

[Federal Register: January 30, 2008 (Volume 73, Number 20)]
[Rules and Regulations]               
[Page 5439-5450]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr30ja08-11]                         

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2005-0145; FRL-8347-3]

 
Boscalid; Denial of Objections

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final order.

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SUMMARY: In this order, EPA denies objections filed by the Natural 
Resources Defense Council (``NRDC'') to a final rule under section 408 
of the Federal Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 
346a), establishing tolerances for the pesticide boscalid on various 
leafy greens. NRDC argues that EPA has unlawfully removed the 
additional safety factor for the protection of infants and children 
required by Food Quality Protection Act of 1996.

FOR FURTHER INFORMATION CONTACT: Tony Kish, Registration Division, 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: 703-308-9443; e-mail address: kish.tony@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), e.g., agricultural 
workers; greenhouse, nursery, and floriculture workers; farmers.
     Animal production (NAICS code 112), e.g., cattle ranchers 
and farmers, dairy cattle farmers, livestock farmers.
     Food manufacturing (NAICS code 311), e.g., agricultural 
workers; farmers; greenhouse, nursery, and floriculture workers; 
ranchers; pesticide applicators.
     Pesticide manufacturing (NAICS code 32532), e.g., 
agricultural workers; commercial applicators; farmers; greenhouse, 
nursery, and floriculture workers; residential users.
    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities that are potentially 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. If you 
have any questions regarding the applicability of this action to a 
particular entity, consult the person listed under FOR FURTHER 
INFORMATION CONTACT.

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

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

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

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


C. How Can I Access Electronic Copies of Materials in the Docket?

    EPA has established a docket for this action under docket 
identification (ID) number EPA-HQ-OPP-2005-0145. To access the 
electronic docket, go to http://www.regulations.gov, select ``Advanced 

Search,'' then ``Docket Search.'' Insert the docket ID number where 
indicated and select the ``Submit'' button. Follow the instructions on 
the regulations.gov web site to view the docket index or access 
available documents.

II. Introduction

A. What Action Is the Agency Taking?

    In this order, EPA denies objections filed by the Natural Resources 
Defense Council (``NRDC'') to a final rule under section 408 of the 
Federal Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 346a), 
establishing tolerances for the pesticide boscalid on various leafy 
greens. (Ref. 1). NRDC argues that EPA must retain an additional ten-
fold (10X) safety factor for the protection of infants and children due 
to data showing that juvenile animals are more sensitive than adults. 
Retention of this additional safety factor, NRDC contends, shows that 
the tolerances are unsafe. Additionally, NRDC contends that EPA's 
tolerance decision was arbitrary and capricious because (1) EPA failed 
to explain adequately its reason for not applying a 10X safety factor 
for infants and children and (2) the safe dose for boscalid established 
by EPA is ``clearly contrary to the data . . . .'' (Id. at 3-4, 7-8).

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

    The procedure for filing objections to tolerance actions and EPA's 
authority

[[Page 5440]]

for acting on such objections is contained in section 408(g) of the 
FFDCA and regulations at 40 CFR part 178. (21 U.S.C. 346a(g)).

III. Statutory and Regulatory Background

A. Statutory Background

    1. In general. EPA establishes maximum residue limits, or 
``tolerances,'' for pesticide residues in food under section 408 of the 
FFDCA. (21 U.S.C. 346a). Without such a tolerance or an exemption from 
the requirement of a tolerance, a food containing a pesticide residue 
is ``adulterated'' under section 402 of the FFDCA and may not be 
legally moved in interstate commerce. (21 U.S.C. 331, 342). Monitoring 
and enforcement of pesticide tolerances are carried out by the U.S. 
Food and Drug Administration and the U.S. Department of Agriculture. 
Section 408 was substantially rewritten by the Food Quality Protection 
Act of 1996 (``FQPA''), which added the provisions discussed below 
establishing a detailed safety standard for pesticides and additional 
protections for infants and children.
    EPA also regulates pesticides under the Federal Insecticide, 
Fungicide, and Rodenticide Act (``FIFRA''), (7 U.S.C. 136 et seq). 
While the FFDCA authorizes the establishment of legal limits for 
pesticide residues in food, FIFRA requires the approval of pesticides 
prior to their sale and distribution, (7 U.S.C. 136a(a)), and 
establishes a registration regime for regulating the use of pesticides. 
FIFRA regulates pesticide use in conjunction with its registration 
scheme by requiring EPA review and approval of pesticide labels and 
specifying that use of a pesticide inconsistent with its label is a 
violation of Federal law. (7 U.S.C. 136j(a)(2)(G)). In the FQPA, 
Congress integrated action under the two statutes by requiring that the 
safety standard under the FFDCA be used as a criterion in FIFRA 
registration actions as to pesticide uses which result in dietary risk 
from residues in or on food, (7 U.S.C. 136(bb)), and directing that EPA 
coordinate, to the extent practicable, revocations of tolerances with 
pesticide cancellations under FIFRA. (21 U.S.C. 346a(l)(1)).
    2. Safety standard for pesticide tolerances. A pesticide tolerance 
may only be promulgated by EPA if the tolerance is ``safe.'' (21 U.S.C. 
346a(b)(2)(A)(i)). ``Safe'' is defined by the statute to mean that 
``there is a reasonable certainty that no harm will result from 
aggregate exposure to the pesticide chemical residue, including all 
anticipated dietary exposures and all other exposures for which there 
is reliable information.'' (21 U.S.C. 346a(b)(2)(A)(ii)). Section 408 
directs EPA, in making a safety determination, to ``consider, among 
other relevant factors- . . . . available information concerning the 
aggregate exposure levels of consumers (and major identifiable 
subgroups of consumers) to the pesticide chemical residue and to other 
related substances, including dietary exposure under the tolerance and 
all other tolerances in effect for the pesticide chemical residue, and 
exposure from other non-occupational sources.'' (21 U.S.C. 
346a(b)(2)(D)(vi)).
    Section 408(b)(2)(C) requires EPA to give special consideration to 
risks posed to infants and children. Specifically, this provision 
states that EPA ``shall assess the risk of the pesticide chemical based 
on 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 . . . .'' (21 
U.S.C. 346a(b)(2)(C)(i)(II) and (III)). This provision further directs 
that ``[i]n the case of threshold effects, . . . an additional tenfold 
margin of safety for the pesticide chemical residue and other sources 
of exposure shall be applied for infants and children to take into 
account potential pre- and post-natal toxicity and completeness of the 
data with respect to exposure and toxicity to infants and children.'' 
(21 U.S.C. 346a(b)(2)(C)). EPA is permitted to ``use a different margin 
of safety for the pesticide chemical residue only if, on the basis of 
reliable data, such margin will be safe for infants and children.'' 
(Id.). The additional safety margin for infants and children is 
referred to throughout this order as the ``children's safety factor.''
    3. Procedures for establishing, amending, or revoking tolerances. 
Tolerances are established, amended, or revoked by rulemaking under the 
unique procedural framework set forth in the FFDCA. Generally, the 
rulemaking is initiated by the party seeking to establish, amend, or 
revoke a tolerance by means of filing a petition with EPA. (See 21 
U.S.C. 346a(d)(1)). EPA publishes in the Federal Register a notice of 
the petition filing and requests public comment. (21 U.S.C. 
346a(d)(3)). After reviewing the petition, and any comments received on 
it, EPA may issue a final rule establishing, amending, or revoking the 
tolerance, issue a proposed rule to do the same, or deny the petition. 
(21 U.S.C. 346a(d)(4)). Once EPA takes final action on the petition by 
either establishing, amending, or revoking the tolerance or denying the 
petition, any affected party has 60 days to file objections with EPA 
and seek an evidentiary hearing on those objections. (21 U.S.C. 
346a(g)(2)). If objections are filed by a party other than the 
petitioner, EPA is required to serve a copy of any objections on the 
petitioner. (Id.). EPA's final order on the objections is subject to 
judicial review. (21 U.S.C. 346a(h)(1)).
    4. Other EPA statutory authority over pesticides. EPA also 
regulates pesticides under the Federal Insecticide, Fungicide, and 
Rodenticide Act (``FIFRA''), (7 U.S.C. 136 et seq). While the FFDCA 
authorizes the establishment of legal limits for pesticide residues in 
food, FIFRA requires the approval of pesticides prior to their sale and 
distribution, (7 U.S.C. 136a(a)), and establishes a registration regime 
for regulating the use of pesticides. FIFRA regulates pesticide use in 
conjunction with its registration scheme by requiring EPA review and 
approval of pesticide labels and specifying that use of a pesticide 
inconsistent with its label is a violation of Federal law. (7 U.S.C. 
136j(a)(2)(G)).

B. Evaluating the Safety of Tolerances Through the Use of Risk 
Assessment Including the Use of Safety Factors

    1. In general. The process EPA follows in evaluating FFDCA 
petitions to establish tolerances and in determining the safety of the 
petitioned-for tolerances includes two steps. First, EPA determines an 
appropriate residue level value for the tolerance taking into account 
data on levels that can be expected in food. Second, EPA evaluates the 
safety of the tolerance relying on toxicity and exposure data and 
guided by the statutory definition of ``safe'' and the statutory 
requirements concerning risk assessment. Only on completion of the 
second step can EPA make a decision on whether a tolerance may be 
established. Below, EPA explains in detail, the reasons for this 
approach.
    2. Choosing a tolerance value. In the first step of the tolerance 
evaluation process (choosing a tolerance value), EPA reviews data from 
experimental crop field trials in which the pesticide has been used in 
a manner, consistent with the draft FIFRA label, that is likely to 
produce the highest residue in the crop in question (e.g., maximum 
application rate, maximum number of applications, minimum pre-harvest 
interval between last pesticide application and harvest). (Refs. 2 and 
3). These crop field trials are generally conducted in several fields 
at several geographical locations. (Ref. 3 at pages

[[Page 5441]]

5, 7, and Tables 1 and 5). Several samples are then gathered from each 
field and analyzed. (Id. at 53). Generally, the results from such field 
trials show that the residue levels for a given pesticide use will vary 
from as low as non-detectable to measurable values in the parts per 
million (ppm) range with the majority of the values falling at the 
lower part of the range. EPA uses a statistical procedure to analyze 
the field trial results and identify the upper bound of expected 
residue values. This upper bound value is used as the tolerance value. 
(Ref. 4). (As discussed below, the safety of the tolerance value chosen 
is separately evaluated.).
    There are three main reasons for closely linking tolerance values 
to the maximum value that could be present from maximum label usage of 
the pesticide. First, EPA believes it is important to coordinate its 
actions under the two statutory frameworks governing pesticides. (See 
61 FR 2378, 2379, January 25, 1996). It would be illogical for EPA to 
set a pesticide tolerance under the FFDCA without considering what 
action is being taken under FIFRA with regard to registration of that 
pesticide use. (Cf. 40 CFR 152.112(g) (requiring all necessary 
tolerances to be in place before a FIFRA registration may be granted)). 
In coordinating its actions, one basic tenet that EPA follows is that a 
grower who applies a pesticide consistent with the FIFRA label 
directions should not run the risk that his or her crops will be 
adulterated under the FFDCA because the residues from that legal 
application exceed the tolerance associated with that use. To further 
this goal, crop field trials require application of the pesticide in 
the manner most likely to produce maximum residues. Second, choosing 
tolerance values based on FIFRA label rates helps to ensure that 
tolerance levels are established no higher than necessary. If tolerance 
values were selected solely in consideration of health risks, in some 
circumstances, tolerance values might be set so as to allow much 
greater application rates than necessary for effective use of the 
pesticide. This could encourage misuse of the pesticide. Finally, 
closely linking tolerance values to FIFRA labels helps EPA to police 
compliance with label directions by growers because detection of an 
overtolerance residue is indicative of use of a pesticide at levels, or 
in a manner, not permitted on the label.
    3. The safety determination--risk assessment. Once a tolerance 
value is chosen, EPA then evaluates the safety of the pesticide 
tolerance using the process of risk assessment. To assess risk of a 
pesticide, EPA combines information on pesticide toxicity with 
information regarding the route, magnitude, and duration of exposure to 
the pesticide.
    In evaluating a pesticide's potential hazards (e.g., liver effects, 
carcinogenicity), EPA examines both short-term (e.g., ``acute'') and 
longer-term (e.g., ``chronic'') adverse effects from pesticide 
exposure. (Ref. 2 at 8-10). EPA also considers whether the ``effect'' 
has a threshold - a level below which exposure has no appreciable 
chance of causing the adverse effect. For non-threshold effects, EPA 
assumes that any exposure to the substance increases the risk that the 
adverse effect may occur. At present, EPA only considers one adverse 
effect, the chronic effect of cancer, to potentially be a non-threshold 
effect. (Ref. 2 at 8-9). Not all carcinogens, however, pose a risk at 
any exposure level (i.e., ``a non-threshold effect or risk''). Advances 
in the understanding of carcinogenesis have increasingly led EPA to 
conclude that some pesticides that cause carcinogenic effects only 
cause such effects above a certain threshold of exposure.
    Once the hazard for a durational scenario is identified, EPA must 
determine the toxicological level of concern and then compare estimated 
human exposure to this level of concern. This comparison is done 
through either calculating a safe dose in humans (incorporating all 
appropriate safety factors) and expressing exposure as a percentage of 
this safe dose (the reference dose (``RfD'') approach) or dividing 
estimated human exposure into an appropriately protective dose from the 
relevant studies (the margin of exposure (``MOE'') approach). How EPA 
determines the level of concern and assesses risk under these two 
approaches is explained in more detail below. EPA's general approach to 
estimating exposure is also briefly discussed.
    a. Levels of concern and risk assessment--i. threshold effects. In 
assessing the risk from a pesticide's threshold effects, EPA evaluates 
an array of toxicological studies on the pesticide. In each of these 
studies, EPA attempts to identify the lowest observed adverse effect 
level (``LOAEL'') and the next lower dose at which there are no 
observed adverse affect levels (``NOAEL''). Generally, EPA will use the 
lowest NOAEL from the available studies, taking into account the route 
and duration of exposure, as a starting point in estimating the level 
of concern for humans for a given exposure scenario (e.g., acute oral 
exposure). This selected NOAEL is usually referred to as the Point of 
Departure. In estimating and describing the level of concern, however, 
the Point of Departure is at times manipulated differently depending on 
whether the risk assessment addresses dietary or non-dietary exposures. 
(Refs. 2 at 3-8; 5 at 8, 52-53; and 6).
    For dietary risks, EPA uses the Point of Departure to calculate a 
safe dose or RfD. The RfD is calculated by dividing the Point of 
Departure by applicable safety or uncertainty factors. Typically, a 
combination of safety or uncertainty factors providing a hundredfold 
(100X) margin of safety is used: 10X to account for uncertainties 
inherent in the extrapolation from laboratory animal data to humans and 
10X for variations in sensitivity among members of the human population 
as well as other unknowns. Further, to account for deficiencies in the 
database or the results seen in the database, EPA has traditionally 
added additional safety factors on a case-by-case basis. The FQPA 
amendments to FFDCA section 408 require an additional safety factor of 
10X to protect infants and children (to address data completeness and 
pre- and post-natal toxicity concerns), unless reliable data support 
selection of a different factor. To some extent, the FQPA safety factor 
addresses concerns related to the factors driving EPA's traditional use 
of additional safety factors.
    In implementing FFDCA section 408, EPA's Office of Pesticide 
Programs, also calculates a variant of the RfD referred to as a 
Population Adjusted Dose (``PAD''). A PAD is the RfD divided by any 
portion of the FQPA children's safety factor that does not correspond 
to one of the traditional additional safety factors used in general 
Agency risk assessment. (Ref. 5 at 13-16). The reason for calculating 
PADs is so that other parts of the Agency, which are not governed by 
FFDCA section 408, can, when evaluating the same or similar substances, 
easily identify which aspects of a pesticide risk assessment are a 
function of the particular statutory commands in FFDCA section 408. 
Today, RfDs and PADs are generally calculated for both acute and 
chronic dietary risks although traditionally a RfD or PAD was only 
calculated for chronic dietary risks. Throughout this document general 
references to EPA's calculated safe dose are denoted as a RfD/PAD.
    To quantitatively describe risk using the RfD/PAD approach, 
estimated exposure is expressed as a percentage of the RfD/PAD. Dietary 
exposures lower than 100 percent of the RfD/PAD are generally not of 
concern.

[[Page 5442]]

    For non-dietary, and often for combined dietary and non-dietary, 
risk assessments of threshold effects, the toxicological level of 
concern is not expressed as a safe dose or RfD/PAD but rather as the 
margin of exposure (MOE) that is necessary to be sure that exposure to 
a pesticide is safe. To calculate the MOE for a pesticide for a given 
exposure scenario, the expected human exposure to the pesticide is 
divided into the dose identified as the Point of Departure. A safe MOE 
is generally considered to be a margin at least as high as the product 
of all applicable safety factors for a pesticide. For example, if a 
pesticide needs a 10X factor to account for interspecies differences, a 
10X factor for intraspecies differences, and a 10X FQPA children's 
safety factor, the safe or target MOE would be a value of at least 
1,000. In contrast to the RfD/PAD approach, the higher the pesticide's 
MOE, the safer the pesticide would be considered. Accordingly, if the 
target MOE for a pesticide is 1,000, MOE's for that pesticide exceeding 
1,000 would generally not be of concern. Like RfD/PADs, specific MOEs 
are calculated for exposures of different durations. For non-dietary 
exposures, EPA typically examines short-term, intermediate-term, and 
long-term exposures. Additionally, non-dietary exposure often involves 
exposures by various routes including dermal, inhalation, and oral.
    The RfD/PAD and MOE approaches are fundamentally equivalent. For a 
given risk and given exposure of a pesticide, if the pesticide were 
found to be safe under a RfD/PAD analysis it would also pass under the 
MOE approach, and vice-versa.
    ii. Non-threshold effects. For risk assessments for non-threshold 
effects, EPA does not use the RfD/PAD or MOE approach if quantitation 
of the risk is deemed appropriate. Rather, EPA calculates the slope of 
the dose-response curve for the non-threshold effects from relevant 
studies using a model that assumes that any amount of exposure will 
lead to some degree of risk. The slope of the dose-response curve can 
then be used to estimate the probability of occurrence of additional 
adverse effects as a result of exposure to the pesticide. For non-
threshold cancer risks, EPA generally is concerned if the probability 
of increased cancer cases exceed the range of 1 in 1 million.
    b. Estimating human exposure. Equally important to the risk 
assessment process as identifying hazards and determining the 
toxicological level of concern is estimating human exposure. Under 
FFDCA section 408, EPA is concerned not only with exposure to pesticide 
residues in food but also exposure resulting from pesticide 
contamination of drinking water supplies and from use of pesticides in 
the home or other non-occupational settings. (See 21 U.S.C. 
346a(b)(2)(D)(vi)). There are two critical variables in estimating 
exposure in food:
    i. the types and amount of food that is consumed; and
    ii. the residue levels in that food.
Consumption is estimated by EPA based on scientific surveys of 
individuals' food consumption in the United States conducted by the 
U.S. Department of Agriculture. (Ref. 2 at 12). Information on residue 
levels comes from a range of sources including crop field trials; data 
on pesticide reduction due to processing, cooking, and other practices; 
information on the extent of usage of the pesticide; and monitoring of 
the food supply. (Id. at 17).
    In assessing exposure from pesticide residues in food, EPA, for 
efficiency's sake, follows a tiered approach in which it, in the first 
instance, conducts its initial, screening-level exposure assessment 
using the worst case assumptions that 100 percent of the crop in 
question is treated with the pesticide and 100 percent of the food from 
that crop contains pesticide residues at the tolerance level. (Id. at 
11). When such an assessment shows no risks of concern, EPA's resources 
are conserved because a more complex risk assessment is unnecessary and 
regulated parties are spared the cost of any additional studies that 
may be needed. If, however, a first tier assessment suggests there 
could be a risk of concern, EPA then attempts to refine its exposure 
assumptions to yield a more realistic picture of residue values through 
use of data on the percent of the crop actually treated with the 
pesticide and data on the level of residues that may be present on the 
treated crop. These latter data are used to estimate what has been 
traditionally referred to by EPA as ``anticipated residues.'' Use of 
percent crop treated data and anticipated residue information is 
appropriate because EPA's worst case assumptions of 100 percent 
treatment and residues at tolerance value significantly overstate 
residue values. (72 FR 52112, July 18, 2007; 71 FR 43906, 43909-43910, 
August 2, 2006).
    In estimating pesticide exposure levels in drinking water, EPA most 
frequently uses mathematical water exposure models rather than 
pesticide-specific monitoring data. (69 FR 30042, 30058, May 26, 2004). 
EPA's models are based on extensive monitoring data and detailed 
information on soil properties, crop characteristics, and weather 
patterns. These models calculate estimated environmental concentrations 
of pesticides using laboratory data that describe how quickly the 
pesticide breaks down to other chemicals and how it moves in the 
environment (i.e., does it bind to the soil or is it highly water 
soluble). Although computer modeling provides an indirect estimate of 
pesticide concentrations, these concentrations can be estimated 
continuously over long periods of time, and for places that are of most 
interest for any particular pesticide. Modeling is a useful tool for 
characterizing vulnerable sites, and can be used to estimate peak 
concentrations from infrequent, large storms. Whether EPA assesses 
pesticide exposure in drinking water through monitoring data or 
modeling, EPA uses the higher of the two values from surface and ground 
water in assessing overall exposure to the pesticide. In most cases, 
pesticide residues in surface water are significantly higher than in 
ground water.
    Generally, in assessing residential exposure to pesticides, EPA 
relies on its Residential Standard Operating Procedures (``SOPs''). 
(Ref. 7). The SOPs establish models for estimating application and 
post-application exposures in a residential setting where pesticide-
specific monitoring data is not available. SOPs have been developed for 
many common exposure scenarios including pesticide treatment of lawns, 
garden plants, trees, swimming pools, pets, and indoor surfaces 
including crack and crevice treatments. The SOPs are based on existing 
monitoring and survey data including information on activity patterns, 
particularly for children. Where available, EPA relies on pesticide-
specific data in estimating residential exposures.

C. Children's Safety Factor Policy

    As part of implementation of the major changes to FFDCA section 408 
included in the FQPA, EPA has issued a number of policy guidance 
documents addressing critical science issues. On January 31, 2002, EPA 
released its science policy guidance on the children's safety factor. 
(Ref. 5) [This policy is hereinafter referred to as the ``Children's 
Safety Factor Policy'']. The Children's Safety Factor Policy emphasizes 
throughout that EPA interprets the children's safety factor provision 
as establishing a presumption in favor of application of an additional 
10X safety factor for the protection of infants and children. (Id. at 
4, 11, 47, A-6). Further, the policy notes that the children's safety 
factor provision permits a different safety factor to be

[[Page 5443]]

substituted for this default 10X factor only if reliable data are 
available to show that the different factor will protect the safety of 
infants and children. (Id.). Given the wealth of data available on 
pesticides, however, the policy indicates a preference for making an 
individualized determination of a protective safety factor if possible. 
(Id. at 11). The policy states that use of the default factor could 
under- or over-protect infants and children due to the wide variety of 
issues addressed by the children's safety factor. (Id.). Further, the 
policy notes that ``[i]ndividual assessments may result in the use of 
additional factors greater or less than, or equal to 10X, or no 
additional factor at all.'' (Id.).
    In making pesticide-specific assessments regarding the magnitude of 
the children's safety factor, the policy stresses the importance of 
focusing on the statutory language that ties the children's safety 
factor to concerns regarding potential pre- and post-natal toxicity and 
the completeness of the toxicity and exposure databases. (Id. at 11-
12). As to the completeness of the toxicity database, the policy 
recommends use of a weight-of-the-evidence approach which considers not 
only the presence or absence of data generally required under EPA 
regulations and guidelines but also the availability of ``any other 
data needed to evaluate potential risks to children.'' (Id. at 20). The 
policy indicates that the principal inquiry concerning missing data 
should center on whether the missing data would significantly affect 
calculation of a safe exposure level. (Id. at 22; accord 67 FR 60950, 
60955, September 27, 2002) (finding no additional safety factor 
necessary for triticonazole despite lack of developmental neurotoxicity 
(``DNT'') study because the ``DNT [study] is unlikely to affect the 
manner in which triticonazole is regulated.'')). When the missing data 
are data above and beyond general regulatory requirements, the policy 
states that the weight of evidence would generally only support the 
need for an additional safety factor where the data ``is being required 
for `cause,' that is, if a significant concern is raised based upon a 
review of existing information, not simply because a data requirement 
has been levied to expand OPP's general knowledge.'' (Ref. 5 at 23).
    As to potential pre- and post-natal toxicity, the Children's Safety 
Factor Policy lists a variety of factors that should be considered in 
evaluating the degree of concern regarding any identified pre- or post-
natal toxicity. (Id. at 27-31). As with the completeness of the 
toxicity database, the policy emphasizes that the analysis should focus 
on whether any identified pre- or post-natal toxicity raises 
uncertainty as to whether the RfD/PAD is protective of infants and 
children. (Id. at 31). Once again, the presence of pre- or post-natal 
toxicity, by itself, is not regarded as determinative as to the 
children's safety factor. Rather, the policy stresses the importance of 
evaluating all of the data under a weight-of-evidence approach focusing 
on the safety of infants and children. (Id.).
    In evaluating the completeness of the exposure database, the policy 
explains that a weight-of-the-evidence approach should be used to 
determine the confidence level EPA has as to whether the exposure 
assessment ``is either highly accurate or based upon sufficiently 
conservative input that it does not underestimate those exposures that 
are critical for assessing the risks to infants and children.'' (Id. at 
32). EPA describes why its methods for calculating exposure through 
various routes and aggregating exposure over those routes generally 
produce conservative exposure estimates - i.e. health-protective 
estimates due to overestimation of exposure. (Id. at 40-43). 
Nonetheless, EPA emphasizes the importance of verifying that the 
tendency for its methods to overestimate exposure in fact were 
adequately protective in each individual assessment. (Id. at 44).

IV. The Challenged Tolerances

    Boscalid is a fungicide used both on agricultural food crops as 
well as turf. It has a wide variety of agricultural uses including 
berries, nuts, soybeans, and various vegetables. (40 CFR 180.589(a)). 
Tolerances have also been established to cover inadvertent residues on 
various other crops as a result of rotation of these crops onto fields 
previously treated with boscalid. (40 CFR 180.589(d)). On December 20, 
2006, EPA promulgated new boscalid tolerances for residues in or on 
leafy greens crop subgroup 4A, except head and leaf lettuce, and leafy 
petioles crop subgroup 4B. (71 FR 76185, December 20, 2006).
    In promulgating these tolerances, EPA assessed the risk from 
boscalid based on aggregate boscalid exposure. Animal studies indicated 
that repeat dosing with boscalid resulted in effects in the liver and/
or thyroid in various species. Mechanistic studies indicated that the 
thyroid effects were derivative of enzymatic effects on the liver. 
(Ref. 8 at 4). The chronic RfD/PAD was based on the results of three 
studies that showed similar effects at similar levels. (Id. at 23-24). 
The boscalid database showed no effects that were attributable to a 
single dose, and thus boscalid was deemed not to pose an acute risk. 
Testing involving in utero and/or post-natal exposure of animals showed 
no developmental or reproductive effects; however, this testing 
resulted in some findings of qualitative or quantitative sensitivity 
with regard to body weight effects in the young. EPA concluded there 
was low concern regarding these sensitivity findings for various 
reasons including that clear NOAELs were identified for these effects 
and the effects were transient in nature or inconsistent. EPA assessed 
exposure to boscalid in food relying on the worst case assumption that 
boscalid residues in all crops to which boscalid may be legally applied 
had residues at the tolerance level.
    EPA concluded that chronic exposures to boscalid did not raise 
safety concerns because the most highly exposed population subgroup, 
children 1-2 years old, had exposures below the PAD or safe dose 
(exposure was at 38 percent of the PAD). (71 FR 76188). Short-term 
exposures from golf course turf was also judged to be safe having a MOE 
of 1,400. (Id.). EPA concluded the cancer risk posed by boscalid was 
negligible given the weak evidence of carcinogenicity in animal 
studies. (Id. at 76189). In conducting these assessments, EPA 
determined that the children's safety factor could be removed because 
the database was complete, there was low concern for increased 
sensitivity in the young, and exposure had been estimated in a 
conservative fashion. (Id. at 76188).

V. NRDC's Objections

    On February 20, 2007, NRDC filed objections to the December 2006 
rule establishing tolerances for boscalid on various leafy greens. 
(Ref. 1). On May 21, 2007, NRDC supplemented and expanded its 
objections by filing comments during the comment period held by EPA on 
NRDC's initial objections. (Ref. 9).
    NRDC's objections have two main thrusts: (1) that EPA erred in 
removing the children's safety factor given the finding of that young 
animals had increased sensitivity to boscalid; and (2) that EPA's 
decision is arbitrary and capricious due to a failure to adequately 
explain its reasons for removing the children's safety factor and 
because EPA's selection of NOAELs and the RfD/PAD ``are clearly 
contrary to the data.'' (Ref. 1).
    With regard to increased sensitivity in young animals, NRDC relied 
in its objections principally on the EPA

[[Page 5444]]

finding in the DNT study that rat pups had decreased body weight and 
decreased body weight gain at a dose of 147 milligrams/kilogram of body 
weight/day (mg/kg/day) whereas no effects were seen in the maternal 
animals even at the highest dose tested (1,442 mg/kg/day). Further, 
NRDC cites the rat reproduction study as evidencing increased 
sensitivity in rat pups. Given this sensitivity, NRDC argues that it 
was wrong for EPA to rely on a study on adult animals to set the RfD/
PAD without retaining the children's safety factor. In addition to 
arguing that EPA did not give proper weight to its findings of 
increased sensitivity to the young, NRDC claims that EPA analyzed the 
data in several studies in a manner that understates the sensitivity of 
the young and has selected a RfD/PAD that is under-protective of the 
young. (NRDC's arguments on these points are presented in more detail 
in Unit VII.A. below.). EPA's allegedly improper analysis is cited as 
grounds for retaining the children's safety factor. NRDC claims that if 
EPA had retained the children's safety factor it could not have 
concluded that the boscalid tolerances are safe.
    NRDC makes no new arguments to justify its claim that EPA's 
decision is arbitrary and capricious; rather, NRDC merely cross-
references its earlier assertions regarding EPA's interpretation of 
science data.
    In its comments on its objections, NRDC expands on these arguments. 
First, it argues that EPA erred in discounting the seriousness of the 
increased sensitivity in the DNT and rat reproduction studies. NRDC 
claims that EPA's analysis is based on nothing more than speculation. 
(Ref. 9 at 2-4). Second, NRDC cites a third study as showing 
sensitivity in young animals, the rabbit developmental study, and 
argues similarly that EPA has relied on nothing more than speculation 
to conclude that the demonstrated sensitivity is of low concern. 
Finally, NRDC provides greater detail in support of its argument that 
EPA's selection of a RfD/PAD for boscalid is not protective of children 
and does not justify removal of the children's safety factor.

VI. Public Comments

    Upon receipt of the objections, EPA provided a copy of the 
objections to the tolerance petitioner, BASF Corporation, as required 
by the statute. Further, on March 28, 2007, EPA published a notice of 
the availability of the objections and established a 60-day comment 
period. (72 FR 14551, March 28, 2007). Other than from BASF, EPA 
received significant comments only from NRDC - commenting on its own 
objections.
    BASF's comments stressed that a complete database had been 
submitted on boscalid including neurotoxicity studies that went beyond 
the core toxicology database requirements. In addition, BASF asserted 
that these studies showed ``no toxicologically meaningful effects [in 
young animals] were observed at a dose below one that produced toxicity 
to the parental animals.'' (Ref. 10 at 2). BASF contended that effects 
in rat pups in the DNT and the two-generation reproduction study that 
occurred at doses lower than effects in maternal animals were small 
and/or transient decreases in pup body weight. (Id.).
    Because NRDC's comments on its own objections were a 
supplementation of its objections, these comments were provided to BASF 
and BASF was given a 30-day period for response. (Ref. 11). As to 
NRDC's new arguments concerning sensitivity in the young, BASF asserts 
that the data did not support that conclusion. As regards the two-
generation reproduction study and the DNT, BASF notes that, although 
toxicity in the parental animals was not seen in the DNT study and was 
seen only at the high dose in the reproduction study, in the chronic/
carcinogenicity study in rat, where systematic toxicity is examined 
more thoroughly, adverse effects were seen at doses corresponding to 
the mid and high doses in the DNT and reproduction studies. Thus, BASF 
concludes that the findings of adverse effects in the young at the mid 
and high doses in the DNT and reproduction studies do not show 
increased sensitivity in the young. As to the rabbit developmental 
study, BASF argues that, because the effects on the fetuses (increased 
number of abortions) occurred at a dose that showed the maternal 
animals were under stress (decreased weight gain), the study does not 
show increased sensitivity in the fetuses. According to BASF, ``[t]he 
rabbit is prone to spontaneously abort as a response to maternal 
stress, and feed restriction alone during the gestational period may 
trigger abortions in rabbits.'' (Id. at 3). Finally, BASF defends EPA's 
use of the NOAEL from the chronic dog study as the Point of Departure 
for setting the cRfD/PAD by presenting a ``benchmark dose'' analysis of 
the relevant studies. Benchmark dose analysis involves fitting a 
mathematical model to the dose response data for the purpose of 
estimating the threshold effect level (i.e., the no adverse effect 
level) reflecting a selected benchmark response (e.g., 5%, 10%). BASF's 
benchmark dose analysis revealed that the NOAEL from the chronic dog 
study was lower than the benchmark dose from DNT and two-generation 
reproduction studies.

VII. EPA's Response to the Objections

    For the reasons stated below, EPA denies each of NRDC's objections.

A. NRDC's Challenge to EPA's Children's Safety Factor Determination

    NRDC contends that EPA's decision to remove the children's safety 
factor was erroneous based on (1) the legal argument that whenever EPA 
identifies increased sensitivity in the young it is required to retain 
the full 10X children's safety factor; and (2) the scientific claim 
that EPA did not have a reasoned basis for its conclusion that the 
sensitivity identified in animal studies was of low concern in 
evaluating whether the 10X children's safety factor should be retained 
or a different factor selected.
    Before reaching the merits of these arguments, one preliminary 
matter needs to be addressed. In a prior order on an objection to EPA's 
removal of the children's safety factor as to different pesticides, EPA 
denied the objection where retention of the children's safety factor 
would not have altered EPA's conclusion on the pesticide's safety (72 
FR 39318, 39323-39324, July 18, 2007). For boscalid, the retention/
removal decision appears to be critical to the safety determination 
because EPA concluded that chronic exposure to boscalid for the highest 
exposed population subgroup is at 38 percent of the RfD/PAD. If no 
other change is made to the boscalid risk assessment other than 
retaining the 10X children's safety factor, then the calculation that 
boscalid exposure uses 38 percent of the RfD/PAD for the most highly-
exposed subgroup would increase by a factor of 10. Because of the 
conservativeness of the exposure assessment for boscalid (assuming all 
foods that may be legally treated bear tolerance level residues), 
however, EPA strongly suspects that a more realistic exposure 
assessment will not show a risk of concern. Exposure refinements from 
the worst case assumptions of all foods containing tolerance level 
residues generally reduce exposure estimates by an order of magnitude 
or more. (70 FR 46706, 46732, August 10, 2005). Nonetheless, because 
EPA has not completed a revised risk assessment for boscalid at this 
time, it will address in this order the substance of NRDC's challenge 
to EPA's decision on the children's safety factor. It should be noted 
that EPA's decision on the children's safety factor for boscalid relied 
in part on the conservativeness of EPA's exposure

[[Page 5445]]

assessment. This consideration continues to be relevant, even if, at 
this point, it does obviate NRDC's objection entirely.
    1. NRDC's legal argument. NRDC argues that, because section 408 
``requires that the additional FQPA tenfold safety factor `shall be 
applied' to `take into account' `potential pre- and post-natal 
toxicity,'' . . . [t]he clear evidence that juveniles are significantly 
more vulnerable than adults compels EPA to retain or increase the 
default FQPA tenfold safety factor for boscalid.'' (Ref. 1 at 3).
    On repeated occasions EPA has rejected the interpretation that the 
children's safety factor provision mandates that the absence of a 
particular study or a finding of pre- or post-natal toxicity or 
increased sensitivity in the young removes EPA's discretion to choose a 
different safety factor. (72 FR 52108, 52115-52117, September 12, 2007; 
71 FR 43906, 43919, August 2, 2006). EPA explained its rationale 
recently in responding to NRDC objections which made precisely the same 
argument in this case:
    The statute does direct EPA to consider ``susceptibility of 
infants and children'' to pesticides. (21 U.S.C. 
346a(b)(2)(C)(i)(II)). It also states that an additional safety 
factor to protect infants and children shall be applied ``to take 
into account potential pre- and post-natal toxicity . . . .'' (21 
U.S.C. 346a(b)(2)(C)). Nonetheless, in clear and unmistakable 
language, Congress decreed that, ``[n]otwithstanding such 
requirement for an additional margin of safety'' to take into 
account potential pre- and post-natal toxicity, EPA is authorized to 
choose a different safety factor if EPA has reliable data showing a 
different factor is safe. (Id.). Interpreting the statute as 
creating a rigid, per se rule that the identification of sensitivity 
in the young removes EPA's discretion to choose a different safety 
factor is inconsistent with this language and the flexibility 
granted to the Agency.

(72 FR at 52117). NRDC has raised no arguments in its current 
objections which convince EPA to vary from its long-held 
interpretation.
    2. NRDC's scientific argument. NRDC makes five claims as to why the 
evidence on increased sensitivity in the young is of such significance 
that it was inappropriate for EPA to remove the children's safety 
factor. NRDC also argues that an alleged lack of reliable data 
supporting EPA's derivation of the boscalid RfD/PAD demonstrates that 
it was unlawful to remove the children's safety factor. Each claim is 
addressed in turn below.
    a. The degree of increased sensitivity seen in the DNT. NRDC claims 
that adverse effects on auditory startle reflex were seen at all doses 
in the offspring in the DNT study and thus the dose EPA identified as a 
NOAEL for the offspring (14 mg/kg/day) is actually a LOAEL. According 
to NRDC, this demonstrates a higher degree of sensitivity in the 
offspring. NRDC notes that a draft EPA assessment of the DNT study 
concluded that there were adverse effects on the auditory startle 
reflex in offspring at all tested doses. The final EPA review of the 
DNT study took the opposite position: that there was not a significant 
effect on the auditory startle reflex at any dose. NRDC argues that 
EPA's final review is flawed because EPA misused data on the historical 
level of the auditory startle reflex in rat controls in other studies 
(``historical control data''). According to NRDC, EPA erred by 
comparing historical control data to the results in the treated animals 
in the boscalid DNT study to determine if the treated animals varied 
from control animals generally. NRDC argues that the only valid use of 
historical control data is as a check on whether there is a problem 
with the controls in a particular study.
    EPA disagrees with NRDC's analysis and reaffirms its conclusion 
that boscalid did not elicit an adverse effect on auditory startle 
reflex in the DNT study. In its initial analysis of the DNT, an EPA 
reviewer concluded that there were treatment-related decreases in 
auditory startle reflex at all doses on post-natal-day (``PND'') 24. 
This finding was based on a statistically significant decrease in 
auditory startle reflex in males at both the low and high doses in the 
first block of five trials and for the average effect over all trials. 
The average decrease was greater in the low dose group (24%) than the 
high dose group (19%). The mid-dose group had a slightly lower decrease 
of 15%. In females, a statistically significant effect was only seen in 
the second block of the low and mid-dose groups but no such effect was 
seen for the average across blocks. Again, there was no dose-response 
effect in that greater decreases were seen at the low dose than at the 
mid or high dose. No statistically significant effects on auditory 
startle reflex were seen on PND 60. Noting the ``limitations'' in the 
data, the EPA reviewer nonetheless tentatively found a treatment-
related effect at all doses.
    In response to this tentative conclusion, the boscalid registrant 
submitted historical control data on auditory startle reflex and data 
concerning one male pup that died on PND 25. After examining the 
historical control data, EPA concluded that the auditory startle reflex 
of the controls from the boscalid DNT study were similar to historical 
controls and thus the controls from the boscalid study ``should be 
considered the primary source for analysis and consideration'' for this 
study. (Ref. DER at 30). As to the rat which died, EPA concluded that 
it was suffering from an underlying illness unrelated to treatment and 
removed its data from the study. As a result, none of the individual 
block trials nor the average from all trials for males evidenced a 
statistically significant decrease in auditory startle reflex at PND 
24. EPA also reanalyzed the statistical significance of the results for 
the females and found a statistically significant effect only at the 
low dose for the second block. Given the revised finding of a 
statistically significant effect in only one block trial (out of five) 
at one dose (out of three) in one sex on one day of testing (out of 
two) and the lack of a dose response (effects only at the low dose), 
EPA concluded that there was no treatment-related effect on auditory 
startle reflex.
    NRDC's objection here is denied. As a preliminary matter, EPA would 
note that it disagrees with NRDC's claim that historical control data 
can only be used for the narrow purpose of evaluating the fitness of a 
study's controls. (Refs. 12a, 12b, and 12c). This disagreement, 
however, is beside the point because for the boscalid DNT study EPA 
used historical control data in precisely the manner that NRDC argues 
they should be used. EPA's review of the DNT specifically found that 
``[h]istorical control data provided indicated that the mean startle 
amplitude on PND 24 for the current study of [boscalid] was similar to 
the control means of the submitted studies on PND 24. Therefore the 
analysis of this group's relation to treatment groups is valid and 
should be considered the primary source for analysis and evaluation.'' 
(Ref. 13 at 30). Finally, EPA's conclusion that the DNT study showed no 
treatment-related effect on auditory startle reflex was based upon a 
reasonable evaluation of the data, as demonstrated above.
    b. The sensitivity of DNT Study. NRDC claims that the DNT study is 
an insensitive study because it involves examination of only one male 
and one female pup per litter and that therefore EPA should have 
attached more significance to the finding of increased sensitivity in 
the young in that study. NRDC also criticizes the statistical analysis 
of the DNT study for only including probability values (``p-values'') 
representing confidence levels of 95 percent (p-value of 0.05) and 99 
percent (p-value of 0.01). (Basically, a p-value defines the 
probability that an observed difference between a control group and a 
treatment group is based on

[[Page 5446]]

chance alone.). NRDC argues that rather than analyze the data against 
the p-values of 0.05 and 0.01, EPA should calculate the ``actual p-
value statistic,'' and thus EPA could use its ``expert judgment on the 
significance of the findings, given the limitations of the study.'' 
(Ref. 1 at 5).
    EPA believes that the significance attached to findings of 
sensitivity in a DNT study should be driven primarily by an evaluation 
of the results of the study itself. EPA would note that the development 
and design of the DNT study underwent an exhaustive independent 
scientific peer review as well as public comment process. (Ref. 14). 
This process included multiple reviews by EPA's FIFRA Scientific 
Advisory Panel and public comment opportunities as well as a scientific 
workshop involving outside experts organized expressly to evaluate 
developmental neurotoxicity testing issues. (Id.). NRDC's criticisms of 
use of reporting statistical significance at the 95 and 99 percent 
confidence levels are misplaced. Use of p-values of 0.01 and 0.05 to 
document statistically significant differences between treated and 
control animal groups is a long-established practice in the scientific 
community. (Refs. 15a, 15b, 15c, 15d, and 15e). EPA can calculate 
different levels of statistical confidence if for some reason the data 
suggest that may be valuable; however, in EPA's judgment no such 
reasons were present in the circumstances of the boscalid DNT study.
    c.  Weight-of-the-evidence evaluation of the two-generation 
reproduction study in rats. NRDC argues that EPA undervalues the 
importance of increased sensitivity identified in the two generation 
reproduction study in rats based on nothing more than speculation. 
According to NRDC, EPA was just ``guess[ing]'' when it stated that: 
``The degree of concern is also low for the quantitative evidence of 
susceptibility seen in the 2-generation reproduction study in rats 
because the decreases in body weight and body weight gains were seen 
primarily in the [second] generation. These may have been due to 
exposure of the parental animals to high doses (above the Limit 
Dose).'' (Ref. 9 at 2 (citing to 76 FR 76188) (emphasis added by 
NRDC)). NRDC also suggests that EPA's ``speculation'' is 
``nonsensical'' because if the second generation pups had effects due 
to high dose exposures of the parents, then these effects should have 
been seen in the first generation pups because their parents had the 
same high dose exposures.
    In comments on NRDC's objections, BASF argues that young animals 
are not more sensitive to boscalid than adult animals given that adult 
animals in the chronic/carcinogenicity study in the rat experienced 
adverse effects at similar dose levels as the pups in the two 
generation rat study. BASF makes the same contention with regard to the 
DNT study. (See Unit VII.A.2.d., below).
    EPA does not believe that the sensitivity evidenced in the pups in 
the two-generation reproduction requires retention of the 10X 
children's safety factor. As discussed in detail in Unit VII.A.2.f., 
the NOAEL from the chronic dog study used for the Point of Departure in 
setting the chronic RfD/PAD for the liver effects is protective of the 
body weight effects seen in the second generation male pups at mid and 
high doses in the two-generation reproduction study. EPA disagrees with 
NRDC that it was somehow improper to take into account that the body 
weight effects in the pups in the two-generation reproduction study 
were only seen in males and only in the second generation. These 
factors bear on significance of the effects seen. Effects seen in only 
one sex and only after dosing for two generations are generally 
regarded as less significant than effects seen in both sexes and in 
both generations of a two-generation study. Moreover, there is other 
evidence from the study suggesting that body weight effects in the 
young were not entitled to great weight in EPA's weight-of-the-evidence 
analysis. First, absolute body weight and bodyweight gain of the male 
F2 offspring of treated dams were similar to those of the 
offspring of the control dams at birth. Birth is a more sensitive time 
point to indicate susceptibility than subsequent time periods. (Refs. 
16a, 16b, and 16c). Second, there was a lack of consistency in the 
observed body weight decreases (i.e, decreased on days 7 and 21 but not 
on days 4 and 17). (Ref. 17 at 20). EPA believes these factors are 
important to informing its expert judgment regarding the level of 
concern regarding, or the significance of, the increased sensitivity 
observed in this study. In any event, EPA's determination that the 
chronic RfD/PAD is protective of the pup effects seen in the 
reproduction study is alone sufficient to allay any concerns regarding 
increased sensitivity and pre- and post-natal toxicity raised by the 
two-generation reproduction study.
    NRDC places special emphasis on EPA's suggestion that the body 
weight effect may be due to the very high dose given the maternal 
animals. EPA's statement on this issue was in error because, as noted, 
the body weight effects were seen at both the mid and high doses in the 
study in the second generation pups. Nonetheless, for the reasons 
described above, identification of a clear NOAEL for body weight 
effects and limited nature of the body weight effects (e.g., one sex 
only, inconsistent findings at the mid dose), EPA concludes that the 
chronic RfD/PAD based on a safety factor of 100X is safe for infants 
and children.
    EPA does not agree that BASF has made an appropriate comparison of 
the results of the two-generation reproduction study and the chronic/
carcinogenicity study given the substantial difference in time of 
exposure to boscalid in the two studies.
    d. Weight-of-the-evidence evaluation of the DNT Study. NRDC argues 
that EPA errs in downplaying the significance of the decreased weight 
gain in pups seen in the DNT. NRDC states that EPA found there to be 
low concern for the decreases in pup body weight on post-natal days 1-4 
because no effects on body weight were seen at any other time and the 
effects only occurred when the maternal animals were receiving an 
extremely high dose (above the Limit Dose) suggesting that pup effects 
were derivative of effects on the maternal animals. This reasoning is 
attacked by NRDC as mere speculation. NRDC claims that ``the Agency 
does not and cannot assert that inadequate weight gain on days 1-4 is 
an insignificant adverse effect. Any significant reduction in weight 
gain during early development is potentially harmful and may cause 
permanent adverse effects.'' (Ref. 9 at 3). Further, NRDC states that 
EPA has presented no empirical evidence to support its conclusion that 
the high dose to the maternal animals might have been the reason for 
the pup effect.
    For similar reasons to those relied upon in rejecting NRDC's 
arguments concerning the two-generation reproduction study, EPA does 
not believe that the sensitivity evidenced in the pups in the DNT study 
requires retention of the 10X children's safety factor. As discussed in 
detail in Unit VII.A.2.f., the NOAEL from the chronic dog study used 
for the Point of Departure in setting the chronic RfD/PAD for the 
liver/thyroid effects is protective of the transient body weight 
effects seen in the pups at mid dose and the more severe pup body 
weight effects at the high dose in the DNT study. EPA disagrees with 
NRDC that it was somehow improper to take into account that the body 
weight effects in the mid-dose pups were transient in nature - i.e., 
statistically significant decreases in body weight were seen on post-
natal

[[Page 5447]]

days 1-4 but the animals had recovered by day 11. The severity of an 
effect aids in evaluation of the dose response curve for a pesticide; 
in this case, it indicates that mid dose was not far from the actual no 
adverse effect level. In any event, EPA's determination that the 
chronic RfD/cPAD is protective of the pup effects seen in the DNT study 
is alone sufficient to allay any concerns regarding increased 
sensitivity and pre- and post-natal toxicity raised by the DNT study.
    NRDC challenges EPA's reasoning that the effects on pups' body 
weight may be due to the maternal animals being exposed above the Limit 
Dose. The Limit Dose is regarded as the highest dose possible that can 
be given an animal without overwhelming its defense mechanisms. As a 
general matter, EPA does not believe NRDC's argument is well-founded 
because discounting the weight of effects seen only at or above the 
Limit Dose is a well-accepted scientific precept. Here, however, EPA 
erred by mentioning the Limit Dose because effects were present in the 
pups at the mid dose as well as at the dose that exceeded the Limit 
Dose. Nonetheless, for the reasons described above, identification of a 
clear NOAEL for body weight effects and limited nature of the body 
weight effects (e.g., one sex only, transient nature of effects at the 
mid dose), EPA concludes that the RfD/PAD based on a safety factor of 
100X is safe for infants and children.
    For the same reason as stated in Unit VII.A.2.c., EPA disagrees 
with BASF's comparison of the DNT study and the chronic/carcinogenicity 
study.
    e. Weight-of-the-evidence evaluation of the rabbit developmental 
study. NRDC claims that EPA wrongfully disregards the qualitative 
evidence of increased sensitivity seen in the rabbit developmental 
study. According to NRDC, EPA expressed a low degree of concern for 
increased abortions or early delivery effects on the young because they 
were seen only at the Limit Dose and may have been caused by maternal 
stress. NRDC faults EPA for not providing empirical evidence to support 
this conclusion and argues that the Limit Dose might not be the maximum 
tolerated dose for boscalid in rabbits. This type of ``speculation,'' 
NRDC claims, cannot meet the ``reliable data'' requirement for choosing 
a different children's safety factor.
    NRDC's claims as to the rabbit developmental study, have even less 
merit than its arguments as to the two-generation reproduction and DNT 
studies. Not only is the chronic RfD/PAD for the thyroid effects 
protective of the qualitative sensitivity seen in the rabbit 
developmental study but the chronic RfD/cPAD is protective by an order 
of magnitude of an effect seen only at a ``limit dose.'' The chronic 
RfD/PAD is based on a NOAEL from the chronic dog study of 21.8 mg/kg/
day as compared to the NOAEL for the fetal effects in the rabbit 
developmental study of 300 mg/kg/day. The fetal effects (abortions and 
early delivery) were seen only at the Limit Dose. (Unlike in the two-
generation reproduction and DNT studies, adverse effects were only seen 
in the young at the high dose.). Moreover, the fetal effects were seen 
only in the presence of adverse effects in the maternal animals. The 
primary adverse effects in the maternal animals were abortions and 
early delivery (considered an adverse effect on both maternal animals 
and fetuses) but the study evidenced decreased food consumption and 
decreased body weight in the maternal animals as well. Although a 
definitive conclusion was not reached on whether the food consumption 
effects were treatment-related, evaluation of the individual animals 
showed that three of the four does that aborted or delivered early 
experienced dramatic reductions in food consumption. Given these 
results, it was reasonable for EPA to take into account its scientific 
expertise with rabbit toxicology studies which indicated that maternal 
animals put under stress had a tendency to abort or deliver early. 
Based on all of this evidence, EPA rejects NRDC's arguments concerning 
the rabbit developmental study and concludes that the qualitative 
sensitivity evidenced in the fetuses in the rabbit developmental study 
does not require retention of the 10X children's safety factor. (Refs. 
18 and 19).
    f. Derivation of the chronic RfD/PAD. NRDC claims that EPA erred in 
its selection of a NOAEL to calculate the chronic RfD/PAD by not 
relying on the lowest NOAEL from the applicable chronic studies. (Ref. 
1 at 5-6). NRDC argues that, because EPA's justification for the RfD/
PAD is allegedly nothing more than speculation, EPA lacks the reliable 
data necessary to remove the children's safety factor. (Ref. 9 at 4-5).
    EPA relied on three co-critical studies in selecting a NOAEL for 
the chronic RfD/PAD: chronic toxicity in the rat, carcinogenicity in 
the rat, and chronic toxicity in the dog. Each of these studies showed 
liver effects and the rat studies also evidenced secondary effects on 
the thyroid. The NOAELs for the studies tightly bunched between 21.8 
and 30 mg/kg/day. EPA selected the 21.8 mg/kg/day NOAEL from the 
chronic dog study to calculate the chronic RfD/PAD. EPA considered but 
rejected lower NOAELs from three other studies: the 90-day subchronic 
toxicity study in the dog; the two-generation reproduction study in the 
rat; and the developmental neurotoxicity study. EPA's rationale for not 
using the NOAELs from these studies was that the lower NOAELs from 
these studies were an artifact of dose selection given the wide range 
between NOAEL and LOAEL in the studies and the minimal effects seen at 
the LOAEL.
    NRDC challenges EPA's conclusion claiming that EPA has ignored 
``effects at significantly lower doses in juvenile animals (2-gen repro 
and DNT).'' (Ref. 1 at 4). NRDC also argues that EPA's decision is 
speculative because (1) ``EPA does not identify any reliable data to 
support its theory that a 10x differential between NOAELs and LOAELs - 
as occurred [with the three studies with lower NOAELs] - can never 
result from well designed and conducted studies;'' and (2) ``EPA offers 
no reliable data to support its assumption that the relationship 
between the LOAELs and NOAELs across studies with different designs and 
with different test species must always be the same . . . .'' (Ref. 9 
at 4).
    NRDC's arguments are without merit. First, NRDC is wrong to contend 
that EPA, in setting the chronic RfD/PAD, ignored ``effects at 
significantly lower doses in juvenile animals'' in the two-generation 
reproduction study and the DNT. EPA based the chronic RfD/PAD on the 
chronic dog study. In that study the lowest dose in which adverse 
effects were seen was 57.4 mg/kg/day. On the other hand, in the two-
generation reproduction study and the DNT, the lowest doses at which 
adverse effects were seen were 101.2 mg/kg/day and 147 mg/kg/day, 
respectively. (Ref. 18 at 17). Second, EPA is not contending, nor does 
its analysis depend on, the supposition that a ``10x differential 
between NOAELs and LOAELs . . . can never result from well designed and 
conducted studies.'' The differential between a study's NOAEL and LOAEL 
depends on the dose spacing in the study - studies with more and 
closely-spaced doses are likely to yield a lower differential than 
studies with fewer and widely-spaced doses. EPA is not arguing that it 
is inappropriate to design a study with a factor of 10 between doses. 
Third, EPA is not contending that the relationship between NOAELs and 
LOAELs across studies must always be the same. Rather, EPA concluded 
that the data for boscalid indicated that the NOAEL it selected as the 
Point of Departure for calculating the chronic

[[Page 5448]]

RfD/PAD would be protective of all effects.
    In making this conclusion, EPA relied on several factors. First, 
EPA compared the NOAELs and LOAELs of the six chronic studies that had 
NOAELs that were relatively close. This exercise is appropriate because 
the NOAEL from any one study is, in part, an artifact of the dose 
selection process, and does not identify the no adverse effect level 
just the level at which no effects were observed in the particular 
study. In animal testing, animals are generally dosed at three or four 
different levels. The dose levels are fairly widely spread (generally 
2X - 10X) so that there is a good chance of identifying both a NOAEL 
and a LOAEL. The actual no adverse effect level or lowest adverse 
effect level will be somewhere between the identified NOAEL and LOAEL. 
When multiple studies produce results in a similar range, they often 
can provide valuable information about where the true no adverse effect 
and lowest adverse effect levels are. The NOAELs and LOAELs for the six 
studies are presented in Table 1.

                         Table 1.--Selected Chronic and Subchronic Studies for Boscalid
----------------------------------------------------------------------------------------------------------------
             Study                NOAEL male/female (m/f) in mg/kg/day            LOAEL m/f in mg/kg/day
----------------------------------------------------------------------------------------------------------------
Chronic toxicity in rats                                        21.9/30                                110/150.3
----------------------------------------------------------------------------------------------------------------
Carcinogenicity in rats                                         23/29.7                              116.1/155.6
----------------------------------------------------------------------------------------------------------------
Chronic toxicity in dogs                                      21.8/22.1                                57.4/58.3
----------------------------------------------------------------------------------------------------------------
Subchronic toxicity in dogs                                         7.6                                     78.1
----------------------------------------------------------------------------------------------------------------
Two-generation reproduction                       10.1/12.3 (offspring)                  101.2/123.9 (offspring)
 study in rats
----------------------------------------------------------------------------------------------------------------
DNT in rats                                              14 (offspring)                          147 (offspring)
----------------------------------------------------------------------------------------------------------------

    Just based on the dose spread alone, the chronic dog study appears 
to provide valuable information because it has the tightest spread 
between NOAEL and LOAEL.
    Second, EPA considered the effects seen in the studies. The NOAEL/
LOAELs for the chronic rat, carcinogenicity rat, and chronic dog 
studies were all based primarily on effects on the liver and/or 
thyroid. The other three studies had NOAEL/LOAELs based on decreased 
body weight and decreased body weight gain. The first three studies 
also demonstrated body weight effects but at the same or higher doses 
than the organ effects. Organ effects are generally judged to be of 
more serious concern than systemic toxicity as shown through body 
weight effects. Given the heightened concern with the liver and thyroid 
effects and the fact that body weight effects only occurred at the same 
or higher doses, evaluation of the effects seen in the studies also 
supported reliance on the NOAEL from the chronic dog study.
    Finally, EPA undertook a one-to-one comparison of the chronic dog 
study with the three studies that had a lower NOAEL. Given that the 
subchronic dog study was conducted in the same species as the chronic 
dog study and that the results of the subchronic dog study were fully 
consistent with the chronic dog study (i.e., based on the chronic dog 
study it would be expected that 7.6 mg/kg/day would be a NOAEL and 78.1 
a LOAEL), the subchronic dog study supported reliance on the NOAEL from 
the chronic dog study. Further, the strength of the findings at the 
LOAEL in the two-generation reproduction study and the DNT study, did 
not suggest that the actual no adverse effect level for the effects 
seen in these studies is far below the identified LOAEL. In the two-
generation reproduction and DNT studies, the body weight effects at the 
LOAEL were either transient in nature (DNT study), not seen in both 
sexes (two-generation reproduction study), or not consistently seen 
post-natally (DNT and two-generation reproduction studies). (See Units 
VII.A.2.c., VII.A.2.d., and VII.A.2.e.).
    Given the weight-of-the-evidence, EPA concludes it was reasonable 
to choose the NOAEL from the chronic dog study in calculating the 
chronic RfD/PAD. Contrary to NRDC's contention, this decision is not 
based on speculation but on careful consideration of the entire 
database - a complete database that provides reliable data on which to 
choose a safety factor that is protective of the safety of infants and 
children. In any event, EPA would note that selecting the NOAEL from 
the DNT study or the two-generation reproduction study would not change 
the safety conclusion on the boscalid tolerances even without any 
further refinement of the worst case exposure assumptions relied upon 
in the tolerance document. EPA estimated exposure was at 38 percent of 
the chronic RfD/PAD and a lowering of the chronic RfD/PAD by a factor 
of two due to reliance on the two-generation reproduction study (i.e. 
using a NOAEL of 10.1 mg/kg/day instead of 21.8 mg/kg/day) would still 
show worst case exposure to be below the chronic RfD/PAD.
    BASF, in its comments, presents a benchmark dose analysis of the 
DNT and two-generation reproduction studies in support of EPA's 
selection of 21.9 mg/kg/day as the Point of Departure. The benchmark 
dose calculated by BASF is supportive of EPA's decision in that all of 
the benchmark doses covering various endpoints in these two studies 
were higher than 21.8 mg/kg/day. Although BASF's description of the 
method it used for calculating these benchmark doses appears 
scientifically appropriate, BASF has not submitted supporting 
documentation for its calculation and EPA has not independently 
verified it.
    3. Conclusion on children's safety factor. EPA disagrees both with 
NRDC's legal claim that a finding of sensitivity always requires 
retention of the children's safety factor and factual assertion that 
the particular evidence of increased sensitivity on boscalid requires 
such a result. NRDC's legal argument ignores the plain language of the 
statute. NRDC's factual argument fails to take into account the entire 
database.
    EPA has a complete toxicity database for boscalid. The toxicity 
studies for boscalid show it generally to have low mammalian toxicity 
and the database reveals no reproductive or developmental concerns, 
including no developmental neurotoxic concerns. Data involving the 
testing of young animals did show increased quantitative sensitivity in 
the young with regard to body weight effects and qualitative

[[Page 5449]]

sensitivity in one developmental study. Clear NOAELs were identified 
for all of these effects. Moreover, the body weight effects at the 
LOAELs in these studies were either transient or inconsistent and 
qualitative sensitivity occurred at the Limit Dose in the presence of 
maternal toxicity. EPA reasonably concluded that using the NOAEL from 
the chronic dog study was protective of all of the effects seen in the 
developmental and reproduction studies. That the chronic dog study only 
involved the testing of adult dogs does not raise concerns for the 
young because, as noted, EPA found the NOAEL from that study to be 
protective of the effects seen in all studies with the young, and the 
effects of concern in the dog study, increased liver weights and 
hepatic enzyme induction, are not common developmental concerns. In any 
event, when rats were exposed to boscalid pre- and post-natally as well 
as into adulthood in the two generation reproduction study, increased 
liver weights were only seen at the Limit Dose. Thus, increased 
sensitivity to liver effects in the young is not a concern. Finally, 
EPA has conservatively estimated human exposure to boscalid, relying on 
worst case exposures in food (assuming all registered crops contain 
residues at the tolerance level), and conservative models as well as 
pesticide-specific data in estimating exposure from residues in 
drinking water and from residential uses. Based on consideration of all 
of these data, EPA reasonably concluded it had reliable data showing 
that infants and children would be safe without application of an 
additional 10X safety factor.

B. NRDC's Claim That EPA's Decision is Arbitrary and Capricious

    NRDC argues that EPA's tolerance decision on boscalid was arbitrary 
and capricious because (1) EPA failed to adequately explain its safety 
factor decision; and (2) ``[t]he NOAELs and cPAD established by EPA for 
boscalid are clearly contrary to the data . . . .'' (Ref. 1 at 7-8). In 
the section of its objections addressing this claim, NRDC provides 
nothing in support of its assertion that EPA provided insufficient 
explanation for its children's safety factor determination. Presumably, 
NRDC is referring to the aspects of the children's safety factor 
determination challenged in an earlier portion of its objections and 
addressed by EPA in Unit VII.A. of this order. Thus, EPA relies on Unit 
VII.A. as responsive to NRDC's arbitrary and capricious claim as to the 
children's safety factor decision, and denies the objection for the 
reasons there stated. Similarly, to the extent NRDC is arguing that 
EPA's selection of a NOAEL in the DNT study or its selection of the 
NOAEL from the chronic dog study as the Point of Departure for deriving 
the chronic RfD/PAD were arbitrary and capricious, EPA denies this 
objection for the reasons contained in Units VII.A.2.a. and VII.A.2.f.

VIII. Regulatory Assessment Requirements

    As indicated previously, this action announces the Agency's final 
order regarding objections filed under section 408 of FFDCA. As such, 
this action is an adjudication and not a rule. The regulatory 
assessment requirements imposed on rulemaking do not, therefore, apply 
to this action.

IX. Submission to Congress and the Comptroller General

    The Congressional Review Act, (5 U.S.C. 801 et seq.), as added by 
the Small Business Regulatory Enforcement Fairness Act of 1996, does 
not apply because this action is not a rule for purposes of 5 U.S.C. 
804(3).

X. References

    1. NRDC, ``Objection To The Establishment Of Tolerances For 
Pesticide Chemical Residues Of Boscalid Docket Id No. EPA-HQ-OPP-2005-
0145'' (February 20, 2007).
    2. Office of Pesticide Programs, U.S. EPA, ``Available Information 
on Assessing Pesticide Exposure From Food: A User's Guide'' (June 21, 
2000).
    3. U.S. EPA, ``Residue Chemistry Test Guidelines: OPPTS 860.1500 
Crop Field Trials'' (August 1996).
    4. Office of Pesticide Programs, U.S. EPA and Pest Regulatory 
Management Agency, Health Canada, ``NAFTA Guidance Document for 
Guidance for Setting Pesticide Tolerances Based on Field Trial Data '' 
(September 28, 2005).
    5. Office of Pesticide Programs, U.S. EPA, ``Determination of the 
Appropriate FQPA Safety Factor(s) in Tolerance Assessment'' (January 
31, 2002).
    6. Office of Pesticide Programs, U.S. EPA, ``The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorous and 
Carbamate Pesticides'' (August 18, 2000).
    7. Office of Pesticide Programs, U.S. EPA, Versar Corporation, 
``Standard Operating Procedures (SOPs) for Residential Exposure 
Assessments'' (Draft, December 19, 1997).
    8. Office of Prevention, Pesticides and Toxic Substances, U. S. 
EPA, Memorandum from Yan Donovan to Dennis McNeilly/R.Keigwin, 
``PP 1F06313 --Human Health Risk Assessment for New Fungicide 
BAS 510 F (Common Name: Boscalid) -- Proposal for Tolerances for 
Residues in/on Numerous Crops and Livestock Commodities'' (September 8, 
2003).
    9. NRDC, ``Objection to the Establishment of Tolerances for 
Pesticide Chemical Residues of Boscalid'' (May 21, 2007.
    10. BASF, ``Docket ID Number EPA-HQ-OPP-2005-0145: BASF Response to 
NRDC Objection to Boscalid Pesticide Tolerances'' (May 29, 2007).
    11. Email Communication, Bryant Crowe, U.S. EPA to Khalid Akkari, 
BASF, ``Notification: Boscalid - Objections'' (July 10, 2007).
    12a. W. Kaufmann. 2003. ``Current Status of Developmental 
Neurotoxicity: An Industry Perspective.'' Toxicology Letters, 140-141; 
pages 161-169.
    12b. U. Deschl, B. Kittle et al. 2002. ``The value of historical 
control data-scientific advantages for pathologists, industry and 
agencies.'' Toxicologic Patholology, Vol. 30, number 1, pages 80-87.
    12c. J.K. Haseman. 1995. ``Data Analysis: Statistical Analysis and 
Use of Historical Control Data.'' Regulatory Toxicology and 
Pharmacology, Vol. 21, pages 52-59.
    13. Health Effects Division, Office of Pesticide Programs, US EPA, 
``Data Evaluation Record: Developmental Neurotoxicity Study - Rat; BAS 
910 F'' (Date) (EPA Reviewer: William F. Sette).
    14. U.S. EPA, ``Response to Petition to Compel the U.S. EPA to 
Repeal Its Test Guidelines for Developmental Neurotoxicity'' (January 
3, 2005) (available at ``http://docket.epa.gov/edkpub/do /

EDKStaffCollection DetailView?objectId =0b0007d480525f44)''.
    15a. H.L. Adler and E. B. Roessler 1977. ``Introduction to 
Probability and Statistics.'' 6th ed. H. Freeman. New York. 1977.
    15b. S. Gad and C.S. Weil. ``Statistics and Experimental Design for 
the Toxicologist.'' Telford Press, NJ. 1986.
    15c. M. Hollander and D.A. Wolfe. ``Non parametric Statistical 
Methods.'' John Wiely & Sons. New York. 1973.
    15d. R.R. Holson et al., 2007. ``Statistical Issues and Techniques 
Appropriate for Developmental Neurotoxicity Testing.'' Neurotoxicology 
and Teratology.
    15e. Haseman, Joseph K. 1981. ``Statistical Issues in the Design, 
Analysis and Interpretation of Animal Carcinogenicity Studies.'' In: 
Environmental Health Perspectives, Vol. 58, pp. 385-392.
    16a. U.S. Environmental Protection Agency. ``Guidelines for 
Reproductive

[[Page 5450]]

Toxicity Risk Assessment.'' Federal Register 61: 56274-56322.
    16b. U.S. Environmental Protection Agency. ``Guidelines for 
Developmental Toxicity Risk Assessment.'' Federal Register. 56: 63798-
63826.
    16c. ``An Evaluation and Interpretation of Reproductive Endpoints 
For Human Health Risk Assessment.'' International Life Science 
Institute. Health and Environmental Sciences Institute. Developmental 
and Reproductive Toxicity Committee. November 1998.
    17. Health Effects Division, Office of Pesticide Programs, US EPA, 
``Data Evaluation Record: Reproduction and Fertility Effects Study - 
Rat; BAS 910 F'' (March 23, 2002) (EPA Reviewer: Alan Levy).
    18. Office of Prevention, Pesticides and Toxic Substances, U. S. 
EPA, Memorandum from Alan Levy to Yan Donovan, ``BAS 510 F - Report of 
the Hazard Identification Assessment Review Committee'' (March 7, 
2003).
    19. Health Effects Division, Office of Pesticide Programs, US EPA, 
``Data Evaluation Record: Prenatal Developmental Toxicity Study - 
Rabbit; BAS 910 F'' (March 23, 2002) (EPA Reviewer: Alan Levy).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.


    Dated: January 17, 2008.
Debra Edwards,
Director, Office of Pesticide Programs.
[FR Doc. E8-1523 Filed 1-29-08; 8:45 am]

BILLING CODE 6560-50-S
