[Federal Register Volume 78, Number 159 (Friday, August 16, 2013)]
[Rules and Regulations]
[Pages 49932-49939]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-19863]



40 CFR Part 180

[EPA-HQ-OPP-2012-0405; FRL-9395-6]

Emamectin; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.


SUMMARY: This regulation establishes a tolerance for residues of 
emamectin benzoate in or on wine grapes. Syngenta Crop Protection, LLC, 
requested this tolerance under the Federal Food, Drug, and Cosmetic Act 
(FFDCA). This document also makes a technical correction to the 
tolerance expression in the section.

DATES: This regulation is effective August 16, 2013. Objections and 
requests for hearings must be received on or before October 15, 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-2012-0405, 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://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Lois Rossi, Registration Division, 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone 
number: (703) 305-7090; email address: RDFRNotices@epa.gov.


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://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-2012-0405 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 
October 15, 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-2012-0405, by one of 
the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the online instructions for submitting comments. Do not submit 
electronically any information you consider to be 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 

[[Page 49933]]

     Hand Delivery: To make special arrangements for hand 
delivery or delivery of boxed information, please follow the 
instructions at http://www.epa.gov/dockets/contacts.html.
    Additional instructions on commenting or visiting the docket, along 
with more information about dockets generally, is available at http://www.epa.gov/dockets.

II. Summary of Petitioned-For Tolerance

    In the Federal Register of August 22, 2012 (77 FR 50661) (FRL-9358-
9) 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 2E8018) 
by Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419. 
The petition requested that 40 CFR 180.505 be amended by establishing 
tolerances for residues of the insecticide emamectin benzoate (a 
benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'- 
deoxyavermectin B1a and a maximum of 10% 4'-epi-methylamino-
4'-deoxyavermectin B1b) resulting from the application of 
emamectin benzoate in or on imported wine at 0.005 parts per million 
(ppm). That document referenced a summary of the petition prepared by 
Syngenta Crop Protection, LLC, the registrant, which is available in 
the docket, http://www.regulations.gov. There were no comments received 
in response to the notice of filing.
    Based upon review of the data supporting the petition, EPA has 
modified the requested tolerance to emamectin, including its 
metabolites and degradates, in or on grape, wine at 0.03 ppm. The 
reason for this change is explained in Unit IV.C.
    This final rule also corrects a typographical error (one ``ZB'' 
missing) in the currently published tolerance expression for Sec.  

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-
gp). P-glycoprotein 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 lowest-observed-adverse-effect-
levels (LOAELs) (0.1 milligram/kiolgram/day (mg/kg/day) with no-
observed-adverse-effect-level (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.''

[[Page 49934]]

    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 NOAEL and 
the LOAEL from the toxicity studies can be found at http://www.regulations.gov on pp. 29-35 of the document entitled ``Emamectin 
Benzoate. Human Health Risk Assessment for a Proposed Tolerance on 
Imported Wine Grapes'' in docket ID number EPA-HQ-OPP-2012-0405.

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/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
                                        Point of departure and
          Exposure/ scenario              uncertainty/safety    RfD, PAD, LOC for  risk  Study and toxicological
                                               factors                 assessment                effects
Acute dietary (All populations)......  NOAEL = 0.075 mg/kg/day  Acute RfD = 0.00025 mg/  15-day mouse study
                                       UFA = 10x..............   kg/day aPAD = 0.00025    LOAEL = 0.1 mg/kg/day
                                       UFH = 10x..............   mg/kg/day.               based on tremors on
                                       FQPA SF = 3x...........                            day 3 of dosing. At
                                                                                          the next higher dose
                                                                                          (0.3 mg/kg/day),
                                                                                          tremors were seen at
                                                                                          day 2 of treatment.
Chronic dietary (All populations)....  NOAEL= 0.075 mg/kg/day.  Chronic RfD = 0.000075   15-day mouse study
                                       UFA = 10x..............   mg/kg/day cPAD =         LOAEL = 0.1 mg/kg/day
                                       UFH = 10x..............   0.000075 mg/kg/day.      based on moribund
                                       FQPA SF = 10x..........                            sacrifices, clinical
                                                                                          signs of
                                                                                          decreases in body
                                                                                          weight and food
                                                                                          consumption, and
                                                                                          lesions in the sciatic
FQPA SF = Food Quality Protection Act Safety Factor. LOC = level of concern. 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 cottonseed oil, tree nuts (including pistachios), and 
wine. Pesticide Data Program (PDP) monitoring data for years 2009 and 
2010 were used for apples since apple juice had a significant impact on 
exposure. The 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 
cottonseed oil, tree nuts (including pistachios), and wine. 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

[[Page 49935]]

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 maximum 
PCT for existing uses as follows: Almonds, 2.5%; apples, 20%; broccoli, 
20%; cabbage, 25%; cauliflower, 20%; celery, 40%; cotton, 2.5%; 
lettuce, 20%; pears, 20%; peppers, 15%; spinach, 10%; and tomatoes, 
    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%; and tomatoes, 10%.
    In most cases, EPA uses available data from United States 
Department of Agriculture/National Agricultural Statistics Service 
(USDA/NASS), proprietary market surveys, and the National Pesticide Use 
Database for the chemical/crop combination for the most recent 6-7 
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 one. 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%.
    Also for the acute dietary assessment, the Agency used the 
following PCT estimates for the following recently approved uses: 
Cantaloupe, 51%; cucumber, 26%; squash, 46%; and watermelon, 21%. For 
the chronic dietary assessment, the Agency used the following PCT 
estimates for the following recently approved uses: Cantaloupe, 40%; 
cucumber, 14%; squash, 29%; and watermelon, 19%.
    These PCT estimates for recently approved uses 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 3 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.

[[Page 49936]]

    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 (EPA, 1999) 
describes the weight of the evidence approach for determining whether 
or not a group of pesticides share a 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 (Abalis et al., 1986; Huang and 
Casida, 1997). 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 (2000) 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 (Soderlund et al., 1987).
    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 (CMT) 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 Food Quality 
Protection Act Safety Factor (FQPA 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 SF for chronic assessments and is using a 3X FQPA SF for 
acute assessments. This decision is based on the following findings:

[[Page 49937]]

    i. Completeness of the toxicity database. The toxicology database 
used to assess pre- 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 dog, 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 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 not impact the Agency's assessment of pre- 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 P-gp, 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 POD. 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 pre- 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:
    a. For the 2-generation reproduction study:
     There was a clear NOAEL for the offspring toxicity.
     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 
    b. For the developmental neurotoxicity study:
     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.
     The offspring LOAEL (at the mid dose) is based on a single 
effect seen on only 1 day (decreased motor activity on PND 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 pre- 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 
SF 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 point of departure 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 SF 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 SF for acute assessments from 
10X to 3X. The Agency determined that a 3X FQPA SF is adequate for 
assessing acute dietary risk based on the following weight of evidence 
     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 developmental neurotoxicity (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 
SF (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

[[Page 49938]]

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 91% of the aPAD for 
females 13-49 years old, the population group receiving the greatest 
    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 
    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. 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 
    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: 

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.
    Harmonization issues regarding the tolerance expression are 
associated with this petition. There is a Codex MRL for grapes of 0.03 
ppm. The Codex residue definition for the MRL and for the risk 
assessment is emamectin B1a benzoate. The recommended U.S. 
tolerance is 0.03 ppm to harmonize with Codex but the U.S. residue 
definition includes additional analytes.

C. Revisions to Petitioned-For Tolerances

    The difference in the proposed tolerance level of 0.005 ppm and the 
recommended tolerance level of 0.03 ppm is because EPA does not set 
tolerances on wine but rather on the raw commodity wine grapes. The 
recommended tolerance level reflects the harmonized residue values in 
the raw commodity as described in Unit IV.B.
    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.
    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 grape, wine at 0.03 
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 

VI. 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

[[Page 49939]]

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 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: August 7, 2013.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.
    Therefore, 40 CFR chapter I is amended as follows:


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

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

2. In Sec.  180.505:
a. Add alphabetically the following commodity and footnote 1 to the 
table in paragraph (a)(1).
b. Revise the introductory text of paragraph (a)(2).
    The amendments read as follows:

Sec.  180.505  Emamectin; tolerances for residues.

    (a) * * *
    (1) * * *

                                                             Parts per
                        Commodity                             million
                                * * * * *
Grape, wine \1\.........................................            0.03
                                * * * * *
\1\ There are no U.S. registrations for use of emamectin on grape, wine.

    (2) Tolerances are established for emamectin, including its 
metabolites and degradates, in or on the commodities in the following 
table. Compliance with the tolerance levels specified in the following 
table is to be determined by measuring only the sum of emamectin 
(MAB1a + MAB1b isomers) and the associated 8,9-Z 
isomers (8,9-ZB1a and 8,9-ZB1b).
* * * * *
[FR Doc. 2013-19863 Filed 8-15-13; 8:45 am]