
[Federal Register Volume 77, Number 172 (Wednesday, September 5, 2012)]
[Rules and Regulations]
[Pages 54402-54421]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-21844]


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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.

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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

[[Page 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 
statutorily-created 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

[[Page 54404]]

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

[[Page 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

[[Page 54406]]

(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) inter- and intraspecies factors to be 
roughly equally divided on a logarithmic basis (i.e., 10\0.5\ 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 chemical-specific 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 chemical-specific 
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, strontium-induced 
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 inter- and 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

[[Page 54407]]

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 highly-prescriptive 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 inter- and 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 post-natal 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:

[[Page 54408]]

[GRAPHIC] [TIFF OMITTED] TR05SE12.000

    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 
long-established 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--decision-making 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

[[Page 54409]]

considers the overall weight-of-evidence to evaluate the significance 
of the data deficiency.'' (Id. at 26).
    With regard to potential pre- and post-natal 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 
weight-of-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 BMD\10\ 
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 intermediate-term inhalation exposure. All of the 
studies from which a Point of Departure was selected were conducted in 
adults

[[Page 54410]]

(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-of-the-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
----------------------------------------------------------------------------------------------------------------
                                   Study from which                        Population groups
            Scenario              point of departure  Age and species of    covered by risk   Uncertainty/safety
                                         taken          study subjects        assessment            factors
----------------------------------------------------------------------------------------------------------------
Acute Dietary...................  Rat acute oral      Adult rats........  All population      Interspecies--10X;
                                   cholinesterase                          groups, including   Intraspecies--10X
                                   study.                                  infants and         ; FQPA--1X.
                                                                           children.
Chronic Dietary.................  1-year dog study..  Adult dogs........  All population      Interspecies--10X;
                                                                           groups, including   Intraspecies--10X
                                                                           infants and         ; FQPA--1X.
                                                                           children.
Short-term Incidental Oral......  Human 21-day oral   Adult humans......  All population      Interspecies--1X;
                                   study.                                  groups, including   Intraspecies--10X
                                                                           infants and         ; FQPA--3X.
                                                                           children.
Acute Dermal and Acute            Rat acute oral      Adult rats........  All population      Interspecies--10X;
 Incidental Oral.                  cholinesterase                          groups, including   Intraspecies--10X
                                   study.                                  infants and         ; FQPA--1X.
                                                                           children.
Short-, Intermediate- and Long-   Human 21-day oral   Adult humans......  All population      Interspecies--1X;
 term Dermal.                      study.                                  groups, including   Intraspecies--10X
                                                                           infants and         ; FQPA--3X.
                                                                           children.
Acute Inhalation................  Rat acute oral      Adult rats........  All population      Interspecies--10X;
                                   cholinesterase                          groups, including   Intraspecies--10X
                                   study.                                  infants and         ; FQPA--1X.
                                                                           children.
Short- and Intermediate-term      Human 21-day oral   Adult humans......  All population      Interspecies--1X;
 Inhalation.                       study.                                  groups, including   Intraspecies--10X
                                                                           infants and         ; FQPA--3X.
                                                                           children.
Long-term Inhalation............  2-year rat          Adult rats........  All population      Interspecies--10X;
                                   inhalation study.                       groups, including   Intraspecies--3X;
                                                                           infants and         FQPA--1X.
                                                                           children.
----------------------------------------------------------------------------------------------------------------

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

[[Page 54411]]

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 half-value 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 ``dichlorvos-
specific 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

[[Page 54412]]

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 post-natal 
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 post-natal 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

[[Page 54413]]

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 child-bearing 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 short- 
and 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 non-Gledhill-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

[[Page 54414]]

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 Gledhill-based 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 post-dating 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.
---------------------------------------------------------------------------

    \1\ The 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 N-methyl 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.

---------------------------------------------------------------------------

[[Page 54415]]

    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 post-natal 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 long-term), incidental oral (short-term), and inhalation (short- 
and intermediate-term) risk for all population subgroups, including 
infants and children. Agency-wide 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 
exposure-response 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-of-the-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

[[Page 54416]]

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 dichlorvos- treated 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 
post-dosing cholinesterase levels for treated subjects for most days 
post-dosing.
---------------------------------------------------------------------------

    \2\ Statistical 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).

                                                         Table 2--Results of the Gledhill study
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                     Placebo (n = 3)                                           Dosed (n = 6)
                                        ----------------------------------------------------------------------------------------------------------------
               Timepoint                                              % pre-dose
                                             Mean           SD           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** [dagger][dagger]      1759.48       91
Day 9..................................      18460          1007.03          100                                 16708.33      2504.97       94
Day 11.................................      19210.00       1035.95          104              16036.67** [dagger][dagger]      1654.38       90
Day 14.................................      18490.00       1642.35          100              15333.33** [dagger][dagger]      1250.34       86
Day 16.................................      17706.67       2470.15           96              15191.67** [dagger][dagger]      1062.59       86
Day 18.................................      18260.00       2298.87           99              14855.00** [dagger][dagger]      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).
[dagger][dagger] 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 well-
characterized 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

[[Page 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 cholinesterase-inhibiting 
substances shows that differences between pre- and post-exposure 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 pre-treatment 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

[[Page 54418]]

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. 10\1\) 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.
---------------------------------------------------------------------------

    \3\ The 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.
---------------------------------------------------------------------------

    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 intermediate-term 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

[[Page 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-to-NOAEL 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 pre- and 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 Gledhill-
based 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

[[Page 54420]]

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.
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DP332823.
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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


