Carbofuran; Proposed Tolerance Revocations, 44864-44892 [E8-17660]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 73, Number 148 (Thursday, July 31, 2008)]
[Proposed Rules]
[Pages 44864-44892]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-17660]



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Part III





Environmental Protection Agency





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40 CFR Part 180



Carbofuran; Proposed Tolerance Revocations; Proposed Rule

Federal Register / Vol. 73, No. 148 / Thursday, July 31, 2008 / 
Proposed Rules

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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: https://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 (703) 305-5805.
    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 
https://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 https://
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: (703) 305-0076; e-mail 
address: andreasen.jude@epa.gov.

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

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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,

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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:

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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 https://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

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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: https://
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

[[Page 44869]]

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.

[[Page 44870]]

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%

[[Page 44871]]

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).
BILLING CODE 6560-50-S

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[GRAPHIC] [TIFF OMITTED] TP31JY08.018

BILLING CODE 6560-50-C

[[Page 44873]]

    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 P