
[Federal Register Volume 78, Number 59 (Wednesday, March 27, 2013)]
[Rules and Regulations]
[Pages 18504-18511]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-06758]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2011-0665; FRL-9381-4]


Emamectin Benzoate; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes a tolerance for residues of 
emamectin benzoate in or on the cucurbit vegetable crop group 9. 
Interregional Research Project Number 4 (IR-4) requested this tolerance 
under the Federal Food, Drug, and Cosmetic Act (FFDCA).

DATES: This regulation is effective March 27, 2013. Objections and 
requests for hearings must be received on or before May 28, 2013, and 
must be filed in accordance with the instructions provided in 40 CFR 
part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: The docket for this action, identified by docket 
identification (ID) number EPA-HQ-OPP-2011-0665, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory 
Public Docket (OPP Docket) in the Environmental Protection Agency 
Docket Center (EPA/DC), EPA West Bldg., Rm. 3334, 1301 Constitution 
Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open 
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal 
holidays. The telephone number for the Public Reading Room is (202) 
566-1744, and the telephone number for the OPP Docket is (703) 305-
5805. Please review the visitor instructions and additional information 
about the docket available at http:[sol][sol]www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Andrew Ertman, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone 
number: (703) 308-9367; email address: ertman.andrew@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. 
The following list of North American Industrial Classification System 
(NAICS) codes is not intended to be exhaustive, but rather provides a 
guide to help readers determine whether this document applies to them. 
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of EPA's 
tolerance regulations at 40 CFR part 180 through the Government 
Printing Office's e-CFR site at http:[sol][sol]www.ecfr.gov/cgi-bin/
text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an 
objection to any aspect of this regulation and may also request a 
hearing on those objections. You must file your objection or request a 
hearing on this regulation in accordance with the instructions provided 
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify 
docket ID number EPA-HQ-OPP-2011-0665 in the subject line on the first 
page of your submission. All objections and requests for a hearing must 
be in writing, and must be received by the Hearing Clerk on or before 
May 28, 2013. Addresses for mail and hand delivery of objections and 
hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing (excluding any Confidential Business Information (CBI)) for 
inclusion in the public docket. Information not marked confidential 
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without 
prior notice. Submit the non-CBI copy of your objection or hearing 
request, identified by docket ID number EPA-HQ-OPP-2011-0665, by one of 
the following methods:
     Federal eRulemaking Portal: 
http:[sol][sol]www.regulations.gov. Follow the online instructions for 
submitting comments. Do not submit electronically any information you 
consider to be Confidential Business Information (CBI) or other 
information whose disclosure is restricted by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket 
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 
20460-0001.
     Hand Delivery: To make special arrangements for hand 
delivery or delivery of boxed information, please follow the 
instructions at http:[sol][sol]www.epa.gov/dockets/contacts.htm.

Additional instructions on commenting or visiting the docket, along 
with more information about dockets generally, is available at 
http:[sol][sol]www.epa.gov/dockets.

II. Summary of Petitioned-For Tolerance

    In the Federal Register of September 7, 2011 (76 FR 55329) (FRL-
8886-7), EPA issued a document pursuant to FFDCA section 408(d)(3), 21 
U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 
1E7904) by IR-4, 500 College Rd. East, Suite 201 W, Princeton, NJ 
08540. The petition requested that 40 CFR 180.505 be amended by 
establishing tolerances for residues of the insecticide emamectin 
benzoate, 4'-epimethylamino-4'-deoxyavermectin B1 benzoate (a mixture 
of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin B1a and a 
maximum of 10% 4'-epi-methlyamino-4'deoxyavermectin B1b benzoate), and 
its metabolites 8,9 isomer of the B1a and B1b component of the parent 
insecticide, in or on vegetable, cucurbit, group 9 at 0.03 parts per 
million (ppm). That document referenced a summary of the petition 
prepared by Syngenta, the registrant, which is available in the docket, 
http:[sol][sol]www.regulations.gov. There were no comments received in 
response to the notice of filing.

[[Page 18505]]

    Based upon review of the data supporting the petition, EPA has 
modified the level at which the tolerance is being established. The 
reason for this change is explained in Unit IV.C.

III. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) of 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. 
Section 408(b)(2)(C) of FFDCA requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance and to ``ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue.* * 
* ''
    Consistent with FFDCA section 408(b)(2)(D), and the factors 
specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available 
scientific data and other relevant information in support of this 
action. EPA has sufficient data to assess the hazards of and to make a 
determination on aggregate exposure for emamectin benzoate including 
exposure resulting from the tolerances established by this action. 
EPA's assessment of exposures and risks associated with emamectin 
benzoate follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
children. Emamectin acts by binding to gamma-aminobutyric acid (GABA) 
gated chloride channels at two different sites, a high affinity binding 
site that activates the channel and a low affinity site that blocks the 
channel. GABA plays a critical role in nervous system development 
through both non-synaptic and synaptic mechanisms. Consequently, 
emamectin may have the potential to influence GABA-mediated events 
important to brain development. Within the mammalian brain, a member of 
this class of compound (abamectin) has been shown to have widespread 
binding but particularly abundant in the cerebellum. Through action on 
the enteric nervous system and induction of longitudinal rhythmic 
contractions in the isolated ileum, emamectin like abamectin may 
therefore influence GABA-mediated regulation of metabolism, food intake 
and body weight at multiple sites. Although GABA receptor mediated 
neurotoxicity is a solid hypothesis, data in mammalian preparations 
linking alterations in GABA receptor function to disruptions in 
neuronal excitability in vitro and in vivo, and ultimately adverse 
outcome are currently lacking.
    Integral to its mechanism of action in mammals, this class of 
compounds is also a substrate for (i.e., binds to) P-glycoprotein. P-
glycoprotein (P-gp) is a member of the adenosine triphosphate (ATP) 
binding cassette transporter proteins, which reside in the plasma 
membrane and function as a transmembrane efflux pump, moving 
xenobiotics from intracellular to the extracellular domain against a 
steep concentration gradient with ATP-hydrolysis providing the energy 
for active transport. P-gp is found in the canallicular surface of 
hepatocytes, the apical surface of proximal tubular cells in the 
kidneys, brush border surface of enterocytes, luminal surface of blood 
capillaries of the brain (blood brain barrier), placenta, ovaries, and 
the testes. As an efflux transporter, P-gp acts as a protective barrier 
to keep xenobiotics out of the body by excreting them into bile, urine, 
and intestinal lumen and prevents accumulation of these compounds in 
the brain and gonads, as well as the fetus. Therefore, some test 
animals, in which genetic polymorphisms compromise P-gp expression, are 
particularly susceptible to abamectin or emamectin-induced 
neurotoxicity. An example is the CF-1 mouse. Some CF-1 mice are 
deficient in P-gp and are found to be highly sensitive to the 
neurotoxicity of abamectin. A small population of humans is also found 
to be deficient of ATP binding cassette (ABC) transporter proteins due 
to polymorphism in the gene encoding ABC transporter proteins (Dubin-
Johnson Syndrome). In addition, collie dogs have been known to be 
deficient in P-gp.
    Consistent with the mode of action, the main target organ for 
emamectin is the nervous system; clinical signs (tremors, ptosis, 
ataxia, and hunched posture) and neuropathology (neuronal degeneration 
in the brain and in peripheral nerves, muscle fiber degeneration) were 
found in most of the emamectin studies in rats, dogs and mice. The 
dose/response curve was very steep in several studies (most notably 
with CF-1 mice and dogs), with severe effects (morbid sacrifice and 
neuropathology) sometimes seen at the LOAELs (0.1 milligram/kilogram/
day (mg/kg/day) with NOAEL of 0.075 mg/kg/day). Although no increased 
sensitivity was seen in developmental toxicity studies in rats and 
rabbits, increased qualitative and/or quantitative sensitivity of rat 
pups was seen in the reproductive toxicity and in the developmental 
neurotoxicity studies.
    The carcinogenicity and mutagenicity studies provide no indication 
that emamectin is carcinogenic or mutagenic. Emamectin is classified as 
``not likely to be carcinogenic to humans.''
    The available emamectin data show that there is a difference in 
species sensitivity, and the data suggest the following order: Rat 
NOAELs/LOAELs greater than dog NOAELs/LOAELs greater than mouse NOAELs/
LOAELs. The toxicity endpoints and points of departure for risk were 
selected from the results of the 15-day CF-1 mouse oral toxicity study.
    Specific information on the studies received and the nature of the 
adverse effects caused by emamectin benzoate as well as the no-
observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse-
effect-level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov on pages 43-50 of the document titled ``Emamectin 
Benzoate. Revised Human Health Risk Assessment for Proposed Uses on 
Cucurbits and Outdoor-Grown Plants in Commercial Nursery Production'' 
in docket ID number EPA-HQ-OPP-2011-0665.

B. Toxicological Points of Departure/Levels of Concern

    Once a pesticide's toxicological profile is determined, EPA 
identifies toxicological points of departure (POD) and levels of 
concern to use in evaluating the risk posed by human exposure to the 
pesticide. For hazards that have a threshold below which there is no 
appreciable risk, the toxicological POD is used as the basis for 
derivation of reference values for risk assessment. PODs are developed 
based on a careful analysis of the doses in each toxicological study to 
determine the dose at which no adverse effects are observed (the NOAEL) 
and the lowest dose at which adverse effects of concern are identified 
(the LOAEL). Uncertainty/

[[Page 18506]]

safety factors are used in conjunction with the POD to calculate a safe 
exposure level--generally referred to as a population-adjusted dose 
(PAD) or a reference dose (RfD)--and a safe margin of exposure (MOE). 
For non-threshold risks, the Agency assumes that any amount of exposure 
will lead to some degree of risk. Thus, the Agency estimates risk in 
terms of the probability of an occurrence of the adverse effect 
expected in a lifetime. For more information on the general principles 
EPA uses in risk characterization and a complete description of the 
risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
    A summary of the toxicological endpoints for emamectin benzoate 
used for human risk assessment is shown in Table 1 of this unit.

    Table 1--Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for Use in Human Health Risk
                                                   Assessment
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                                    Point of departure    RfD, PAD, LOC for
        Exposure/scenario            and uncertainty/    risk assessment (mg/   Study and toxicological effects
                                      safety factors           kg/day)
----------------------------------------------------------------------------------------------------------------
Acute dietary (All Populations)..  NOAEL = 0.075 mg/kg/  aRfD = 0.00025.....  15-day mouse. LOAEL = 0.1 mg/kg/
                                    day.                 aPAD = 0.00025.....   day based on tremors on day 3 of
                                   UFA = 10x...........                        dosing. At the next higher dose
                                   UFH = 10x...........                        (0.3 mg/kg/day), tremors were
                                   FQPA SF = 3x........                        seen at day 2 of treatment.
Chronic dietary (All populations)  NOAEL= 0.075 mg/kg/   cRfD = 0.000075....  15-day mouse. LOAEL = 0.1 mg/kg/
                                    day.                 cPAD = 0.000075....   day based on moribund sacrifices,
                                   UFA = 10x...........                        clinical signs of neurotoxicity,
                                   UFH = 10x...........                        decreases in body weight and food
                                   FQPA SF = 10x.......                        consumption and histopathological
                                                                               lesions in the sciatic nerve.
----------------------------------------------------------------------------------------------------------------
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. mg/kg/day =
  milligram/kilogram/day. NOAEL = no-observed-adverse-effect-level. PAD = population adjusted dose (a = acute, c
  = chronic). RfD = reference dose. UF = uncertainty factor. UFA = extrapolation from animal to human
  (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies).

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to emamectin benzoate, EPA considered exposure under the 
petitioned-for tolerances as well as all existing emamectin benzoate 
tolerances in 40 CFR 180.505. EPA assessed dietary exposures from 
emamectin benzoate in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk 
assessments are performed for a food-use pesticide, if a toxicological 
study has indicated the possibility of an effect of concern occurring 
as a result of a 1-day or single exposure.
    Such effects were identified for emamectin benzoate. In estimating 
acute dietary exposure, EPA used food consumption information from the 
U.S. Department of Agriculture (USDA) 2003-2008 National Health and 
Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). As 
to residue levels in food, a probabilistic acute dietary exposure 
assessment was conducted. The anticipated residue estimates, used for 
most crops, were based on field trial data. Tolerance-level residues 
were used for tree nuts (including pistachios) and cottonseed oil. 
Pesticide Data Program (PDP) monitoring data for years 2009 and 2010 
were used for apples since apple juice had a significant impact on 
exposure. Dietary Exposure Evaluation Model (DEEM) default processing 
factors were used except for commodities with chemical-specific 
processing studies. Percent crop treated (PCT) data were used.
    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment EPA used the food consumption data from the USDA 2003-2008 
NHANES/WWEIA. As to residue levels in food, a somewhat refined chronic 
dietary exposure assessment was conducted. The anticipated residue 
estimates, used for most crops, were single point estimates (averages) 
based on field trial data. Tolerance-level residues were used for tree 
nuts (including pistachios) and cottonseed oil. DEEM default processing 
factors were used except for commodities with chemical-specific 
processing studies. PCT data were used.
    iii. Cancer. Based on the data summarized in Unit III.A., EPA has 
concluded that emamectin benzoate does not pose a cancer risk to 
humans. Therefore, a dietary exposure assessment for the purpose of 
assessing cancer risk is unnecessary.
    iv. Anticipated residue and PCT information. Section 408(b)(2)(E) 
of FFDCA authorizes EPA to use available data and information on the 
anticipated residue levels of pesticide residues in food and the actual 
levels of pesticide residues that have been measured in food. If EPA 
relies on such information, EPA must require pursuant to FFDCA section 
408(f)(1) that data be provided 5 years after the tolerance is 
established, modified, or left in effect, demonstrating that the levels 
in food are not above the levels anticipated. For the present action, 
EPA will issue such data call-ins as are required by FFDCA section 
408(b)(2)(E) and authorized under FFDCA section 408(f)(1). Data will be 
required to be submitted no later than 5 years from the date of 
issuance of these tolerances.
    Section 408(b)(2)(F) of FFDCA states that the Agency may use data 
on the actual percent of food treated for assessing chronic dietary 
risk only if:
     Condition a: The data used are reliable and provide a 
valid basis to show what percentage of the food derived from such crop 
is likely to contain the pesticide residue.
     Condition b: The exposure estimate does not underestimate 
exposure for any significant subpopulation group.
     Condition c: Data are available on pesticide use and food 
consumption in a particular area, the exposure estimate does not 
understate exposure for the population in such area.
    In addition, the Agency must provide for periodic evaluation of any 
estimates used. To provide for the periodic evaluation of the estimate 
of PCT as required by FFDCA section 408(b)(2)(F), EPA may require 
registrants to submit data on PCT.
    For the acute dietary assessment, the Agency estimated the PCT for 
existing uses as follows:
    Almonds, 2.5%; apples, 20%; broccoli, 20%; cabbage, 25%;

[[Page 18507]]

cauliflower, 20%; celery, 40%; cotton, 2.5%; lettuce, 20%; pears, 20%; 
peppers, 15%; spinach, 10%; tomatoes, 20%.
    For the chronic dietary assessment, the Agency estimated the PCT 
for existing uses as follows:
    Almonds, 1%; apples, 10%; broccoli, 5%; cabbage, 10%; cauliflower, 
10%; celery, 25%; cotton, 1%; lettuce, 10%; pears, 5%; peppers, 5%; 
spinach, 5%; tomatoes, 10%.
    In most cases, EPA uses available data from USDA/National 
Agricultural Statistics Service (NASS), proprietary market surveys, and 
the National Pesticide Use Database for the chemical/crop combination 
for the most recent 6 to 7 years. EPA uses an average PCT for chronic 
dietary risk analysis. The average PCT figure for each existing use is 
derived by combining available public and private market survey data 
for that use, averaging across all observations, and rounding to the 
nearest 5%, except for those situations in which the average PCT is 
less than 1. In those cases, 1% is used as the average PCT and 2.5% is 
used as the maximum PCT. EPA uses a maximum PCT for acute dietary risk 
analysis. The maximum PCT figure is the highest observed maximum value 
reported within the recent 6 years of available public and private 
market survey data for the existing use and rounded up to the nearest 
multiple of 5%.
    For the acute dietary assessment, the Agency estimated the PCT for 
new uses as follows:
    Cantaloupe, 51%; cucumber, 26%; squash, 46%; watermelon, 21%.
    For the chronic dietary assessment, the Agency estimated the PCT 
for new uses as follows:
    Cantaloupe, 40%; cucumber, 14%; squash, 29%; watermelon, 19%.
    EPA estimates of the PCT for new uses of emamectin benzoate 
represent the upper bound of the use expected during the pesticide's 
initial 5 years of registration; that is, PCT for new uses of emamectin 
benzoate is a threshold of use that EPA is reasonably certain will not 
be exceeded for each registered use site. The PCT recommended for use 
in the chronic dietary assessment for new uses is calculated as the 
average PCT of the market leader or leaders, (i.e., the pesticide(s) 
with the greatest PCT) on that site over the three most recent years of 
available data. The PCT recommended for use in the acute dietary 
assessment for new uses is the maximum observed PCT over the same 
period. Comparisons are only made among pesticides of the same 
pesticide types (e.g., the market leader for insecticides on the use 
site is selected for comparison with a new insecticide). The market 
leader included in the estimation may not be the same for each year 
since different pesticides may dominate at different times.
    Typically, EPA uses USDA/NASS as the source data because it is 
publicly available and directly reports values for PCT. When a specific 
use site is not reported by USDA/NASS, EPA uses proprietary data and 
calculates the PCT given reported data on acres treated and acres 
grown. If no data are available, EPA may extrapolate PCT for new uses 
from other crops, if the production area and pest spectrum are 
substantially similar.
    A retrospective analysis to validate this approach shows few cases 
where the PCT for the market leaders were exceeded. Further review of 
these cases identified factors contributing to the exceptionally high 
use of a new pesticide. To evaluate whether the PCT for new uses for 
emamectin benzoate could be exceeded, EPA considered whether there may 
be unusually high pest pressure, as indicated in emergency exemption 
requests for emamectin benzoate; the pest spectrum of the new pesticide 
in comparison with the market leaders and whether the market leaders 
are well established for that use; and whether pest resistance issues 
with past market leaders provide emamectin benzoate with significant 
market potential. Given currently available information, EPA concludes 
that it is unlikely that actual PCT for emamectin benzoate will exceed 
the estimated PCT for new uses during the next 5 years.
    The Agency believes that the three conditions discussed in Unit 
III.C.1.iv. have been met. With respect to Condition a, PCT estimates 
are derived from Federal and private market survey data, which are 
reliable and have a valid basis. The Agency is reasonably certain that 
the percentage of the food treated is not likely to be an 
underestimation. As to Conditions b and c, regional consumption 
information and consumption information for significant subpopulations 
is taken into account through EPA's computer-based model for evaluating 
the exposure of significant subpopulations including several regional 
groups. Use of this consumption information in EPA's risk assessment 
process ensures that EPA's exposure estimate does not understate 
exposure for any significant subpopulation group and allows the Agency 
to be reasonably certain that no regional population is exposed to 
residue levels higher than those estimated by the Agency. Other than 
the data available through national food consumption surveys, EPA does 
not have available reliable information on the regional consumption of 
food to which emamectin benzoate may be applied in a particular area.
    2. Dietary exposure from drinking water. The Agency used screening 
level water exposure models in the dietary exposure analysis and risk 
assessment for emamectin benzoate in drinking water. These simulation 
models take into account data on the physical, chemical, and fate/
transport characteristics of emamectin benzoate. Further information 
regarding EPA drinking water models used in pesticide exposure 
assessment can be found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the Pesticide Root Zone Model/Exposure Analysis Modeling 
System (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-
GROW) models, the estimated drinking water concentrations (EDWCs) of 
emamectin benzoate for acute exposures are estimated to be between 0 
and 0.465 parts per billion (ppb) for surface water and 0.00054 ppb for 
ground water, and for chronic exposures are estimated to be 0.150 ppb 
for surface water and 0.00054 ppb for ground water.
    Modeled estimates of drinking water concentrations were directly 
entered into the dietary exposure model. For acute dietary risk 
assessment, a drinking water residue distribution based on the PRZM/
EXAMS modeling was used. For chronic dietary risk assessment, the water 
concentration value of 0.150 ppb was used to assess the contribution to 
drinking water.
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., for lawn and garden pest control, indoor pest control, 
termiticides, and flea and tick control on pets).
    Emamectin benzoate is not registered for any specific use patterns 
that would result in residential exposure.
    4. Cumulative effects from substances with a common mechanism of 
toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when 
considering whether to establish, modify, or revoke a tolerance, the 
Agency consider ``available information'' concerning the cumulative 
effects of a particular pesticide's residues and ``other substances 
that have a common mechanism of toxicity.''
    OPP's ``Guidance For Identifying Pesticide Chemicals and Other 
Substances that have a Common Mechanism of Toxicity'' (Ref. 1) 
describes the weight of the evidence approach for determining whether 
or not a group of pesticides share a

[[Page 18508]]

common mechanism of toxicity. This guidance defines mechanism of 
toxicity as the major steps leading to a toxic effect following 
interaction of a pesticide with biological targets. All steps leading 
to an effect do not need to be specifically understood. Rather, it is 
the identification of the crucial events following chemical interaction 
that are required in order to describe a mechanism of toxicity. For 
example, a mechanism of toxicity may be described by knowing the 
following: A chemical binds to a given biological target in vitro, and 
causes the receptor-related molecular response; in vivo it also leads 
to the molecular response and causes a number of intervening biological 
and morphological steps that result in an adverse effect. In this 
context a common mechanism of toxicity pertains to two or more 
pesticide chemicals or other substances that cause a common toxic 
effect to human health by the same, or essentially the same, sequence 
of major biochemical events. Hence, the underlying basis of the 
toxicity is the same, or essentially the same, for each chemical. In 
the case of the macrocyclic lactone pesticides (e.g., abamectin, 
emamectin, and avermectin), there is a wealth of data on the 
insecticidal mechanism of action for avermectin: Its insecticidal 
actions are mediated by interaction with the glutamate-gated chloride 
channels and GABAA gated chloride channels. This is presumed 
to be the insecticidal mechanism of action of emamectin and abamectin 
as well. Insecticidal mechanism of action does not indicate a common 
mechanism of toxicity for human health. Further, mammals lack 
glutamate-gated chloride channels; the toxic actions of avermectin 
appear to be mediated via interaction with GABAA and 
possibly glycine gated chloride channels. There is evidence that 
avermectin B1a binds to GABAA receptors and 
activates Cl\-\ flux into neurons (Refs. 2 and 3). However, there is a 
paucity of data regarding the resultant alterations in cellular 
excitability of mammalian neurons and neural networks (i.e., changes in 
cellular excitability and altered network function as documented with 
pyrethroids), as well as in vivo measurements of altered excitability 
associated with adverse outcomes. Thus, while the downstream steps 
leading to toxicity via disruption of GABAA receptor 
function for avermectin can be postulated, experimental data supporting 
these actions are lacking. In addition, specific data demonstrating 
GABAA receptor interaction in mammalian preparations are 
lacking for abamectin and emamectin. Moreover, the specificity of such 
interaction on the adverse outcome would need to be shown 
experimentally. GABAA receptors have multiple binding sites 
which have been proposed to relate to adverse outcomes. For example, 
Dawson et al. (Ref. 4) showed for a group of avermectin-like compounds 
that rank order for anticonvulsant activity did not parallel the rank 
order for affinity at the [3H]ivermectin site. The authors hypothesized 
that these findings may be related to differential affinity or efficacy 
at subtypes of the GABAA receptor. Other reports have 
indicated species differences in abamectin effects on GABAA 
receptor function in the mouse as compared to the rat (Ref. 5).
    In conclusion, although GABAA receptor mediated 
neurotoxicity may be a common mechanism endpoint for the macrocyclic 
lactone pesticides, data demonstrating the interactions of emamectin 
and abamectin with mammalian GABAA receptors are not 
available, and data in mammalian preparations linking alterations in 
GABAA receptor function to disruptions in neuronal 
excitability in vitro and in vivo, and ultimately adverse outcome, are 
also currently lacking for this class of compounds. In the absence of 
such data, the key biological steps leading to the adverse outcome 
(i.e., the mammalian mechanism of action) cannot be established and by 
extension a common mechanism of toxicity cannot be established.
    For information regarding EPA's efforts to determine which 
chemicals have a common mechanism of toxicity and to evaluate the 
cumulative effects of such chemicals, see EPA's Web site at http://www.epa.gov/pesticides/cumulative.

D. Safety Factor for Infants and Children

    1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA 
shall apply an additional tenfold (10X) 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 database on toxicity 
and exposure unless EPA determines based on reliable data that a 
different margin of safety will be safe for infants and children. This 
additional margin of safety is commonly referred to as the FQPA Safety 
Factor (SF). In applying this provision, EPA either retains the default 
value of 10X, or uses a different additional safety factor when 
reliable data available to EPA support the choice of a different 
factor.
    2. Prenatal and postnatal sensitivity. Although no increased 
sensitivity was seen in developmental toxicity studies in rats and 
rabbits, increased qualitative and/or quantitative sensitivity of rat 
pups was seen in the reproductive toxicity study and in the 
developmental neurotoxicity study. In the reproduction study, whole 
body tremors, hind limb extension, and hind limb splay were seen in the 
F1 and F2 pups while these clinical signs were 
not seen in F0 parental animals at similar dose levels. In 
addition, a greater incidence of decreased fertility was seen in the 
F1 parental females than in the F0 females. In 
the developmental neurotoxicity study, no maternal effect was seen at 
the highest dose tested whereas dose-related decrease in open-field 
motor activity was seen in the mid-dose in pups on postnatal day 17. 
Body tremors, hind-limb extension, and auditory startle were also found 
in the high dose pups.
    3. Conclusion. Based on currently available data, EPA is retaining 
the 10X FQPA safety factor for chronic assessments and is using a 3X 
FQPA safety factor for acute assessments. This decision is based on the 
following findings:
    i. Completeness of the toxicity database. The toxicology database 
used to assess prenatal and postnatal exposure to emamectin contains 
all required studies with exception of an immunotoxicity study and a 
subchronic inhalation toxicity study, which are data gaps.
    The Agency evaluated subchronic, chronic, carcinogenicity, 
developmental and reproduction studies as well as acute and subchronic 
neurotoxicity studies for any effects that might indicate that 
emamectin induced changes in the organs generally associated with 
immunological toxicity. In the studies evaluated, only the 14-week oral 
toxicity study in dogs showed an increase in the incidence of thymus 
atrophy at 1 mg/kg/day. In the 1-year feeding study in dogs, thymus 
atrophy was not reported at similar dose levels tested. Currently, the 
point of departure for risk assessment is 0.075 mg/kg/day, which is 
more than 10 times less than the dose where thymus atrophy had been 
reported. Therefore, since the acute and chronic RfD's are 0.00025 mg/
kg/day and 0.000075 mg/kg/day, respectively, the Agency does not 
believe an immunotoxicity study will result in a lower point of 
departure (POD) than that which is currently in use for overall risk 
assessment. As such, a database uncertainty factor is not necessary to 
account for the lack of an immunotoxicity study.
    In regards to the inhalation toxicity study, there are currently no 
residential uses registered for emamectin benzoate, and therefore, lack 
of this study does

[[Page 18509]]

not impact the Agency's assessment of prenatal and postnatal exposure.
    Another completeness issue with regard to the toxicity database is 
that EPA is using a short-term study for long-term risk assessment. The 
data submitted show that CF-1 mice, which lack glycoprotein, are the 
most sensitive species/strand of animal tested. EPA only has data on 
CF-1 mice in short-term studies. Longer-term studies used CD-1 mice. 
Hence a short-term study in CF-1 mice was used to choose the chronic 
Point of Departure. The extrapolation from a short-term study in CF-1 
mice to a long-term POD introduces additional uncertainty into the risk 
assessment process.
    ii. Potential prenatal and postnatal toxicity. Although no 
increased sensitivity was seen in developmental toxicity studies in 
rats and rabbits, increased qualitative and/or quantitative sensitivity 
of rat pups was seen in the reproductive toxicity study and in the 
developmental neurotoxicity study. A degree-of-concern analysis was 
conducted to determine whether or not an additional safety factor is 
needed to account for the increased susceptibility in pups; it was 
concluded that the degree-of-concern was low for both 2-generation 
reproduction and developmental neurotoxicity studies. The reasons are 
as follows:
    For the 2-generation reproduction study, (1) there was a clear 
NOAEL for the offspring toxicity, and (2) the decreased fertility seen 
in F1 adults might have been due to histopathological 
lesions in the brain and central nervous system (seen in both 
F0 and F1 generations), rather than due to a 
direct effect on the reproductive system.
    For the developmental neurotoxicity study, (1) although multiple 
offspring effects (including decreased pup body weight, head and body 
tremors, hindlimb extension and splay, changes in motor activity and 
auditory startle) were seen at the highest dose, and no maternal 
effects were seen at any dose, there was a clear NOAEL for offspring 
toxicity at the low dose, and (2) the offspring LOAEL (at the mid dose) 
is based on a single effect seen on only one day (decreased motor 
activity on postnatal day 17) and no other offspring toxicity was seen 
at the LOAEL.
    Two other considerations raise residual concerns about whether the 
traditional safety factors are protective of potential prenatal and 
postnatal toxicity. First, the steepness of the dose-response curve 
means that there is a small margin of error provided by reliance on the 
study NOAEL. Second, the severity of effects at the LOAEL (death and 
neuropathology), exacerbate the concern raised by the steep dose 
response curve.
    iii. The completeness of the exposure database. The assessment for 
food incorporates somewhat refined anticipated residue estimates for 
most commodities that were derived from field trial data and PCT. The 
availability and use of monitoring data and food preparation-reduction 
factors for washing, cooking, etc. may have resulted in a more refined 
estimate of dietary exposure. Therefore, exposures to residues in food 
are not expected to be exceeded.
    The dietary drinking water assessment utilizes water concentration 
values generated by model and associated modeling parameters which are 
designed to provide conservative, health protective, high-end estimates 
of water concentrations which will not likely be exceeded.
    Taking all of these findings into account, EPA has concluded that 
there are not reliable data supporting lowering of the default 10X FQPA 
safety factor for chronic exposures. Specifically, EPA does not have 
reliable data showing that infants and children will be adequately 
protected using the traditional inter- and intra-species safety factors 
due to the steepness of the dose-response curve, the severity of 
effects at the LOAEL (death and neuropathology), and the use of a 
short-term study for long-term risk assessment. The Agency did not use 
a chronic study for the POD because the chronic studies were conducted 
in rats, dogs, and CD-1 mice.
    Taking all of these findings into account, for acute exposures, EPA 
has concluded that there are reliable data supporting lowering the 
default 10X FQPA safety factor to 3X. Although the steepness of the 
dose-response curve and the severity of the effects at the LOAEL 
introduce uncertainty with regard to whether the inter- and intra-
species safety factors are protective of infants and children from 
acute effects, EPA has concluded that use of the 15-day neurotoxicity 
CF-1 mouse study provides reliable data to reduce the FQPA safety 
factor for acute assessments from 10X to 3X. The Agency determined that 
a 3X FQPA Safety Factor is adequate for assessing acute dietary risk 
based on the following weight of evidence considerations:
     An endpoint of concern attributable to a single exposure 
was not identified for in utero effects since there was no concern for 
developmental toxicity and there was no indication of increased 
susceptibility (qualitative or quantitative) of rat or rabbit fetuses 
to in utero exposure to emamectin;
     Although there was evidence of increased susceptibility in 
the DNT study, an endpoint of concern was not identified for acute 
dietary risk assessment for prenatal exposures because the adverse 
effect at the LOAEL (i.e., decrease in open field motor activity) was 
seen only on postnatal day 17 and not seen after a single exposure;
     The POD selected for acute dietary risk assessment is a 
NOAEL (with a clear LOAEL) seen after repeated dosing but is used for 
assessing acute risk (i.e., a very conservative approach).
    Therefore, the Agency is confident that the retention of a 3X FQPA 
Safety Factor (to account for the steepness of the dose response curve) 
will not underestimate risk and provides reasonable certainty of no 
harm from exposure to emamectin benzoate.

E. Aggregate Risks and Determination of Safety

    EPA determines whether acute and chronic dietary pesticide 
exposures are safe by comparing aggregate exposure estimates to the 
acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer risks, EPA 
calculates the lifetime probability of acquiring cancer given the 
estimated aggregate exposure. Short-, intermediate-, and chronic-term 
risks are evaluated by comparing the estimated aggregate food, water, 
and residential exposure to the appropriate PODs to ensure that an 
adequate MOE exists.
    1. Acute risk. Using the exposure assumptions discussed in this 
unit for acute exposure, the acute dietary exposure from food and 
drinking water to emamectin benzoate will occupy 60% of the aPAD for 
children 1-2 years old, the population group receiving the greatest 
exposure.
    2. Chronic risk. Using the exposure assumptions described in this 
unit for chronic exposure, EPA has concluded that chronic exposure to 
emamectin benzoate from food and water will utilize 16% of the cPAD for 
all infants less than 1 year old, the population group receiving the 
greatest exposure. There are no residential uses for emamectin 
benzoate.
    3. Short-term risk. Short- and intermediate-term aggregate exposure 
takes into account short- and intermediate-term residential exposure 
plus chronic exposure to food and water (considered to be a background 
exposure level).
    Both short- and intermediate-term adverse effects were identified; 
however, emamectin benzoate is not registered for any use patterns that 
would result in either short- or intermediate-term residential 
exposure.

[[Page 18510]]

Short- and intermediate-term risk is assessed based on short- and 
intermediate-term residential exposure plus chronic dietary exposure. 
Because there is no short- or intermediate-term residential exposure 
and chronic dietary exposure has already been assessed under the 
appropriately protective cPAD (which is at least as protective as the 
POD used to assess short- or intermediate-term risk), no further 
assessment of short- or intermediate-term risk is necessary, and EPA 
relies on the chronic dietary risk assessment for evaluating short- and 
intermediate-term risk for emamectin benzoate.
    4. Aggregate cancer risk for U.S. population. Based on the lack of 
evidence of carcinogenicity in two adequate rodent carcinogenicity 
studies, emamectin benzoate is not expected to pose a cancer risk to 
humans.
    5. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
to the general population or to infants and children from aggregate 
exposure to emamectin benzoate residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

    Adequate enforcement methodology (high performance liquid 
chromatography with fluorescence detection (HPLC/FLD)) is available to 
enforce the tolerance expression.
    The method may be requested from: Chief, Analytical Chemistry 
Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 
20755-5350; telephone number: (410) 305-2905; email address: 
residuemethods@epa.gov.

B. International Residue Limits

    In making its tolerance decisions, EPA seeks to harmonize U.S. 
tolerances with international standards whenever possible, consistent 
with U.S. food safety standards and agricultural practices. EPA 
considers the international maximum residue limits (MRLs) established 
by the Codex Alimentarius Commission (Codex), as required by FFDCA 
section 408(b)(4). The Codex Alimentarius is a joint United Nations 
Food and Agriculture Organization/World Health Organization food 
standards program, and it is recognized as an international food safety 
standards-setting organization in trade agreements to which the United 
States is a party. EPA may establish a tolerance that is different from 
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain 
the reasons for departing from the Codex level.
    The Codex has not established a MRL for emamectin benzoate on 
cucurbits.

C. Revisions to Petitioned-For Tolerances

    Based on the review of the residue data submitted with the 
petition, the proposed tolerance level of 0.03 ppm is being modified to 
0.02 ppm.
    Also, EPA has revised the tolerance expression to clarify (1) that, 
as provided in FFDCA section 408(a)(3), the tolerance covers 
metabolites and degradates of emamectin benzoate not specifically 
mentioned; and (2) that compliance with the specified tolerance levels 
is to be determined by measuring only the specific compounds mentioned 
in the tolerance expression.

V. Conclusion

    Therefore, a tolerance is established for residues of emamectin, 
including its metabolites and degradates, in or on the cucurbit 
vegetable group 9 at 0.02 ppm. Compliance with the tolerance levels 
specified is to be determined by measuring only the sum of emamectin (a 
mixture of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin 
B1a and maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin 
B1b) and its metabolites 8,9-isomer of the B1a 
and B1b component of the parent (8,9-ZMA), or 4'-deoxy-4'-
epi-amino-avermectin B1a and 4'-deoxy-4'-epi-amino-
avermectin B1b; 4'-deoxy-4'-epi-amino avermectin 
B1a (AB1a); 4'-deoxy-4'-epi-(N-formyl-N-
methyl)amino-avermectin (MFB1a); and 4'-deoxy-4'-epi-(N-
formyl)amino-avermectin B1a (FAB1a), calculated 
as the stoichiometric equivalent of emamectin.

VI. References

    The following literature was referenced in the preamble of this 
document.

1. OPP's ``Guidance for Identifying Pesticide Chemicals and Other 
Substances that have a Common Mechanism of Toxicity'' (USEPA, 1999); 
http://www.epa.gov/fedrgstr/EPA-PEST/1999/February/Day-05/6055.pdf.
2. balis IM, Eldefrawi AT, Eldefrawi ME. Actions of avermectin 
B1a on the gamma-aminobutyric acidA receptor and chloride 
channels in rat brain. Journal of Biochemical Toxicology. 1986 
Mar;1(1):69-82.
3. Huang J, Casida JE. (1997) Avermectin B1a binds to 
high- and low-affinity sites with dual effects on the gama-
aminobutyric acid-gated chloride channel of cultured cerebellar 
granule neurons. Journal of Pharmacology and Experimental 
Therapeutics. 281: 261-266.
4. Dawson GR, Wafford KA, Smith A, Marshall GR, Bayley PJ, Schaeffer 
JM, Meinke PT, McKernan RM. (2000) Anticonvulsant and adverse 
effects of avermectin analogs in mice are mediated through the gama-
aminobutyric acid (A) receptor. Journal of Pharmacology and 
Experimental Therapeutics 295: 1051-1060.
5. Soderlund DM, Adams PM, Bloomquist JR. Differences in the action 
of avermectin B1a on the GABAA receptor 
complex of mouse and rat. Biochemical Biophysical Research 
Communications. 1987 Jul 31;146(2):692-8.

VII. Statutory and Executive Order Reviews

    This final rule establishes tolerances under FFDCA section 408(d) 
in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled ``Regulatory Planning and 
Review'' (58 FR 51735, October 4, 1993). Because this final rule has 
been exempted from review under Executive Order 12866, this final rule 
is not subject to Executive Order 13211, entitled ``Actions Concerning 
Regulations That Significantly Affect Energy Supply, Distribution, or 
Use'' (66 FR 28355, May 22, 2001) or Executive Order 13045, entitled 
``Protection of Children from Environmental Health Risks and Safety 
Risks'' (62 FR 19885, April 23, 1997). This final rule does not contain 
any information collections subject to OMB approval under the Paperwork 
Reduction Act (PRA) (44 U.S.C. 3501 et seq.), nor does it require any 
special considerations under Executive Order 12898, entitled ``Federal 
Actions to Address Environmental Justice in Minority Populations and 
Low-Income Populations'' (59 FR 7629, February 16, 1994).
    Since tolerances and exemptions that are established on the basis 
of a petition under FFDCA section 408(d), such as the tolerance in this 
final rule, do not require the issuance of a proposed rule, the 
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et 
seq.), do not apply.
    This final rule directly regulates growers, food processors, food 
handlers, and food retailers, not States or tribes, nor does this 
action alter the relationships or distribution of power and 
responsibilities established by Congress in the preemption provisions 
of FFDCA section 408(n)(4). As such, the Agency has determined that 
this action will not have a substantial direct effect on States or 
tribal governments, on the relationship between the national government 
and the States or tribal governments, or on the distribution of power 
and responsibilities among the

[[Page 18511]]

various levels of government or between the Federal Government and 
Indian tribes. Thus, the Agency has determined that Executive Order 
13132, entitled ``Federalism'' (64 FR 43255, August 10, 1999) and 
Executive Order 13175, entitled ``Consultation and Coordination with 
Indian Tribal Governments'' (65 FR 67249, November 9, 2000) do not 
apply to this final rule. In addition, this final rule does not impose 
any enforceable duty or contain any unfunded mandate as described under 
Title II of the Unfunded Mandates Reform Act of 1995 (UMRA) (2 U.S.C. 
1501 et seq.).
    This action does not involve any technical standards that would 
require Agency consideration of voluntary consensus standards pursuant 
to section 12(d) of the National Technology Transfer and Advancement 
Act of 1995 (NTTAA) (15 U.S.C. 272 note).

VII. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.), 
EPA will submit a report containing this rule and other required 
information to the U.S. Senate, the U.S. House of Representatives, and 
the Comptroller General of the United States prior to publication of 
the rule in the Federal Register. This action is not a ``major rule'' 
as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

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

    Dated: March 19, 2013.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

    Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

0
1. The authority citation for part 180 continues to read as follows:

    Authority: 21 U.S.C. 321(q), 346a and 371.


0
2. Sec.  180.505, is amended by:
0
i. Revise paragraph (a)(1) introductory text and paragraph (a)(2) 
introductory text;
0
ii. Add alphabetically an entry for ``Vegetable, cucurbit, group 9'' to 
the table in paragraph (a)(1).
    The added and revised text read as follows:


Sec.  180.505  Emamectin; tolerances for residues.

    (a) General. (1) Tolerances are established for emamectin, 
including its metabolites and degradates, in or on the commodities in 
the table below. Compliance with the tolerance levels specified below 
is to be determined by measuring only the sum of emamectin (a mixture 
of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin 
B1a and maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin 
B1b) and its metabolites 8,9-isomer of the B1a 
and B1b component of the parent (8,9-ZMA), or 4'-deoxy-4'-
epi-amino-avermectin B1a and 4'-deoxy-4'-epi-amino-
avermectin B1b; 4'-deoxy-4'-epi-amino avermectin 
B1a (AB1a); 4'-deoxy-4'-epi-(N-formyl-N-
methyl)amino-avermectin (MFB1a); and 4'-deoxy-4'-epi-(N-
formyl)amino-avermectin B1a (FAB1a), calculated 
as the stoichiometric equivalent of emamectin.

------------------------------------------------------------------------
                                                            Parts per
                       Commodity                             million
------------------------------------------------------------------------
 
                                * * * * *
Vegetable, cucurbit, group 9...........................            0.02
 
                                * * * * *
------------------------------------------------------------------------

     (2) Tolerances are established for emamectin, including its 
metabolites and degradates, in or on the commodities in the table 
below. Compliance with the tolerance levels specified below is to be 
determined by measuring only the sum of emamectin (MAB1a + 
MAB1b isomers) and the associated 8,9-Z isomers (8,9-
1a and 8,9-ZB1b).
* * * * *
[FR Doc. 2013-06758 Filed 3-26-13; 8:45 am]
BILLING CODE 6560-50-P


