[Federal Register: December 5, 2007 (Volume 72, Number 233)]
[Rules and Regulations]
[Page 68661-68698]
[DOCID:fr05de07-21]

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Part IV

Environmental Protection Agency

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40 CFR Part 180

Dichlorvos (DDVP); Order Denying NRDC's Petition to Revoke All
Tolerances; Final Rule

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2002-0302; FRL-8341-9]

Dichlorvos (DDVP); Order Denying NRDC's Petition to Revoke All
Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Order.

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SUMMARY: In this Order, EPA denies a petition requesting that EPA
revoke all pesticide tolerances for dichlorvos (DDVP) under section
408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA). The
petition was filed on June 2, 2006, by the Natural Resources Defense
Council (NRDC).

DATES: This order is effective December 5, 2007. Objections and
requests for hearings must be received on or before February 4, 2008,
and must be filed in accordance with the instructions provided in 40
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: EPA has established a docket for this action under docket
identification (ID) number EPA-HQ-OPP-2002-0302. To access the
electronic docket, go to http://www.regulations.gov, select ``Advanced

Search,'' then ``Docket Search.'' Insert the docket ID number where
indicated and select the ``Submit'' button. Follow the instructions on
the regulations.gov website to view the docket index or access
available documents. All documents in the docket are listed in the
docket index available in regulations.gov. Although listed in the
index, some information is not publicly available, e.g., Confidential
Business Information (CBI) or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available in the electronic docket at http://www.regulations.gov, or,

if only available in hard copy, at the OPP Regulatory Public Docket in
Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr.,
Arlington, VA. The Docket Facility is open from 8:30 a.m. to 4 p.m.,
Monday through Friday, excluding legal holidays. The Docket Facility
telephone number is<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Susan Bartow, Special Review and
Reregistration Division (7508P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001; telephone number:<PHONE_NUMBER>; e-mail
address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    In this document EPA denies a petition by the Natural Resources
Defense Council (``NRDC'') 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.
    This listing is not intended to be exhaustive, but rather to
provide a guide for readers regarding entities likely to be affected by
this action. Other types of entities not listed in this unit could also
be affected. The NAICS codes have been provided to assist you and
others in determining whether this action might apply to certain
entities. If you have any questions regarding the applicability of this
action to a particular entity, consult the person listed under FOR
FURTHER INFORMATION CONTACT.

B. How Can I Access Electronic Copies of this Document?

    In addition to accessing an electronic copy of this Federal
Register document through the electronic docket at http://www.regulations.gov
, you may access this Federal Register document

electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr. You may also access a

frequently updated electronic version of EPA's tolerance regulations at
40 CFR part 180 through the Government Printing Office's pilot e-CFR
site at http://www.gpoaccess.gov/ecfr.

C. Can I File an Objection or Hearing Request?

    Under section 408(g) of FFDCA, any person may file an objection to
any aspect of this order and may also request a hearing on those
objections. You must file your objection or request a hearing on this
order in accordance with the instructions provided in 40 CFR part 178.
To ensure proper receipt by EPA, you must identify docket ID number
EPA-HQ-OPP-2002-0302 in the subject line on the first page of your
submission. All requests must be in writing, and must be mailed or
delivered to the Hearing Clerk as required by 40 CFR part 178 on or
before February 4, 2008.
    In addition to filing an objection or hearing request with the
Hearing Clerk as described in 40 CFR part 178, please submit a copy of
the filing that does not contain any CBI for inclusion in the public
docket that is described in ADDRESSES. Information not marked
confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA
without prior notice. Submit this copy, identified by docket ID number
EPA-HQ-OPP-2002-0302, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.

Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket's normal hours of operation (8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays). Special
arrangements should be made for deliveries of boxed information. The
Docket Facility telephone number is<PHONE_NUMBER>.

II. Introduction

A. What Action Is the Agency Taking?

    On June 2, 2006, the Natural Resources Defense Council (NRDC) filed
a petition with EPA which, among other things, requested that EPA
revoke all tolerances for the pesticide dichlorvos (DDVP) established
under section 408 of the Federal Food, Drug, and Cosmetic Act
(``FFDCA''), 21 U.S.C. 346a. (Ref. 1). NRDC's petition asserts that the
DDVP tolerances are unsafe and should be revoked for numerous reasons,
including: EPA has improperly assessed the toxicity of DDVP; EPA has
erred in

estimating dietary and residential exposure to DDVP; and EPA has
unlawfully removed the additional safety factor for the protection of
infants and children. This order finds NRDC's claims regarding the DDVP
tolerances to be without merit and, accordingly, denies that aspect of
NRDC petition. The other aspects of NRDC's petition are addressed in
another EPA action.

B. What Is the Agency's Authority for Taking This Action?

    Under section 408(d)(4) of the FFDCA, EPA is authorized to respond
to a section 408(d) petition to revoke tolerances either by issuing a
final rule revoking the tolerances, issuing a proposed rule, or issuing
an order denying the petition. (21 U.S.C. 346a(d)(4)).

III. Statutory and Regulatory Background

A. Statutory Background

    1. In general. EPA establishes maximum residue limits, or
``tolerances,'' for pesticide residues in food under 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 and the U. S. Department of Agriculture.
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 estrogenic substances
screening program.
    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)). In the FQPA, Congress integrated
action under the two statutes by requiring that the safety standard
under the FFDCA be used as a criterion in FIFRA registration actions as
to pesticide uses which result in dietary risk from residues in or on
food, (7 U.S.C. 136(bb)), and directing that EPA coordinate, to the
extent practicable, revocations of tolerances with pesticide
cancellations under FIFRA. (21 U.S.C. 346a(l)(1)).
    2. Safety standard for pesticide tolerances. A pesticide tolerance
may only be promulgated by EPA if the tolerance is ``safe.'' (21 U.S.C.
346a(b)(2)(A)(i)). ``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)). Section
408(b)(2)(D) directs EPA, in making a safety determination, to:
    consider, among other relevant factors- ....
    (v) available information concerning the cumulative effects of
such residues and other substances that have a common mechanism of
toxicity;
    (vi) available information concerning the aggregate exposure
levels of consumers (and major identifiable subgroups of consumers)
to the pesticide chemical residue and to other related substances,
including dietary exposure under the tolerance and all other
tolerances in effect for the pesticide chemical residue, and
exposure from other non-occupational sources;
    (viii) such information as the Administrator may require on
whether the pesticide chemical may have an effect in humans that is
similar to an effect produced by a naturally occurring estrogen or
other endocrine effects. ...
(21 U.S.C. 346a(b)(2)(D)(v), (vi) and (viii)).
    Section 408(b)(2)(C) requires EPA to give special consideration to
risks posed to infants and children. Specifically, this provision
states that EPA:
    shall assess the risk of the pesticide chemical based on-- ...
    (II) available information concerning the special susceptibility
of infants and children to the pesticide chemical residues,
including neurological differences between infants and children and
adults, and effects of in utero exposure to pesticide chemicals; and
    (III) available information concerning the cumulative effects on
infants and children of such residues and other substances that have
a common mechanism of toxicity. ...
(21 U.S.C. 346a(b)(2)(C)(i)(II) and (III)).
    This provision further 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.). The additional safety
margin for infants and children is referred to throughout this Order as
the ``children's 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, the
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
either establishing, amending, or revoking the tolerance or denying the
petition, any affected party has 60 days to file objections with EPA
and seek an evidentiary hearing on those objections. (21 U.S.C.
346a(g)(2)). EPA's final order on the objections is subject to judicial
review. (21 U.S.C. 346a(h)(1)).
    4. Tolerance Reassessment and FIFRA Reregistration. The FQPA
requires, among other things, that EPA reassess the safety of all
pesticide tolerances existing at the time of its enactment. (21 U.S.C.
346a(q)). In this reassessment, EPA is required to review existing
pesticide tolerances under the new ``reasonable certainty that no harm
will result'' standard set forth in section 408(b)(2)(A)(i). (21 U.S.C.
346a(b)(2)(A)(i)). This reassessment was substantially completed by the
August 3, 2006 deadline. Tolerance reassessment is generally handled in
conjunction with a similar program involving reregistration of
pesticides under FIFRA. (7 U.S.C. 136a-1). Reassessment and
reregistration decisions are generally combined in a document labeled a
Reregistration Eligibility Decision (``RED'').
    5. Estrogenic Substances Screening Program. Section 408(p) of the
FFDCA creates the estrogenic substances screening program. This
provision gives EPA 2 years from enactment of the FQPA to ``develop a
screening program ... to determine whether certain substances may have
an effect in humans that is similar to an effect produced by a
naturally occurring

estrogen, or such other endocrine effect as the Administrator may
designate.'' This screening program must use ``appropriate validated
test systems and scientifically relevant information.'' (21 U.S.C.
346a(p)(1)). Once the program is developed, EPA is required to take
public comment and seek independent scientific review of it. Following
the period for public comment and scientific review, and not later than
3 years following enactment of the FQPA, EPA is directed to ``implement
the program.'' (21 U.S.C. 346a(p)(2)).
    The scope of the estrogenic screening program was expanded by an
amendment to the Safe Drinking Water Act (SDWA) passed
contemporaneously with FQPA. That amendment gave EPA the authority to
provide for the testing, under the FQPA estrogenic screening program,
``of any other substance that may be found in sources of drinking water
if the Administrator determines that a substantial population may be
exposed to such substance.'' (42 U.S.C. 300j-17).

B. Setting and Reassessing Pesticide Tolerances Under the FFDCA

    1. In general. The process EPA follows in setting and reassessing
tolerances under the FFDCA includes two steps. First, EPA determines an
appropriate residue level value for the tolerance taking into account
data on levels that can be expected in food. Second, EPA evaluates the
safety of the tolerance relying on toxicity and exposure data and
guided by the statutory definition of ``safety'' and requirements
concerning risk assessment. Only on completion of the second step can a
tolerance be established or reassessed. Both stages of this process are
relevant to EPA's analysis of petitions to revoke tolerances based on
risk concerns because both stages bear on the assessment of risk.
    2. Choosing a tolerance value. In the first step of the tolerance
setting or reassessment process (choosing a tolerance value), EPA
evaluates data from experimental crop field trials in which the
pesticide has been used in a manner, consistent with the draft FIFRA
label, that is likely to produce the highest residue in the crop in
question (e.g., maximum application rate, maximum number of
applications, minimum pre-harvest interval between last pesticide
application and harvest). (Refs. 2 and 3). These crop field trials are
generally conducted in several fields at several geographical
locations. (Id. at 5, 7 and Tables 1 and 5). Several samples are then
gathered from each field and analyzed. (Id. at 53). Generally, the
results from such field trials show that the residue levels for a given
pesticide use will vary from as low as non-detectable to measurable
values in the parts per million (ppm) range with the majority of the
values falling at the lower part of the range. EPA uses a statistical
procedure to analyze the field trial results and identify the upper
bound of expected residue values. This upper bound value is used as the
tolerance value. (Ref. 4). (As discussed below, the safety of the
tolerance value chosen is separately evaluated.).
    There are three main reasons for closely linking tolerance values
to the maximum value that could be present from maximum label usage of
the pesticide. First, EPA believes it is important to coordinate its
actions under the two statutory frameworks governing pesticides. (See
61 FR 2378, 2379 (January 25, 1996)). It would be illogical for EPA to
set a pesticide tolerance under the FFDCA without considering what
action is being taken under FIFRA with regard to registration of that
pesticide use. (Cf. 40 CFR 152.112(g) (requiring all necessary
tolerances to be in place before a FIFRA registration may be granted)).
In coordinating its actions, one basic tenet that EPA follows is that a
grower who applies a pesticide consistent with the FIFRA label
directions should not run the risk that his or her crops will be
adulterated under the FFDCA because the residues from that legal
application exceed the tolerance associated with that use. Crop field
trials require application of the pesticide in the manner most likely
to produce maximum residues to further this goal. Second, choosing
tolerance values based on FIFRA label rates helps to ensure that
tolerance levels are established no higher than necessary. If tolerance
values were selected solely in consideration of health risks, in some
circumstances, tolerance values might be set so as to allow much
greater application rates than necessary for effective use of the
pesticide. This could encourage misuse of the pesticide. Finally,
closely linking tolerance values to FIFRA labels helps EPA to police
compliance with label directions by growers because detection of an
over-tolerance residue is indicative of use of a pesticide at levels,
or in a manner, not permitted on the label.
    3. The safety determination - risk assessment. Once a tolerance
value is chosen, EPA then evaluates the safety of the pesticide
tolerance using the process of risk assessment. To assess risk of a
pesticide, EPA combines information on pesticide toxicity with
information regarding the route, magnitude, and duration of exposure to
the pesticide.
    In evaluating toxicity or hazard, EPA examines both short-term
(e.g., ``acute'') and longer-term (e.g., ``chronic'') adverse effects
from pesticide exposure. (Ref. 2 at 8-10). EPA also considers whether
the ``effect'' has a threshold - a level below which exposure has no
appreciable chance of causing the adverse effect. For non-threshold
effects, EPA assumes that any exposure to the substance increases the
risk that the adverse effect may occur. At present, EPA only considers
one adverse effect, the chronic effect of cancer, to potentially be a
non-threshold effect. (Ref. 2 at 8-9). Not all carcinogens, however,
pose a risk at any exposure level (i.e., ``a non-threshold effect or
risk''). Advances in the understanding of carcinogenesis have
increasingly led EPA to conclude that some pesticides that cause
carcinogenic effects only cause such effects above a certain threshold
of exposure. EPA has traditionally considered adverse effects on the
endocrine system to be a threshold effect; that determination is being
reexamined in conjunction with the endocrine disruptor screening
program.
    Once the hazard for a durational scenario is identified, EPA must
determine the toxicological level of concern and then compare estimated
human exposure to this level of concern. This comparison is done
through either calculating a safe dose in humans (incorporating all
appropriate safety factors) and expressing exposure as a percentage of
this safe dose (the reference dose (``RfD'') approach) or dividing
estimated human exposure into an appropriate dose from the relevant
studies at which no adverse effects from the pesticide are seen (the
margin of exposure (``MOE'') approach). How EPA determines the level of
concern and assesses risk under these two approaches is explained in
more detail below. EPA's general approach to estimating exposure is
also briefly discussed.
    a. Levels of concern and risk assessment--i. Threshold effects. In
assessing the risk from a pesticide's threshold effects, EPA evaluates
an array of toxicological studies on the pesticide. In each of these
studies, EPA attempts to identify the lowest observed adverse effect
level (``LOAEL'') and the next lower dose at which there are no
observed adverse affect levels (``NOAEL''). Generally, EPA will use the
lowest NOAEL from the available studies as a starting point in
estimating the level of concern for humans. In estimating and
describing the level of

concern, however, the chosen NOAEL is at times manipulated differently
depending on whether the risk assessment addresses dietary or non-
dietary exposures.
    For dietary risks, EPA uses the chosen NOAEL to calculate a safe
dose or RfD. The RfD is calculated by dividing the chosen NOAEL by all
applicable safety or uncertainty factors. Typically, a combination of
safety or uncertainty factors providing a hundredfold (100X) margin of
safety is used: 10X to account for uncertainties inherent in the
extrapolation from laboratory animal data to humans and 10X for
variations in sensitivity among members of the human population as well
as other unknowns. Additional safety factors may be added to address
data deficiencies or concerns raised by the existing data. Further,
under the FQPA, an additional safety factor of 10X is presumptively
applied to protect infants and children, unless reliable data support
selection of a different factor. In implementing FFDCA section 408,
EPA's Office of Pesticide Programs, also calculates a variant of the
RfD referred to as a Population Adjusted Dose (``PAD''). A PAD is the
RfD divided by any portion of the FQPA safety factor that does not
correspond to one of the traditional additional safety factors used in
general Agency risk assessments. (Ref. 5 at 13-16). The reason for
calculating PADs is so that other parts of the Agency, which are not
governed by FFDCA section 408, can, when evaluating the same or similar
substances, easily identify which aspects of a pesticide risk
assessment are a function of the particular statutory commands in FFDCA
section 408. Today, RfDs and PADs are generally calculated for both
acute and chronic dietary risks although traditionally a RfD or PAD was
only calculated for chronic dietary risks. Throughout this document
general references to EPA's calculated safe dose are denoted as a RfD/
PAD.
    To quantitatively describe risk using the RfD/PAD approach,
estimated exposure is expressed as a percentage of the RfD/PAD. Dietary
exposures lower than 100 percent of the RfD are generally not of
concern.
    For non-dietary, and often for combined dietary and non-dietary,
risk assessments of threshold effects, the toxicological level of
concern is not expressed as a safe dose or RfD/PAD but rather as the
margin of exposure (MOE) that is necessary to be sure that exposure to
a pesticide is safe. A safe MOE is generally considered to be a margin
at least as high as the product of all applicable safety factors for a
pesticide. For example, if a pesticide needs a 10X factor to account
for interspecies differences, 10X factor for intraspecies differences,
and 10X factor for FQPA, the safe or target MOE would be a MOE of at
least 1,000. To calculate the MOE for a pesticide, human exposure to
the pesticide is divided into the lowest NOAEL from the available
studies. In contrast to the RfD/PAD approach, the higher the MOE, the
safer the pesticide. Accordingly, if the level of concern for a
pesticide is 1,000, MOEs exceeding 1,000 would generally not be of
concern. Like RfD/PADs, specific MOEs are calculated for exposures of
different durations. For non-dietary exposures, EPA typically examines
short-term, intermediate-term, and long-term exposures. Additionally,
non-dietary exposure often involves exposures by various routes
including dermal, inhalation, and oral.
    The RfD/PAD and MOE approaches are fundamentally equivalent. For a
given risk and given exposure of a pesticide, if the pesticide were
found to be safe under an RfD/PAD analysis it would also pass under the
MOE approach, and vice-versa.
    ii. Non-threshold effects. For risk assessments for non-threshold
effects, EPA does not use the RfD/PAD or MOE approach if quantitation
of the risk is deemed appropriate. Rather, EPA calculates the slope of
the dose-response curve for the non-threshold effects from relevant
studies using a model that assumes that any amount of exposure will
lead to some degree of risk. The slope of the dose-response curve can
then be used to estimate the probability of occurrence of additional
adverse effects as a result of exposure to the pesticide. For non-
threshold cancer risks, EPA generally is concerned if the probability
of increased cancer cases exceeds the range of 1 in 1 million.
    b. Estimating human exposure. Equally important to the risk
assessment process as determining the toxicological level of concern is
estimating human exposure. Under FFDCA section 408, EPA is concerned
not only with exposure to pesticide residues in food but also exposure
resulting from pesticide contamination of drinking water supplies and
from use of pesticides in the home or other non-occupational settings.
(See 21 U.S.C. 346a(b)(2)(D)(vi)).
    i. Exposure from food. (A) In General. There are two critical
variables in estimating exposure in food: (1) The types and amount of
food that is consumed; and (2) the residue level in that food.
Consumption is estimated by EPA based on scientific surveys of
individuals' food consumption in the United States conducted by the
U.S. Department of Agriculture. (Ref. 2 at 12). Information on residue
values comes from a range of sources including crop field trials, data
on pesticide reduction due to processing, cooking, and other practices,
information on the extent of usage of the pesticide, and monitoring of
the food supply. (Id. at 17).
    In assessing exposure from pesticide residues in food, EPA, for
efficiency's sake, follows a tiered approach in which it, in the first
instance, conducts its exposure assessment using the extreme case
assumptions that 100 percent of the crop in question is treated with
the pesticide and 100 percent of the food from that crop contains
pesticide residues at the tolerance level. (Id. at 11). When such an
assessment shows no risks of concern, a more complex risk assessment is
unnecessary. By avoiding a more complex risk assessment, EPA's
resources are conserved and regulated parties are spared the cost of
any additional studies that may be needed. If, however, a first tier
assessment suggests there could be a risk of concern, EPA then attempts
to refine its exposure assumptions to yield a more realistic picture of
residue values through use of data on the percent of the crop actually
treated with the pesticide and data on the level of residues that may
be present on the treated crop. These latter data are used to estimate
what has been traditionally referred to by EPA as ``anticipated
residues.''
    Use of percent crop treated data and anticipated residue
information is appropriate because EPA's worst-case assumptions of 100
percent treatment and residues at tolerance value significantly
overstate residue values. There are several reasons this is true.
First, all growers of a particular crop would rarely choose to apply
the same pesticide to that crop; generally, the proportion of the crop
treated with a particular pesticide is significantly below 100 percent.
Second, as discussed above, the tolerance value is set above the
highest value observed in crop field trials using maximum use rates.
There may be some commodities from a treated crop that approach the
tolerance value where the maximum label rates are followed, but most
generally fall significantly below the tolerance value. If less than
the maximum legal rate is applied, residues will be even lower. Third,
residue values in the field do not take into account the lowering of
residue values that frequently occurs as a result of degradation over
time and through food processing and cooking.
    EPA uses several techniques to refine residue value estimates. (Id.
at 17-28).

First, where appropriate, EPA will take into account all the residue
values reported in the crop field trials, either through use of an
average or individually. Second, EPA will consider data showing what
portion of the crop is not treated with the pesticide. Third, data can
be produced showing pesticide degradation and decline over time, and
the effect of commercial and consumer food handling and processing
practices. Finally, EPA can consult monitoring data gathered by the
Food and Drug Administration, the U.S. Department of Agriculture, or
pesticide registrants, on pesticide levels in food at points in the
food distribution chain distant from the farm, including retail food
establishments.
    Another critical component of the exposure assessment is how data
on consumption patterns are combined with data on pesticide residue
levels in food. Traditionally, EPA has calculated exposure by simply
multiplying average consumption by average residue values for
estimating chronic risks and high-end consumption by maximum residue
values for estimating acute risks. Although using average residues is a
realistic approach for chronic risk assessment due to the fact that
variations in residue levels and consumption amounts average out over
time, using maximum residue values for acute risk assessment tends to
greatly overstate exposure in narrow increments of time where it
matters how much of each treated food a given consumer eats and what
the residue levels are in the particular foods consumed. To take into
account the variations in short-term consumption patterns and food
residue values for acute risk assessments, EPA has more recently begun
using probabilistic modeling techniques for estimating exposure when
more simplistic models appear to show risks of concerns.
    All of these refinements to the exposure assessment process, from
use of food monitoring data through probabilistic modeling, can have
dramatic effects on the level of exposure predicted, reducing worst
case estimates by 1 or 2 orders of magnitude or more.
    (B) Computer modeling of dietary exposure. EPA uses a computer
program known as the Dietary Exposure Evaluation Model - Food Commodity
Intake Database (``DEEM-FCID'') to estimate exposure by combining data
on human consumption amounts with residue values in food commodities.
DEEM-FCID also compares exposure estimates to appropriate RfD/PAD
values to estimate risk. DEEM-FCID can estimate exposure for the
general U.S. population as well as 32 subgroups based on age, sex,
ethnicity, and region. DEEM-FCID is closely modeled on its predecessor
program DEEM. DEEM-FCID includes the DEEM software modeling program but
has revised inputs bearing on consumption patterns that were developed
by EPA to insure that all underlying aspects of the model are publicly
available. (Ref. 6).
    EPA uses a computer program to make exposure and risk estimates
because EPA has great volumes of data on human consumption amounts and
residue levels. Matching consumption and residue data can be done more
efficiently by computer. Additionally, certain risk assessment
techniques involve thousands of repeated analyses of the consumption
database and this cannot practically be done by hand. However, the
actual structure and logic of DEEM-FCID is relatively simple.
    DEEM-FCID contains consumption and demographic information on the
individuals who participated in the USDA's Continuing Surveys of Food
Intake by Individuals (``CSFII'') in 1994-1996 and 1998. The 1998
survey was a special survey required by the FQPA to supplement the
number of children survey participants. DEEM-FCID also contains
translation factors that convert foods as consumed (e.g., pizza) back
into their component raw agricultural commodities. This is necessary
because residue data are generally gathered on raw agricultural
commodities rather than on finished ready-to-eat food. Data on residue
values for a particular pesticide and the RfD/PADs for that pesticide
have to be inputted into the DEEM-FCID program to estimate exposure and
risk.
    DEEM-FCID can make three types of risk estimates: a single point
estimate; a simple distribution; or a probabilistic distribution. A
point estimate provides a single exposure and risk value for each
population subgroup. Generally, these exposure and risk values are
derived by combining single values for consumption and residue amount
on consumed commodities. For example, point estimates are commonly
computed for chronic exposure and risk by combining data on average
consumption with data on average residue levels. (Ref. 7-).
    In contrast to a point estimate, DEEM-FCID can also do two types of
distributional analyses. A simple distribution combines a single
residue value for each food with the full range of data on individual
consumption amounts to create a distribution of exposure and risk
levels. More specifically, DEEM-FCID creates this distribution by
calculating an exposure value for each reported day of consumption per
person (``person/day'') in CSFII assuming that all foods potentially
bearing the pesticide residue contain such residue at the chosen value.
The exposure amounts for the thousands of person/days in the CSFII are
then collected in a frequency distribution.
    Added complexity is introduced if DEEM-FCID computes a distribution
taking into account both the full range of data on consumption levels
and the full range of data on potential residue levels in food.
Combining these two independent variables (consumption and residue
levels) into a distribution of potential exposures and risk requires
use of probabilistic techniques.
    The probabilistic technique that DEEM-FCID uses to combine
differing levels of consumption and residues involves the following
steps:
    1. for each person/day in the CSFII, identification of any food(s)
that could possibly bear the residue of the pesticide in question;
    2. calculation of an exposure level for each person/day based on
the foods identified in Step 1 by randomly selecting residue
values for the foods from the residue database;
    3. repetition of Step 2 one thousand times for each
person/day; and
    4. collection of all of the hundreds of thousands of potential
exposures estimated in Steps 2 and 3 in a frequency
distribution.
    In this manner, a probabilistic assessment presents a range of
exposure/risk estimates.
    Point estimates are used for chronic risk assessments. EPA does not
use DEEM-FCID to calculate distributional assessments for chronic risk
because EPA's current view is that its consumption database is not
sufficiently robust to support a distributional analysis for chronic
exposure. Both simple and probabilistically-derived distributions are
used for acute risk assessment. EPA generally estimates exposure and
risk from a simple distribution based on the 95th percentile of such a
distribution. EPA's reason for relying on the 95th percentile with
simple distribution assessments is that for these assessments EPA
typically uses very conservative assumptions regarding residue levels
(100 percent of the crop is treated and all treated food bears residues
at the tolerance level) and thus the 95th percentile is protective of
the general population as well as all major, identifiable population
subgroups. Because probabilistic assessments generally use more
realistic residue levels, EPA's starting point for estimating exposure
and risk for such assessments is the 99.9th percentile.

This value can change depending on the degree of conservatism in the
residue estimates. (Ref. 8).
    ii. Exposure from water. EPA may use either or both field
monitoring data and mathematical water exposure models to generate
pesticide exposure estimates in drinking water. Monitoring and modeling
are both important tools for estimating pesticide concentrations in
water and can provide different types of information. Monitoring data
can provide estimates of pesticide concentrations in water that are
representative of specific agricultural or residential pesticide
practices and under environmental conditions associated with a sampling
design. Although monitoring data can provide a direct measure of the
concentration of a pesticide in water, it does not always provide a
reliable estimate of exposure because sampling may not occur in areas
with the highest pesticide use, and/or the sampling may not occur when
the pesticides are being used.
    In estimating pesticide exposure levels in drinking water, EPA most
frequently uses mathematical water exposure models. EPA's models are
based on extensive monitoring data and detailed information on soil
properties, crop characteristics, and weather patterns. (69 FR 30042,
30058-30065 (May 26, 2004)). These models calculate estimated
environmental concentrations of pesticides using laboratory data that
describe how fast the pesticide breaks down to other chemicals and how
it moves in the environment. These concentrations can be estimated
continuously over long periods of time, and for places that are of most
interest for any particular pesticide. Modeling is a useful tool for
characterizing vulnerable sites, and can be used to estimate peak
concentrations from infrequent, large storms.
    EPA has developed models for estimating exposure in both surface
water and ground water. EPA uses a two-tiered approach to modeling
pesticide exposure in surface water. In the initial tier, EPA uses the
FQPA Index Reservoir Screening Tool (FIRST) model. FIRST replaces the
GENeric Estimated Environmental Concentrations (GENEEC) model that was
used as the first tier screen by EPA from 1995-1999. If the first tier
model suggests that pesticide levels in water may be unacceptably high,
a more refined model is used as a second tier assessment. The second
tier model is actually a combination of the models, Pesticide Root Zone
Model (PRZM) and the Exposure Analysis Model System (EXAMS). For
estimating pesticide residues in groundwater, EPA uses the Screening
Concentration In Ground Water (SCI-GROW) model. Currently, EPA has no
second tier groundwater model.
    EPA's water exposure models have been extensively peer-reviewed
and/or validated, and have proved highly conservative in practice. In
fact, an evaluation conducted in conjunction with NRDC objections to
tolerances for other pesticides found that EPA's surface water models
never under-estimated the highest values measured in monitoring
studies, and that EPA's groundwater model had only rarely under-
estimated such results, and those underestimations were relatively
small. (69 FR at 30061-30064).
    Whether EPA estimates pesticide exposure in drinking water through
monitoring data or modeling, EPA uses the higher of the two values from
surface and ground water in quantifying overall exposure to the
pesticide. In most cases, pesticide concentrations in surface water are
significantly higher than in groundwater.
    iii. Residential exposures. Generally, in assessing residential
exposure to pesticides EPA relies on its Residential Standard Operating
Procedures (``SOPs''). The SOPs establish models for estimating
application and post-application exposures in a residential setting
where pesticide-specific monitoring data are not available. SOPs have
been developed for many common exposure scenarios including pesticide
treatment of lawns, garden plants, trees, swimming pools, pets, and
indoor surfaces including crack and crevice treatments. The SOPs are
based on existing monitoring and survey data including information on
activity patterns, particularly for children. Where available, EPA
relies on pesticide-specific data in estimating residential exposures.

C. EPA Policy on Cholinesterase Inhibition as a Regulatory Endpoint

    On August 18, 2000, EPA issued a science policy document entitled
``The Use of Data on Cholinesterase Inhibition for Risk Assessments of
Organophosphorous and Carbamate Pesticides.'' (Ref. 9). Although
assessing the risk from organophosphorous and carbamate pesticides was
a primary reason for updating EPA guidance on cholinesterase
inhibition, the policy addressed the topic generally and not just in
the context of these two families of pesticides.
    Cholinesterase inhibition is a disruption of the normal enzymatic
process in the body by which the nervous system chemically communicates
with muscles and glands. Communication between nerve cells and a target
cell (i.e., another nerve cell, a muscle fiber, or a gland) is
facilitated by the enzyme, acetylcholine. When a nerve cell is
stimulated it releases acetylcholine into the synapse (or space)
between the nerve cell and the target cell. The released acetylcholine
binds to receptors in the target cell, stimulating the target cell in
turn. As the policy explains, ``the end result of the stimulation of
cholinergic pathway(s) includes, for example, the contraction of smooth
(e.g., in the gastrointestinal tract) or skeletal muscle, changes in
heart rate or glandular secretion (e.g., sweat glands) or communication
between nerve cells in the brain or in the autonomic ganglia of the
peripheral nervous system.'' (Id. at 10).
    Acetylcholinesterase is an enzyme that breaks down acetylcholine
and terminates its stimulating action in the synapse between nerve
cells and target cells. When acetylcholinesterase is inhibited,
acetylcholine builds up prolonging the stimulation of the target cell.
This excessive stimulation potentially results in a broad range of
adverse effects on many bodily functions including muscle cramping or
paralysis, excessive glandular secretions, or effects on learning,
memory, or other behavioral parameters. Depending on the degree of
inhibition these effects can be serious, even fatal.
    The cholinesterase inhibition policy statement explains EPA's
approach to evaluating the hazard posed by cholinesterase-inhibiting
pesticides. The policy focuses on three types of effects associated
with cholinesterase-inhibiting pesticides that may be assessed in
animal and human toxicological studies: (1) Physiological and
behavioral/functional effects; (2) cholinesterase inhibition in the
central and peripheral nervous system; and (3) cholinesterase
inhibition in red blood cells and blood plasma. The policy discusses
how such data should be integrated in deriving a safe dose (RfD/PAD)
for a cholinesterase-inhibiting pesticide.
    Clinical signs or symptoms of cholinesterase inhibition in humans,
the policy concludes, provide the most direct evidence of the adverse
consequences of exposure to cholinesterase-inhibiting pesticides. Due
to strict ethical limitations, however, studies in humans are ``quite
limited.'' (Id. at 19). Although animal studies can also provide direct
evidence of cholinesterase inhibition effects, animal studies cannot
easily measure cognitive effects of cholinesterase inhibition such as
effects on perception, learning, and memory. For these

reasons, the policy recommends that ``functional data obtained from
human and animal studies should not be relied on solely, to the
exclusion of other kinds of pertinent information, when weighing the
evidence for selection of the critical effect(s) that will be used as
the basis of the RfD or RfC.'' (Id. at 20).
    After clinical signs or symptoms, cholinesterase inhibition in the
nervous system provides the next most important endpoint for evaluating
cholinesterase-inhibiting pesticides. 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.'' (Id. at
25). As such, the policy states that it should be treated as ``direct
evidence of potential adverse effects'' and ``data showing this
response provide valuable information in assessing potential hazards
posed by anticholinesterase pesticides.'' (Id.). Unfortunately, useful
data measuring cholinesterase inhibition in the central and peripheral
nervous systems has only been relatively rarely captured by standard
toxicology testing, particularly as to peripheral nervous system
effects. For central nervous system effects, however, more recent
neurotoxicity studies ``have sought to characterize the time course of
inhibition in ... [the] brain, including brain regions, after acute and
90-day exposures.'' (Id. at 27).
    Cholinesterase inhibition in the blood is one step further removed
from the direct harmful consequences of cholinesterase-inhibiting
pesticides. According to the policy, inhibition of blood
cholinesterases ``is not an adverse effect, but may indicate a
potential for adverse effects on the nervous system.'' (Id. at 28). The
policy states that ``[a]s a matter of science policy, blood
cholinesterase data are considered appropriate surrogate measures of
potential effects on peripheral nervous system acetylcholinesterase
activity in animals, for central nervous system (CNS)
acetylcholinesterase activity in animals when CNS data are lacking and
for both peripheral and central nervous system acetylcholinesterase in
humans.'' (Id. at 29). The policy notes that ``there is often a direct
relationship between a greater magnitude of exposure [to a
cholinesterase-inhibiting pesticide] and an increase in incidence and
severity of clinical signs and symptoms as well as blood cholinesterase
inhibition.'' (Id. at 30). Thus, the policy regards blood
cholinesterase data as ``appropriate endpoints for derivation of
reference doses or concentrations when considered in a weight-of-the-
evidence analysis of the entire database ....'' (Id. at 29). Between
cholinesterase inhibition measured in red blood cell (``RBC'') or blood
plasma, the policy states a preference for reliance on RBC
acetylcholinesterase measurements because plasma is composed of a
mixture of acetylcholinesterase and butyrylcholinesterase, and
inhibition of the latter is less clearly tied to inhibition of
acetylcholinesterase in the nervous system. (Id. at 29, 32).
    The policy advises that, in selection of a Point of Departure for
deriving a RfD/PAD, all data on clinical signs and cholinesterase
inhibition should be considered in a weight-of-the-evidence analysis.
This weight-of-the-evidence analysis should focus, according to the
policy, on (1) ``[a] comparison of the pattern of doses required to
produce physiological and behavioral effects and cholinesterase
inhibition'' in the central and peripheral nervous systems and in
blood; (2) ``comparisons of the temporal aspects (e.g., time of onset
and peak effects and duration of effects) of each relevant endpoint;''
and (3) ``the potential for differential sensitivity/susceptibility of
adult versus young animals (i.e., effects following perinatal or
postnatal exposures).'' (Id. at 35). This analysis can lead EPA to
``select as the critical effects any one or more of the behavioral and
physiological changes or enzyme measures listed above.'' (Id.). In
comparing studies across the entire database to select an endpoint for
the Point of Departure, the policy stresses that ``parallel analyses of
the dose-response (i.e., changes in magnitude of enzyme inhibition or
of a different effect with increasing dose) and the temporal pattern of
all relevant effects will be compared across all of the different
compartments affected (e.g., plasma, RBC, peripheral nervous system,
brain), and for the functional changes to the extent the database
permits.'' (Id. at 38). Further, the policy states that ``[t]he
consistency (or, the lack thereof) of LOAELs, NOAELs, or BMDs for each
category of effects (e.g., clinical signs, cholinesterase inhibition in
the various compartments, etc.) for the test species/strains/sex
available and for each duration and route of exposure should be
noted.'' (Id.).

D. EPA Policy on the Children's Safety Factor

    As the above brief summary of EPA's risk assessment practice
indicates, the use of safety factors plays a critical role in the
process. This is true for traditional 10X safety factors to account for
differences between animals and humans when relying on studies in
animals (inter-species safety factor) and differences among humans
(intra-species safety factor) as well as the additional 10X children's
safety factor added by the FQPA.
    In applying the children's safety factor provision, EPA has
interpreted it as imposing a presumption in favor of applying an
additional 10X safety factor. (Ref. 5 at 4, 11). Thus, EPA generally
refers to the additional 10X factor as a presumptive or default 10X
factor. EPA has also made clear, however, that this presumption or
default in favor of the additional 10X is only a presumption. The
presumption can be overcome if reliable data demonstrate that a
different factor is safe for children. (Id.). In determining whether a
different factor is safe for children, EPA focuses on the three factors
listed in section 408(b)(2)(C) - the completeness of the toxicity
database, the completeness of the exposure database, and potential pre-
and post-natal toxicity. In examining these factors, EPA strives to
make sure that its choice of a safety factor, based on a weight-of-the-
evidence evaluation, does not understate the risk to children. (Id. at
24-25, 35).

E. Endocrine Disruptor Screening Program

    To aid in the design of the endocrine screening program called for
in the FQPA and SDWA amendments, EPA created the Endocrine Disruptor
Screening and Testing Advisory Committee (EDSTAC), which was comprised
of members representing the commercial chemical and pesticides
industries, Federal and State agencies, worker protection and labor
organizations, environmental and public health groups, and research
scientists. (63 FR 71542, 71544, Dec. 28, 1998). The EDSTAC presented a
comprehensive report in August 1998 addressing both the scope and
elements of the endocrine screening program. (Ref. 10). The EDSTAC's
recommendations were largely adopted by EPA.
    As recommended by EDSTAC, EPA expanded the scope of the program
from focusing only on estrogenic effects to include androgenic and
thyroid effects as well. (63 FR at 71545). Further, EPA, again on the
EDSTAC's recommendation, chose to include both human and ecological
effects in the program. (Id.). Finally, based on EDSTAC's
recommendation, EPA established the universe of chemicals to be
screened to include not just pesticides but also a wide range of other
chemical substances. (Id.). As to the program elements, EPA adopted

EDSTAC's recommended two-tier approach with the first tier involving
screening ``to identify substances that have the potential to interact
with the endocrine system'' and the second tier involving testing ``to
determine whether the substance causes adverse effects, identify the
adverse effects caused by the substance, and establish a quantitative
relationship between the dose and the adverse effect.'' (Id.). Tier 1
screening is limited to evaluating whether a substance is ``capable of
interacting with'' the endocrine system, and is ``not sufficient to
determine whether a chemical substance may have an effect in humans
that is similar to an effect produced by naturally occurring
hormones.'' (Id. at 71550). Based on the results of Tier 1 screening,
EPA will decide whether Tier 2 testing is needed. Importantly, ``[t]he
outcome of Tier 2 is designed to be conclusive in relation to the
outcome of Tier 1 and any other prior information. Thus, a negative
outcome in Tier 2 will supersede a positive outcome in Tier 1.'' (Id.
at 71554-71555).
    The EDSTAC provided detailed recommendations for Tier 1 screening
and Tier 2 testing. The panel of the EDSTAC that devised these
recommendations was comprised of distinguished scientists from
academia, government, industry, and the environmental community.
(Endocrine Disruptor Screening and Testing Advisory Committee Final
Report, Appendix B). As suggested by the EDSTAC, EPA has proposed a
battery of short-term in vitro and in vivo assays for the Tier 1
screening exercise. (63 FR at 71550-71551). Validation of these assays,
however, is not yet complete. As to Tier 2 testing, EPA, on the
recommendation of the EDSTAC, has proposed using five longer-term
reproduction studies that, with one exception, ``are routinely
performed for pesticides with widespread outdoor exposures that are
expected to affect reproduction.'' (Id. at 71555). EPA is examining,
pursuant to the suggestion of the EDSTAC, modifications to these
studies to enhance their ability to detect endocrine effects.
    Recently, EPA has published a draft list of the first group of
chemicals that will be tested under the Agency's endocrine disruptor
screening program. (72 FR 33486 (June 18, 2007)). The draft list was
produced based solely on the exposure potential of the chemicals and
EPA has emphasized that ``[n]othing in the approach for generating the
initial list provides a basis to infer that by simply being on this
list these chemicals are suspected to interfere with the endocrine
systems of humans or other species, and it would be inappropriate to do
so.'' (Id.)

IV. DDVP Tolerances

A. Regulatory Background

    Dichlorvos (2, 2-dichlorovinyl dimethyl phosphate), also known as
DDVP, is an insecticide used in controlling flies, mosquitoes, gnats,
cockroaches, fleas, and other insect pests. DDVP is registered for use
on agricultural sites; commercial, institutional, and industrial sites;
and for domestic use in and around homes. Agricultural and other
commercial uses include in greenhouses; mushroom houses; storage areas
for bulk, packaged and bagged raw and processed agricultural
commodities; food manufacturing/processing plants; animal premises; and
non-food areas of food-handling establishments. It is also registered
for treatment of cattle, poultry and swine. DDVP is not registered for
direct use on any field grown commodities. Currently, there are 27
tolerances listed in 40 CFR 108.235 for DDVP on agricultural (food and
feed) crops and animal commodities. DDVP is applied with aerosols,
fogging equipment, and spray equipment, and through use of impregnated
materials such as resin strips which result in slow release of the
pesticide.
    DDVP is closely related to the pesticides naled and trichlorfon.
Naled and trichlorfon both metabolize or degrade to DDVP in food,
water, or the environment. All three pesticides are within a family of
pesticides known as the organophosphates. EPA has classified the
organophosphate pesticides and their common cholinesterase-inhibiting
degradates as having a common mechanism of toxicity and thus, in
addition to assessing the risks posed by exposure to these pesticides
individually, EPA has assessed the potential cumulative effects from
concurrent exposure to organophosphate pesticides.

B. FFDCA Tolerance Reassessment and FIFRA Pesticide Reregistration

    As required by the Food Quality Protection Act of 1996, EPA
reassessed the safety of the DDVP tolerances under the new safety
standard established in the FQPA. In the Interim Reregistration
Eligibility Document (``IRED'') for DDVP, EPA determined that aggregate
exposure to DDVP as a result of use of DDVP, naled, and trichlorfon,
complied with the FQPA safety standard. (Ref. 11). Separately, EPA
determined that cumulative effects from exposure to all organophosphate
residues were safe. (Ref. 12). In combination, these findings satisfied
EPA's obligation to review the DDVP tolerances under the new safety
standard.
    As a result of the FIFRA reregistration and FFDCA tolerance
reassessment process, there were numerous changes made to DDVP's
registration that affect non-occupational exposure to DDVP.
Specifically, on May 9, 2006, EPA received from the only technical
product registrant, Amvac Corporation (``Amvac''), an irrevocable
request to cancel certain uses and include additional pest strip label
restrictions on the DDVP technical product labels. Pursuant to section
6(f) of FIFRA, on June 30, 2006, the Agency published a notice in the
Federal Register that it had received the request and sought comment on
EPA's intention to grant the request and cancel the specified uses. (71
FR 37570 (June 30, 2006)). On October 20, 2006, EPA issued the final
cancellation order. (71 FR 61968 (October 20, 2006)). The added
restrictions on the use of the pest strip products were approved on
October 11, 2006, and provided, among other things, that large pest
strips could no longer be used in homes except for garages, attics,
crawl spaces, and sheds that are occupied for less than 4 hours per
day. Additionally, in early March, 2007, Amvac requested the voluntary
cancellation of all its pet collar and bait registrations and deletion
of those uses from its technical label. Pursuant to section 6(f) of
FIFRA, Amvac's requests to cancel the pet collar and bait registrations
as well as deleting such uses from the technical label were published
in the Federal Register on March 23, 2007. (72 FR 13786 (March 23,
2007)). On June 27, 2007, EPA issued the final cancellation notice for
the pet collar and bait registrations. (72 FR 35235 (June 27, 2007)).

C. Toxicity Overview

    Animal and human studies with DDVP demonstrate that the toxic
effect of concern for DDVP is inhibition of cholinesterase activity.
These studies showed decreases in cholinesterase activity in plasma,
red blood cell, and the brain. These effects were consistently found
whether the exposure duration was acute or chronic and across all
tested routes of exposure. Studies involving in utero, as well as pre-
and post-natal, exposure of young animals showed no evidence of
increased sensitivity in the young to these effects. Cholinesterase
inhibition was also the effect used to assess potential cumulative
effects from exposure to organophosphate pesticides. Based on numerous
cancer studies with DDVP, EPA has classified the evidence

on DDVP's potential carcinogenicity as ``suggestive;'' however, due to
the lack of relevance to humans of the tumors identified, EPA has
determined that DDVP poses a negligible cancer risk to humans.

D. Exposure Overview

    Exposure to DDVP can occur through the consumption of food treated
with DDVP, naled, or trichlorfon, consumption of drinking water bearing
DDVP residues, or from exposure in the residential setting from use of
DDVP or trichlorfon. EPA has extensive food monitoring data on DDVP.
These data show that with one exception, strawberries, DDVP is rarely
found at detectable amounts in food. About 5 percent of sampled
strawberries have shown detectable DDVP residues. These monitoring
results are consistent with metabolism data on DDVP which shows that it
is rapidly degraded into non-toxic substances. EPA has limited water
monitoring data showing no detectable residues of DDVP. Due to the fact
that these data do not identify whether they were collected from areas
of DDVP, naled, or trichlorfon usage and the lack of data from shallow
groundwater wells, EPA has relied upon conservative modeling estimates
of drinking water. EPA has estimated residential exposure to DDVP based
primarily on one of several monitoring studies conducted using DDVP
pest strips in houses.

V. The Petition to Revoke Tolerances

    On June 2, 2006, the Natural Resources Defense Council (NRDC) filed
a petition with EPA which, among other things, requested that EPA (1)
conclude the DDVP Special Review by August 3, 2006, with a finding that
DDVP causes unreasonable adverse effects on the environment; (2)
conclude the DDVP FIFRA reregistration process by August 3, 2006, with
a finding that DDVP is not eligible for reregistration; (3) submit
draft notices of intent to cancel all DDVP registrations to the SAP and
USDA by August 3, 2006, and issue those notices 60 days thereafter; (4)
conclude the DDVP tolerance reassessment process by August 3, 2006,
with a finding that the DDVP tolerances do not meet the FFDCA safety
standard; and (5) issue a final rule by August 3, 2006, revoking all
DDVP tolerances. (Ref. 1). Shortly after the petition was filed, on
June 30, 2006, EPA released the Interim Reregistration Eligibility
Decision (``IRED'') for DDVP which addressed DDVP's eligibility for
reregistration under FIFRA and assessed whether DDVP's tolerances met
the new safety standard enacted by the FQPA. NRDC submitted comments on
the IRED and some of these comments bore on issues in its petition.
(Ref. 13).
    NRDC asserted numerous grounds as to why the DDVP tolerances do not
meet the FQPA safety standard and should be revoked. EPA has divided
NRDC's grounds for revocation into four categories - toxicology;
dietary exposure; residential exposure; and risk characterization - and
addressed separately each claim under these categories. Each specific
claim of NRDC is summarized in Unit VII immediately prior to EPA's
response to the claim.

VI. Public Comment

    In response to the aspects of the petition addressing the DDVP
tolerances, EPA published notice of the petition for comment on October
11, 2006. (71 FR 59784, October 11, 2006). EPA received roughly 1,500
brief comments in support of the petition. These comments added no new
information pertaining to whether the tolerances were in compliance
with the FFDCA. Detailed comments in opposition to the petition were
submitted by Amvac, the party holding the registration for DDVP under
FIFRA. (Ref. 14). Amvac's comments on the specific claims by NRDC are
summarized in Unit VII immediately following the summary of NRDC's
claim but prior to EPA's response to the claim.

VII. Ruling on Petition

    This order addresses NRDC's petition to revoke DDVP tolerances. As
noted, in responding to NRDC's petition, EPA has broken the issues into
four categories -- toxicology; dietary exposure; residential exposure;
and risk characterization. Below, EPA addresses each of the claims
raised in these categories and explains why they do not support
revocation of the tolerances.
    EPA has not addressed claims that concern DDVP uses that have been
canceled since the time of the petition. Specific uses cancelled were
the largest (100 gram) pest strip; lawn, turf, and ornamentals; pet
collars; and in-home crack and crevice. Additionally, the remaining
``large'' pest strips (80 and 65 grams) were limited to unoccupied
portions of the home. The only pest strips permitted in occupied areas
were smaller strips (16, 10.5, 5.25 grams) for use in closets,
wardrobes, and cupboards.

A. Toxicological Issues

    1. Cancer--a. NRDC's claims. NRDC claims that ``the rejection by
EPA of the `probable carcinogen' cancer classification of previous
Agency reviews is inadequately supported .. ..'' (Ref. 1 at 17).
According to NRDC, EPA has not explained why its prior analysis was
``flawed,'' and the reasons EPA has given for the change in cancer
classification are ``speculative, at best.'' (Id.). NRDC urges EPA to
drop its new classification of DDVP as having ``suggestive'' evidence
of carcinogenicity and restore the ``original classification.'' (Id. at
18).
    Specifically, NRDC argues with EPA's decision to discount, in its
weight-of-the-evidence evaluation for DDVP, mononuclear cell leukemia
(MCL) seen in a rat study and forestomach tumors identified in a mouse
study. NRDC claims that EPA's assertion that a finding of MCL in the
Fischer rat is of limited usefulness due to variability of occurrence
of this cancer in the Fischer rat ``may be an artifact of the design of
such studies and is not an adequate basis for ignoring a positive
result.'' (Id. at 17). NRDC suggests that a larger scale study could
have resolved this issue. As to forestomach tumors, NRDC disputed EPA's
conclusion that these tumors have limited relevance to humans given
that humans do not have forestomachs. NRDC notes that all animals have
some difference in their organs and tissues and thus the lack of a
forestomach in humans does not ``automatically mean that the effect is
irrelevant to humans.'' (Id.). According to NRDC, EPA ``must provide
convincing explanations based on reliable data that their rejection of
forestomach tumors is a reasonable certainty and will adequately
protect the public health.'' (Id.).
    NRDC also suggests that a study in Denver, Colorado ``specifically
linked'' DDVP pest strips to leukemia in children under 15 (Leiss,
J.K., Savitz, D.A. ``Home pesticide use and childhood cancer: a case-
control study,'' American Journal of Public Health 1995; 85:249-52) and
a study of adult men with leukemia in Iowa and Minnesota (Brown, L.M.,
Blair, A., Gibson, R., et al. ``Pesticide exposures and other
agricultural risk factors for leukemia among men in Iowa and
Minnesota,'' Cancer Research 1990;50(20):6585-91) found that these men
were twice as likely to have a history of exposure to DDVP.
    b. Amvac's comments. Disagreeing with NRDC's claims, Amvac argues
that NRDC has ignored an extensive DDVP cancer database and the
confounding effect that corn oil played in the two positive studies
relied upon by NRDC. (Ref. 14 at 27-28). Amvac asserts that 11 cancer
studies have been performed with DDVP, involving both oral and
inhalation exposure routes, and that the only two positive studies were
gavage studies in which the DDVP was administered by gavage in corn
oil.

Amvac claims that it is well-recognized that corn oil as a confounding
factor in cancer studies and that, in fact, the National Toxicology
Program (``NTP'') has found corn oil to be carcinogenic. Finally, Amvac
cites to a recent review by the European Food Safety Agency, which
Amvac asserts concluded, after reviewing all of the evidence, ``that
the carcinogenic risk from exposure to DDVP is very low.'' (Ref. 15).
    c. EPA's response. Initially, EPA responds to NRDC's claims
regarding EPA's cancer classification by noting that NRDC's request to
amend the cancer classification is not a sufficient ground for seeking
revocation of the DDVP tolerances. A cancer classification does not
determine whether a pesticide is safe or not; rather, a cancer
classification is one step in a multi-stage risk assessment process
that ascertains and examines not only the toxicological effects a
pesticide causes, but also the potency of the pesticide and the extent
of human exposure to the pesticide. A pesticide found to be a
``probable'' human carcinogen may nonetheless meet the FFDCA section
408 safety standard if it has a low potency and/or low exposure. NRDC's
petition contains no arguments or evidence that if DDVP is reclassified
as a probable human carcinogen, a cancer risk assessment would show
that DDVP is not safe. Accordingly, EPA denies NRDC's petition to
revoke DDVP tolerances to the extent that the petition cites EPA's
alleged cancer misclassification of DDVP as grounds for such a
revocation.
    Nonetheless, to clarify the issue, EPA will explain the basis for
its revision of the cancer classification of DDVP. EPA's Cancer
Assessment Review Committee (CARC) in the Health Effects Division of
the Office of Pesticide Programs has held six cancer reviews for DDVP
over the past two decades. These multiple reviews have been necessary
due to the development of new information on DDVP as well as on
carcinogenicity generally. What these reviews show is that EPA has
taken a conservative approach to the cancer classification of DDVP,
only weakening the classification (i.e., adopting a classification of
lower human carcinogenic potential) upon the repeated advice of
independent expert scientific panels.
    EPA's reviews bridge two versions of its cancer assessment
guidelines. These guidelines have slightly different descriptive
categories for classifying chemicals as to their carcinogenic
potential. In its 1986 Cancer Assessment Guidelines, EPA created the
following categories regarding cancer potential: ``human carcinogen''
(Group A), ``probable human carcinogen'' (Group B), ``possible human
carcinogen'' (Group C), ``not classifiable as to human
carcinogenicity'' (Group D), and ``evidence of non-carcinogenicity for
humans'' (Group E). (51 FR 33992 (September 24, 1986)). Under the 1986
Guidelines, Group B was further subdivided into Groups B1 and B2 with
the former for chemicals categorized on the basis of data from humans
and the latter based on data in animals. In an update to these
guidelines in 2005, EPA adopted the following classifications:
``carcinogenic to humans,'' ``likely to be carcinogenic to humans,''
``suggestive evidence of carcinogenic potential,'' ``inadequate
information to assess carcinogenic potential,'' and ``not likely to be
carcinogenic to humans.'' (70 FR 17765, April 7, 2005). The revised
guidelines dropped the alphabetic labeling of the classifications.
    In its first review of DDVP in June 1987, the CARC's predecessor,
the Carcinogenicity Cancer Peer Review Committee [hereinafter referred
to as the CARC for simplicity], classified DDVP as a probable human
carcinogen (Group B2), under EPA's 1986 cancer classification system.
(Ref. 16). The CARC's classification of DDVP as a probable human
carcinogen was based on its conclusion that the evidence showed DDVP
satisfied two separate criteria for a ``probable human carcinogen:''
(1) carcinogenicity seen in multiple species; and (2) carcinogenicity
seen in an unusual degree in a single experiment. To show cancer in
multiple species, the CARC cited (1) a finding of statistically
significant dose-related trend and statistically significant increase
in forestomach tumors (combined papillomas and carcinomas) in female
mice in a cancer study in the mouse conducted by the National
Toxicology Program (NTP); and (2) a finding of a statistically
significant dose-related trend and statistically significant increase
in mononuclear cell leukemia (MCL) and pancreatic acinar adenomas in
male rats in a cancer study in the rat conducted by the NTP. These two
findings were supported by a significant positive trend for forestomach
tumors in male mice in the NTP mouse study and a finding of
statistically significant increased (but overall numbers within the
range of historical controls) lung adenomas and combined mammary
fibroadenomas and carcinomas in male and female rats, respectively, in
the NTP rat study. To satisfy the criterion of cancer in an unusual
degree in a single study, the CARC noted that forestomach tumors are a
rare tumor in the female mouse. Finally, the CARC relied on positive in
vitro mutagenicity data in support of the ``probable human carcinogen''
classification.
    In September, 1987, the CARC's classification was evaluated by the
FIFRA Scientific Advisory Panel (``SAP''), an independent expert panel
created by statute for the purpose of providing EPA advice on
scientific matters concerning pesticides. The SAP disagreed with EPA's
classification and recommended that DDVP be classified as only a
possible human carcinogen (Group C) based on its conclusions that: (1)
DDVP only induced benign tumors; (2) the tumors did not show a dose-
related trend; and (3) DDVP was not mutagenic in in vivo assays. (Ref.
17).
    The CARC met for a second time on DDVP in September, 1987, to take
the SAP's view into consideration. The CARC refused to alter its Group
B2 carcinogen classification. It cited essentially the same reasons
from the first review and emphasized the following evidence of
malignancy to explain its difference with the SAP: (1) MCL is
considered a malignant tumor; (2) both the pancreatic adenomas in rats
and forestomach papillomas in mice had the potential to progress to
malignancies; and (3) the presence of ``some'' rare forestomach
carcinomas in female mice. (Id.)
    A third meeting of the CARC was held in July, 1988 to review a
report from the NTP Panel of Experts on the classification of DDVP.
(Ref. 18). NTP scientists had reexamined the pancreata of the rats in
the NTP rat study and concluded that the statistically significant
increase in pancreatic lesions was diminished. For this reason, the NTP
recommended that the evidence for carcinogenicity in male rats be
downgraded from ``clear'' evidence to ``some'' evidence. Nonetheless,
the CARC again refused to change DDVP's cancer classification relying
on the MCL finding in rats, findings of multiple benign tumors in rat
and mouse NTP studies, and DDVP's mutagenic properties. The CARC noted
this classification was interim until new cancer and mutagenicity data
could be reviewed.
    A fourth meeting of the CARC in September, 1989, again reviewed the
reanalysis of the pancreatic lesions in the rat, and also examined new
cancer studies. (Ref. 19). The CARC noted that, although the NTP
reexamination had found pancreatic tumors in treated rats to be
statistically increased, albeit to a diminished degree than first
thought, a new statistical review by EPA using two common statistical
procedures found no statistical significance at all. Further, the CARC
examined a DDVP inhalation cancer study in rats and two cancer

studies in which DDVP was administered in drinking water. The
inhalation study was negative for cancer effects. The drinking water
studies had several deficiencies making quantitative analysis
inappropriate but had qualitative evidence that showed some of the
tumors seen in previous studies. Taking this information into account,
as well as new information questioning the relevance of MCL in rats and
forestomach tumors in mice to humans, the CARC downgraded DDVP to a
possible human carcinogen (Group C). Nonetheless, the CARC maintained
that a quantitative cancer assessment was warranted using the geometric
mean of the tumor rates of MCL in rats and forestomach tumors in mice.
    The fifth meeting of the CARC, in March 1996, considered new
information from Amvac including an evaluation of the severity of the
MCL seen in the NTP rat study, studies on the mechanism of forestomach
tumors, and in vivo mutagenicity testing. (Ref. 20). The evaluation of
the severity of the rat MCL in the NTP study showed that there was no
statistically significant difference in the severity of the MCL between
control and treated animals. (Ref. 21 at 10). Further, the new in vivo
testing was negative. The CARC, however, rejected Amvac's argument that
the studies it submitted demonstrated the mechanism of tumor formation
for the mouse forestomach tumors. Weighing all of this information, the
CARC retained the possible human carcinogen classification (Group C)
and recommendation for quantitative low dose linear cancer assessment.
Based on its conclusion that the MCL in rats but not the forestomach
papillomas are malignant tumors, however, the CARC concluded that the
linear low dose extrapolation should be based on the MCL in rats alone.
    The sixth cancer review, finalized in February, 2000, principally
focused on the significance of the MCL in the rat NTP study taking into
account three new analyses of this cancer. (Ref. 22). The first was a
report submitted by Amvac titled ``An Evaluation of the Potential
Carcinogenicity of Dichlorvos: Final Report of the Expert Panel.''
(Ref. 23). That report was prepared by various experts in the field,
primarily academics, who had been assembled by a consulting firm hired
by Amvac. The report describes the steps taken to avoid conflicts of
interest and to insure that the substance of the report was not
influenced by its sponsor. The report concludes that the ``incidence of
MCL in the NTP DDVP rat study (1989) . . . does not support a
conclusion of carcinogenicity.'' (Id. at 21). The report summarized the
main reasons for this conclusion as follows:
    1. The results are species-, strain-, and sex-specific.
    2. The endpoint is dramatically affected by administration of corn
oil by gavage.
    3. There was no significant effect on the relative severity of the
disease, time-to-tumor latencies or percentage of rats surviving to
study termination.
    4. The data do not demonstrate a classic dose-response.
    5. The results are not replicated in a very large number of
carcinogenicity studies on DDVP and related substances (e.g.,
Trichlorfon, Metrifonate, Naled).
    6. Many other studies are more appropriate to estimate human risks
since the routes of administration employed more closely approximated
potentially hazardous routes in man (e.g., inhalation, dietary or in
drinking water) rather than the gavage method employed in the NTP
study.
    7. The incidences are similar to normal background rates that are
increasing over time.
(Id.). The report further stated that effects seen in the NTP rat study
showed ``the extremely wide variability that is typically observed with
this tumor.'' (Id.). The finding of a lack of carcinogenicity, the
report asserted, is consistent with ``similar positions taken by other
organizations (e.g., Joint FAO/WHO Panel of Experts on Pesticide
Residues, NTP, and OSTP).'' (Id.). Additionally, the report concluded
that ``metabolic considerations and the genotoxic potential of DDVP''
do not support a finding of carcinogenicity. Finally, the report
concluded that DDVP does cause forestomach tumors in mice but that this
``endpoint has no relevance to man and therefore, should not be
employed for extrapolation to human risk.'' (Id.).
    The second new analysis was from the SAP review of the CARC's
fourth review of the carcinogenicity of DDVP. (Ref. 24). The SAP
concluded that ``[t]here is compelling evidence to disregard MCL in the
Fischer rat.'' The SAP gave several reasons for this conclusion based
both on general information on MCL in Fischer rats and specific
information on the NTP rat cancer study with DDVP. In terms of general
evidence, the SAP explained that (1) ``MCL is one of the most common
background tumor types'' in the Fischer rat; (2) that there is a high
variability in MCL in Fischer rats; and (3) MCL is a strain specific
cancer. (Id. at 17). On this last point, the SAP noted that MCL ``has
been referred to as Fischer rat leukemia . . . [and] [o]ther rat
strains and mice do not develop MCL, and there is no human correlate to
this disease.'' (Id.). Turning to the NTP rat study with DDVP, the SAP
noted that (1) although MCL was seen at both the low and high doses in
the study there was no clear dose-response relationship seen in the
study; and (2) chemically-related increases in MCL are marked by
advanced severity of the MCL but that the NTP rat study ``showed no
significant increase in severity of the MCL with increasing dose,
indicating that these lesions are background.'' (Id.).
    The SAP also ratified the CARC's earlier position that the
forestomach tumors in the NTP mouse study should not be relied upon to
estimate risk to humans. The SAP explained that these tumors are
``likely due to the chronic irritancy, inflammation, and cytotoxicity
during chronic bolus dosing, resulting in extraordinary high local
concentration of the chemical.'' (Id.). Such conditions would not exist
outside of the laboratory. Further, such tumors have only limited
relevance to humans because ``the forestomach in rodents acts as a
storage site where irritant chemicals in food have prolonged contact
with the sensitive squamous epithelium lining, a situation that does
not pertain to humans.'' (Id.).
    The SAP reached an overall conclusion that ``the weight of the
evidence suggests carcinogenicity in animals treated with DDVP with a
non-linear dose-response. However, the compound is considered a weak
carcinogen acting via a secondary or indirect mechanism.'' (Id. at
18.).
    The third new analyses was a short memorandum summarizing a
conversation with Dr. Gary Boorman of the NTP. (Ref. 25). Dr. Boorman
opined that the MCL ``tumor type in males[] [Fisher rats] had a high
and variable background.'' (Id.). Further, Dr. Boorman is cited as
stating that although ``this tumor type can not be dismissed as
[ir]relevant to humans, [] it does seem to be found mainly in the
Fisher rat and does not appear to be the same type of leukemia as found
in [human] adults or children.'' (Id.).
    Relying heavily on the advice of these expert scientific opinions
(particularly, the views of the SAP), the CARC in its sixth report
softened its view regarding the importance of the MCL seen in the NTP
rat study and reaffirmed its view that the forestomach tumors in the
NTP mouse study were a localized tumor of limited relevance to humans.
Although the CARC maintained that the MCL in the rat study could ``not
be totally disregarded,'' it accepted the advice of the expert panel of
the SAP and as well

as the report commissioned by Amvac that the evidence on MCL did not
warrant use of this cancer to quantitatively estimate cancer risk to
humans using a low-dose linear extrapolation. The CARC specifically
cited the high background rates and variability of MCL in the Fischer
rat, the lack of a dose-response effect in the NTP rat study, and
negative results in other cancer studies as justifying its decision to
change the cancer classification of DDVP from a ``possible human
carcinogen'' to ``suggestive evidence of carcinogenic potential'' and
to recommend that the data did not support a quantitative cancer risk
assessment.
    To recap, EPA's initial DDVP cancer classification of ``probable
human carcinogen'' was based on a MCL and pancreatic adenomas in the
rat, forestomach papillomas in the mouse, and positive in vitro
mutagenicity data. EPA only downgraded this classification following:
(1) a re-analysis of the rat study showed no statistically significant
increase in pancreatic adenomas; (2) presentation of strong evidence
concerning the non-relevance of MCL in rats and forestomach tumors in
mice to humans; (3) submission of a negative DDVP cancer study in rats
by the inhalation route; (4) submission of in vivo data showing a lack
of mutagenicity for DDVP; and (5) repeated recommendations from
independent scientific groups to downgrade the DDVP cancer
classification.
    A recent review by the European Food Safety Agency (``EFSA'')
supports EPA's DDVP cancer assessment. (Ref. 15). The EFSA found the
only treatment-related tumors from the DDVP studies to be the mouse
forestomach tumors: ``[The Scientific Panel on Plant health, Plant
protection products and their Residues] concludes that with the
exception of tumours of the forestomach in the mouse, there was no
convincing evidence for a compound-related, relevant tumour response.
Tumours observed in other tissues (pancreas, mammary, mononuclear
leukaemia) showed no dose-response, were inconsistent between studies
and sexes, were reduced in control animals relative to historical
control data, or were unique to the experimental conditions of the
assay.'' (Id. at 33). Further, the EFSA found the forestomach tumors to
be ``a site of contact effect, and a consequence of the very high,
sustained concentrations of dichlorvos to the forestomach that would be
achieved by gavage dosing in corn oil.'' (Id.). These tumors, the EFSA
concluded, were subject to a threshold dose unlikely to be exceeded in
humans due to cholinesterase inhibition effects at a much lower
threshold. (Id. at 34).
    NRDC is wrong to suggest that variability in MCL occurrence alone
drove EPA's decision to change its views regarding the importance of
the MCL findings. To the contrary, variability along with several other
factors were considered in EPA's weight of the evidence approach. If
anything, EPA took a more conservative approach to this cancer than its
scientific advisory panel. Further, EPA did not discount the
forestomach tumors simply because humans do not have forestomachs.
Rather, both EPA and the SAP explained why the unique aspects of the
rodent forestomach in connection with the artificial condition of corn
oil bolus dosing are likely to produce results of limited relevance to
humans.
    Further, NRDC's reliance on epidemiological studies by Liess and
Brown is misplaced. EPA reviewed the Liess study and identified biases
and confounders in the studies that are a more likely explanation for
the findings of increased cancer than exposure to pest strips. (Ref. 11
at 142). As to the Brown study, EPA has rejected it as inadequate
because the subjects were exposed to other pesticides in addition to
DDVP and there was no adjustment made for these other exposures. Other
confounders such as multiple statistical comparisons were identified as
well. (Ref. 26).
    2. NOAEL/LOAEL--a. NRDC's claims. NRDC notes that a NOAEL for
cholinesterase inhibition was not established in a mouse oncogenicity
study relied upon by EPA. NRDC claims that failure to identify a NOAEL
not only renders the mouse oncogenicity study invalid but ``undermines
the entire risk assessment and precludes the Agency from finding that
the DDVP tolerances are safe . . . .'' (Ref. 1 at 47). NRDC argues that
if there is no NOAEL identified in a study, the LOAEL from that study
is ``virtually meaningless information.'' (Id.). Finally, NRDC argues
that EPA cannot legally make the reasonable certainty of no harm
finding for DDVP or any other pesticide if EPA is relying on a LOAEL
rather than a NOAEL.
    b. EPA's response. EPA has repeatedly rejected NRDC's legal
arguments concerning reliance on LOAELs in making safety findings under
FFDCA section 408. (70 FR 46706, 46729; 69 FR 30042, 30066-30067; Ref.
27 at 165-166). EPA incorporates those prior responses herein. Further,
EPA disagrees with NRDC's contention that a LOAEL in a study that does
not identify a NOAEL provides ``virtually meaningless information.''
Depending on the severity and consistency of the effect at the LOAEL as
well as the severity and consistency at higher doses, the LOAEL can
provide substantial information bearing on the no adverse effect level.
It is for this reason that EPA and FDA, as well as other public health
agencies, have long relied on LOAELs, in appropriate circumstances, in
making safety findings. (69 FR at 30066; Ref. 28).
    EPA relied upon a LOAEL in assessing the risk posed by DDVP for the
following exposure scenarios: short-term incidental oral; short-,
intermediate-, and long-term dermal; short- and intermediate-term
inhalation. The LOAEL was from a single blind, placebo controlled,
randomized study to investigate the effects of multiple oral dosing on
erythrocyte cholinesterase inhibition in healthy male volunteers and
involved a dose of 0.1 milligrams/kilogram of body weight/day (``mg/kg/
day''). This value was adjusted with a safety factor of 3X to
approximate the value of a NOAEL. The LOAEL provided sufficient
information to estimate the NOAEL (using a 3X safety factor) because
the study measured the severity of the cholinesterase inhibition
response observed. Cholinesterase inhibition is a continuous endpoint
where no fixed generic percentage of change from baseline separates
potential adverse effects from non-adverse effects. Generally,
cholinesterase inhibition of 20 percent from baseline is regarded as
showing a potential for adverse effects on the nervous system with
lower levels evaluated on a case-by-case basis. (Ref. 9 at 37-38). In
the DDVP human study, the cholinesterase inhibition fell at the very
low end of the scale (cholinesterase inhibition in individuals varied
from baseline within a range from 8 to 23 percent at the end of the
study) indicating that the NOAEL was not significantly lower.
    NRDC is mistaken to claim that the mouse oncogenicity study was
invalid for failure to identify a NOAEL. Oncogenicity (carcinogenicity)
studies are not designed to produce NOAELs but rather to examine the
cancer responses at high doses. EPA relies on chronic studies in the
rodent and non-rodent (generally the rat and dog, respectively) to
evaluate and define the level of threshold chronic, non-cancer effects.
(40 CFR 158.340(a)). Acceptable chronic rat and dog studies are
available for DDVP. (Ref. 11). NRDC also errs in contending that EPA,
by examining cholinesterase effects in the mouse oncogenicity study,
indicates that it does not have valid and reliable chronic toxicity
data. As noted, EPA does not specifically require a chronic toxicity

study in the mouse and it has an acceptable study meeting the
requirement for a chronic study in rodents. Nonetheless, where an
oncogenicity study in the mouse does shed light on effects seen in
chronic studies, EPA certainly will consider that information in its
overall weight-of-the-evidence evaluation for the pesticide.
    3. Human studies--a. NRDC's claims. NRDC asserts that none of the
DDVP human studies satisfy the standards in EPA's human testing rule
because they ``violate the Nuremburg Code and fail to satisfy the
standards in EPA's human testing rule.'' (Ref. 1 at 26.). Therefore,
NRDC petitions EPA to reject all intentional dosing human studies for
DDVP as unethical and unscientific.
    NRDC raises various specific concerns as to a particular human
study commonly referred to as the Gledhill study (MRID
44248801). Citing a draft report by EPA's Human Studies Review Board
(HSRB), NRDC claims that this study is ``statistically meaningless''
because it had too few test subjects. Further, NRDC argues that the
variability in the cholinesterase inhibition in the study demonstrates
that ``even greater than the customary numbers of test subjects would
be required to permit detection of effects caused by the test substance
above background variation.'' (Ref. 13 at 15). Other scientific defects
in the Gledhill study alleged by NRDC include failing to promptly
measure red blood cell (``RBC'') effects; failing to measure blood
plasma effects; not restricting subjects in controlled conditions for
living and eating; and failing to properly obtain informed consent.
NRDC claims the study was ethically deficient because reference in the
consent form to DDVP as a drug made it impossible to obtain informed
consent and study conductors failed to monitor the health of subjects
after the conclusion of the study. Finally, NRDC argues that if EPA
relies on the study, EPA cannot conclude that the DDVP tolerances are
safe because the LOAEL for humans in the study (reported by NRDC to be
0.01 mg/kg/day) is well below the lowest LOAEL in animal studies (0.1
mg/kg/day).
    NRDC also objects to EPA's reliance on a number of other human
studies which NRDC describes as ``ethically repugnant'' due to
involvement of children as test subjects.
    b. Amvac's comments. In its comments, Amvac argues that ``there is
a large body of human data from a variety of sources that provide
information directly relevant to the DDVP risk assessment process.''
(Ref. 14 at 32). According to Amvac these human studies show that the
most sensitive endpoint for DDVP is inhibition of red blood cell
cholinesterase; DDVP operates by a common mechanism in animals and
humans; DDVP inhibits RBC cholinesterase at similar levels in animals
and humans; and DDVP has similar effects no matter what the route of
exposure. (Id. at 33). As to the Gledhill study, Amvac disputes NRDC's
criticisms of its scientific value and ethics. (Id. at 37). Amvac
claims that ``[t]he number of subjects employed, six per dose, is . . .
a standard number of test subjects sufficient to provide statistical
power in human studies.'' (Id. at 38). Measuring plasma cholinesterase
was not essential, according to Amvac, because RBC cholinesterase ``is
relevant to assessing the risk of inhibition of the toxicologically
important brain cholinesterase enzyme.'' (Id. at 37).
    c. EPA's response. In responding to the petition, EPA would first
note that the petition simply asks EPA not to rely on any of the DDVP
human studies but does not contend that reliance on animal studies
instead of the human studies will show the DDVP tolerances to be
unsafe. Subsequent to NRDC's petition, EPA did rely on the Gledhill
study in assessing the risk posed by DDVP. (Ref. 11 at 133). To clarify
the basis for EPA's decision to rely on the Gledhill study, EPA has
described its decision-making process below.
    EPA decisions regarding the ethics and scientific value of human
studies are governed by the Protection for Subjects in Human Research
final rule (Human Research Rule), which significantly strengthened and
expanded protections for subjects of human research. (71 FR 6138
(February 6, 2006)). The framework of the Research Rule rests on the
basic principle that EPA will not, in its actions, rely on data derived
from unethical research. The rule divides human studies into two
groups: ``new'' studies--those initiated after April 7, 2006--and
``old'' studies--those initiated before April 7, 2006. The Human
Research Rule forbids EPA from relying on data from any ``new'' study,
unless EPA has adequate information to determine that the research was
conducted in substantial compliance with the ethical requirements
contained therein. (40 CFR 26.1705). These ethical rules are derived
primarily from the ``Common Rule,'' (40 CFR part 26), a rule setting
ethical parameters for studies conducted or supported by the federal
government. In addition to requiring informed consent and protection of
the safety of the subjects, among other things, the Rule specifies that
``[r]isks to subjects [must be] reasonable in relation to . . . the
importance of the knowledge that may reasonably be expected to result
[from the study].'' (40 CFR 26.1111(a)(2)). In other words, a study
would be judged unethical if it did not have scientific value
outweighing any risks to the test subjects.
    As to ``old'' studies, the Human Research Rule forbids EPA from
relying on such data if there is clear and convincing evidence that the
conduct of the research was fundamentally unethical or significantly
deficient with respect to the ethical standards prevailing at the time
the research was conducted. (40 CFR 26.1704). EPA has indicated that in
evaluating ``the ethical standards prevailing at the time the research
was conducted'' it will consider the Nuremburg Code, various editions
of the Declaration of Helsinki, the Belmont Report, and the Common
Rule, as among the standards that may be applicable to any particular
study. (71 FR at 6161).
    Whether the data are ``new'' or ``old,'' the Human Research Rule
forbids EPA to rely on data from any study involving intentional
exposure of pregnant women, fetuses, or children. (40 CFR 26.1704).
    To aid EPA in making ethical determinations under the Human
Research Rule, the rule established an independent Human Studies Review
Board (HSRB) to review both proposals for new research and reports of
covered human research on which EPA proposes to rely. (40 CFR 26.1603).
The HSRB is comprised of non-EPA employees ``who have expertise in
fields appropriate for the scientific and ethical review of human
research, including research ethics, biostatistics, and human
toxicology.'' (40 CFR 26.1603(a)). If EPA intends to rely on the
results from ``old'' human research, EPA must submit the results of its
assessment to the HSRB for evaluation of the ethical and scientific
merit of the research. (40 CFR 26.1602(b)(2)). EPA has established the
HSRB as a Federal advisory committee under the Federal Advisory
Committee Act (``FACA'') to take advantage of ``the benefits of the
transparency and opportunities for public participation'' that
accompany a FACA committee. (71 FR at 6156).
    In the risk assessment for DDVP, EPA has relied upon one human
study for several exposure scenarios. The study, conducted by A.J.
Gledhill, involved a single blind, randomized placebo-controlled oral
study in which 6 healthy male volunteers were administered a daily dose
of DDVP for 21 days at approximately 0.1/mg/kg/day and 3 volunteers
were administered a placebo

(Ref. 11 at 133). Prior to relying on the Gledhill study in the IRED,
EPA presented this study as well as 10 other DDVP human studies to the
HSRB for review. In its presentation to the HSRB, EPA stated that it
had concluded 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'' for the purpose of
assessing DDVP by itself but not for conducting a cumulative assessment
of DDVP and other organophosphate pesticides. (Ref. 29 at 19). EPA
recommended that the other 10 studies should not be used. (Id. at 20).
    As part of the public participation procedures that have been
adopted by the HSRB, NRDC appeared before the HSRB when DDVP was being
considered to make the points it has raised in this petition. (Ref.
30).
    The HSRB agreed with EPA on the appropriateness of using the
Gledhill study after a detailed evaluation of the scientific merit of
the study as well as an evaluation of other ethical considerations.
(Ref. 31). In examining scientific merit, the HSRB identified both
strengths and weaknesses of the Gledhill study. Identified as strengths
were: 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. Weaknesses seen included: use
of a single dose; preventing establishment of a dose-response
relationship; small sample size and use of males subjects only;
measurement of RBC cholinesterase inhibition at 24 hours after dosing
which may have missed peak inhibition; no analysis of plasma
cholinesterase; sampling and analysis of enzyme inhibition ended 3 days
before the end of dosing; lack of clarity as to whether steady state
inhibition was achieved; and lack of follow-up with subjects following
completion of dosing. After carefully considering these factors, the
HSRB concluded that despite the ``numerous technical difficulties''
with the study that it ``was sufficiently robust for developing a Point
of Departure for estimating dermal, incidental oral, and inhalation
risk from exposure to DDVP in a single chemical assessment.'' (Id. at
41). The HSRB's reasoning was 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.).
    Turning to other ethical considerations, the HSRB examined whether
there was clear and convincing evidence that prevailing ethical
standards had been violated. Specifically, the HSRB considered whether
informed consent had been compromised by certain references in test
subject disclosure forms to DDVP as a ``drug,'' or by deficiencies in
the monitoring of subjects both during and after conclusion of the
study. Ultimately, the HSRB concluded that although the study ``failed
to fully meet the specific ethical standards prevalent at the time the
research was conducted, . . . [t]here was no clear and convincing
evidence that the research was fundamentally unethical--intended to
seriously harm participants or that informed consent was not
obtained.'' (Id. at 46). The HSRB reasoned that references to DDVP as a
drug did not vitiate informed consent because ``the consent materials
clearly advised subjects that this was a study involving consuming an
insecticide.'' (Id.). Deficiencies in monitoring of subjects were found
not to provide clear and convincing evidence that the study was
ethically deficient by subjecting the test subjects to the threat of
serious harm because prior studies by this researcher involving higher
doses had only invoked minimal responses. (Id.).
    The HSRB also agreed with EPA that the technical difficulties
identified with the Gledhill study limited its usefulness in the
organophosphate cumulative assessment. (Id. at 41). Finally, the HSRB
agreed with EPA that there were scientific value or other ethical
considerations that precluded reliance by EPA on the other ten DDVP
human studies. (Id. at 41-42).
    EPA adopts the HSRB's reasoning and finds it persuasive in
rejecting NRDC's arguments concerning why the Gledhill study should not
be relied upon. In fact, NRDC has not raised in its petition any
arguments not considered and rejected by the HSRB.
    EPA would add the following further information regarding NRDC's
criticisms of the Gledhill study's use of males only, the number of
test subjects in the study, the 24-hour period between dosing and
measurement of cholinesterase inhibition, the failure to measure plasma
cholinesterase, and purported increased sensitivity in humans
demonstrated by the study.
    As to the use of males only, EPA would note that no sex differences
were observed in the comparative cholinesterase studies in animals.
(Ref. 32). With regard to statistical significance of the study results
due to the number of test subjects, EPA strongly disagrees with the
claims of NRDC. The results of the repeated dose study of 9 subjects (6
DDVP and 3 placebo) in the Gledhill study were analyzed statistically
for significance in addition to being analyzed for biological
significance. Although as a general matter more subjects would provide
greater ``statistical power,'' in this case the use of 6 to 9 subjects
with the appropriate statistical methodology is acceptable to EPA
because a positive response was seen. Indeed, all of the 6 dosed
subjects exhibited statistically significant (with respect to their
pre-dose levels) RBC cholinesterase depression on one or more days. One
of the three placebo controls exhibited statistically significant
depression on one day. However, the group means of RBC cholinesterase
activity in treated subjects are statistically below the group means of
the placebo controls on days 7, 11, 14, 16 and 18 by repeated measures
analysis of variance. (Ref. 33). The statistics of the study clearly
show the ability to demonstrate a statistically significant response.
For the sake of comparison it is worth noting that use of 6 male test
subjects exceeds the long-standing EPA recommendation for 4/sex/dose
subjects in non-rodent (usually dog) animal studies. (Ref. 34). Nor
does EPA agree with NRDC that the variability in cholinesterase
inhibition for test subjects shows that more subjects are required to
detect effects above background variations. First, the variability seen
in the study (cholinesterase inhibition in individuals varied from
baseline within a range from 8 to 23 percent at the end of the study)
is not large, particularly since the percentage inhibition in all
instances was at the marginal end of the range. Second, EPA concluded,
and the HSRB agreed, that the study did identify an effect above
background. Moreover, an intra-species safety factor of 10X was applied
to the study results to address variability in human sensitivity.
    As to failure of the study to assess inhibition of plasma
cholinesterase, EPA does not believe that this deficiency has much
significance. Although the study should have had measurements of both
RBC and plasma cholinesterase, the use of RBC cholinesterase findings
provides a more

useful regulatory estimate for assessing the effects of DDVP on brain
and peripheral cholinesterase depression in humans. In its policy on
use of data on cholinesterase inhibition in assessing the risk of
organophosphates and carbamates, EPA made clear that ``[r]ed blood cell
measures of acetylcholinesterase inhibition, if reliable, generally are
preferred over plasma data.'' (Ref. 9 at 29). EPA explained that
``[s]ince the red blood cell contains only acetylcholinesterase, the
potential for exerting effects on neural or neuroeffector
acetylcholinesterase may be better reflected by changes in red blood
cell acetylcholinesterase than by changes in plasma cholinesterases
which contain both butyrylcholinesterase and acetylcholinesterase in
varying ratios depending upon the species.'' (Id.). Although testing
for plasma inhibition may have provided additional information, given
that the study identified statistically significant effects on RBC at a
marginal level, data on a less preferred endpoint such as plasma
cholinesterase adds little meaningful information.
    With regard to the study procedure of waiting 24 hours after dosing
to measure cholinesterase inhibition, the study was designed to
evaluate the cumulative effect of repeat dosing with DDVP. While a
shorter interval between dosing and measurement would have provided
more information about acute effects of DDVP, this study has not been
relied upon to assess acute risks.
    Finally, NRDC is mistaken to claim that the Gledhill study showed
humans to be more sensitive than test animals. The LOAEL from the
Gledhill study is 0.1 mg/kg/day, not 0.01 mg/kg/day, as claimed by
NRDC. (Ref. 11 at 133). The correct LOAEL is similar to the LOAEL from
animal studies.
    4. Mutagenicity--a. NRDC's claim. NRDC claims that EPA cannot find
the DDVP tolerances are safe because EPA has not ``reliably
establish[ed] the bounds of risk posed by the mutagenic potential of
DDVP.'' (Ref. 1 at 47). NRDC notes that EPA has found DDVP to be
mutagenic in in vitro assays and asserts EPA has not taken this
mutagenic risk into account in assessing the safety of DDVP.
    b. Amvac's Comment. Amvac claims that NRDC has focused on in vitro
assays to the exclusion of the more important in vivo studies. These
later studies, Amvac asserts ``provide[] support for the lack of in
vivo carcinogenic activity seen in the DDVP animal bioassays.'' (Ref.
14 at 31). According to Amvac, ``[p]harmacokinetic data have
demonstrated that DDVP is quickly metabolized and this likely accounts
for the difference in the in vitro and in vivo response in the
mutagenicity testing.'' (Id.).
    c. EPA's response. NRDC's claim that EPA has not taken mutagenic
risk into account is mistaken. EPA has fully examined the data on
DDVP's potential for mutagenic effects and concluded that these data do
not raise a safety concern.
    Mutagenicity data on DDVP shows the following: (1) DDVP does
produce positive in vitro results in the absence of activation by rat
derived liver enzymes; (2) these positive results generally disappear
in the presence of activation by liver enzymes; (3) there is some
evidence that DDVP is a weak mutagen in in vivo testing; and (4) an in
vivo chromosome aberrations study requested to address the in vivo
mutagenicity study was negative. (Refs. 11, 20 at 13, 35 and 36).
    Mutagenicity data are considered by EPA both as evidence bearing on
a pesticide's carcinogenic potential and on whether the pesticide can
result in heritable mutagenic effects. As described in Unit VII.A.1.c.,
EPA fully considered the mutagenicity data in its cancer evaluation. As
to DDVP's potential to cause heritable mutagenic effects, EPA
specifically requested that an in vivo chromosome aberrations study be
performed in which germ cells as well as somatic cells were examined to
address this question. This study was negative resolving any concern
with heritable mutagenic effects. (Ref. 20 at 13). One agency reviewer
suggested a further mutagenicity study at higher doses addressing
heritable effects but EPA has not required such testing because
existing testing already tests at the maximum tolerated dose. (Ref.
37).
    5. Endocrine effects--a. NRDC's claim. NRDC asserts that EPA has
failed to assess the endocrine disruption effects of DDVP. NRDC notes
that the statute requires EPA to consider, in making safety
determinations as to tolerances, whether a pesticide has an effect that
mimics estrogen or has other endocrine effects, (see 21 U.S.C.
346a(b)(2)(D)(viii)), and to establish an endocrine screening program,
(see 21 U.S.C. 346a(p)), but that EPA has not collected any data under
this program. NRDC claims that ``[i]n light of [EPA's] failure to carry
out its mandatory statutory duty to investigate the potential of DDVP
to cause endocrine disruption, EPA cannot conclude that . . . the
[DDVP] tolerances are safe.'' (Ref. 1 at 49).
    b. Amvac's Comment. Amvac, in its comments, notes that EPA has
already indicated that it will rely on several studies currently
required for pesticides to assess endocrine effects and that EPA has
these studies for DDVP. (Ref. 14 at 74-75).
    c. EPA's response. In a prior order adjudicating a petition to
revoke tolerances, EPA has rejected the argument that data gathered
under the Endocrine Disruptor Screening Program (``EDSP'') is a
prerequisite to a safety determination under FFDCA section 408. (71 FR
43906, 43919-43921 (August 2, 2006)). There, EPA noted that the
proposed study to be used for chemicals that initial screening suggests
may have the potential to interact with the endocrine system (the two
generation reproduction study in rats) is a study that is currently
required for approval of agricultural or other food use pesticides.
(Id. at 43920). Additionally, EPA pointed out that several other
toxicological studies required for pesticides provide information
relevant to potential endocrine disruption.
    EPA has adequate data on DDVP's potential endocrine effects to
evaluate DDVP's safety. In the 1989 NTP cancer studies with rats and
mice, male and female reproductive organs (prostate, testes,
epididymis, ovaries, uterus) were examined and no changes attributable
to DDVP were found. The 52-week dog study with DDVP also was without
effect in the reproductive organs (testes, prostate, epididymides,
cervix, ovaries, uterus, vagina). EPA also has a 1992 two-generation
rat reproduction study with DDVP (via drinking water) that is similar
to the most recent guidelines (1998) for conduct of such a study with
respect to endocrine-related endpoints. Although that study did not
include certain evaluations that the 1998 guidelines recommended
related to endocrine-related effects (age of vaginal opening and
preputial separation), it did incorporate other aspects of the 1998
guidelines such as an examination of estrous cycling in females and
sperm number, motility, and morphology in males. The study did identify
an adverse effect on estrous cycling in females but only at the high
dose (8.3 mg/kg/day). All doses in the study showed significant
cholinesterase inhibition. Further, the NOAEL and LOAEL from the
estrous cycling endpoint in the reproduction study are nearly two
orders of magnitude higher than the NOAEL and LOAEL used as a Point of
Departure in setting the chronic RfD/PAD for DDVP.
    Finally, based on a comprehensive evaluation of the testicular
toxicity of dichlorvos in rats, a recent publication reported that
there were no testicular effects, except for slightly decreased

sperm motility, at doses causing significant inhibition of
cholinesterase. (Ref. 38). The NOAEL for dichlorvos with respect to
reproductive organ weights, sperm counts, sperm morphology, plasma
testosterone, and testes histopathology was 4 mg/kg, the highest dose
tested.
    Given that EPA has (1) data bearing on potential endocrine effects
from a two-generation reproduction study as well as other chronic data
in which effects on reproductive organs were examined; (2) EPA well
understands DDVP's most sensitive mechanism of toxicity (cholinesterase
inhibition); and (3) the potential endocrine-related effects seen for
DDVP appeared in the presence of significant cholinesterase inhibition
and at levels nearly two orders of magnitude above the most sensitive
cholinesterase effects, EPA believes it has adequate data to make a
safety finding as to DDVP's potential endocrine-related effects.
    6. Neurotoxicity--a. NRDC's claim. NRDC notes that in the 2000
preliminary risk assessment, EPA imposed a 3X uncertainty factor
because there was no measurement for cholinesterase inhibition in an
acute neurotoxicity rat study. NRDC contends that in light of the
failure to measure cholinesterase inhibition, EPA should have required
the study to be redone and that in the absence such data, EPA cannot
make its FFDCA safety finding. (Ref. 1 at 47-48). NRDC also faults the
Agency for failing to explain why, in these circumstances, a 3X
uncertainty factor is safe.
    b. EPA's response. Subsequent to the 2000 preliminary risk
assessment, EPA has received additional acute neurotoxicity data in the
rat which measured cholinesterase inhibition and thus the deficiency in
the prior acute neurotoxicity study has been cured. (Ref. 11 at 130).
Accordingly, the Agency has removed the 3X uncertainty factor that had
been retained due to the deficiency in the prior study.
    7. Translation of oral study to dermal endpoint--a. NRDC's claim.
NRDC asserts that EPA cannot make a safety finding for DDVP because EPA
relied on a rabbit oral study to derive a safe level of acute dermal
exposure. (Ref. 1 at 48). According to NRDC, this approach is ``based
on unwarranted and unsubstantiated assumption that the toxicology and
pharmacokinetics of oral exposure are the same as for dermal
exposure.'' (Id.) Moreover, NRDC argues that even if it were
appropriate to use oral data in place of dermal data, the ``inherent''
uncertainty requires the imposition of a properly supported uncertainty
factor. (Id.). Similarly, NRDC argues that using an oral dog study for
an intermediate-term dermal toxicity scenario is legally inappropriate
and scientifically unsupportable.
    b. Amvac's comments. Amvac states that ``[i]t is common practice in
risk assessments . . . to extrapolate across exposure routes if the
characteristics of the chemical being considered, and the available
data, support such extrapolation.'' (Ref. 14 at 40). Amvac argues that
extrapolation from the oral route to the dermal route is appropriate
for DDVP because the data show that both DDVP's metabolism and types of
toxicity it causes are consistent across all routes of exposure. (Id.).
Additionally, Amvac asserts that the greater absorption of DDVP in oral
studies than in dermal studies makes it more likely that oral studies
will show DDVP-related effects than dermal studies.
    c. EPA's response. Initially, EPA would note that in the IRED EPA
relied upon an oral rat and oral human study for assessing dermal
risks. Presumably, however, NRDC would have similar objections to
reliance on translation of these oral data to the dermal route.
    Use of oral studies to assess dermal risks is, and has been, a
common practice at EPA for some time. (Ref. 39). Data specific to DDVP
confirm that this is a reasonable approach for this pesticide. First,
numerous toxicity studies have been performed with DDVP, involving both
acute and chronic dosing and dosing by all routes of exposure. These
studies consistently show that DDVP is an inhibitor of cholinesterase,
if doses are high enough, regardless of the duration or route of
exposure. Similar results are consistently found across the class of
organophosphate pesticides. (See, e.g., Refs. 40 and 41). Second, oral
metabolism studies indicate both that DDVP is well-absorbed from the
gastro-intestinal tract and that there are no significant differences
in excretion of DDVP doses given orally and intravenously. (Refs. 42
and 43). Accordingly, an orally-administered dose is a reliable
prediction of systemic dose. Thus, it is reasonable to use a RfD
derived from an oral DDVP study to evaluate the safety of systemic
exposures occurring as a result of dermal absorption of DDVP. Moreover,
there are two reasons to believe that EPA's use of a dermal absorption
factor of 11 percent for DDVP in translating the oral RfD into dermal
RfD tends to overstate dermal absorption, exposure, and risk. (Ref.
44). First, dermal absorption studies with volatile chemicals such as
DDVP are likely to overstate the degree of absorption because such
studies attempt to minimize losses of the chemical through evaporation.
Outside of the laboratory, there are usually no such barriers to
evaporation. Second, human skin is generally less permeable than the
rat skin (largely due to species differences in epidermal anatomy, such
as skin thickness, sebaceous secretions, and the density of hair
follicles, (Ref. 45), and thus dermal absorption studies with the rat,
such as the DDVP dermal absorption study, tend to overstate absorption
in humans.
    For all of these reasons, EPA concludes that using oral DDVP
studies in assessing risk from dermal DDVP exposures is a well-
supported scientific assessment technique that would not underestimate
risks from dermal DDVP exposure. Consequently, the application of an
additional safety factor to account for uncertainty of the route to
route extrapolation is not necessary.
    8. Degradates--a. NRDC's claim. NRDC asserts that the Agency has an
incomplete database regarding degradates of DDVP. (Ref. 1 at 9).
Specifically, NRDC contends that degradates identified by the Agency
were never searched for ``or even detectable in the various monitoring
and metabolism studies relied upon by the Agency.'' (Id.). Further,
NRDC states that ``[t]here is no indication whether these degradates
were ever separately subjected to toxicological testing.'' (Id.). Based
upon this assumption, NRDC contends that it is impossible for EPA to
find that the DDVP tolerances are ``safe.''
    b. Amvac's comments. Amvac claims that NRDC has failed to consider
whether the DDVP degradates are toxicologically significant. (Ref. 14
at 68). According to Amvac, ``[i]t is clear just from the structures of
some of these degradates that they are either not toxicologically
significant, and/or, based on structure activity relationships and
knowledge concerning mechanisms of toxicity, that these degradates have
much lower toxicity than the parent compound.'' (Id.).
    c. EPA's response. NRDC's concern that EPA has not searched for
DDVP's major metabolites in magnitude of the residue studies is
misplaced because EPA has determined that these metabolites are rapidly
degraded to harmless chemicals in the normal course of plant and
mammalian metabolism. The residue of concern is DDVP and that is the
chemical identified by DDVP's analytical method.
    EPA has a robust understanding of DDVP's metabolites and degradates
derived from multiple metabolism studies in several different animal
and

plant species. (Refs. 46, 47, 48, 49, 50 and 51). In animals, DDVP's
primary metabolites are dichloroacetaldehyde or (minor pathway) des-
methyl DDVP. Des-methyl DDVP also breaks down into
dichloroacetaldehyde. Dichloroacetaldehyde is rapidly dechlorinated and
oxidized and either expelled from the body through respiration as
carbon dioxide or through excretion in the urine and feces as urea or
hippuric acid or converted into basic carbon compounds which are
incorporated in amino acids (e.g., glycine, serine) and proteins. In
metabolism studies using radioactive-labeled DDVP, little or no DDVP or
its primary metabolites were found in animal tissues and milk.
    In plants, DDVP is hydrolyzed to dimethyl phosphate and
dichloroacetaldehyde. Dimethyl phosphate is sequentially degraded to
monomethyl phosphate and inorganic phosphates. Dichloroacetaldehyde is
converted to 2,2-dichloroethanol which is conjugated and/or
incorporated into naturally-occurring plant components after additional
metabolism.
    9. Inerts--a. NRDC's claims. NRDC asserts that the ``apparent
absence of data on the risks posed by the inert ingredients and
impurities in all DDVP end-use products compels . . . the revocation of
all DDVP tolerances.'' (Ref. 1 at 68).
    b. EPA's response. If an inert ingredient that is combined with
DDVP in an end-use product poses a risk of concern, then there would be
grounds for modifying or revoking the tolerance or tolerance exemption
pertaining to the inert ingredient. It would not be grounds for
revoking the DDVP tolerance, which is evaluated based on the safety of
DDVP. All impurities in technical active ingredient DDVP, which would
be included at lower levels in DDVP end use products, were tested as
part of the technical active ingredient when the toxicology tests on
the technical active ingredient DDVP were conducted.
    10. Other allegedly missing toxicity data--a. NRDC's claims. NRDC
contends that the Agency cannot make its statutory determination of
safety for DDVP dependent upon the submission of data. Specifically,
NRDC asserts that in the absence of a dermal sensitization study and a
developmental neurotoxicity test (DNT) study, EPA cannot make a safety
finding for DDVP under the FFDCA.
    b. EPA's response. EPA has received and reviewed a DNT study for
DDVP. (Ref. 11 at 127). Additionally, NRDC is incorrect in asserting
that EPA does not have any dermal sensitization data for DDVP. On the
contrary, the Agency has four dermal sensitization studies for DDVP.
(Refs. 52, 53, 54 and 55). The DDVP dermal sensitization studies were
conducted with formulations, containing varying levels of technical
DDVP. All four of the studies were negative for sensitization in guinea
pigs. Although none of the studies tested DDVP in isolation, sufficient
information was obtained from the four studies to define the dermal
sensitization toxicity of DDVP.

B. Dietary Exposure Issues

    1. Revised dietary exposure and risk assessment. NRDC's petition
challenges numerous aspects of EPA's 2000 proposed dietary exposure and
risk assessment of DDVP. This exposure and risk assessment was
incorporated into the 2006 DDVP IRED without major changes. In
responding to NRDC's petition, EPA has updated the DDVP dietary
exposure and risk assessment. The main changes in the revised
assessment include: (1) use of EPA's current dietary assessment
program, DEEM-FCID, instead of DEEM; (2) incorporation of residue
estimates for drinking water directly into the DEEM-FCID program; (3)
updated monitoring data (principally from the USDA-Pesticide Data
Program (``PDP'')) and percent crop treated data; and (4) incorporation
of estimated exposure from use of naled as a wide area treatment for
mosquitoes. A summary of the revised dietary risk assessment is
presented in this unit and NRDC's specific comments are responded to
individually below. (Ref. 56).
    The estimated risk levels, presented in Table 1, are largely
unchanged from the 2006 IRED when both food and water are considered.
Although this risk assessment is highly refined as to some commodities
it still contains numerous conservatisms. More details concerning the
revised risk assessment are provided in responding to NRDC's specific
objections.

                          Table 1.--Dietary (Food and Water) Exposure and Risk for DDVP
----------------------------------------------------------------------------------------------------------------
                                      Acute Dietary (99.9 Percentile)                 Chronic Dietary
                                 -------------------------------------------------------------------------------
       Population Subgroup         Dietary Exposure                        Dietary Exposure
                                      (mg/kg/day)           % aPAD            (mg/kg/day)           % cPAD
----------------------------------------------------------------------------------------------------------------
General U.S. Population           0.001313            16                  0.000060            *COM041*12
----------------------------------------------------------------------------------------------------------------
All Infants (<  1 year old)        0.003735            47                  0.000116            23
----------------------------------------------------------------------------------------------------------------