a wellcharacterized endpoint for compounds 

that inhibit acetylcholinesterase activity 

and therefore, because the decreased 

activity in RBC cholinesterase activity 

observed in this study was at or near the 

limit of what could be distinguished 

from baseline values, it was unlikely 

that a lower dose would produce a 

measurable effect in RBC cholinesterase 

activity.’’ (Id. at 41). 

There is one significant deficiency 

with the Gledhill study, however. 

Because the study used a single dose 

level, and that dose was found to cause 

an adverse effect on RBC cholinesterase 

activity, the study does not identify a 

NOAEL. As discussed earlier, this type 

of deficiency is incorporated and 

addressed as part of the FQPA safety 

factor because it relates to the first 

consideration noted in FFDCA section 

408(b)(2)(C)—completeness of the 

toxicity database. (See Unit III.B.2.vi.). 

In deciding what level of safety factor 

is necessary to address this data 

deficiency, EPA is guided by EPA 

science policy on use of uncertainty 

factors, the scientific literature on safety 

factors, and EPA prior practice with 

regard to FQPA safety factor decisions. 

EPA’s RfD policy recommends a default 

value of 10X for an uncertainty factor 

addressing the lack of a NOAEL but 

makes clear that ‘‘[t]he size of the 

LOAEL-to-NOAEL uncertainty factor 

may be altered, depending on the 

magnitude and nature of the response at 

the LOAEL.’’ (Ref. 19 at 4–44). Further, 

as discussed in Unit III.B.2.v, Dourson 

et al. concluded that ‘‘[t]he data indicate 

that when faced with a LOAEL and not 

a NOAEL, the choice of uncertainty 

factor should generally depend on the 

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Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 54417 

severity of the effect at the LOAEL.’’ 

(Ref. 9). In specific FQPA safety factor 

decisions, the magnitude of the 

response has frequently been an 

important consideration supporting use 

of a 3X FQPA safety factor to address 

reliance on a LOAEL for the Point of 

Departure. (See, e.g., 75 FR 22245, 

22249, April 28, 2010 (selecting a 3X 

FQPA safety factor for lack of a NOAEL 

where ‘‘[t]he neurotoxic effects in this 

study showed a good dose response 

which resulted in minimal effects on 

motor activity and locomotor activity at 

the LOAEL.’’); 74 FR 67090, 67094, 

December 18, 2009 (selecting a 3X 

FQPA safety factor for lack of a NOAEL 

where ‘‘[t]he gastric lesions (most 

sensitive effect) are due to the direct 

irritant properties of endothall (i.e., 

portal effects) and not as a result of 

frank systemic toxicity; the severity of 

the lesions were minimal to mild; and 

there was no apparent dose-response for 

this effect.’’); 74 FR 53172, 53177, 

October 16, 2009 (‘‘The concern is low 

for the use of a LOAEL to extrapolate a 

NOAEL, given the relatively 

insignificant nature of the effect 

(transient diarrhea seen in the rat); the 

fact that diarrhea was only seen in 

studies involving gavage dosing in the 

rat but not in repeat dosing through 

dietary administration in rats, mice, 

rabbits, and dogs; the very high dose 

level needed to reach the acute oral 

lethal dose (LD)50 (>5,000 milligrams/ 

kilogram (mg/kg)), and the overall low 

toxicity of azoxystrobin.’’); 74 FR 26536, 

26541, June 3, 2009 (selecting a 3X 

FQPA safety factor for lack of a NOAEL 

where ‘‘[t]he response was marginal at 

the LOAEL.’’); 72 FR 41224, 41228, July 

27, 2007 (‘‘The uncertainty factor of 3X 

for use of the LOAEL instead of the 

NOAEL is considered appropriate 

because an increased incidence and 

severity of epithelial hyperplasia, 

hyperkeratosis and ulceration of the 

non-glandular region of the stomach in 

females were seen in few animals and 

were minimal in severity and observed 

in one sex only.’’); 72 FR 33901, 33905, 

June 20, 2007 (‘‘The 3X factor is 

considered to be protective because the 

incidence of the effects at the lowest 

dose tested was only marginally higher 

than the historical controls.’’); 71 FR 

71052, 71056, December 8, 2006 (‘‘A 3x 

safety factor (as opposed to a 10x) for 

the lack of a NOAEL in this critical 

study is adequate because the 

magnitude of the response was low (low 

incidences without dose response) and 

the effect of concern was seen in an 

unusual strain (Chinchilla) of rabbits 

and not in the New Zealand strain 

commonly used in developmental 

toxicity studies.’’)). 

EPA’s policy on cholinesterase 

inhibition provides important guidance 

on characterizing the magnitude of a 

RBC cholinesterase finding. The policy 

explains that cholinesterase activity 

data is treated ‘‘like most continuous 

endpoints (i.e., graded measures of 

response such as changes in organ 

weight, hormone levels or enzyme 

activity),’’ in that ‘‘no fixed generic 

percentage of change from the baseline 

is considered to separate adverse from 

non-adverse effects.’’ (Ref. 27 at 14). 

Given the continuous nature of the 

inhibition response, ‘‘OPP has used 

statistical significance, rather than a 

fixed percentage of response from 

baseline, as the primary, but not 

exclusive, determinant of toxicological 

and biological significance in selecting 

Points of Departure.’’ (Id.) Nonetheless, 

the policy advises that, in examining 

what level of cholinesterase inhibition 

will be judged an adverse effect, the 

level of inhibition must be critically 

evaluated ‘‘in the context of both 

statistical and biological significance.’’ 

(Id. at 37) (emphasis in original). 

Although the policy notes that ‘‘[n]o 

fixed percentage of change (e.g., 20% for 

cholinesterase enzyme inhibition) is 

predetermined to separate adverse from 

non-adverse effects,’’ (Id.), it explains 

that ‘‘OPP’s experience with the review 

of toxicity studies with cholinesteraseinhibiting substances shows that 

differences between pre- and postexposure of 20% or more in enzyme 

levels is nearly always statistically 

significant and would generally be 

viewed as biologically significant.’’ (Id. 

at 37–38). The policy recommends that 

‘‘[t]he biological significance of 

statistically-significant changes of less 

than 20% would have to be judged on 

a case-by-case basis, noting, in 

particular the pattern of changes in the 

enzyme levels and the presence or 

absence of accompanying clinical signs 

and/or symptoms.’’ (Id. at 38). The 

policy notes that similar or higher levels 

of cholinesterase inhibition are used ‘‘in 

monitoring workers for occupational 

exposures (even in the absence of signs, 

symptoms, or other behavioral effects).’’ 

(Id. at 31). For example, the policy 

points out that the California 

Department of Health Services requires 

that workers exposed to toxic chemicals 

such as organophosphate pesticides be 

removed from the workplace if ‘‘red 

blood cell cholinesterase levels show 

30% or greater inhibition,’’ and that the 

World Health Organization ‘‘has 

guidelines with the same RBC action 

levels (i.e., 30% or greater inhibition).’’ 

(Id.). In conducting Benchmark Dose 

analyses for dichlorvos, as well as other 

organophosphate pesticides, EPA 

generally has used a 10 percent 

inhibition level as indicating an adverse 

effect for both RBC and brain 

compartments given that both of these 

compartments were used for developing 

Points of Departure. (Ref. 37 at I.B p.17). 

A close examination of the 

cholinesterase inhibition data for 

dichlorvos, however, has shown that, 

while both brain and RBC 

compartments have similar levels of 

inhibition for acute or very short-term 

exposures, for longer-term exposures 

brain cholinesterase inhibition is much 

less sensitive than RBC inhibition and 

thus 20 percent RBC inhibition would 

be adequately protective. (72 FR 68691; 

Ref. 38). RBC cholinesterase inhibition 

is not itself an adverse effect; rather, it 

is used as a surrogate for effects on the 

nervous system. 

In the Gledhill study, the average 

level of RBC cholinesterase inhibition of 

the final day of treatment was 16 

percent. Although the level of RBC 

cholinesterase inhibition was relatively 

low and not accompanied by clinical 

signs, EPA concluded, contrary to the 

study’s author, that the 7 mg dose did 

produce an adverse effect. In reaching 

this conclusion, EPA relied on the 

uniform nature of the results in the 

subjects that showed a clear pattern of 

increasing response over time and a 

high level of statistical significance in 

the differences in cholinesterase 

inhibition both between treated and 

control subjects and between pretreatment and post-treatment of 

individual subjects. Nonetheless, 

consistent with its cholinesterase policy 

and its conclusions in regard to other 

dichlorvos cholinesterase data, EPA 

found the magnitude of the change in 

cholinesterase levels to be marginal. The 

Human Studies Review Board agreed 

both with EPA’s determination on 

adversity and the marginality of the 

response. As to the marginality of the 

response, the Board specifically noted 

that ‘‘because the decreased activity in 

RBC cholinesterase activity observed in 

this study was at or near the limit of 

what could be distinguished from 

baseline values, it was unlikely that a 

lower dose would produce a measurable 

effect in RBC cholinesterase activity.’’ 

(Ref. 36 at 41). Under EPA’s 

cholinesterase policy, the level of 

cholinesterase inhibition in the Gledhill 

study falls at the low end of the scale 

of what might be considered an adverse 

effect and the policy recommends a 

case-by-case inquiry into the adversity 

determination for inhibition at this 

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54418 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

3The court stated that EPA had found the 

Gledhill study to ‘‘have had sufficient statistical 

power to detect a cholinesterase inhibition greater 

than 0, [but] EPA did not explain whether the 9- 

person study (six dosed subjects, 3 placebo 

subjects) had sufficient power to determine with 

any level of precision the magnitude of the 

cholinesterase inhibition.’’ (Ref. at 218) (emphasis 

added). To clarify, EPA did not do a ‘‘statistical 

power’’ calculation because statistical power is a 

way of determining the probability of whether a 

study would detect an effect of a given size if such 

an effect is there to find. The concern is that a study 

may indicate that there is no effect when, in fact, 

the study missed the effect because it had a low 

probability of finding it (i.e., the study gives a false 

negative). Because the Gledhill study identified the 

positive effect it was looking for (cholinesterase 

inhibition), EPA dismissed NRDC’s arguments 

regarding statistical power as irrelevant. (73 FR 

42704–42706). What EPA’s statistical analysis of the 

Gledhill study did show was that there was a 

statistically significant difference (at the level of 1 

percent) in cholinesterase inhibition between 

control and treated subjects and between pre- and 

post-dosing for treated subjects on most days of 

treatment. That is, the differences in cholinesterase 

inhibition between controlled and treated subjects 

and between pre- and post-dosing of treated 

subjects were very unlikely to have been due to 

chance. 

level. Accordingly, EPA determined 

previously, and reaffirms in this order, 

that a full 10X safety factor is not 

needed to address the lack of a NOAEL 

in the Gledhill study. When a full order 

of magnitude of additional protection 

(i.e. 101) is unnecessary, EPA will 

generally use a half of that value (i.e, 

10.5 or approximately 3X) if that value 

is protective. Here, EPA determined, 

and in this order reaffirms, that the 

marginal nature of the cholinesterase 

response shows that a 3X factor is safe. 

In reaching its determination, EPA 

placed, and continues to place, great 

weight on the view of the Human 

Studies Review Board. This Board was 

created by EPA in response to a 

congressional mandate. (71 FR 6138 

(February 6, 2006)). It is comprised of 

non-EPA scientists, overwhelmingly 

from academia, who are specialists in 

the field of bioethics, biostatistics, 

human health risk assessment, and 

human toxicology. (73 FR 42690). The 

members of the Board at the time the 

Gledhill study was considered are listed 

in Appendix 1 to EPA’s prior denial 

order. (73 FR 42713). The Board is 

charged with reviewing both the ethics 

and scientific merit of intentional 

exposure human studies. Its 

proceedings are conducted in public 

and it accepted three rounds of public 

comment on review of the Gledhill 

study: (1) Written comment submitted 

prior to its open meeting on dichlorvos; 

(2) oral comments at the open meeting; 

and (3) oral comments at a telephone 

conference on its proposed decision. (73 

FR 42692). No comments were 

submitted prior to the Board’s review 

suggesting that the cholinesterase 

response was greater than a marginal 

response and no meaningful comments 

were submitted to the Board or EPA, 

following release of the proposed and 

final Board opinions, contesting the 

conclusions of this independent and 

expert scientific panel on this point. 

The Board’s conclusion with regard to 

the marginality of the cholinesterase 

inhibition effects in the Gledhill study 

are strongly supportive of EPA’s choice 

of a 3X factor to address the lack of a 

NOAEL in the Gledhill study. After all, 

the Board concluded that ‘‘it was 

unlikely that a lower dose would 

produce a measurable effect in RBC 

cholinesterase activity.’’ (Ref. 36 at 41). 

Use of a 3X factor is protective because 

it represents a choice of not simply of 

any lower dose (decreasing the dose by 

10 percent fits this criterion) but of a 

significantly lower dose than that in the 

Gledhill study for estimating risk (by 

applying a 3X factor EPA was 

essentially dividing the dose by a factor 

of 3). 

The court suggested in its opinion 

that EPA had not conducted an 

adequate statistical analysis to 

determine the accuracy of the 16 

percent cholinesterase inhibition figure 

and thus had no basis for making a 

conclusion ‘‘with any level of precision 

[as to] the magnitude of the 

cholinesterase inhibition.’’ 3 658 F.3d at 

218. Although EPA scientists and the 

scientists on the Human Studies Review 

Board, including the three 

biostatisticians, found the statistical 

analysis sufficient to support their 

conclusion on the marginality of the 

cholinesterase effect, EPA agrees that a 

precision analysis, i.e., the calculation 

of confidence intervals, conveys 

valuable information on the plausible 

range in which, within a certain degree 

of probability, the true value lies. 

Accordingly, EPA has calculated the 

confidence intervals for the mean 

cholinesterase inhibition levels. (Ref. 

39). For the days 14, 16, and 18 which 

had average cholinesterase inhibition 

levels of 14 percent, 14 percent, and 16 

percent, respectively, this calculation 

shows a 95 percent confidence that 

average inhibition is between 9- and 18 

percent, 9- and 19 percent, and 8- and 

24 percent, respectively. Because these 

ranges of RBC cholinesterase inhibition 

consistently fall at the low end of what 

might be found to be a statistically and 

biologically significant effect on RBC 

cholinesterase activity, EPA reaffirms its 

conclusion that the RBC cholinesterase 

inhibition seen in the Gledhill study 

was marginal. 

Finally, the determination to retain a 

FQPA safety of 3X for assessments for 

which the Point of Departure was 

selected from the Gledhill study is also 

supported by two BMD analyses on the 

dose levels causing cholinesterase 

inhibition in animals performed in 

conjunction with the IRED. As 

explained earlier, BMD analysis is 

preferred by EPA to the NOAEL/LOAEL 

approach of selecting a Point of 

Departure from studies because all of 

the data from a study can be used in 

deriving a dose response curve. (Ref. 

23). In the absence of the Gledhill study, 

these analyses would substitute for the 

LOAEL in the Gledhill study for 

selection of the Point of Departure for 

short- and intermediate-term risk 

assessments because they define the 

most sensitive effect for these exposure 

durations. The first of these analyses is 

a BMD analysis of comparative 

cholinesterase studies conducted in 

adult and juvenile rats. (This BMD 

analysis is discussed in more detail 

immediately below in the section on 

‘‘pre- and post-natal toxicity.’’) The 

lowest BMDL from that analysis 

(focusing on pooled historical controls) 

is 0.38 mg/kg/day. (Ref. 42). The second 

BMD analysis is an analysis of the 

cholinesterase inhibition results of the 

subchronic toxicity rat study. (Ref. 40). 

There, the BMDL was calculated as 0.4 

mg/kg/day. The only other potential 

animal study for use in selecting a Point 

of Departure for short- and intermediateterm exposures, the subchronic 

neurotoxicity study, had a significantly 

higher LOAEL (7.5 mg/kg/day) and 

produced percentage inhibition levels 

consistent with, or lower than, the other 

animal cholinesterase studies. (Ref. 41). 

A 100X safety factor to address 

interspecies extrapolation and 

interspecies variability would be used 

with these BMDLs if they were chosen 

as Points of Departure. No additional 

FQPA factor would be needed for the 

same reasons that a FQPA factor was not 

applied to the other assessments relying 

on animal data. (72 FR 68694–68695). 

Reliance on the BMD analyses for the 

Point of Departure with a 100X safety 

factor produces a level of concern that 

is comparable to using the Gledhill 

study for the Point of Departure with a 

30X safety factor. This is most easily 

seen if alternative RfD/PADs are 

calculated using the BMD analyses from 

the comparative cholinesterase studies 

and the subchronic study and from the 

LOAEL in the Gledhill study. With 

Gledhill study, the LOAEL of 0.1 mg/kg/ 

day would be divided by 30 (10X for 

intraspecies and 3X for FQPA) yielding 

a RfD/PAD of 0.0033 mg/kg/day. With 

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Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 54419 

the BMD analyses, the BMDL of 0.38 

mg/kg/day or 0.4 mg/kg/day would be 

divided by 100 (10x for interspecies and 

10X for intraspecies) for a RfD/PAD of 

0.0038 mg/kg/day or 0.004 mg/kg/day, 

respectively. The similarity of these 

results, whether extrapolating from the 

animal or human data, provides extra 

confidence in EPA’s FQPA safety factor 

decision. Additionally, EPA notes that 

reliance of the Gledhill study produces 

a marginally lower and thus more 

protective level of concern. 

Thus, the completeness of the toxicity 

database consideration indicates that an 

additional safety factor of no greater 

than 3X is needed to protect the safety 

of all populations, including infants and 

children, due to a data deficiency in the 

Gledhill study. This decision is 

consistent with EPA policies on RfD 

selection, the FQPA safety factor, and 

cholinesterase inhibition, and with the 

scientific literature on safety/ 

uncertainty factors. It is also consistent 

with long-established practice in 

making FQPA safety factor decisions in 

circumstances where a LOAEL-toNOAEL extrapolation is necessary. 

Finally, EPA’s scientific conclusions 

underlying this determination have 

been concurred in by the Human 

Studies Review Board, an independent 

panel of scientific experts in the field of 

toxicology and bio-statistics. 

ii. Pre- and post-natal toxicity. There 

was no evidence for increased 

susceptibility of rat and rabbit offspring 

to prenatal or postnatal exposure to 

dichlorvos. In both rat and rabbit 

developmental studies, no 

developmental effects were observed. In 

the rat reproduction study, the parental/ 

systemic NOAEL/LOAEL was 2.3/8.3 

mg/kg/day, which was identical to the 

reproductive/offspring NOAEL/LOAEL. 

The developmental neurotoxicity study 

showed evidence of sensitivity in one 

parameter, auditory startle amplitude. 

However, there are no residual concerns 

for sensitivity from this parameter 

because the effects in pups were seen at 

a dose well above the Points of 

Departure upon which EPA is regulating 

and a clear NOAEL for the effect (again, 

well above the Points of Departure) was 

identified. 

In addition, EPA evaluated the 

relative sensitivity of adult and juvenile 

animals to cholinesterase inhibition 

from dichlorvos exposure using a 

Benchmark Dose (BMD) analysis. For 

dichlorvos, EPA did a BMD analysis of 

the rodent toxicity studies for adult and 

juvenile cholinesterase inhibition (in 

both brain and RBC) in acute and 

repeated dose scenarios. (Refs. 3 at 129; 

42). EPA analyzed for a BMD showing 

a 10 percent inhibition of 

cholinesterase. EPA found similar 

results for BMDs and BMDLs for 

cholinesterase inhibition in both the 

acute and repeated dose scenarios for 

compartments (brain or RBC), sex, and 

age. In other words, this analysis 

indicated that there was no significant 

sensitivity difference with regard to 

cholinesterase inhibition between adults 

and juveniles. 

These data showing a lack of 

sensitivity of juvenile animals relative 

to adults indicate a low level of concern 

that the intraspecies factor applied to 

the Point of Departure from the Gledhill 

study will fail to protect infants and 

children. Therefore, the potential preand post-natal toxicity consideration, by 

itself, indicates that risks to infants and 

children can be safely assessed absent 

an additional safety factor. 

iii. Completeness of the exposure 

database. EPA has extensive data for 

estimating human exposure levels to 

dichlorvos. Although NRDC objected to 

portions of EPA’s dietary exposure 

assessment, after a careful re-analysis of 

that assessment EPA concluded that its 

dichlorvos exposure estimate from food, 

if anything, overstates dichlorvos 

exposure given the many conservatisms 

retained in the food exposure 

assessment and dichlorvos’ documented 

volatility and rapid degradation. (73 FR 

42699; 72 FR 68686). Further, EPA 

concluded that drinking water exposure 

to dichlorvos was also likely to have 

over-estimated exposure because of 

conservative assumptions. (72 FR 

68679–68680). A similar conclusion was 

reached as to residential exposure to 

dichlorvos after EPA revised this 

assessment taking into account concerns 

raised by NRDC. (72 FR 68691). Thus, 

the completeness of the exposure base 

consideration, by itself, also does not 

indicate a need for an additional safety 

factor to protect infants and children. 

3. Conclusion. The FQPA safety factor 

provision requires EPA to 

presumptively retain an additional 10X 

safety factor for the protection of infants 

and children. EPA may apply a different 

factor only if reliable data show that 

factor to be safe. Under EPA policy, EPA 

considers whether the additional FQPA 

safety factor is warranted taking into 

account the other safety factors being 

applied. 

For the Gledhill-based risk 

assessments, EPA has applied a 10X 

intraspecies safety/uncertainty factor to 

account for the potential for variable 

sensitivity among humans. EPA has not 

applied an interspecies factor in these 

risk assessments because the Point of 

Departure is drawn from a study in 

humans, not laboratory animals. (See 

Unit VII.B.2). Thus, the precise question 

under the FQPA safety factor provision 

for dichlorvos is whether EPA should 

retain the presumptive additional 10X 

factor for the protection of infants and 

children or whether there are reliable 

data showing that a different additional 

factor will, in conjunction with the 10X 

intraspecies factor, protect the safety of 

infants and children. As the above 

discussion of the all-important FQPA 

safety factor considerations indicates, 

there are (1) reliable data from animal 

studies on adult/juvenile sensitivity 

showing that the standard 10X 

intraspecies factor will be protective of 

potential pre- and post-natal toxicity to 

infants and children; (2) reliable data on 

human exposure to dichlorvos 

demonstrating that an additional safety 

factor is not needed to protect infants 

and children due to exposure concerns; 

and (3) reliable data with regard to the 

one toxicity data deficiency identified to 

show that a 3X additional factor will be 

protective of all human populations, 

including infants and children, as to the 

only toxicity data completeness issue. 

Therefore, EPA reaffirms its selection of 

a 3X FQPA safety factor for Gledhillbased assessments. 

D. Conclusion 

For all of the reasons set forth above, 

EPA denies NRDC’s objection to the use 

of a 3X FQPA safety factor for 

assessments relying on the Gledhill 

study for a Point of Departure. Based on 

the revised explanation provided in this 

order, EPA concludes, like it did in the 

July 23, 2008 order, that a 3X additional 

safety factor will protect the safety of 

infants and children. Because this 

revised explanation addresses the 

court’s reason for finding portions of the 

July 23, 2008 order to be arbitrary and 

capricious, EPA has not otherwise 

reopened or reconsidered that prior 

order. 

VIII. Statutory and Executive Order 

Reviews 

This action denies an objection to a 

denial of a petition to revoke tolerances, 

is in the form of an order and not a rule. 

(21 U.S.C. 346a(g)(2)(C)). Under the 

Administrative Procedure Act (APA), 

orders are expressly excluded from the 

definition of a rule. (5 U.S.C. 551(4)). 

Accordingly, the regulatory assessment 

requirements imposed on a rulemaking 

do not apply to this action, as explained 

further in the following discussion. 

A. Executive Order 12866 and Executive 

Order 13563 

Because this order is not a ‘‘regulatory 

action’’ as that term is defined in 

Executive Order 12866 entitled 

‘‘Regulatory Planning and Review’’ (58 

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54420 Federal Register / Vol. 77, No. 172 / Wednesday, September 5, 2012 / Rules and Regulations 

FR 51735, October 4, 1993), this action 

is not subject to review by the Office of 

Management and Budget (OMB) under 

Executive Orders 12866 and 13563 

entitled ‘‘Improving Regulation and 

Regulatory Review’’ (76 FR 3821, 

January 21, 2011). 

B. Paperwork Reduction Act 

This action does not contain any 

information collections subject to OMB 

approval under the Paperwork 

Reduction Act (PRA), 44 U.S.C. 3501 et 

seq. 

C. Regulatory Flexibility Act 

Since this order is not a rule under 

the APA (5 U.S.C. 551(4)), and does not 

require the issuance of a proposed rule, 

the requirements of the Regulatory 

Flexibility Act (RFA) (5 U.S.C. 601 et 

seq.) do not apply. 

D. Unfunded Mandates Reform Act; and 

Executive Orders 13132 and 13175 

This order denies an objection to a 

denial of a petition to revoke tolerances; 

it does not alter the relationships or 

distribution of power and 

responsibilities established by Congress 

in the preemption provisions of section 

408(n)(4) of FFDCA. As such, the 

Agency has determined that this action 

will not have a substantial direct effect 

on States or tribal governments, on the 

relationship between the national 

government and the States or tribal 

governments, or on the distribution of 

power and responsibilities among the 

various levels of government or between 

the Federal Government and Indian 

tribes. Thus, the Agency has determined 

that Executive Order 13132 entitled 

‘‘Federalism’’ (64 FR 43255, August 10, 

1999) and Executive Order 13175 

entitled ‘‘Consultation and Coordination 

with Indian Tribal Governments’’ (65 FR 

67249, November 9, 2000) do not apply 

to this order. In addition, this order does 

not impose any enforceable duty or 

contain any unfunded mandate as 

described under Title II of the Unfunded 

Mandates Reform Act (UMRA) (2 U.S.C. 

1531–1538). 

E. Executive Orders 13045, 13211 and 

12898 

As indicated previously, this action is 

not a ‘‘regulatory action’’ as defined by 

Executive Order 12866. As a result, this 

action is not subject to Executive Order 

13045, entitled ‘‘Protection of Children 

from Environmental Health Risks and 

Safety Risks’’, (62 FR 19885, April 23, 

1997) and Executive Order 13211 

entitled ‘‘Actions Concerning 

Regulations That Significantly Affect 

Energy Supply, Distribution, or Use’’, 

(66 FR 28355, May 22, 2001). In 

addition, this order also does not 

require any special considerations 

under Executive Order 12898 entitled 

‘‘Federal Actions to Address 

Environmental Justice in Minority 

Populations and Low-Income 

Populations’’ (59 FR 7629, February 16, 

1994). 

F. National Technology Transfer and 

Advancement Act 

This action does not involve any 

technical standards that would require 

Agency consideration of voluntary 

consensus standards pursuant to section 

12(d) of the National Technology 

Transfer and Advancement Act 

(NTTAA), (15 U.S.C. 272 note). 

IX. Congressional Review Act 

The Congressional Review Act, 5 

U.S.C. 801 et seq. does not apply 

because this action is not a rule as that 

term is defined in 5 U.S.C. 804(3). 

X. References 

1. Natural Resources Defense Council. 

(February 1, 2008). Objection to the Order 

Denying NRDC’s Petition to Revoke All 

Tolerances for Dichlorvos (DDVP), and 

Request for Public Evidentiary Hearing. 

2. Natural Resources Defense Council. 

(June 2, 2006). Petition of Natural Resources 

Defense Council To Conclude Special 

Review, Reregistration and Tolerance 

Reassessment Processes and To Revoke All 

Tolerances and Cancel All Registrations for 

the Pesticide DDVP. 

3. Office of Prevention, Pesticides and 

Toxic Substances, EPA. (June 2006). Interim 

Reregistration Eligibility Decision for 

Dichlorvos (DDVP). Available from: http://

www.epa.gov/oppsrrd1/reregistration/REDs/

ddvp_ired.pdf. 

4. Lu, F. and Sielken, R. (1991). 

Assessment of safety/risk of chemicals: 

inception and evolution of the ADI and doseresponse modeling procedures. Toxicology 

Letters 59, 5–40. 

5. Schueplein, R. (2002). Pesticides and 

Infant Risk: Is There a Need for an Additional 

Margin of Safety. Regulatory and 

Toxicological Pharmacology. 31, 267–279. 

6. Lehman, A. and Fitzhugh, O. (1954). 

Hundredfold margin of safety. Quarterly 

Bulletin of the Association of Food and Drug 

Officials of the United States. 33–35. 

7. Food and Agriculture Organization. 

(1965). Evaluation of the toxicity of pesticide 

residues in food. Joint report of the FAO 

working party on pesticide residues and the 

WHO Expert Committee on Pesticide 

Residues FAO Meeting Report PL/1965/10/1, 

WHO/Food Add./27.65, Rome. Stoner, H. 

(1964). The Concept of acceptable Daily 

Intakes of Pesticides for Man. Food and 

Cosmetics Toxicology. 2, 457–466. 

8. International Programme on Chemical 

Safety. (2005). Chemical-specific adjustment 

Factors for Interspecies Differences and 

Human Variability: Guidance Document for 

use of DATA in Dose/ConcentrationResponse Assessment. Available from: http:// 

whqlibdoc.who.int/publications/2005/ 

v9241546786_eng.pdf. 

9. Dourson, M., Felter, S., and Robinson, D. 

(1996). Evolution of Science-Based 

Uncertainty Factors in Noncancer Risk 

Assessment. Regulatory Toxicology and 

Pharmacology. 24, 108–120. 

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Office of Pesticide Programs’ Policy on the 

Determination of the Appropriate FQPA 

Safety Factor(s) for Use in the Tolerance 

Setting Process (February 28, 2002). 

Available from: http://www.epa.gov/

oppfead1/trac/science/determ.pdf. 

11. Barnes, D. and Dourson, M. (1988). 

Reference Dose (RfD): Description and Use in 

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Science and Decisions: Advancing Risk 

Assessment. (The National Academies Press). 

13. Burin, G. and Saunders, D. (1999). 

Addressing Human Variability in Risk 

Assessment—The Robustness of the 

Intraspecies Uncertainty Factor. Regulatory 

Toxicology and Pharmacology. 30, 209–216. 

14. Renwick, A. and Lazarus, N. (1998). 

Human Variability and Noncancer Risk 

Assessment—An analysis of the Default 

Uncertainty Factor. Regulatory Toxicology 

and Pharmacology. 27, 3–20. 

15. Dourson, M. and Stara, J. (1983). 

Regulatory History and Experimental 

Support of Uncertainty (Safety) Factors. 

Regulatory Toxicology and Pharmacology. 3, 

224–238. 

16. Renwick, A.G. (1991). Safety factors 

and establishment of acceptable daily intake. 

Food Additives & Contaminants. 8, 135–150. 

17. Dourson, M., Charnley, G., and 

Scheuplein, R. (2002). Differential Sensitivity 

of children and Adults to Chemical Toxicity. 

Regulatory Toxicology and Pharmacology. 

35, 448–467. 

18. National Research Council. (1993). 

Pesticides in the Diets of Infants and 

Children. (National Academy Press). 

19. EPA. (2002). A review of the Reference 

Dose and Reference Concentration Processes. 

EPA/630/P–02/002F. 

20. U.S. EPA. (1994) Methods for 

derivation of inhalation reference 

concentrations and application of inhalation 

dosimetry. EPA/600/8–90/066F. 

21. U.S. EPA. (1999) Toxicology Data 

Requirements For Assessing Risks Of 

Pesticide Exposure To Children’s Health: 

Report of the Toxicology Working Group of 

the 10X Task Force [April 28, 1999 draft]. 

Available from: http://www.epa.gov/scipoly/

sap/meetings/1999/may/10xtx428.pdf. 

22. Dourson, M., Knauf, L., and Swartout, 

J. (1992). On Reference Dose (RfD) and its 

underlying toxicity data base. Toxicology and 

Industrial Health 8(3), 171–189. 

23. U.S. EPA. (2012). Benchmark Dose 

Technical Guidance Document. EPA/100/R– 

12/001. 

24. FIFRA Science Advisory Panel. (March 

19, 2002). Methods Used to Conduct a 

Preliminary Cumulative Risk Assessment for 

Organophosphate Pesticides. Final Report 

from the FIFRA Scientific Advisory Panel 

Meeting of February 5–7, 2002 Available 

from: http://www.epa.gov/scipoly/sap/

meetings/2002/february/final.pdf. 

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25. FIFRA Science Advisory Panel. (April 

15, 2005). Final report on N-Methyl 

Carbamate Cumulative Risk Assessment: 

Pilot Cumulative Analysis. Final Report from 

the FIFRA Scientific Advisory Panel Meeting 

of February 2005. Available from: http://

www.epa.gov/scipoly/sap/meetings/2005/

february/minutes.pdf. 

26. FIFRA Science Advisory Panel. 

(October 13, 2005). Final report on 

Preliminary N-Methyl Carbamate Cumulative 

Risk Assessment. Final Report from the 

FIFRA Scientific Advisory Panel Meeting of 

July 29–30, 2005. Available from: http://

www.epa.gov/scipoly/sap/meetings/2005/

august/minutes.pdf. 

27. Office of Pesticide Programs, U.S. EPA. 

(2000). The Use of Data on Cholinesterase 

Inhibition for Risk Assessments of 

Organophosphorous and Carbamate 

Pesticides. Available from: http://www.epa.

gov/oppfead1/trac/science/cholin.pdf. 

28. Natural Resources Defense Council. 

(July 30, 2010). Petitioner’s Brief, NRDC v. 

U.S. EPA, No. 08–3771–ag (2d Cir.). 

29. U.S. EPA, Respondent’s Brief. 

(November 18, 2010). NRDC v. U.S. EPA, No. 

08–3771–ag (2d Cir.). 

30. Office of Chemical Safety and Pollution 

Prevention, U.S. EPA. (August 8, 2012). 

Memorandum from Ray Kent to Melanie 

Biscoe, ‘‘Lists of chemicals for which human 

studies were either: Approved by the Human 

Studies Review Board, or the basis for RfDs 

or RfCs in IRIS.’’ 

31. Office of Prevention, Pesticides and 

Toxic Substances, U.S. EPA. (June 15, 2006). 

Report of the Food Quality Protection Act 

(FQPA) Tolerance Reassessment and Risk 

Management Decision (TRED) for Ethephon. 

Available from: http://www.epa.gov/

oppsrrd1/REDs/ethephon_tred.pdf. 

Regulatory Toxicology and Pharmacology. 

32. Office of Prevention, Pesticides and 

Toxic Substances. (June 19, 2007). U.S. EPA, 

Memorandum from Feleica Fort to Tom 

Myers, ‘‘Methomyl. Acute, Probabilistic 

Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for the 

Reregistration Eligibility Decision.’’ 

33. Office of Prevention, Pesticides and 

Toxic Substances, U.S. EPA. (June 25, 2008). 

Memorandum from Elissa Reaves and Anna 

Lowit to Karen Santora, ‘‘Mode of Action, 

Eye Irritation, and the Intra-Species Factor: 

Comparison of Chloropicrin and MITC.’’ 

34. Office of Pesticide Programs, U.S. EPA. 

(March 24, 1998). ‘‘Data Evaluation Report: 

Dichlorvos: A Single Blind, Placebo 

Controlled, Randomized Study to Investigate 

the Effects of Multiple Oral Dosing on 

Erythrocyte Cholinesterase Inhibition in 

Healthy Male Volunteers.’’ 

35. Gledhill, A.J. (1997). Dichlorvos: A 

Single Blind, Placebo controlled, 

Randomised Study to Investigate the Effects 

of Multiple Oral Dosing on Erythrocyte 

Cholinesterase Inhibition in Healthy Male 

Volunteers. 

36. EPA Human Studies Review Board. 

(May 15, 2006). Minutes of the United States 

Environmental Protection Agency (EPA) 

Human Studies Review Board (HSRB) April 

4–6, 2006 Public Meeting. 

37. Office of Pesticide Programs, U.S. EPA. 

(June 2002). Revised Cumulative Risk 

Assessment of the Organophosphorus 

Pesticides. Available from: http://www.epa.

gov/pesticides/cumulative/rra-op/. 

38. Office of Prevention, Pesticides and 

Toxic Substances, U. S. EPA. (November 16, 

2007). Memorandum from Ray Kent to Robert 

McNally, Dichlorvos (PC 084001). Additional 

characterization of inhalation risk posed by 

use of dichlorvos-containing resin strips. 

DP332823. 

39. Office of Chemical Safety and Pollution 

Prevention, U.S. EPA. (August 9, 2010). 

Memorandum from Bayasid Sarkar to Ray 

Kent, Precision analysis of Gledhill study for 

litigation of DDVP. 

40. Kent, R., Office of Pesticide Programs, 

U.S. EPA. (April 5, 2006). Dichlorvos: WOE 

Comparison of Human and Animal Studies 

for Single Chemical Assessment and OP 

Cumulative Assessment. 

41. Office of Pesticide Programs, U.S. EPA. 

(June 20, 1994). Memorandum from Brigid 

Lowery to Jocelyn E. Steward, Dichlorvos 

(DDVP). Review of Subchronic Neurotoxicity 

Study in Sprague-Dawley Rats. 

42. Office of Prevention, Pesticides and 

Toxic Substances, U.S. EPA. (June 9, 2006). 

Memorandum from Anna Lowit to Ray Kent, 

Benchmark Dose analysis of cholinesterase 

inhibition in neonatal and adult rats (MRID 

no. 46688914) following exposure to DDVP. 

43. National Research Council, Reference 

Manual on Scientific Evidence 249–252 (3rd 

ed. 2011). 

List of Subjects in 40 CFR Part 180 

Environmental protection, 

Administrative practice and procedure, 

Agricultural commodities, Pesticides 

and pests, Reporting and recordkeeping 

requirements. 

Dated: August 29, 2012. 

Steven Bradbury, 

Director, Office of Pesticide Programs. 

[FR Doc. 2012–21844 Filed 9–4–12; 8:45 am] 

BILLING CODE 6560–50–P 

FEDERAL COMMUNICATIONS 

COMMISSION 

47 CFR Part 101 

[WT Docket No. 10–153; RM–11602; FCC 

12–87] 

Facilitating the Use of Microwave for 

Wireless Backhaul and Other Uses and 

Providing Additional Flexibility To 

Broadcast Auxiliary Service and 

Operational Fixed Microwave 

Licensees 

AGENCY: Federal Communications 

Commission. 

ACTION: Final rule. 

SUMMARY: In this document, the 

Commission takes further steps to 

remove regulatory barriers and lowering 

costs for the wireless microwave 

backhaul facilities that are an important 

component of many mobile wireless 

networks. The steps we take will 

remove regulatory barriers that today 

limit the use of spectrum for wireless 

backhaul and other point-to-point and 

point-to-multipoint communications. 

This will also facilitate better use of 

Fixed Service (FS) spectrum and 

provide additional flexibility to enable 

FS licensees to reduce operational costs 

and facilitate the use of wireless 

backhaul in rural areas. By enabling 

more flexible and cost-effective 

microwave services, the Commission 

can help foster deployment of 

broadband infrastructure across 

America. In addition, a number of 

parties sought reconsideration of the 

Backhaul Report and Order, and we 

address those requests and deny 

reconsideration, for the most part. 

DATES: Effective October 5, 2012. 

The effective date for the Rural 

Microwave Flexibility Policy, which 

contains new or modified information 

collection requirements has not been 

approved by the Office of Management 

and Budget (OMB). The Commission 

will publish a document in the Federal 

Register announcing the effective date 

of that policy. 

ADDRESSES: Federal Communications 

Commission, 445 12th Street SW., 

Washington, DC 20554. A copy of any 

comments on the Paperwork Reduction 

Act information collection requirements 

contained herein should be submitted to 

Judith B. Herman, Federal 

Communications Commission, Room 1– 

B441, 445 12th Street SW., Washington, 

DC 20554 or via the Internet at Judith B. 

Herman@fcc.gov. 

FOR FURTHER INFORMATION CONTACT: John 

Schauble, Wireless Telecommunications 

Bureau, Broadband Division, at 202– 

418–0797 or by email to 

John.Schauble@fcc.gov. For additional 

information concerning Paperwork 

Reduction Act information collection 

requirements contained in this 

document, contact Judith B. Herman at 

(202) 418–0214, or via the Internet at 

PRA@fcc.gov. 

SUPPLEMENTARY INFORMATION: This is a 

summary of the Commission’s 

document, FCC 12–87, adopted and 

released on August 3, 2012. The full text 

of this document is available for 

inspection and copying during normal 

business hours in the FCC Reference 

Information Center, Room CY–A257, 

445 12th Street SW., Washington, DC 

20554. The complete text of the 

Backhaul Second Report and Order, 

Order on Reconsideration, and 

Memorandum Opinion and Order 

(Backhaul 2nd R&O, OOR, and MO&O) 

and related Commission documents 

may be purchased from the 

mstockstill on DSK4VPTVN1PROD with RULES