[Federal Register Volume 78, Number 159 (Friday, August 16, 2013)]
[Rules and Regulations]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-19863]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
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
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
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.''
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
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
decreases in body
weight and food
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
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
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
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
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
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:
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
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
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
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
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
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
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
2. That compliance with the specified tolerance levels is to be
determined by measuring only the specific compounds mentioned in the
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'-
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
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
Dated: August 7, 2013.
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) * * *
* * * * *
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]
BILLING CODE 6560-50-P