[Federal Register: July 31, 2008 (Volume 73, Number 148)]
[Proposed Rules]
[Page 44863-44892]
[DOCID:fr31jy08-21]

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Part III

Environmental Protection Agency

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40 CFR Part 180

Carbofuran; Proposed Tolerance Revocations; Proposed Rule

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2005-0162; FRL-8373-8]

Carbofuran; Proposed Tolerance Revocations

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: EPA is proposing to revoke all tolerances for carbofuran. The
Agency has determined that the risk from aggregate exposure from the
use of carbofuran does not meet the safety standard of section
408(b)(2) of the Federal Food, Drug, and Cosmetic Act (FFDCA). EPA is
specifically soliciting comment on whether there is an interest in
retaining any individual tolerance, or group of tolerances, and whether
information exists to demonstrate that such tolerance(s) meet(s) the
FFDCA section 408(b)(2) safety standard. EPA encourages interested
parties to comment on the tolerance revocations proposed in this
document and on the proposed time frame for tolerance revocation.
Issues not raised during the comment period may not be raised as
objections to the final rule, or in any other challenge to the final
rule.

DATES: Comments must be received on or before September 29, 2008.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2005-0162, 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
Building), 2777 S. Crystal Drive, 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 telephone number is<PHONE_NUMBER>.
    Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2005-0162. EPA's policy is that all comments received will be included
in the docket without change and may be made available on-line at
http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The Federal regulations.gov website is an ``anonymous access''
system, which means EPA will not know your identity or contact
information unless you provide it in the body of your comment. If you
send an e-mail comment directly to EPA without going through
regulations.gov, your e-mail address will be automatically captured and
included as part of the comment that is placed in the docket and made
available on the Internet. If you submit an electronic comment, EPA
recommends that you include your name and other contact information in
the body of your comment and with any disk or CD-ROM you submit. If EPA
cannot read your comment due to technical difficulties and cannot
contact you for clarification, EPA may not be able to consider your
comment. Electronic files should avoid the use of special characters,
any form of encryption, and be free of any defects or viruses.
    Docket: All documents in the docket are listed in the docket index.
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available either in the electronic docket at 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
Building), 2777 S. Crystal Drive, Arlington, VA. The hours of operation
of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The Docket telephone number is (703)
305-5805.

FOR FURTHER INFORMATION CONTACT: Jude Andreasen Special Review and
Reregistration Division (7508C), 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?

    You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).
    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. To determine
whether you or your business may be affected by this action, you should
carefully examine the applicability provisions in [Unit II.A]. 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. What Should I Consider as I Prepare My Comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through
regulations.gov or e-mail. Clearly mark the part or all of the
information that you claim to be CBI. For CBI information in a disk or
CD ROM that you mail to EPA, mark the outside of the disk or CD ROM as
CBI and then identify electronically within the disk or CD ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When submitting comments,
remember to:
    i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
    ii. Follow directions. The Agency may ask you to respond to
specific questions or organize comments by referencing a

Code of Federal Regulations (CFR) part or section number.
    iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
    iv. Describe any assumptions and provide any technical information
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
    vi. Provide specific examples to illustrate your concerns and
suggest alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
    viii. Make sure to submit your comments by the comment period
deadline identified.

C. What Can I Do if I Wish the Agency to Maintain a Tolerance that the
Agency Proposes to Revoke?

    This proposed rule provides a comment period of 60 days for any
interested person to submit comments on the Agency's proposal. EPA
issues a final rule after considering comments that are submitted in
response to this proposed rule. Comments should be limited only to the
pesticide and tolerances subject to this proposed notice.
    EPA's finding that aggregate exposure from all existing uses of
carbofuran is not safe does not necessarily mean that no individual
tolerance or group of tolerances could meet the FFDCA 408(b)(2) safety
standard and be maintained. For example, in its Interim Reregistration
Eligibility Decision (IRED), EPA concluded that the Agency could
maintain import tolerances for bananas, coffee, rice, and sugarcane,
because dietary risks from the food residues from the import tolerances
are below the Agency's level of concern when considered together with
the food residues from the phase-out crops, but with no other domestic
uses (Ref. 35). However, as discussed in more detail below, EPA can
only maintain tolerances that it can determine will be ``safe'' within
the meaning of section 408(b)(2)(A)(ii). Accordingly, commenters
interested in retaining any tolerance or group of tolerances should
consider submitting information to demonstrate that the tolerance(s)
meet the statutory standard, rather than merely indicating an interest
in retaining the tolerance. Commenters should also be aware that even
if EPA determines that any carbofuran tolerance(s) meet the safety
standard, those tolerances can only be maintained if EPA can also
determine that the cumulative effects from those tolerances, when
considered with the exposures from other N-methyl carbamate pesticide
chemicals, will meet the FFDCA 408(b)(2) safety standard. EPA will not
respond to any comments on subjects that do not relate to the
evaluation or safety of the pesticide tolerances subject to this
proposed notice.
    After consideration of comments, EPA will issue a final regulation
determining whether revocation of the tolerances is appropriate and
making a final finding on whether these tolerances are ``safe'' within
the meaning of section 408(b)(2)(A)(ii). Such regulation will be
subject to objections pursuant to section 408(g) (21 U.S.C. 346a(g)).
    In addition to submitting comments in response to this proposal,
you may also submit an objection at the time of the final rule. If you
anticipate that you may wish to file objections to the final rule, you
must raise those issues in your comments on this proposal. EPA will
treat as waived, any issue not originally raised in comments on this
proposal. Similarly, if you fail to file an objection to the final rule
within the time period specified, you will have waived the right to
raise any issues resolved in the final rule. After the specified time,
issues resolved in the final rule cannot be raised again in any
subsequent proceedings on this rule.

II. Introduction

A. What Action is the Agency Taking?

    EPA is proposing to revoke all of the existing tolerances for
residues of carbofuran. Currently, tolerances have been established on
the following crops: alfalfa, fresh; alfalfa, hay; artichoke, globe;
banana; barley, grain; barley, straw, sugar beet; sugar beet, tops;
coffee bean; corn, forage; corn, fresh (including sweet corn); corn,
grain (including popcorn); corn, stover; cotton, undelinted seed;
cranberry; cucumber; grape; grape (raisin); melon; milk; oat, grain;
oat, straw; pepper; potato; pumpkin; raisins, waste; rice, grain; rice,
straw; sorghum, fodder; sorghum, forage; sorghum, grain; strawberry;
soybean; soybean, forage; soybean, hay; squash; sugarcane, cane;
sunflower, seed; wheat, grain; wheat, straw. The Agency is proposing to
revoke tolerances for these crops because aggregate dietary exposure to
residues of carbofuran, including all anticipated dietary exposures and
all other exposures for which there is reliable information, is not
safe.
    EPA has determined that aggregate exposure to carbofuran greater
than 0.000075 mg/kg/day (i.e., greater than the acute Population
Adjusted Dose (aPAD)) does not meet the safety standard of section
408(b)(2) of the FFDCA. Based on the contribution from food alone, the
more sensitive children's subpopulations receive unsafe exposures to
carbofuran. At the 99.9th percentile of exposure, aggregate carbofuran
dietary exposure from food alone was estimated to range between
0.000121 mg/kg/day for children 6-12 (160% of the aPAD) and 0.000156
mg/kg/day (210% of the aPAD) for children 3-5 years old, the population
subgroup with the highest estimated dietary exposure. In addition,
EPA's analyses show that those individuals-both adults and children--
who receive their drinking water from vulnerable sources are also
exposed to levels that exceed EPA's level of concern--in some cases by
orders of magnitude. This primarily includes those populations
consuming drinking water from groundwater from shallow wells in acidic
aquifers overlaid with sandy soils that have had crops treated with
carbofuran. Aggregate exposures from food and from drinking water
derived from ground water in vulnerable areas (i.e., from shallow wells
associated with sandy soils and acidic aquifers, such as are found in
the Delmarva Peninsula of Delaware, Maryland, and Virginia) result in
even higher estimated exceedances. The aggregate estimates for food and
ground water exposure range between 1100% of the aPAD for adults over
50 years, to over 10,000% of the aPAD for infants. Similarly, EPA
analyses show substantial exceedances for those populations that obtain
their drinking water from reservoirs (i.e., surface water) located in
small agricultural watersheds, prone to runoff, and predominated by
crops that are treated with carbofuran, even though there is more
uncertainty associated with these exposure estimates. For example,
estimated aggregate exposures from food and drinking water derived from
surface water, based on the corn use in Nebraska, range between 340% of
the aPAD for youths 13-19, and 3900% of the aPAD for infants.
    Every sensitivity analysis EPA has performed has shown that
estimated exposures (both for food alone as well as for food and water)
significantly exceed EPA's level of concern for children. Although the
magnitude of the exceedance varies depending the level of conservatism
in the assessment, the fact that in each case aggregate exposures from
carbofuran fail to meet the FFDCA section 408(b)(2) safety standard,
including where EPA relied on highly refined estimates of risk,

using all relevant data and methods, strongly corroborates EPA's
conclusion that aggregate exposures from carbofuran are not safe.

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

    EPA is taking this action, pursuant to the authority in FFDCA
sections 408(b)(1)(b), 408(b)(2)(A), and 408(e)(1)(A). 21 U.S.C.
346a(b)(1)(b), (b)(2)(A), (e)(1)(A).

III. Statutory and Regulatory Background

    A ``tolerance'' represents the maximum level for residues of
pesticide chemicals legally allowed in or on raw agricultural
commodities (including animal feed) and processed foods. Section 408 of
the FFDCA, 21 U.S.C. 346a, as amended by the Food Quality Protection
Act (FQPA) of 1996, Public Law 104-170, authorizes the establishment of
tolerances, exemptions from tolerance requirements, modifications in
tolerances, and revocation of tolerances for residues of pesticide
chemicals in or on raw agricultural commodities and processed foods.
Without a tolerance or exemption, food containing pesticide residues is
considered to be unsafe and therefore ``adulterated'' under section
402(a) of the FFDCA, 21 U.S.C. 342(a). Such food may not be distributed
in interstate commerce (21 U.S.C. 331(a)). For a food-use pesticide to
be sold and distributed, the pesticide must not only have appropriate
tolerances under the FFDCA, but also must be registered under the
Federal Insecticide Fungicide and Rodenticide Act (FIFRA) (7 U.S.C. 136
et seq.). Food-use pesticides not registered in the United States must
have tolerances in order for commodities treated with those pesticides
to be imported into the United States.
    Section 408(e) of the FFDCA, 21 U.S.C. 346a(e), authorizes EPA to
modify or revoke tolerances on its own initiative. EPA is proposing to
revoke these tolerances to implement the Agency's findings made during
the reregistration and tolerance reassessment processes. As part of
these processes, EPA is required to determine whether each of the
existing tolerances meets the safety standard of section 408(b)(2) (21
U.S.C. 346a(b)(2)). Section 408(b)(2)(A)(i) of the FFDCA requires EPA
to modify or revoke a tolerance if EPA determines that the tolerance is
not ``safe.'' (21 U.S.C. 346a(b)(2)(A)(i)). Section 408(b)(2)(A)(ii) of
the FFDCA defines ``safe'' 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.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure.
    Risks to infants and children are given special consideration.
Specifically, section 408(b)(2)(C) 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 proposal
as the ``children's safety factor.''

IV. Carbofuran Background and Regulatory History

    In July 2006, EPA completed a refined acute probabilistic dietary
risk assessment for carbofuran as part of the reassessment program
under section 408(q) of the FFDCA. The assessment was conducted using
Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-
FCID(TM), Version 200-2.02), which incorporates consumption
data from the United States Department of Agriculture's (USDA's)
Nationwide Continuing Surveys of Food Intake by Individuals (CSFII),
1994-1996 and 1998, as well as carbofuran monitoring data from USDA's
Pesticide Data Program\1\ (PDP), estimated percent crop treated
information, and processing/cooking factors, where applicable. The
assessment was conducted applying an additional 500-fold safety factor
that included a 5X children's safety factor, pursuant to section
408(b)(2)(C). That refined assessment showed acute dietary risks from
carbofuran residues in food above EPA's level of concern (Ref 15).
Since 2006, EPA has evaluated additional data submitted by the
registrant, FMC Corporation, and has further refined its original
assessment by incorporating more recent 2005/2006 PDP data, and by
conducting additional analyses. In January 2008, EPA published a draft
Notice of Intent to Cancel (NOIC) all carbofuran registrations, based
in part on carbofuran's dietary risks. As mandated by FIFRA, EPA
solicited comments from the Scientific Advisory Panel (SAP) on its
draft NOIC. Having considered the comments from the SAP, EPA is
initiating the process to revoke all carbofuran tolerances. As noted
above, aggregate exposures from food and water to the US population at
the upper percentiles of exposure substantially exceed the safe daily
levels and thus are ``unsafe'' within the meaning of FFDCA section
408(b)(2) (Ref 12). It is particularly significant that under every
analysis EPA has conducted, the levels of carbofuran exceed the safe
daily dose for children, even when EPA used the most refined data and
models available. Based on these findings, EPA has decided to move as
expeditiously as possible to address the unacceptable dietary risks to
children. EPA still expects to issue the NOIC subsequent to undertaking
the activities required to revoke the carbofuran tolerances.
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    \1\ USDA's Pesticide Data Program monitors for pesticides in
certain foods at the distribution points just before release to
supermarkets and grocery stores.
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    In May 2008, FMC Corporation, the sole U.S. registrant, submitted a
conditional request to cancel use of carbofuran on certain crops and to
add use restrictions intended to mitigate ground and surface water
contamination from use on other crops (Ref. 32). The tolerances that
would have been affected by that proposal are: alfalfa, fresh; alfalfa,
hay; artichoke, globe; barley, grain; barley, straw; sugar beet, tops;
cranberry; cucumber; grape; grape (raisin); oat, grain; oat, straw;
pepper; sorghum, fodder; sorghum, forage; sorghum, grain; strawberry;
soybean; soybean, forage; soybean, hay; squash; wheat, grain; wheat,
straw. FMC, however, conditioned the request on receiving assurance
from EPA that the Agency would permit the retention of several uses
that do not meet the FFDCA 408(b)(2) safety standard or the FIFRA
registration standard (Id.). EPA, therefore, could not accept the
request, and FMC has withdrawn it (Id.). The tolerances that FMC would
have sought to retain under that proposal were:

banana, coffee bean; corn, forage; corn, fresh; corn, grain (including
popcorn); corn, stover; cotton, undelinted seed; melon; milk; potato;
rice, grain; rice, straw; sugarcane, cane; and sunflower, seed. Based
on the contribution from these foods alone, dietary exposures to
carbofuran would still be unsafe for the more sensitive children's
subpopulations. At the 99.9th percentile, carbofuran dietary exposure
from food alone was estimated at 0.000082 mg/kg/day (110% of the aPAD)
for children 3-5 years old, the population subgroup with the highest
estimated dietary exposure (Ref. 12). In addition, as discussed in more
detail in Refs 18 and 54, although FMC's proposed groundwater
restrictions would have protected against further contamination in the
most vulnerable locations, the Agency could not conclude that the
restrictions would be protective of all vulnerable groundwater. EPA
also has substantial questions about the efficacy of FMC's proposed
surface water restrictions to reduce drinking water exposure in
vulnerable reservoirs (Refs. 18 and 54). Accordingly, it has not been
shown that drinking water residues of carbofuran would no longer
contribute significantly to unsafe aggregate exposures, nor that such
exposures would meet the FFDCA safety standard.

V. EPA's Approach to Dietary Risk Assessment

    EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. A short summary is provided
below to aid the reader. For further discussion of the regulatory
requirements of section 408 of the FFDCA and a complete description of
the risk assessment process, see http://www.epa.gov/fedrgstr/EPA-PEST/
1999/January/Day-04/p34736.htm.
    To assess the risk of a pesticide tolerance, EPA combines
information on pesticide toxicity with information regarding the route,
magnitude, and duration of exposure to the pesticide. The risk
assessment process involves four distinct steps: (1) identification of
the toxicological hazards posed by a pesticide; (2) determination of
the exposure ``level of concern'' for humans; (3) estimation of human
exposure; and (4) characterization of human risk based on comparison of
human exposure to the level of concern.

A. Hazard Identification and Selection of Toxicological Endpoint

    Any risk assessment begins with an evaluation of a chemical's
inherent properties, and whether those properties have the potential to
cause adverse effects (i.e., a hazard identification). EPA then
evaluates the hazards to determine the most sensitive and appropriate
adverse effect of concern, based on factors such as the effect's
relevance to humans and the likely routes of exposure.
    Once a pesticide's potential hazards are identified, EPA determines
a toxicological level of concern for evaluating the risk posed by human
exposure to the pesticide. In this step of the risk assessment process,
EPA essentially evaluates the levels of exposure to the pesticide at
which effects might occur. An important aspect of this determination is
assessing the relationship between exposure (dose) and response (often
referred to as the dose-response analysis). In evaluating a chemical's
dietary risks EPA uses a reference dose (RfD) approach, which involves
a number of considerations including:
     A `point of departure'(PoD) -- the value from a dose-
response curve that is at the low end of the observable data and that
is the toxic dose that serves as the `starting point' in extrapolating
a risk to the human population;
     An uncertainty factor to address the potential for a
difference in toxic response between humans and animals used in
toxicity tests (i.e., interspecies extrapolation);
     An uncertainty factor to address the potential for
differences in sensitivity in the toxic response across the human
population (for intraspecies extrapolation); and
     The need for an additional safety factor to protect
infants and children, as specified in FFDCA section 408(b)(2)(C).
    EPA uses the chosen PoD to calculate a safe dose or RfD. The RfD is
calculated by dividing the chosen PoD by all applicable safety or
uncertainty factors. Typically in EPA risk assessments, a combination
of safety or uncertainty factors providing at least a hundredfold
(100X) margin of safety is used: 10X to account for interspecies
extrapolation and 10X to account for intraspecies extrapolation.
Further, in evaluating the dietary risks for pesticide chemicals, 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 also
calculates a variant of the RfD referred to as a PAD. A PAD is the RfD
divided by any portion of the children's safety factor that does not
correspond to one of the traditional additional uncertainty/safety
factors used in general Agency risk assessment. 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. For acute assessments, the risk is expressed as a
percentage of a maximum acceptable dose or the acute PAD (i.e., the
acute dose which EPA has concluded will be ``safe''). As discussed
below in Unit V.C., dietary exposures greater than 100 percent of the
acute PAD are generally cause for concern and would be considered
``unsafe'' within the meaning of FFDCA section 408(b)(2)(B). Throughout
this document general references to EPA's calculated safe dose are
denoted as an acute PAD, or aPAD, because the relevant point of
departure for carbofuran is based on an acute risk endpoint.

B. Estimating Human Dietary Exposure Levels

    Pursuant to section 408(b) of the FFDCA, EPA has evaluated
carbofuran's dietary risks based on ``aggregate exposure'' to
carbofuran. By ``aggregate exposure,'' EPA is referring to exposure to
carbofuran alone by multiple pathways of exposure. EPA uses available
data, together with assumptions designed to be protective of public
health and standard analytical methods, to produce separate estimates
of exposure for a highly exposed subgroup of the general population,
for each potential pathway and route of exposure. For acute risks, EPA
then calculates potential aggregate exposure and risk by using
probabilistic\2\ techniques to combine distributions of potential
exposures in the population for each route or pathway. For dietary
analyses, the relevant sources of potential exposure to carbofuran are
from the ingestion of residues in food and drinking water. The Agency
uses a combination of monitoring data and predictive models to evaluate

environmental exposure of humans to carbofuran.
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    \2\ Probabilistic analysis is used to predict the frequency with
which variations of a given event will occur. By taking into account
the actual distribution of possible consumption and pesticide
residue values, probabilistic analysis for pesticide exposure
assessments ``provides more accurate information on the range and
probability of possible exposure and their associated risk values.''
(Ref. 58). In capsule, a probabilistic pesticide exposure analysis
constructs a distribution of potential exposures based on data on
consumption patterns and residue levels and provides a ranking of
the probability that each potential exposure will occur. People
consume differing amounts of the same foods, including none at all,
and a food will contain differing amounts of a pesticide residue,
including none at all.
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    1. Exposure from food. Data on the residues of carbofuran in foods
are available from a variety of sources. One of the primary sources of
the data comes from federally-conducted surveys, including the PDP
conducted by the USDA. Further, market basket studies, which are
typically performed by registrants, can provide additional residue
data. These data generally provide a characterization of pesticide
residues in or on foods consumed by the U.S. population that closely
approximates real world exposures because they are sampled closer to
the point of consumption in the chain of commerce than field trial
data, which are generated to establish the maximum level of legal
residues that could result from maximum permissible use of the
pesticide. In certain circumstances, EPA will rely on field trial data,
as it can provide more accurate exposure estimates (see below in Unit
VI.E.1).
    EPA uses a computer program known as the 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 or PAD values to estimate risk. EPA uses DEEM-FCID
to estimate exposure for the general U.S. population as well as for 32
subgroups based on age, sex, ethnicity, and region. DEEM-FCID allows
EPA to process extensive volumes of data on human consumption amounts
and residue levels in making risk estimates. Matching consumption and
residue data, as well as managing the thousands of repeated analyses of
the consumption database conducted under probabilistic risk assessment
techniques, requires the use of a computer.
    DEEM-FCID contains consumption and demographic information on the
individuals who participated in the USDA's 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
``recipes'' that convert foods as consumed (e.g., pizza) back into
their component raw agricultural commodities (e.g., wheat from flour,
or tomatoes from sauce, etc.). 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 or PADs for that pesticide are inputs to the
DEEM-FCID program to estimate exposure and risk.
    For carbofuran's assessment, EPA used DEEM-FCID to calculate risk
estimates based on a probabilistic distribution. DEEM-FCID combines the
full range of residue values 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. EPA also uses
DEEM-FCID to compute 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 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) Identification of any food(s) that could bear the residue in
question for each person/day in the CSFII;
    (2) Calculation of an exposure level for each of the thousands of
person/days in the CSFII database, 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.
    The resulting probabilistic assessment presents a range of
exposure/risk estimates.
    2. Exposure from water. EPA may use field monitoring data and/or
simulation water exposure models to generate pesticide concentration
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 the
specific agricultural or residential pesticide practices in specific
locations, under the environmental conditions associated with a
sampling design (i.e., the locations of sampling, the times of the year
samples were taken, and the frequency by which samples were collected).
Although monitoring data can provide a direct measure of the
concentration of a pesticide in water, it does not always provide a
reliable basis for estimating spatial and temporal variability in
exposures because sampling may not occur in areas with the highest
pesticide use, and/or when the pesticides are being used and/or at an
appropriate sampling frequency to detect high concentrations of a
pesticide that occur over the period of a day to several days.
    Because of the limitations in most monitoring studies, EPA's
standard approach is to use simulation water exposure models as the
primary means to estimate pesticide exposure levels in drinking water.
Modeling is a useful tool for characterizing vulnerable sites, and can
be used to estimate peak pesticide water concentrations from
infrequent, large rain events. EPA's computer models use detailed
information on soil properties, crop characteristics, and weather
patterns to estimate water concentrations in vulnerable locations where
the pesticide could be used according to its label. (69 FR 30042,
30058-30065 (May 26, 2004)). These models calculate estimated water
concentrations of pesticides using laboratory data that describe how
fast the pesticide breaks down to other chemicals and how it moves in
the environment at these vulnerable locations. The modeling provides an
estimate of pesticide concentrations in ground and surface water.
Depending on the modeling algorithm (e.g., surface water modeling
scenarios), daily concentrations can be estimated continuously over
long periods of time, and for places that are of most interest for any
particular pesticide.
    EPA relies on models it has developed for estimating pesticide
concentrations in both surface water and ground water. Typically EPA
uses a two-tiered approach to modeling pesticide concentrations in
surface and ground water. 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 two models: the Pesticide Root Zone Model
(PRZM) and the Exposure Analysis Model System (EXAMS).
    A detailed description of the models routinely used for exposure
assessment is available from the EPA OPP Water Models web site: http://
www.epa.gov/oppefed1/models/water/index.htm. These models provide a
means for EPA to estimate daily pesticide concentrations in surface
water sources of drinking water (a reservoir) using local soil, site,
hydrology, and weather

characteristics along with pesticide application and agricultural
management practices, and pesticide environmental fate and transport
properties. Consistent with the recommendations of the FIFRA SAP, EPA
also considers regional percent cropped area factors (PCA) which takes
into account the potential extent of cropped areas that could be
treated with pesticides in a particular area. The PRZM and EXAMS models
used by EPA were developed by EPA's Office of Research and Development
(ORD), and are used by many international pesticide regulatory agencies
to estimate pesticide exposure in surface water. EPA's use of the
percent cropped area factors and the Index Reservoir scenario was
reviewed by the FIFRA SAP in 1999 and 1998, respectively (Refs. 25 and
26).
    In modeling potential surface water concentrations, EPA attempts to
model areas of the country that are highly vulnerable to surface water
contamination rather than simply model ``typical'' concentrations
occurring across the nation. Consequently, EPA models exposures
occurring in small highly agricultural watersheds in different growing
areas throughout the country, over a 30 year period. The scenarios are
designed to capture residue levels in drinking water from reservoirs
with small watersheds with a large percentage of land use in
agricultural production. EPA believes these assessments are likely
reflective of a small subset of the watersheds across the country that
maintain drinking water reservoirs, representing a drinking water
source generally considered to be more vulnerable to frequent high
concentrations of pesticides than most locations that could be used for
crop production.
    EPA uses the output of daily concentration values from tier two
modeling as an input to DEEM-FCID, which combines water concentrations
with drinking water consumption information in the daily diet to
generate a distribution of exposures from consumption of drinking water
contaminated with pesticides. These results are then used to calculate
a probabilistic assessment of the aggregate human exposure and risk
from residues in food and drinking water.

C. Selection of Acute Dietary Exposure Level of Concern

    Because probabilistic assessments generally present a realistic
range of residue values to which the population may be exposed, EPA's
starting point for estimating exposure and risk for such aggregate
assessments is the 99.9th percentile of the population under
evaluation. When using a probabilistic method of estimating acute
dietary exposure, EPA typically assumes that, when the 99.9th
percentile of acute exposure is equal to or less than the aPAD, the
level of concern for acute risk has not been exceeded. By contrast,
where the analysis indicates that estimated exposure at the 99.9th
percentile exceeds the aPAD, EPA would generally conduct one or more
sensitivity analyses to determine the extent to which the estimated
exposures at the high-end percentiles may be affected by unusually high
food consumption or residue values. To the extent that one or a few
values seem to ``drive'' the exposure estimates at the high end of
exposure, EPA would consider whether these values are reasonable and
should be used as the primary basis for regulatory decision making (Ref
58).

VI. Aggregate Risk Assessment and Conclusions Regarding Safety

    Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA's assessment of exposures and risks associated with
carbofuran use follows:

A. Toxicological Profile

    Carbofuran is an N-methyl carbamate (NMC) pesticide. Like other
pesticides in this class, the primary toxic effect seen following
carbofuran exposure is neurotoxicity resulting from inhibition of the
enzyme acetylcholinesterase (AChE). AChE breaks down acetylcholine
(ACh), a compound that assists in transmitting signals through the
nervous system. Carbofuran inhibits the AChE activity in the body. When
AChE is inhibited at nerve endings, the inhibition prevents the ACh
from being degraded and results in prolonged stimulation of nerves and
muscles. Physical signs and symptoms of carbofuran poisoning include
headache, nausea, dizziness, blurred vision, excessive perspiration,
salivation, lacrimation (tearing), vomiting, diarrhea, aching muscles,
and a general feeling of severe malaise. Uncontrollable muscle
twitching and bradycardia (abnormally slow heart rate) can occur.
Severe poisoning can lead to convulsions, coma, pulmonary edema, muscle
paralysis, and death by asphyxiation. Carbofuran poisoning also may
cause various psychological, neurological and cognitive effects,
including confusion, anxiety, depression, irritability, mood swings,
difficulty concentrating, short-term memory loss, persistent fatigue,
and blurred vision (Refs. 15 and 16).
    The most sensitive and appropriate effect associated with the use
of carbofuran is its toxicity following acute exposure. Acute exposure
is defined as an exposure of short duration, usually characterized as
lasting no longer than a day. EPA classifies carbofuran as Toxicity
Category I, the most toxic category, based on its potency by the oral
and inhalation exposure routes. The lethal potencies of chemicals are
usually described in terms of the ``dose'' given orally or the
``concentration'' in air that is estimated to cause the death of 50
percent of the animals exposed (abbreviated as LD50 or
LC50). Carbofuran has an oral LD50 of 7.8-6.0 mg/
kg, and an inhalation LC50 of 0.08 mg/l (Refs. 12, 16 and
48). The lethal dose and lethal concentration levels for the oral and
inhalation routes fall well below the limits for the Toxicity Category
I, < 50 mg/kg and < 0.2 mg/l, respectively (40 CFR 156.62).
    Carbofuran has a steep dose-response curve. In other words, a
marginal increase in administered doses of carbofuran can result in a
significant change in the toxic effect. For example, carbofuran data in
juvenile rats (postnatal day 11 and 17) demonstrate that small
differences in carbofuran doses (0.1 mg/kg to 0.3 mg/kg) can change the
measured effect from significant brain and red blood cell (RBC) AChE
inhibition without clinical signs (0.1 mg/kg) to significant AChE
inhibition, and resultant tremors, and decreased motor activity (0.3
mg/kg) (Refs. 31 and 46). In other words there is a slight difference
in exposure levels that produce no noticeable outward effects and the
level that causes adverse effects. This means that small differences in
human exposure levels can have significant adverse consequences for
large numbers of individuals. For example, as discussed in greater
detail in Unit VI.E.1.b below, the difference between the amount of
food with carbofuran residues that can be safely consumed without
adverse effect, and the amount that provides a dose that exceeds safe
levels is minimal. Children who consume typical amounts of watermelon
(i.e., 8 grams) containing carbofuran residues of 0.009 ppm-a residue
level detected in PDP data--receive a safe daily dose, but those
consuming the same amount of watermelon with a PDP residue level of
0.013 receive an exposure of 130% of the safe daily dose.

B. Deriving Carbofuran's point of departure

    EPA uses a weight of evidence approach to determine the toxic
effect that will serve as the appropriate PoD for a risk assessment for
AChE inhibiting pesticides, such as carbofuran (Ref. 61). The
neurotoxicity that carbofuran causes can occur in both the central
(brain) and peripheral nervous systems (PNS). In its weight of the
evidence analysis, EPA reviews data, such as AChE inhibition data from
the brain, peripheral tissues and blood (e.g., RBC or plasma), in
addition to data on clinical signs and other functional effects related
to AChE inhibition. Based on these data, EPA selects the most
appropriate effect on which to regulate; such effects can include
clinical signs of AChE inhibition, central or peripheral nervous tissue
measurements of AChE inhibition or RBC AChE measures (Id.). Although
RBC AChE inhibition is not adverse in itself, it is a surrogate for
inhibition in peripheral tissues when peripheral data are not
available. As such, RBC AChE inhibition provides an indirect indication
of adverse effects on the nervous system (Id.). Due to technical
difficulties regarding dissection of peripheral nerves and the rapid
nature of carbofuran toxicity, measures of AChE inhibition in the PNS
are very rare for NMC pesticides. For these reasons, other state and
national agencies such as California, Washington, Canada, the European
Union, as well as the World Health Organization (WHO), all use blood
measures in human health risk assessment and/or worker safety
monitoring programs.
    AChE inhibition in brain and the PNS is the initial adverse
biological event which results from exposure to carbofuran, and with
sufficient levels of inhibition leads to other effects such as tremors,
dizziness, as well as gastrointestinal and cardiovascular effects,
including bradycardia (Ref. 16). Thus, AChE inhibition provides the
most appropriate effect to use in risk extrapolation for derivation of
RfDs and PADs. Protecting against AChE inhibition ensures that the
other adverse effects mentioned above do not occur.
    EPA has relied on a benchmark dose approach for deriving the PoD
from the available rat toxicity studies. A benchmark dose, or BMD, is a
point estimate along a dose-response curve that corresponds to a
specific response level. For example, a BMD10 represents a
10% change from the background or typical value for the response of
concern. Generically, the direction of change from background can be an
increase or a decrease depending on the biological parameter and the
chemical of interest. In the case of carbofuran, inhibition of AChE is
the toxic effect of concern. Following exposure to carbofuran, the
normal biological activity of the AChE enzyme is decreased (i.e., the
enzyme is inhibited). Thus, when evaluating BMDs for carbofuran, the
Agency is interested in a decrease in AChE activity compared to normal
activity levels, which are also termed ``background'' levels.
Measurements of ``background'' AChE activity levels are usually
obtained from animals in experimental studies that are not treated with
the pesticide of interest (i.e., ``negative control'' animals).
    In addition to the BMD, a ``confidence limit'' was also calculated.
Confidence limits express the uncertainty in a BMD that may be due to
sampling and/or experimental error. The lower confidence limit on the
dose used as the BMD is termed the BMDL, which the Agency uses as the
PoD. Use of the BMDL for deriving the PoD rewards better experimental
design and procedures that provide more precise estimates of the BMD,
resulting in tighter confidence intervals. Use of the BMDL also helps
ensure with high confidence (e.g., 95% confidence) that the selected
percentage of AChE inhibition is not exceeded. From the PoD, EPA
calculates the RfD and aPAD.
    Numerous scientific peer review panels over the last decade have
supported the Agency's application of the BMD approach as a
scientifically supportable method for deriving PoDs in human health
risk assessment, and as an improvement over the historically applied
approach of using no-observed-adverse-effect levels (NOAELs) or lowest-
observed-adverse-effect-levels (LOAELs). The NOAEL/LOAEL approach does
not account for the variability and uncertainty in the experimental
results, which are due to characteristics of the study design, such as
dose selection, dose spacing, and sample size. With the BMD approach,
all the dose response data are used to derive a PoD. Moreover, the
response level used for setting regulatory limits can vary based on the
chemical and/or type of toxic effect (Refs. 27, 28, 29 and 57).
Specific to carbofuran and other NMCs, the FIFRA SAP has reviewed and
supported the statistical methods used by the Agency to derive BMDs and
BMDLs on two occasions, February 2005 and August 2005 (Refs. 28 and
29). Recently, in reviewing EPA's draft NOIC, the SAP again unanimously
concluded that the Agency's approach in using a benchmark dose to
derive the PoD from carbofuran brain AChE data in juvenile rats is
``state of the art science and the Panel strongly encouraged the Agency
to follow this approach for all studies where possible'' (Ref. 30).
    There are laboratory data on carbofuran for cholinesterase activity
in plasma, RBC, and brain. EPA evaluated the quality of the AChE data
in all the available studies. In this review, particular attention was
paid to the methods used to assay AChE inhibition in the laboratory
conducting the study. Because of the nature of carbofuran inhibition of
AChE, care must be taken in the laboratory such that experimental
conditions do not promote enzyme reactivation (i.e., recovery) while
samples of blood and brain are being processed and analyzed. If this
reactivation occurs during the assay, the results of the experiment
will underestimate the toxic potential of carbofuran (Refs. 33, 37, 43,
66 and 67). Through its review of available studies, the Agency
identified problems and irregularities with the RBC AChE data from both
FMC supported studies. These problems are described in detail in the
Agency's study review (Refs. 19 and 20). As such, the Agency determined
that the RBC AChE inhibition data from both FMC studies were unreliable
and not useable in extrapolating human health risk. In addition, RBC
data from a study performed at EPA ORD did not provide doses low enough
to adequately characterize the full dose-response in postnatal day 11
(PND11) rats. In the recent SAP review of the draft carbofuran NOIC,
the Panel unanimously agreed with the Agency's conclusion, remarking
that ``[t]he Agency is well-justified in taking the position that the
data on AChE inhibition in rat RBC, particularly with regard to the
PND11 pups, are not acceptable for the purpose of predicting health
risk from carbofuran'' (Ref. 30). By contrast, the brain AChE data from
the FMC and EPA-ORD studies are acceptable and have been used in the
Agency's BMD analysis.
    In EPA's BMD dose analysis to derive PoDs for carbofuran, the
Agency used a response level of 10% brain AChE inhibition and thus
calculated BMD10s and BMDL10s based on the
available carbofuran brain data. These values (the central estimate and
lower confidence bound, respectively) represent the estimated dose
where AChE is inhibited by 10% compared to untreated animals. In the
last few years EPA has used this 10% value to regulate AChE inhibiting
pesticides, including organophosphate pesticides and NMCs including
carbofuran. For a variety of toxicological and statistical reasons, EPA
chose 10%

brain AChE inhibition as the response level for use in BMD and BMDL
calculations. EPA analyses have demonstrated that 10% is a level that
can be reliably measured in the majority of rat toxicity studies; is
generally at or near the limit of sensitivity for discerning a
statistically significant decrease in AChE activity across the brain
compartment; and is a response level close to the background AChE level
(Refs. 28 and 29)
    The Agency used a meta-analysis to calculate the BMD10
and BMDL10 for pups and adults; this analysis includes brain
data from studies where either adult or juvenile rats or both were
exposed to a single oral dose of carbofuran. The Agency used a dose-
time-response exponential model where benchmark dose and half-life to
recovery can be estimated together. This model and the statistical
approach to deriving the BMD10s, BMDL10s, and
half-life to recovery have been reviewed and supported by the FIFRA SAP
(Refs. 28 and 29). The meta-analysis approach offers the advantage over
using single studies by combining information across multiple studies
and thus provides a robust PoD.
    There are three studies available which compare the effects of
carbofuran on PND11 rats with those in young adult rats (herein called
`comparative AChE studies') (Refs. 1, 2 and 46). Two of these studies
were submitted by FMC, the registrant, and one was performed by EPA-
ORD. An additional study conducted by EPA-ORD involved PND17 rats (Ref.
45). Although it is not possible to directly correlate ages of juvenile
rats to humans, PND11 rats are believed to be close in development to
newborn humans. PND17 rats are believed to be closer developmentally to
human toddlers (Ref. 9). Other studies in adult rats used in the
Agency's analysis included additional data from EPA-ORD (Refs 44 and
46).
    Using quality brain AChE data from the three studies (2 FMC, 1 EPA-
ORD) conducted with PND11 rats, in combination, provides data to
describe both low and high doses. By combining the three studies in
PND11 animals together in a meta-analysis, the entire dose-response
range is covered (see Figure 1 in Unit VI.C. below). The Agency
believes the BMD analysis for the PND11 brain AChE data is the most
robust analysis for purposes of PoD selection.
    The studies in juvenile rats show a consistent pattern that
juvenile rats are more sensitive than adult rats to the effects of
carbofuran. These effects include inhibition in AChE in addition to
incidence of clinical signs of neurotoxicity such as tremors. This
pattern has also been observed for other NMC pesticides, which exhibit
the same mechanism of toxicity as carbofuran (Ref. 63). It is not
unusual for juvenile rats, or indeed, for infants or young children, to
be more sensitive to chemical exposures as metabolic detoxification
processes in the young are still developing. Because juvenile rats,
called `pups' herein, are more sensitive than adult rats, data from
pups provide the most relevant information for evaluating risk to
infants and young children and are thus used to derive the PoD. In
addition, typically (and is the case for carbofuran) young children
(ages 0-5) tend to be the most exposed age groups because they tend to
eat larger amounts of food per their body weight than do teenagers or
adults. As such, the focus of EPA's analysis of carbofuran's dietary
risk from residues in food and water is on young children (ages 0-5).
Since these age groups experience the highest levels of dietary risk,
protecting these groups against the effects of carbofuran will, in
turn, also protect other age groups.
    Using data from PND11 pup brain AChE levels, the estimated oral
dose that will result in 10% brain AChE inhibition (BMD10)
is 0.04 mg/kg. The lower 95% confidence limit on the BMD10
(BMDL10) is 0.03 mg/kg--this BMDL10 of 0.03 mg/kg
provides the PoD.
    As noted, although EPA does not consider RBC AChE inhibition as an
adverse effect in its own right, in the absence of data from peripheral
tissues, RBC AChE inhibition data are a critical component to
determining that a selected PoD will be sufficiently protective of PNS
effects. Because of the problems discussed previously with the
available RBC AChE inhibition data, there remains uncertainty
surrounding the dose-response relationship for RBC AChE inhibition in
pups, which the EPA-ORD data clearly show to be a more sensitive
endpoint than brain AChE. Consequently, EPA cannot reliably estimate
the BMD10 and BMDL10 for RBC AChE data in pups.
Furthermore, given that the EPA-ORD data clearly show RBC AChE to be
more sensitive than brain AChE, EPA cannot conclude that reliance on
the pup brain data as the PoD would be sufficiently protective of PNS
effects in pups. This uncertainty provides the scientific basis, in
part, for retention of the children's safety factor as described below.

C. Safety Factor for Infants and Children

    1. In general. Section 408 of the FFDCA provides that EPA shall
apply an additional tenfold margin of safety for infants and children
in the case of threshold effects to account for prenatal and postnatal
toxicity and the completeness of the data base on toxicity and exposure
unless EPA determines that a different margin of safety will be safe
for infants and children. Margins of safety are incorporated into EPA
assessments either directly through use of a margin of exposure
analysis or through using uncertainty (safety) factors in calculating a
dose level that poses acceptable risk to humans.
    In applying the children's safety factor provision, EPA has
interpreted the statutory language as imposing a presumption in favor
of applying an additional 10X safety factor (Ref. 60). Thus, EPA
generally refers to the additional 10X factor as a presumptive or
default 10X factor. EPA has also made clear, however, that 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.).
    2. Prenatal and postnatal sensitivity. As noted in the previous
section, there are several studies in juvenile rats that show they are
more sensitive than adult rats to the effects of carbofuran. These
effects include inhibition of brain AChE in addition to the incidence
of clinical signs of neurotoxicity (such as tremors) at lower doses in
the young rats. The SAP concurred with EPA that the data clearly
indicate that the juvenile rat is more sensitive than the adult rat
with regard to brain AChE (Ref. 30). However, the Agency does not have
AChE data for cabofuran in the peripheral tissue of adult or juvenile
animals; nor does the Agency have adequate RBC AChE inhibition data at
low doses relevant to risk assessment to serve as a surrogate in pups.
As previously noted the RBC AChE data from both FMC supported studies
are not reliable and thus are not appropriate for use in risk
assessment. Although the EPA studies did provide reliable RBC data,
they did not include data at the low end of the dose-response curve,
which is the area on the dose-response curve most relevant for risk
assessment (see Figure 1).
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    There is indication in a toxicity study where pregnant rats were
exposed to carbofuran that effects on the PNS are of concern;
specifically, chewing motions or mouth smacking was observed in a clear
dose-response pattern immediately following dosing each day (Ref. 64).
Based on this study, the California Department of Pesticide Regulation
calculated a BMD05 and BMDL05 of 0.02 and 0.01
mg/kg/day, and established the acute PoD (Refs. 11 and 30). These BMD
estimates are notable as they are close to the values EPA has
calculated for brain AChE inhibition and being used as the PoD for
extrapolating risk to children. It is important to note that these
clinical signs have been reported for at least one other cholinesterase
inhibiting pesticide at doses producing only blood, not brain, AChE
inhibition (Ref. 38). Thus, although RBC AChE inhibition is not an
adverse effect, per se, blood measures are used as surrogates in the
absence of peripheral tissue data. Assessment of potential for
neurotoxicity in peripheral tissues is a critical element of hazard
characterization for NMCs, like carbofuran. The lack of an appropriate
surrogate to assess the potential for RBC AChE inhibition is a key
uncertainty in the carbofuran toxicity database. Thus, EPA cannot
conclude that reliance on the pup brain data solely as the PoD will be
protective of PNS effects in pups.
    To account for the lack of RBC data in pups at the low end of the
response curve, and for the fact that RBC AChE inhibition appears to be
a more sensitive point of departure compared to brain AChE inhibition
(and is considered an appropriate surrogate for the peripheral nervous
system), EPA is retaining a portion of the children's safety factor. On
the other hand, there are data available, albeit incomplete, which
characterize the toxicity of carbofuran in juvenile animals, and the
Agency believes the weight of the evidence supports reducing the
statutory factor of 10X to a value lower than 10X. This results in a
children's safety factor that is less than 10 but more than 1.
    This modified safety factor should take into account the greater
sensitivity of the RBC AChE. The preferred approach to comparing the
relative sensitivity of brain and RBC AChE inhibition would be to
compare the BMD10 estimates. However, as described above,
BMD10 estimates from the available RBC AChE inhibition data
are not reliable due to lack of data at the low end of the dose
response curve (Figure 1). As an alternative approach, EPA has used the
ratio of brain to RBC AChE inhibition at the BMD50, since
there are quality data at or near the 50% response level such that a
reliable estimate can be calculated. There is, however, an assumption
associated with using the 50% response level--namely that the magnitude
of difference between RBC and brain AChE inhibition is constant across
dose. In other words, EPA is assuming the RBC and brain AChE dose
response curves are parallel. There are currently no data to test this
assumption for carbofuran.
    The Agency has recommended the application of a children's safety
factor of 4X, based on a weight-of-evidence approach. This safety
factor is calculated using the difference in RBC and brain AChE
inhibition, using the data on administered dose for the animals from
the EPA-ORD studies and the FMC studies combined. In other words, EPA
estimated the BMD50 for PND11 animals from each quality
study and used the ratio from the combined analysis, resulting in a
BMD50 ratio of 4.1X\3\. EPA also compared the
BMD50 ratios for PND17 pups (who are slightly less sensitive
than 11-day olds; see Figure 2) in the EPA-ORD study, resulting in a
BMD50 of 3.3 X. Conceptually, the RBC to brain potency ratio
could be estimated using two different approaches: 1) EPA's data for
RBC (the only reliable RBC data in PND11 animals for carbofuran) and
all available data in PND11 animals for brain; or 2) using only EPA's
data in PND11 animals for both RBC and brain. The former procedure, the
approach used by EPA, yields a ratio of about fourfold, while the
latter gives a twofold ratio for carbofuran. EPA has elected to use the
4X factor as the more health protective choice. This selection was made
based on: 1) uncertainty regarding lack of an appropriate measure of
peripheral toxicity (i.e., lack of RBC AChE inhibition data at the low
end of the dose response curve), and 2) the RBC to brain AChE ratio at
the BMD50 for PND17 animals of 3.3X which suggests that a
factor of 2X would not be protective of PND11 pups.
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    \3\ EPA made a mathematical error when it originally calculated
the children's safety factor, which resulted in a factor of 5X (Ref.
50). Correcting the mathematical error results in a 4X actor.

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    EPA recently presented its dietary risk assessment of carbofuran to
the FIFRA SAP, and requested comment on the Agency's approach to
selecting the point of departure and the children's safety factor.
Overall, the Agency believes that the Panel's responses support the
Agency's approach with regard to carbofuran's hazard identification and
hazard characterization. For example, the Agency notes that the Panel
``unanimously'' agreed with the Agency with regard to the conclusion
that the second FMC comparative cholinesterase (ChE) study provides
reliable brain, but not RBC, AChE data. The Panel further remarked
that, ``EPA is well-justified in taking the position that the data on
AChE inhibition in rat RBC, particularly with PND11 pups, are not
acceptable for the purpose of predicting health risk from carbofuran''
(Ref. 30). The Panel went on to concur with the Agency that the brain
AChE inhibition data from the FMC and EPA-ORD studies show ``good
concordance.'' With regard to the use of a benchmark dose approach to
derive a PoD from brain AChE data in pups, the Panel stated that the
Agency's approach is ``state-of-the-art science and the Panel strongly
encouraged the Agency to follow this approach for all studies where
possible'' (Id.).
    The Panel provided five `scenarios' or options for applying the
children's safety factor and/or PoD. Four of the five scenarios
included the application of a children's safety factor. Because the
Panel report stated that the Panel was ``not in agreement regarding the
magnitude of a [children's] safety factor,'' it is reasonable to
conclude that a majority did not support any one of the five scenarios,
including the one advocating removal of the children's safety factor
(Ref. 30). It follows that a majority of the Panel agreed with the
Agency that at least a portion of the safety factor should be retained;
however, recommendations for the appropriate factor ranged between a 2X
and 10X. Two of the scenarios were consistent with the Agency's
approach in which the magnitude of the safety factor is derived based
on the differences in RBC and brain AChE responses, quantified by the
administered dose. The remaining two scenarios were based on retention
of the 10X safety factor. Those Panel members supporting retention of
the 10X safety factor did so on the basis that the statutory
requirement that EPA may use a different factor ```only if, on the
basis of reliable data, such margin will be safe for infants and
children.' Given the uncertainty in the data and in its interpretation
for risk assessment by the entire Panel, these Panel members believes
that this standard for change had not been met'' (Id.). EPA believes
that, on balance, the application of a 4X children's safety factor is
consistent with the SAP's advice. Additional detail on the SAP's advice
and EPA's responses can be found at Ref. 23.
    In sum, EPA has concluded that there is reliable data to support
the application of a 4X safety factor and has therefore applied this
safety factor in its dietary risk estimates. However, in light of the
disagreement among the SAP panelists on the appropriate factor to
apply, the Agency solicits comment on this issue.

D. Hazard Characterization and Point of Departure Conclusions

    The doses and toxicological endpoints selected and Margins of
Exposures for various exposure scenarios are summarized in Table 1
below.

                                     Table 1--Toxicology Endpoint Selection
----------------------------------------------------------------------------------------------------------------
                                                                    FQPA factor and
          Exposure Scenario               Dose Used in Risk        Endpoint for Risk     Study and Toxicological
                                            Assessment, UF             Assessment                Effects
----------------------------------------------------------------------------------------------------------------
Acute Dietary Infants and Children     BMDL 10 = 0.03 mg/kg/    Children's SF = 4X       Comparative AChE
                                        day                     aPAD = 0.000075 mg/kg/    Studies in PND11 rats
                                       UF = 100...............   day.                     (FMC and EPA-ORD)
                                       Acute RfD = 0.0003 mg/                            BMD10 = 0.04 mg/kg/day
                                        kg/day.                                          BMDL10 = 0.03 mg/kg/
                                                                                day, based on brain
                                                                                AChE inhibition of
                                                                                postnatal day 11
                                                                                (PND11) pups
----------------------------------------------------------------------------------------------------------------
Acute Dietary Youth (13 and older)     BMDL10 = 0.02 mg/kg/day  Children's SF = 1X       Comparative AChE Study
 and Adults                            UF = 100...............  aRfD = 0.0002 mg/kg/day   (EPA-ORD), Padilla et
                                       Acute RfD = 0.00024 mg/                            al (2007), McDaniel et
                                        kg/day.                                           al (2007)
                                                                                BMD10 = 0.06 mg/kg/day
                                                                                BMDL10 = 0.02 mg/kg/
                                                                                day, based on RBC AChE
                                                                                inhibition in adult
                                                                                rat
----------------------------------------------------------------------------------------------------------------

E. Dietary Exposure and Risk Assessment

    1. Dietary exposure to carbofuran (food)--a. EPA methodology and
background. EPA conducted a refined (Tier 3) acute probabilistic
dietary risk assessment for carbofuran residues in food. Carbofuran is
registered for use on the following crops: alfalfa, artichokes, banana,
barley, corn, cranberry, cucumber, grapes, melons, milk, oats, peppers,
potatoes, pumpkin, rice, sorghum, soybean, spinach, squash, strawberry,
sugar beets, sugar cane, sunflower seed, and wheat. To conduct the
assessment, EPA relied on DEEM-FCID, Version 2.00-2.02, which uses food
consumption data from the USDA's CSFII from 1994-1996 and 1998.
    Using data on the percent of the crop actually treated with
carbofuran and data on the level of residues that may be present on the
treated crop, EPA developed estimates of combined anticipated residues
of carbofuran and 3-hydroxycarbofuran on food. 3-Hydroxycarbofuran is a
degradate of carbofuran and is assumed to have toxic potency equivalent
to carbofuran (Refs. 12, 16 and 48). Anticipated residues of carbofuran
for most foods were derived using USDA PDP monitoring data from recent
years (through 2006 for all available commodities). In some cases,
where PDP data were not available for a particular crop, EPA translated
PDP monitoring data from surrogate crops based on the characteristics
of the crops and the use patterns. For example, PDP data for
cantaloupes were used to derive anticipated residues for casaba and
honeydew.
    USDA PDP provides the most comprehensive sampling design, and the
most extensive and intensive sampling procedures for pesticide residues
of the various data sources available to EPA. Additionally, the intent
of PDP's sampling design is to provide statistically representative
samples of food commodities eaten by the U.S. population specifically
for the purpose of performing dietary risk assessments for pesticides.
The program focuses on high-consumption foods for

children and reflects foods typically available throughout the year. A
complete description of the PDP program (including all data through
2006) is available online.
    The PDP analyzed for parent carbofuran and its metabolite of
concern, 3-hydroxycarbofuran. Most of the samples analyzed by the PDP
were measured using a high Level of Detection (LOD) and contained no
detectable residues of carbofuran or 3-hydroxycarbofuran. Consequently,
the acute assessment for food assumed a concentration equal to [frac12]
of the LOD for PDP monitoring samples with no detectable residues, and
0.00 ppm carbofuran to account for the percent of the crop not treated
with carbofuran.
    An additional source of data on carbofuran residues was provided by
a market basket survey of NMC pesticides in single-serving samples of
fresh fruits and vegetables collected in 1999-2000 (Ref. 14), which was
sponsored by the Carbamate Market Basket Survey Task Force. EPA relied
on these data to construct the residue distribution files for 2 crops
(bananas and grapes) because the use of these data resulted in more
refined exposure estimates. The combined Limits of Quantitation (LOQs)
for carbofuran and its metabolite in the Market Basket Survey (MBS)
were between tenfold and twentyfold lower than the combined LODs in the
PDP monitoring data.
    For certain crops where PDP data were not available (sugar beets,
sugarcane, and sunflower seed), anticipated residues were based on
field trial data. EPA also relied on field trial data for particular
food commodities that are blended during marketing (barley, field corn,
popcorn, oats, rice, soybeans and wheat), as use of PDP data can result
in significant overestimates of exposure when evaluating blended foods.
Field trial data are typically considered to overestimate the residues
that are likely to occur in food as actually consumed because they
reflect the maximum application rate and shortest preharvest interval
allowed by the label. However, for crops that are blended during
marketing, such as corn or wheat, use of field trial data can provide a
more refined estimate than PDP data, by allowing EPA to better account
for the percent of the crop actually treated with carbofuran.
    EPA used average and maximum percent crop treated (PCT) estimates
for most crops, following the guidance provided in HED SOP 99.6
(Classification of Food Forms with Respect to level of Blending; 8/20/
99), and available processing and/or cooking factors. The maximum PCT
estimates were used to refine the acute dietary exposure estimates.
Maximum PCT ranged from <1 to 35%. The estimated percent of the crop
imported was applied to crops with tolerances currently maintained
solely for import purposes (cranberry, rice, strawberry).
    b. Acute dietary exposure (food alone) results and conclusions. The
estimated acute dietary exposure from carbofuran residues in food alone
(i.e., assuming no additional carbofuran exposure from drinking water),
exceeds EPA's level of concern for all but one of the children's
population subgroups at the 99.9th percentile of exposure. Carbofuran
dietary exposure at the 99.9th percentile was estimated at 0.000156 mg/
kg/day (210% of the aPAD) for children 3-5 years old, the population
subgroup with the highest estimated dietary exposure. Estimated dietary
exposure to carbofuran also exceeds EPA's level of concern for children
1-2 years old and 6-12 years at the 99.9th percentile of exposure. (See
results Table 2 below).

                       Table 2--Results of Acute Dietary Exposure Analysis for Food Alone
----------------------------------------------------------------------------------------------------------------
                                                                   99th Percentile          99.9th Percentile
                                                 aPAD (mg/kg/---------------------------------------------------
              Population Subgroup                    day)       Exposure                  Exposure
                                                              (mg/kg/day)     % aPAD    (mg/kg/day)     % aPAD
----------------------------------------------------------------------------------------------------------------
All Infants (< 1 year old)                          0.000075     0.000025           33     0.000070           93
----------------------------------------------------------------------------------------------------------------
Children 1-2 years old                              0.000075     0.000045           60     0.000152          200
----------------------------------------------------------------------------------------------------------------
Children 3-5 years old                              0.000075     0.000036           48     0.000156          210
----------------------------------------------------------------------------------------------------------------
Children 6-12 years old                             0.000075     0.000024           32     0.000121          160
----------------------------------------------------------------------------------------------------------------

    Exposure estimates for all of the major food contributors were
based on PDP monitoring data adjusted to account for the percent of the
crop treated with carbofuran and, therefore, may be considered highly
refined.
    As noted previously, because most of the PDP samples contained no
detectable residues of carbofuran or its 3-hydroxy metabolite, the
acute assessment for food assumed a concentration equal to [frac12] of
the LOD for PDP monitoring samples with no detectable residues, with
0.00 ppm carbofuran incorporated to account for the percent of the crop
not treated with carbofuran. In accordance with OPP policy for
analyzing commodities with non-detectable residues, EPA performed
additional analyses to determine the impact of using [frac12] the LOD
to estimate exposure (Ref. 56).
    In the first analysis (Sensitivity Analysis 1), those
commodities that had no detectable residues at all in either the
monitoring data or field trials were eliminated from the assessment.
The commodities that were eliminated included barley, coffee, corn,
cranberry, oats, potato, raisin, rice, soybean, spinach, strawberry,
sugar beet, sunflower, winter squash, and wheat. For the remaining
commodities, on which carbofuran was detected, EPA continued to
substitute the [frac12] LOD values for the percent of the crop treated
with carbofuran, with 0.00 ppm carbofuran incorporated to account for
the remaining untreated percent of the crop. This analysis resulted in
estimated exposures that were still above EPA's level of concern for
children 1-2 at the 99.9th percentile (115% of the aPAD; see Table 3
below).
    To further understand the extent to which the [frac12] LODs from
the PDP monitoring data were affecting the risk assessment, EPA
conducted an additional sensitivity analysis, (Sensitivity Analysis
2) that excluded the crops for which PDP and MBS data were not
available and assigned 0.00 ppm carbofuran for all non-detected
residues in commodities sampled in the PDP or MBS. In other words, an
analysis using only detectable residues from residue monitoring
programs was conducted. In this analysis, estimated dietary exposures
at the 99.9th percentile of exposure remained above EPA's level of
concern for children 1-2 yrs. old (114% of the aPAD). The

results of these sensitivity analyses at the 99.9th percentile of
exposure are compared to the results using [frac12] LOD for non-
detectable residues in Table 3 below.

                          Table 3--Impact of Using [frac1s2] LOD for Non-Detectable Residues on Estimated Exposure From Food\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Analysis Assuming     Sensitivity Analysis    Sensitivity Analysis
                                                                                [frac1s2] LOD for Non-       1\2\           2\3\
                                                                     aPAD (mg/kg/   Detectable Residues  -----------------------------------------------
                        Population Subgroup                              day)    ------------------------
                                                                                Exposure                Exposure     % aPAD     Exposure     % aPAD
                                                                                (mg/kg/day)    % aPAD   (mg/kg/day)             (mg/kg/day)
--------------------------------------------------------------------------------------------------------------------------------------------------------
All Infants (< 1 year old)                                              0.000075     0.000070         93     0.000044         58     0.000043         57
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1-2 years old                                                  0.000075     0.000152        200     0.000086        115     0.000086        114
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 3-5 years old                                                  0.000075     0.000156        210     0.000066         88     0.000065         87
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 6-12 years old                                                 0.000075     0.000121        160     0.000039         52     0.000038         51
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ At the 99.9th Percentile of Exposure.
\2\ Non-detectable PDP residues assumed to be zero only for commodities having no detectable residues at all in the PDP monitoring data and field trials
  (i.e., these commodities were eliminated from the analysis). Crops without PDP data and detectable residues in field trials were included, based on
  the distribution of residues from field trial studies.
\3\ Non-detectable residues assumed to be zero for all commodities. Commodities without PDP or Market Basket data were excluded from the analysis.

    The major contributors in Sensitivity Analysis 2, to the
estimated dietary exposure of children are listed in Table 4 below.

 Table 4--Major Contributors to Carbofuran Acute Exposure at the 99.9th
     Percentile in Sensitivity Analysis 2 (Expressed as an
                 Approximate Percent of Total Exposure)
------------------------------------------------------------------------
                                                Children, 1- Children, 3-
               Food                Infants, <1  2 Years Old  5 Years Old
                                     year old
------------------------------------------------------------------------
Cantaloupe                                   9           18           20
------------------------------------------------------------------------
Squash                                      10            2            1
------------------------------------------------------------------------
Grape                                       15           10            5
------------------------------------------------------------------------
Cucumbers                                    2           20           29
------------------------------------------------------------------------
Milk                                        32           <1            1
------------------------------------------------------------------------
Watermelon                                  29           39           41
------------------------------------------------------------------------

    EPA's evaluation of these two sensitivity analyses and other
information on carbofuran residue levels yields three conclusions.
First, the results of the sensitivity analyses indicate that the
dietary risk assessment for carbofuran is sensitive to the assumed
concentrations (i.e., [frac12] LOD) for non-detectable residues in the
PDP monitoring data. This sensitivity appears to be more of a factor
for commodities with no detections because the main difference between
the Sensitivity Analyses 1 and 2 was substituting
0.00 ppm for [frac12] LODs for commodities with detects in the second
analysis yet that analysis yielded similar results to the first
sensitivity analysis. On the other hand, both sensitivity analyses were
approximately 2X lower than the analysis that used [frac12] LOD for all
treated commodities. The finding that the use of a [frac12] LOD
assumption had a noticeable impact on the risk estimate is contrary to
EPA's experience in conducting pesticide risk assessments. Generally,
risk estimates do not show noticeable differences whether non-detects
are treated as true zeros or [frac12] LODs. In all likelihood, this is
a factor of the relatively insensitive level of the carbofuran method's
LOD.
    Second, given that there are data showing that carbofuran is found
at levels below the LOD when a more sensitive method was used, EPA
finds that use of either of the approaches in the sensitivity analyses
will understate carbofuran risk. The available information demonstrates
that carbofuran residues are present; when a lower level of detection
was utilized, both in the most recent PDP milk analyses and in the
Carbamate MBS data; residues of carbofuran and 3-hydroxycarbofuran were
detected in commodities that previously had no detections. Moreover,
detected residues ranged between levels below and above [frac12] LOD.
Thus, unlike the circumstance where a relatively sensitive method of
detection is used and there is some uncertainty as to whether a non-
detect may mask an actual exposure, with cabofuran there is no question
- treating all non-detects as zero clearly would mask actual exposures
to carbofuran. Thus, these sensitivity analyses do not provide a basis
for concluding that EPA has overestimated risk.
    Third, and most important, EPA would call attention to the fact
that these sensitivity analyses, although clearly underestimating
actual carbofuran exposure and risk, still indicate that one group of
children will have exposures exceeding the safe level.
    Because it appears that carbofuran's dietary risks to children are
driven by

relatively low residues in a small percentage of commodities, and to
try to gain further insight into the potential impact of using [frac12]
LOD in this case, EPA conducted a third sensitivity analysis to
evaluate whether its estimates that food only and aggregate carbofuran
exposure results in risks of concern were overstated. EPA combined
actual residue values measured in the food supply (from PDP and MBS
data) with the typical (50th percentile) and high-end (90th percentile)
amounts of a single commodity that a child would be expected to
consume, and compared that to the aPAD, without considering the
likelihood that a child would be exposed to that residue value. The
results one of these analyses are summarized in Table 5 below.

                                  Table 5--Risk to Children Consuming Typical or High-End Amounts of Fresh (Uncooked) Cucumbers Containing Carbofuran Residues
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Typical: 50th Percentile of Consumption                     High-End: 90th Percentile of Consumption
                                                                        ------------------------------------------------------------------------------------------------------------------------
                   Food                         Population Subgroup                                       PDP       Exposure                                     PDP       Exposure
                                                                            Consumption (g/kg bw)      Residue\1\    (mg/kg      % aPAD     Consumption (g/   Residue\1\    (mg/kg      % aPAD
                                                                                (ppm)        bw)                        kg bw)         (ppm)        bw)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Cucumbers (Uncooked) DEEM food form 110    Children 1-2                  1.0                                0.005   0.000005            7              4.3         0.005   0.000022           29
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.029   0.000029           39                          0.029   0.000125          170
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.063   0.000063           84                          0.063   0.000271          360
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.117   0.000117          160                          0.117   0.000503          670
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.137   0.000137          180                          0.137   0.000589          790
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.147   0.000147          200                          0.147   0.000632          840
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.437   0.000437          580                          0.437   0.001879        2,500
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.537   0.000537          720                          0.537   0.002309        3,100
                                          ======================================================================================================================================================
                                           Children 3-5                  0.8                                0.005   0.000004            5              5.1         0.005   0.000026           34
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.029   0.000023           31                          0.029   0.000148          200
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.063   0.000050           67                          0.063   0.000321          430
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.117   0.000094          120                          0.117   0.000597          800
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.137   0.000110          150                          0.137   0.000699          930
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.147   0.000118          160                          0.147   0.000750        1,000
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.437   0.000350          470                          0.437   0.002229        3,000
                                                                                --------------------------------------                 ------------------------------------
                                                                                0.537   0.000430          570                          0.537   0.002739        3,700
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ The PDP detected residues of carbofuran in 11 of 1479 cucumber samples at levels ranging from 0.005 ppm to 0.537 ppm.

    Detectable residues of carbofuran and/or 3-hydroxycarbofuran were
found in only a few samples of cucumber in monitoring data (11 out of
1479 or less than one percent). However, if young children aged 1 to 5
consume moderate amounts of cucumber (i.e., the median or 50th
percentile of consumption, corresponding to approximately 1 gram per kg
of body weight of cucumber) that contain actual levels of carbofuran
measured in the food supply, the percent of the aPAD that would be
utilized ranges from about 7% of the safe daily dose for the lower
observed residue values to 720% of the safe daily dose for the higher
observed values. For children who consume larger amounts of cucumber
(i.e., the 90th percentile of consumption, corresponding to 5 grams per
kg of body weight of cucumber or roughly [frac12] cup), exposure
increases approximately tenfold (29% to over 3700% of the aPAD). Many
of these values significantly exceed the Agency's level of concern
based on the consumption of a single daily serving of one commodity.
    Additional analyses are summarized in Table 6 below, and analyses
on additional foods can be found in Ref. 12. EPA focused on children in
making these calculations, because children have the highest estimated
dietary exposure to carbofuran; however, it is reasonable to assume
that adult exposures from a single treated food item could also exceed
EPA's level of concern, particularly at the high end of consumption.

                                   Table 6--Risk to Children Consuming Typical or High-End Amounts of Cantaloupe or Watermelon Containing Carbofuran Residues
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                  Typical: 50th Percentile of Consumption                                 High-End: 90th Percentile of Consumption
                                                ------------------------------------------------------------------------------------------------------------------------------------------------
              Population Subgroup                                                   PDP Residue    Exposure                 Consumption (g/kg                       Exposure
                                                       Consumption (g/kg bw)           (ppm)      (mg/kg bw)     % aPAD            bw)         PDP Residue (ppm)   (mg/kg bw)        % aPAD
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Cantaloupe
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1-2                                     Approx. 6g                               0.009    0.0000531           71        Approx. 12 g              0.009    0.0001035                140
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.01     0.000059           79                                   0.01     0.000115                150
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.02     0.000118          160                                   0.02      0.00023                310
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.06     0.000354          470                                   0.06      0.00069                920
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.085    0.0005015          670                                  0.085    0.0009775              1,300
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.357    0.0021063        2,800                                  0.357    0.0041055              5,500
================================================================================================================================================================================================
Children 3-5                                     approx. 5g                               0.009    0.0000441           59      approx. 15g or              0.009    0.0001368                180
                                                                                [frac1s2] cup
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.01     0.000049           65                                   0.01     0.000152                200
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.02     0.000098          130                                   0.02     0.000304                400
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.06     0.000294          390                                   0.06     0.000912              1,200
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.085    0.0004165          560                                  0.085     0.001292              1,700
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.357    0.0017493        2,300                                  0.357    0.0054264              7,200
================================================================================================================================================================================================
                                                                                Watermelon
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1-2                                     approx. 8g                              0.0057   0.00004332           58       less than 30g             0.0057   0.00014706                200
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.009    0.0000684           91                                  0.009    0.0002322                310
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.0132   0.00010032          130                                 0.0132   0.00034056                450
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.014    0.0001064          140                                  0.014    0.0003612                480
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.062    0.0004712          630                                  0.062    0.0015996              2,100
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.081    0.0006156          820                                  0.081    0.0020898              2,800
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.205     0.001558        2,100                                  0.205     0.005289              7,100
================================================================================================================================================================================================
Children 3-5                                     approx. 12g                             0.0057   0.00007125           95         approx. 35g             0.0057   0.00019893                270
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.009    0.0001125          150                                  0.009    0.0003141                420
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.0132     0.000165          220                                 0.0132   0.00046068                610
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.014     0.000175          230                                  0.014    0.0004886                650
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.062     0.000775        1,000                                  0.062    0.0021638              2,900
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.081    0.0010125        1,400                                  0.081    0.0028269              3,800
                                                                                ----------------------------------------                   --------------------------------------------------
                                                                                0.205    0.0025625        3,400                                  0.205    0.0071545              9,500
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

    The analyses in Tables 5 and 6 demonstrate three significant
points. First, the fact that individual children, consuming typical
amounts of a single food item receive unsafe levels of carbofuran,
based on actual residue levels measured in the food supply, strongly
supports EPA's findings that aggregate exposures to carbofuran are
unsafe. It is true that the results described in Tables 5 and 6, as
well as the additional analyses in Ref. 12, do not describe the
probability that an individual child will receive those residues on the
foods they consume. By contrast, EPA's analyses in Tables 2 and 3
account for the probability that a particular level of residues will be
present on a food item, as well as the likelihood that an individual
will consume a particular food. It is EPA's typical approach, as was
done with carbofuran, to conduct its estimates of exposure across the
entire population, generally assuming that as long as the 99.9th
percentile of the estimated daily exposure is equal to or less than the
aPAD, there is a reasonable certainty of no harm to the general
population, including all significant subpopulations (Ref. 58). In
practice, this can mean that if only a small portion of the population
reported eating the commodity, or if the residues are infrequently
detected, individual high-end risks may fall above EPA's usual
benchmark of the 99.9th percentile, or in other words, fall in the
``tail end'' of the distribution curve. Admittedly, some of the results
described in Tables 5 and 6 would be expected to fall within this tail
end, given the relatively infrequent detections of carbofuran in
sampled commodities. However, taking into account the analysis of the
risk drivers in Table 4 above, it is clear that some of these values do
fall within the 99.9th percentile.
    In any event, given all of the facts, it is just as appropriate for
EPA to evaluate whether the eating occasions that drive a conclusion
that risks at the 99.9th percentile yield unacceptable risks are
realistic, as it is for EPA to examine whether eating occasions in the
tail of a distribution curve are examples of consumption events the
Agency should be concerned about. In this regard, it is notable that
even the high-end consumption values described in Tables 5 and 6 are
extremely likely to be valid reported consumption events--or in other
words, consumption of the amounts at the 90th percentile are quite
realistic. For example, a child between 3-5 years, who consumes a
[frac12] cup of cantaloupe would receive a dose ranging between 180%
and 7,200% of the aPAD. Accordingly, this analysis by itself supports a
conclusion that the carbofuran tolerances are not safe and certainly
buttresses EPA's conclusions that exposures from carbofuran in food or
water alone or from carbofuran residues in food and water aggregated
when assessed at the 99.9th percentile are not safe.
    Additionally, because of the uncertainty surrounding carbofuran's
exposure potential, investigation of individual children's risks, even
if in the ``tail end,'' is particularly relevant. There are a number of
reasons that significant uncertainty remains with respect to
carbofuran's exposure potential. One primary consideration stems from
the high LOD for carbofuran and consequent large numbers of non-detects
in the PDP data. The LOD for most commodities is tenfold to twentyfold
higher than the more precise methods used for the CMS and some of the
more recent PDP data. Generally, EPA would consider use of [frac12] LOD
as a conservative way of addressing non-detects but that may not be the
case where the LOD is relatively insensitive and the risk of concern is
an acute exposure. For acute risks, the higher values in a
probabilistic risk assessment are often driven by relatively high
values in a few commodities rather than relatively lower values in a
greater number of commodities. This is due to the fact that an acute
assessment looks at a narrow window of exposure where there are
unlikely to be a great variety of foods consumed. Thus, to the extent
that there is a high exposure it will be more likely due to a high
residue value in a single commodity. However, assuming [frac12] LOD for
non-detects does not reflect that the non-detects actually will bear a
range of values from close to or near zero to close to or near the LOD.
Importantly, those commodities bearing residues only slightly below the
LOD may result in an exceedance of the aPAD where assuming [frac12] LOD
would not. In this way, the [frac12] LOD analysis may actually
understate risk. In these circumstances, reliance on [frac12] LOD can
skew the distribution of residues, which in turn masks the true ``tail
end'' of exposures. In other words, to the extent that the [frac12] LOD
underestimates exposures for some individual commodities, it
effectively decreases the probability of receiving higher residues,
thereby shifting those values with greater risks to the tail end of the
distribution curve, above the 99.9th percentile.
    The second important point from these tables is that the
exceedances from both the 50th and 90th percentile consumer are quite
large--sometimes orders of magnitude above safe doses. The size of
these exceedances gives rise to concerns that the exceedances are more
likely to result in actual harm to exposed individuals, particularly if
they are also consuming carbofuran-contaminated drinking water.
Additionally worrisome in this regard is that carbofuran is a highly
potent (i.e., has a very steep dose-response curve), acute toxicant,
and therefore any aPAD exceedances are more likely to have greater
significance in terms of the potential likelihood of actual harm.
    Finally, that Tables 5 and 6 show large exceedances across several
crops for which relatively more residue data are available suggests
these results are not unique to the specific crops for which precise
residues have been detected in PDP and MBS. In other words, crops for
which such residue data are not available may be posing similar risks.
    In sum, these results strongly support EPA's conclusion that its
dietary exposure assessment for carbofuran has not overstated exposure
and risk. Further, serious questions remain as to the extent to which
similar exceedances exist for all crops, but which remain undetected,
because, as result of the high LOD, EPA lacks precise residue levels
for the majority of crops.
    2. Drinking water exposures. EPA's drinking water assessment uses
both monitoring data for carbofuran and modeling methods, and takes
into account contributions from both surface water and groundwater
sources (Refs. 3, 4, 13, 36 and 47). Concentrations of carbofuran in
drinking water, as with any pesticide, are in large part determined by
the amount, method, timing and location of pesticide application, the
chemical properties of the pesticide, the physical characteristics of
the watersheds and/or aquifers in which the community water supplies or
private wells are located, and other environmental factors, such as
rainfall, which can cause the pesticide to move from the location where
it was applied. While there is a considerable body of monitoring data
that has measured carbofuran residues in surface and groundwater
sources, the locations of sampling and the sampling frequencies
generally are not sufficient to capture peak concentrations of the
pesticide in a watershed or aquifer where carbofuran is used. Capturing
these peak concentrations is particularly important for assessing risks
from carbofuran because the toxicity end-point of concern results from
single-day exposure (acute effects). Because pesticide loads in surface
water tend to move in relatively quick pulses in

flowing water, frequent targeted sampling is necessary to reliably
capture peak concentrations for surface water sources of drinking
water. Pesticide concentrations in ground water, however, are generally
the result of longer-term processes and less frequent sampling can
better characterize peak ground water concentrations. However, such
data must be targeted at vulnerable aquifers in locations where
carbofuran applications are documented in order to capture peak
concentrations. As a consequence, monitoring data for both surface and
groundwater tends to underestimate exposure for acute endpoints.
Simulation modeling complements monitoring by making estimations at
vulnerable sites and can be used to represent daily concentration
profiles, based on a distribution of weather conditions. Thus, modeling
can account for the cases when a pesticide is used in drinking water
watersheds at any rate and is applied to a substantial proportion of
the crop. It can also account for stochastic processes, such as
rainfall represented by 30 years of existing weather data maintained by
the National Oceanic and Atmospheric Administration.
    a. Exposure to carbofuran from drinking water derived from ground
water sources. Drinking water taken from shallow wells is particularly
vulnerable to contamination in areas where carbofuran is used around
sandy, highly acidic soil. Some areas with these characteristics
include Long Island, parts of Florida, and the Atlantic coastal plain,
in addition to other areas of the country. Exposure estimates for this
assessment are drawn primarily from (1) the results of a prospective
groundwater (PGW) study developed by the registrant in the early 1980s;
and (2) additional groundwater modeling conducted as part of the NMC
cumulative assessment in 2007. The results of the PGW study are
consistent with a number of other targeted groundwater studies
conducted in the 1980s showing that high concentrations of carbofuran
can occur in vulnerable areas; the results of these studies as well as
the PGW study are summarized in (Refs. 13 and 47). For example, a study
in Manitoba, Canada assessed the movement of carbofuran into tile
drains and groundwater from the application of liquid carbofuran to
potato and corn fields. The application rates ranged between 0.44-0.58
pounds a.i./acre, and the soils at the site included fine sand, loamy
fine sand, and silt loam, with pH ranging between 6.5-8.3.
Concentrations of carbofuran in groundwater samples ranged between 0
(non-detect) and 158 ppb, with a mean of 40 ppb (Refs. 13 and 47).
    While there have been additional groundwater monitoring studies
that included carbofuran as an analyte since that time, there has been
no additional monitoring targeted to carbofuran use in areas where
aquifers are vulnerable. Accordingly, EPA believes the PGW study
continues to be the most relevant monitoring data for assessing
drinking water exposures from private wells at vulnerable sites.
Because this study was conducted over only one growing season, however,
and was conducted at use rates that now exceed current label maximum
rates for the use being studied (3 lb ai/acre vs. the current 2 lb ai/
acre for corn), EPA has scaled the results to represent impacts from
carbofuran use over a long-term period (25 years) at current label
rates. Temporal scaling was necessary because the PGW study represents
water quality impacts from a single application rather than repeated
years of use. Based on EPA's assessment, the maximum 90-day average
carbofuran concentrations in vulnerable groundwater for various
application rates were estimated to range from a low of 11 parts per
billion (ppb) based on a 1 pound per acre application rate, to a high
of 34 ppb, based on a 3 pound per acre application rate. The peak
concentration measured in the PGW study was 65 ppb. Because the
degradate 3-hydroxycarbofuran, which is assumed to be of equal potency
with the parent compound, was not measured in this study, exposure was
not estimated. Although the failure to include the degradate is
expected to underestimate exposure to some degree, the extent to which
it would contribute to exposure is unclear.
    EPA conducted additional groundwater modeling for the NMC
cumulative risk assessment, and developed a time series of exposures at
locations selected based on potential for exposure to a combination of
carbamate insecticides relevant for cumulative exposure assessment for
use in probabilistic dietary assessments using DEEM. EPA estimated
carbofuran groundwater concentrations associated with two possible use
scenarios: potatoes in northeastern Florida and cucurbits on the
Delmarva Peninsula in the Mid-Atlantic region. While the modeled potato
use scenario in Florida did not show concentrations of carbofuran of
concern, estimated carbofuran concentrations associated with the
cucurbit use in the Delmarva Peninsula - a region with shallow, acidic
groundwater and acidic, sandy soils - are consistent with EPA's
assessment of the PGW study discussed above. Specifically, the
assessment indicated that at an application rate of 1.25 pounds a.i.
per acre, on cucurbits, maximum concentrations were 38.5 ppb (Ref. 63).
EPA does not believe the results of this assessment are particularly
conservative, since the application rate used in this assessment was
less than the maximum rate of 1.94 lb/acre that growers can use. Also,
concentrations of the degradate, 3-hydroxycarbofuran were not included
in modeling simulations, which would tend to underestimate exposure to
some degree.
    Based on these estimates, EPA compiled a distribution of estimated
carbofuran concentrations in water that could be used to generate
probabilistic assessments of the potential exposures from drinking
water derived from vulnerable ground water sources. The results of
EPA's probabilistic assessments are represented below in Table 7. As
discussed in the previous section, it is important to remember that the
aPAD for carbofuran is quite low, hence, relatively low concentrations
of carbofuran monitored or estimated in vulnerable groundwater can have
a significant impact on the aPAD utilized.

      Table 7--Results of Acute Dietary (Ground Water Only) Exposure Analysis Using DEEM FCID and Incorporating the Delmarva Ground Water Scenario
                                                              (Representing Private Wells)
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                                                                                95th Percentile         99th Percentile        99.9th Percentile
                                                                     aPAD (mg/kg/-----------------------------------------------------------------------
                        Population Subgroup                              day)       Exposure                Exposure                Exposure
                                                                                (mg/kg/day)    % aPAD   (mg/kg/day)    % aPAD   (mg/kg/day)    % aPAD
--------------------------------------------------------------------------------------------------------------------------------------------------------
All Infants (< 1 year old)                                              0.000075     0.003800      5,100     0.006006      8,000     0.010030    >10,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1-2 years old                                                  0.000075     0.001612      2,100     0.002732      3,600     0.004628      6,200
--------------------------------------------------------------------------------------------------------------------------------------------------------

Children 3-5 years old                                                  0.000075     0.001459      1,900     0.002405      3,200     0.004613      5,600
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 6-12 years old                                                 0.000075     0.001018      1,360     0.001710      2,300     0.002792      3,700
--------------------------------------------------------------------------------------------------------------------------------------------------------
Youth 13-19 years old                                                     0.0002     0.000809        400     0.001441        720     0.002919      1,500
--------------------------------------------------------------------------------------------------------------------------------------------------------
Adults 20-49 years old                                                    0.0002     0.000955        480     0.001632        820     0.003073      1,500