[Federal Register Volume 81, Number 155 (Thursday, August 11, 2016)]
[Rules and Regulations]
[Pages 53019-53025]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19118]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[EPA-HQ-OPP-2012-0919; FRL-9946-30]
Halauxifen-methyl; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of
halauxifen-methyl and its metabolite, XDE-729 acid, in or on multiple
commodities which are identified and discussed later in this document.
Dow AgroSciences LLC requested these tolerances under the Federal Food,
Drug, and Cosmetic Act (FFDCA).
DATES: This regulation is effective August 11, 2016. Objections and
requests for hearings must be received on or before October 11, 2016,
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-2012-0919, 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), West William Jefferson Clinton 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: Susan Lewis, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; main telephone
number: (703) 305-7090; email address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this action apply to me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
B. How can I get electronic access to other related information?
You may access a frequently updated electronic version of EPA's
tolerance regulations at 40 CFR part 180 through the Government
Printing Office's e-CFR site at http://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-2012-0919 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 11, 2016. 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-2012-0919, 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
20460-0001.
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 February 15, 2013 (78 FR 11126) (FRL-
9378-4), 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
2F8086) by Dow AgroSciences, 9330 Zionsville Road, Indianapolis, IN
46268. The petition requested that 40 CFR part 180 be amended by
establishing tolerances for residues of the herbicide, halauxifen-
methyl (methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-
methoxyphenyl)pyridine-2-carboxylate) and its major metabolite, XDE-729
acid, expressed as halauxifen-methyl (parent) equivalents, in or on
barley, grain at 0.01 parts per million (ppm); barley, hay at 0.01 ppm;
barley, straw at 0.01 ppm; cattle, fat at 0.01 ppm; cattle, meat at
0.01 ppm; cattle, meat byproducts at 0.01 ppm; goat, fat at 0.01 ppm;
goat, meat at 0.01 ppm; goat, meat byproducts at 0.01 ppm; horse, fat
at 0.01 ppm; horse, meat at 0.01 ppm; horse, meat byproducts at 0.01
ppm; milk at 0.01 ppm; sheep, fat at 0.01 ppm; sheep, meat at 0.01 ppm;
sheep, meat byproducts at 0.01 ppm; wheat, forage at 0.5 ppm; wheat,
grain at 0.01 ppm; wheat, hay at 0.04 ppm; and wheat, straw at 0.015
ppm. That document referenced a summary of the petition
[[Page 53020]]
prepared by Dow AgroSciences 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
determined that livestock commodity tolerances are not required for the
proposed uses. In addition, the proposed ``wheat, hay'' tolerance level
of 0.04 ppm will be set at a reduced tolerance level of 0.03 ppm. The
reason for these changes are explained in Unit IV.C.
III. Aggregate Risk Assessment and Determination of Safety
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a
reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information.'' This includes exposure through drinking water and in
residential settings, but does not include occupational exposure.
Section 408(b)(2)(C) of FFDCA requires EPA to give special
consideration to exposure of infants and children to the pesticide
chemical residue in establishing a tolerance and to ``ensure that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to the pesticide chemical residue. . .
.''
Consistent with FFDCA section 408(b)(2)(D), and the factors
specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available
scientific data and other relevant information in support of this
action. EPA has sufficient data to assess the hazards of and to make a
determination on aggregate exposure for halauxifen-methyl and its acid
metabolite, including exposure resulting from the tolerances
established by this action. EPA's assessment of exposures and risks
associated with halauxifen-methyl and its major metabolite, XDE-729
acid, 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.
The toxicology database for halauxifen-methyl is considered
adequate at this time. Following oral exposure and absorption, the
liver is exposed pre-systemically to halauxifen-methyl, where it is
hydrolyzed to its major metabolite, XDE-729 acid, before entering the
systemic circulation. Therefore, systemic exposure to organs and
tissues other than the liver is to XDE-729 acid, whereas the liver is
also exposed to the parent prior to its metabolism. The guideline
studies were conducted on XDE-729 acid and identified the kidney as the
main target organ. Bridging studies on halauxifen-methyl identified the
liver as the target organ, but the data could not bridge to the acid
metabolite because liver toxicity from exposure to halauxifen-methyl
occurred at lower doses than the kidney toxicity resulting from
exposure to XDE-729 acid. In lieu of conducting long-term oral studies
on halauxifen-methyl, mechanistic studies were performed to
characterize the mode of action (MOA) for liver toxicity. These studies
identified activation of the liver aryl hydrocarbon receptor (AhR) as
the MOA, and the molecular initiating event (MIE), for liver toxicity,
for which increased liver Cyp1a1 gene expression serves as a biomarker.
In the absence of this MIE, liver toxicity from parent halauxifen-
methyl, including induction of hepatocellular proliferation, will not
be observed. A point of departure (POD) of 3 mg/kg/day for increased
Cyp1a1 expression (observed at 10 mg/kg/day, the study NOAEL) was
identified in the rat 90-day dietary study on halauxifen-methyl and was
selected for chronic dietary risk assessment, since it protects for the
initial step in liver toxicity, regardless of exposure duration.
Therefore, the bridging and mechanistic studies were considered along
with the guideline studies in selection of the dose and endpoint for
halauxifen-methyl. Based on the abundance of guideline and mechanistic
data available, a MOA approach was used for the identification and
characterization of hazard. Due to the distinct toxicities of the two
compounds and the unique MOA for liver toxicity of halauxifen-methyl,
risk from the two compounds was assessed separately.
There is no evidence of neurotoxicity or immunotoxicity for either
compound. Inhalation studies (including the acute LD50
study) were waived because MOEs for inhalation exposure, calculated
using a highly conservative endpoint from oral data, were high
(>=2,500), and the available oral and dermal studies did not indicate
the potential for portal of entry effects. In addition, halauxifen-
methyl has a low vapor pressure and adequate particle sizes for test
atmospheres could not be generated. Guideline rat or rabbit dermal
toxicity, rat two-generation reproductive toxicity, dog chronic
toxicity, rat chronic toxicity/carcinogenicity, mouse carcinogenicity,
rat acute and subchronic neurotoxicity studies on halauxifen-methyl
were also waived. The waivers were granted because adequate data were
available for XDE-729 acid, to which systemic exposure would occur. The
available data, when combined with the bridging and MOE data on
halauxifen-methyl, allowed identification of a protective POD for AhR-
mediated liver toxicity. Therefore, an additional database uncertainty
factor (UFDB) is not required for either compound. Both are
mild eye irritants (Category III) but not dermal irritants or
sensitizers. XDE-729 acid is classified as ``not likely to be
carcinogenic to humans.'' Halauxifen-methyl is classified as ``not
likely to be carcinogenic to humans at doses that do not induce Cyp1a1
expression,'' based on the premise that AhR activation and subsequent
promotion of hepatocellular tumors (via a prolonged increase in
hepatocellular proliferation), a well-known non-genotoxic mechanism of
liver carcinogenesis that has been previously described for other
chemicals, depend upon this molecular initiating event (MIE). Moreover,
based on its rapid metabolism to XDE-729 acid, halauxifen-methyl is not
expected to persist in the body; therefore, progression of liver
toxicity (including carcinogenic potential) from sustained AhR
activation is not expected. Neither compound showed evidence of
genotoxicity.
There is no evidence of increased prenatal susceptibility to either
compound in developmental toxicity studies in two species. No
developmental toxicity was observed in the presence of maternal
toxicity for rats exposed to halauxifen-methyl or rabbits exposed to
XDE-729 acid. In rats exposed to XDE-729 acid, mild fetal effects
(decreased body weight and delayed ossification of the thoracic centra)
were observed in the presence of more significant maternal toxicity
(moribund sacrifice due to excessively decreased body weight and food
consumption, along with increased relative kidney weight). In rabbits
exposed to halauxifen-methyl, the fetal effects (decreased body weight,
increases in delayed ossification of the pubis) were observed in the
presence of maternal liver histopathology and
[[Page 53021]]
increased liver weight, at a dose greater than the maternal LOAEL, and
were therefore not considered indicative of greater sensitivity. In a
rat two-generation reproductive toxicity study on XDE-729 acid, there
was no evidence of increased postnatal susceptibility. Parental
toxicity in the rat two-generation reproductive toxicity study was
observed at 443 mg/kg/day (NOAEL 103 mg/kg/day), but no offspring or
reproductive toxicity was reported. A reproductive toxicity study was
not conducted on halauxifen-methyl. Residual concerns for postnatal
susceptibility to halauxifen-methyl in the absence of this study are
low, due to selection of a highly conservative endpoint and assumptions
for dietary exposure, as well as the low level of exposure expected
from proposed use patterns.
Specific information on the studies received and the nature of the
adverse effects caused by halauxifen-methyl and its metabolite, XDE-729
acid, as well as the no-observed-adverse-effect-level (NOAEL) and the
lowest-observed-adverse-effect-level (LOAEL) from the toxicity studies
can be found at http://www.regulations.gov in document Halauxifen-
methyl--New Active Ingredient Human Health Risk Assessment for Proposed
Uses on Cereal Grains (Barley, Wheat, and Triticale) at page 42 in
docket ID number EPA-HQ-OPP-2012-0919.
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 halauxifen-methyl used
in the Agency's human health risk assessment is shown in Table 1(a) of
this unit. No hazard from a single exposure was identified in the
available database; therefore, no risk is expected from acute dietary
exposure to halauxifen-methyl. For chronic dietary exposure, the rat
90-day oral study was selected. Although long-term oral toxicity
studies are not available for halauxifen-methyl, a dose and an endpoint
protective of long-term toxicity could be identified using the
subchronic data together with the MOA data. The rat 90-day study NOAEL
of 10.3 mg/kg/day was based on increased liver weight, hypertrophy and
vacuolization consistent with fatty change at the LOAEL of 53.4 mg/kg/
day. Liver effects at the LOAEL were of low severity but were
considered treatment-related. A marked increase (1,500-fold above
controls) in Cyp1a1 expression was also observed at the LOAEL. As
previously noted, mechanistic studies on halauxifen-methyl identified
activation of liver AhR as the MOA for liver toxicity, for which
increased expression of Cyp1a1 in the liver is a biomarker for AhR
activation, the MIE. In the absence of AhR activation, liver toxicity
will not occur. Although there were no liver effects observed at the
study NOAEL, a 52-fold increase in Cyp1a1 expression was observed. This
increase is well below the increase that was associated which mild
liver toxicity. Long-term effects on the liver from this lower level
increase are not known in the absence of chronic data, but the lowest
dose in the study, 3 mg/kg/day, showed essentially no Cyp1a1
activation. Cyp1a1 expression at 3 mg/kg/day was comparable to controls
in both the 28- and 90-day studies (1.2- and 3.6-fold higher than
controls, respectively), indicating that there is not expected to be
significant activation of the AhR receptor at this dose level over
time. Therefore, in order to be protective of potential adverse effects
on the liver following long-term exposure, the point of departure (POD)
of 3 mg/kg/day was selected, based on increased expression of liver
Cyp1a1 (52-fold) at 10 mg/kg/day. The selected dose and endpoint are
considered conservative, since the dose is below the study NOAEL, but
protective of residual uncertainty due to the lack of chronic data
because liver toxicity may not occur in the absence of the MIE,
regardless of exposure duration. They are also protective of chronic
effects from XDE-729 acid, which are observed at higher doses. A UF of
100 is based on the combined interspecies (10x) and intraspecies (10x)
UFs. An additional 10x UF for lack of chronic data was not applied for
the following reasons: (1) Progression of toxicity was not observed in
the 28- and 90-day dietary studies in the rat: the NOAELs and LOAELs
for both studies were the same, and the severity of the findings was
minimal at both exposure durations; (2) evaluation of Cyp1a1 expression
in the rat 28- and 90-day studies indicated that at the selected POD of
3 mg/kg/day, which is below the NOAELs for these studies, there is no
expectation of significant AhR activation that could lead to liver
toxicity. Observable liver toxicity in these studies was only
associated with significantly greater levels of Cyp1a1; (3) halauxifen-
methyl is rapidly metabolized to the acid, and neither bioaccumulate;
and (4) based on comparative in vitro studies, humans are not
anticipated to be more sensitive to liver effects of halauxifen-methyl
than rats.
Carcinogenicity studies on halauxifen-methyl were not conducted.
Systemic exposure from halauxifen-methyl is primarily to XDE-729 acid,
which showed no evidence of carcinogenicity. However, pre-systemic
exposure of the liver to halauxifen-methyl was shown to activate the
AhR receptor, an effect that induces an increase in hepatocellular
proliferation and, subsequently, may promote an increased incidence of
liver tumors with long-term exposure. The molecular marker for AhR
activation, the MIE for liver toxicity, is increased expression of
hepatic Cyp1a1, which was observed at a dose below the LOAEL for
observable adverse effects of any type. The chronic dietary endpoint
for halauxifen-methyl is based on the point of departure (POD) from the
rat subchronic study for Cyp1a1 induction, as described above. The
selected POD is considered very conservative because it is below the
study NOAEL (the LOAEL was based on mild liver effects). Since Cyp1a1
induction is one of the early key events in the MOA leading to
hepatotoxicity and promotion of hepatocellular proliferation, a dose
that is protective of this event will be protective of the potential
risk for liver cancer with chronic exposure, based on the rapid onset
of AhR activation following initiation of exposure, and the lack of
evidence of temporal progression of
[[Page 53022]]
liver toxicity in the available studies (28- and 90-day). The MOA is
considered relevant to human health risk assessment, but in vitro data
suggest that humans are unlikely to be more sensitive than the rat.
Based on a weight-of-the-evidence consideration, halauxifen-methyl is
classified as ``not likely to be carcinogenic to humans'' at doses that
do not induce liver Cyp1a1 expression.
Table 1(a)--Summary of Toxicological Doses and Endpoints for Halauxifen-methyl for Use in Human Health Risk
Assessment
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Point of departure
Exposure/Scenario and uncertainty/ RfD, PAD, LOC for Study and toxicological effects
safety factors risk assessment
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Acute dietary (General population No hazard from a single exposure was identified in the available database;
including infants and children therefore, no risk is expected from this exposure scenario.
and females age 13-49).
rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr
Chronic dietary (All populations) POD = 3.0 mg/kg/day. Chronic RfD = 0.03 90-day oral toxicity in the rat
UFA = 10x........... mg/kg/day. (halauxifen-methyl).
UFH = 10x........... cPAD = 0.03 mg/kg/ NOAEL = 10 mg/kg/day.
FQPA SF = 1x........ day. At the NOAEL, increased Cyp1a1
expression was observed (endpoint
selected for risk assessment).
The lowest dose of 3.0 mg/kg/day
was selected to be protective of
potential long-term effects from
increased AhR expression in the
liver.\1\
LOAEL = 52 mg/kg/day based on mild
liver enlargement and pathology.
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Cancer (Oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans at dose levels that
do not induce Cyp1a1 expression. The cRfD is considered protective of
potential cancer effects because it protects for the MIE for hepatocellular
proliferation (AhR activation) that, over time, may result in promotion of
liver tumors.
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Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data
and used to mark the beginning of extrapolation to determine risk associated with lower environmentally
relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect
level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential
variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor.
PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MIE = molecular initiating
event.
1. The POD selected for risk assessment was based on a non-adverse finding, increased liver Cyp1a1 expression in
a rat 90-day dietary study, which was observed below the study NOAEL of 10 mg/kg/day for liver toxicity. This
effect is a biomarker for activation of AhR, which causes liver toxicity and hepatocellular proliferation. The
POD was selected to be protective of potential liver effects resulting from chronic dietary exposure to
halauxifen-methyl. Other tissues and organs will not be exposed to halauxifen-methyl due to rapid conversion
to XDE-729 acid. The POD is protective of effects from exposure to XDE-729 acid.
A summary of the toxicological endpoints for XDE-729 acid used for
human risk assessment is shown in Table 1(b) of this unit. No hazard
from a single exposure was identified in the available database;
therefore, no risk is expected from acute dietary exposure to XDE-729
acid. The chronic toxicity/carcinogenicity study using the rat was
chosen to assess chronic dietary risk to XDE-729 acid. A NOAEL of 20.3
was chosen based on hyperplasia of the renal pelvic epithelium in
females observed at 101 mg/kg/day. This NOAEL is protective of
developmental effects, observed in the rat at 526 mg/kg/day (NOAEL =
140 mg/kg/day), and of maternal toxicity in both the rat (LOAEL = 526
mg/kg/day) and rabbit (LOAEL 1094 mg/kg/day).
There was no evidence of carcinogenicity in rat and mouse cancer
studies on XDE-729 acid, which is classified as ``not likely to be
carcinogenic to humans.''
Table 1(b)--Summary of Toxicological Doses and Endpoints for XDE-729 Acid for Use in Human Health Risk
Assessment
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Point of departure
Exposure/Scenario and uncertainty/ RfD, PAD, LOC for Study and toxicological effects
safety factors risk assessment
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Acute dietary (General population No hazard from a single exposure was identified in the available database;
including infants and children therefore, no risk is expected from this exposure scenario.
and females age 13-49).
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Chronic dietary (All populations) NOAEL = 20.3 mg/kg/ Chronic RfD = 0.20 Rat two-year dietary chronic
day (females). mg/kg/day. toxicity/carcinogenicity study
NOAEL = 101/20.3 mg/kg/day [M/F].
UFA = 10x........... cPAD = 0.20 mg/kg/ LOAEL = 404/101 mg/kg/day [M/F]
UFH = 10x........... day. based on increased mortality,
FQPA SF = 1x........ altered urinalysis parameters,
decreased body weight, increased
kidney weights, adrenal zone
glomerulosa hypertrophy,
increased degeneration and
regeneration of renal tubules and
kidney stones, and bladder
pathology in males; in females,
hyperplasia of pelvic epithelium
of the kidney.
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[[Page 53023]]
Cancer (Oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans.
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Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data
and used to mark the beginning of extrapolation to determine risk associated with lower environmentally
relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect
level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential
variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor.
PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to halauxifen-methyl and the XDE-729 acid metabolite, EPA
considered exposure under the petitioned-for tolerances. EPA assessed
dietary exposures to these compounds 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. No such effects were
identified in the toxicological studies for halauxifen-methyl or XDE-
729 acid; therefore, quantitative acute dietary exposure assessments
were determined unnecessary.
ii. Chronic exposure. In conducting individual chronic dietary
exposure assessments for these two compounds, EPA used the food
consumption data collected between 2003 and 2008 for USDA's National
Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA). As
to residue levels in food, EPA used tolerance-level residues and
assumed 100 percent of all wheat, barley and triticale acres are
treated. No processing factors were used due to the lack of residue
concentration in processed commodities. Residue chemistry data indicate
that halauxifen-methyl (parent compound) converts to the XDE-729 acid
metabolite so quickly in the environment that dietary exposure to
halauxifen-methyl is expected to be minimal.
iii. Cancer. Based on the data summarized in Unit III.A., EPA has
concluded that halauxifen-methyl does not pose a cancer risk to humans
at dose levels that do not induce liver toxicity or Cypla1 expression.
EPA has also concluded that its XDE-729 acid metabolite does not pose a
cancer risk to humans. Therefore, separate dietary exposure assessments
for the purpose of assessing cancer risk are determined to be
unnecessary.
iv. Anticipated residue and percent crop treated (PCT) information.
EPA did not use anticipated residue and/or PCT information in the
dietary assessment for halauxifen-methyl. Tolerance-level residues and
100% CT were assumed for all food commodities.
2. Dietary exposure from drinking water. The Agency used screening-
level water exposure models in the dietary exposure analysis and risk
assessment for halauxifen-methyl and its metabolites (primarily XDE-729
acid) in drinking water. These simulation models take into account data
on the physical, chemical, and fate/transport characteristics of
halauxifen-methyl and its metabolites. 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 Pesticide Root Zone Model Ground Water (PRZM
GW), the estimated drinking water concentrations (EDWCs) of halauxifen-
methyl were estimated for chronic exposure in a non-cancer assessment.
Based on the Screening Concentration in Groundwater (SCI-GROW) model,
the EDWCs of the XDE-729 acid metabolite were estimated for chronic
exposure in a non-cancer assessment. Modeled estimates of drinking
water concentrations were directly entered into the dietary exposure
model. For chronic dietary risk assessment of halauxifen-methyl only,
the water concentration value of 0.007 ppb was used to assess the
contribution to drinking water. For chronic dietary risk assessment of
XDE-729 acid, a drinking water concentration value of 19.5 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). Halauxifen-methyl is
not used, nor is it being proposed for use in 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.'' EPA has not found
halauxifen-methyl or XDE-729 acid to share a common mechanism of
toxicity with any other substances, nor do they appear to produce any
toxic metabolites produced by other substances. For the purposes of
this tolerance action, therefore, EPA has assumed that neither of these
compounds have a common mechanism of toxicity with other substances.
For information regarding EPA's efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see EPA's Web site at http://www.epa.gov/pesticides/cumulative.
D. Safety Factor for Infants and Children
1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA
shall apply an additional tenfold (10X) margin of safety for infants
and children in the case of threshold effects to account for prenatal
and postnatal toxicity and the completeness of the database on toxicity
and exposure unless EPA determines based on reliable data that a
different margin of safety will be safe for infants and children. This
additional margin of safety is commonly referred to as the FQPA Safety
Factor (SF). In applying this provision, EPA either retains the default
value of 10X, or uses a different additional safety factor when
reliable data available to EPA support the choice of a different
factor.
[[Page 53024]]
2. Prenatal and postnatal sensitivity. There was no evidence of
increased prenatal susceptibility to either compound and no evidence of
postnatal susceptibility to XDE-729 acid. Residual concerns for
postnatal susceptibility to halauxifen-methyl in the absence of
reproductive toxicity data are low, due to selection of a conservative
endpoint and assumptions for dietary exposure, as well as the low level
of exposure expected from proposed use patterns.
3. Conclusion. EPA has determined that reliable data show the
safety of infants and children would be adequately protected if the
FQPA SF were reduced to 1x. That decision is based on the following
findings:
i. The toxicity database for halauxifen-methyl and XDE-729 acid are
complete.
ii. There is no indication that halauxifen-methyl or XDE-729 acid
are neurotoxic chemicals and there is no need for developmental
neurotoxicity studies or additional UFs to account for neurotoxicity.
iii. There is no evidence to suggest that exposure to halauxifen-
methyl or XDE-729 acid results in increased in utero susceptibility in
rats or rabbits in the prenatal developmental studies or in young rats
in the 2-generation reproduction study.
iv. There are no residual uncertainties identified in the exposure
databases. The chronic dietary food exposure assessment was based on
100 PCT and tolerance-level residues. EPA also made conservative
assumptions in the ground and surface water modeling used to assess
exposure to halauxifen-methyl and XDE-729 acid in drinking water. These
assessments will not underestimate the exposure and risks posed by
these compounds.
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. An acute aggregate risk assessment takes into
account acute exposure estimates from dietary consumption of food and
drinking water. No adverse effect resulting from a single oral exposure
was identified and no acute dietary endpoint was selected. Therefore,
neither halauxifen-methyl, nor XDE-729 acid are expected to pose an
acute risk.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that chronic exposure to
halauxifen-methyl from food and water will utilize < 1% of the cPAD for
all infants, the population group receiving the greatest exposure. In
addition, EPA has concluded that chronic exposure to XDE-729 acid from
drinking water will also utilize < 1% of the cPAD for all infants. XDE-
729 is not a residue of concern in food; therefore, the chronic
assessment was based on drinking water only for this acid metabolite.
There are no residential uses for halauxifen-methyl being proposed at
this time; therefore chronic aggregate risk reflects only dietary
exposure to potential residues in food and drinking water.
3. Short-term risk. Short-term risk is assessed based on short-term
residential exposure plus chronic dietary exposure. Because there is no
short-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-term risk), no
further assessment of short-term risk is necessary.
4. Intermediate-term risk. Intermediate-term risk is assessed based
on intermediate-term residential exposure plus chronic dietary
exposure. Because there is no intermediate-term residential exposure
and chronic dietary exposure has already been assessed under the
appropriately protective cPAD, no further assessment of intermediate-
term risk is necessary.
5. Aggregate cancer risk for U.S. population. Long-term dietary
studies conducted with XDE-729 acid in the rat and the mouse showed no
evidence of carcinogenicity. Based on the MOA and bridging data on
halauxifen-methyl, which allowed identification of a POD for liver
cancer, halauxifen-methyl is not expected to pose a cancer risk to
humans at dose levels below those that induce liver Cyp1a1 expression.
Genotoxicity studies were negative for both compounds.
6. 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 halauxifen-methyl and XDE-729 acid residues.
IV. Other Considerations
A. Analytical Enforcement Methodology
Adequate enforcement methodology (LC-MS/MS) with a limit of
quantitation of 0.01 ppm is available to enforce the tolerance
expression. The multi-residue method, QuEChERS, is adequate for the
determination of both residues of halauxifen-methyl and XDE-729 acid in
crop commodities. 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:
[email protected].
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.
No MRLs have been established by Codex for halauxifen-methyl on the
commodities affected by this action.
C. Revisions to Petitioned-For Tolerances
As noted in Unit II, the petitioned-for livestock commodity
tolerances (milk; fat, meat, meat byproducts of cattle, goat, horse,
and sheep) are not being established due to the lack of quantifiable
residues in livestock commodities associated with the proposed uses in
wheat, barley and triticale. In addition, although the petitioner
proposed a tolerance of 0.04 ppm for wheat, hay, EPA has determined
that a tolerance of 0.03 ppm is appropriate. When the petitioner
determined the proposed tolerances, the metabolite XDE-729 acid was
included as a residue of concern. EPA has subsequently determined that
this metabolite is not a residue of concern for tolerance enforcement.
Residues of metabolite XDE-729 acid were not
[[Page 53025]]
quantifiable in any of the residue field trials. Therefore, the values
for measuring compliance with these tolerances only include residues of
halauxifen-methyl. With the exception of wheat, hay, this revision to
the residues of concern for tolerance enforcement had no impact on the
plant commodity tolerances.
V. Conclusion
Therefore, tolerances are established for residues of halauxifen-
methyl, (methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)
pyridine-2-carboxylate) and its major metabolite, XDE-729 acid,
expressed as halauxifen-methyl (parent) equivalents, in or on barley,
(grain, hay, straw) and wheat, grain at 0.01 ppm; wheat, forage at 0.50
ppm; wheat, hay at 0.03 ppm; and wheat, straw at 0.015 ppm.
VI. Statutory and Executive Order Reviews
This action 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 action has been
exempted from review under Executive Order 12866, this action 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 action 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 tolerances 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 action 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 action. In addition, this
action does not impose any enforceable duty or contain any unfunded
mandate as described under Title II of the Unfunded Mandates Reform Act
(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 (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: July 28, 2016.
Jack E. Housenger,
Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
0
1. The authority citation for part 180 continues to read as follows:
Authority: 21 U.S.C. 321(q), 346a and 371.
0
2. Add Sec. 180.691 to subpart C to read as follows:
Sec. [emsp14]180.691 Halauxifen-methyl; tolerances for residues.
(a) General. Tolerances are established for residues of the
herbicide, halauxifen-methyl, including its metabolites and degradates,
in or on the commodities in the table below. Compliance with the
tolerance levels specified below is to be determined by measuring only
halauxifen-methyl (methyl (4-amino-3-chloro-6-(4-chloro-2-fluoro-3-
methoxyphenyl)-2-pyridine carboxylate).
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Barley, grain......................................... 0.01
Barley, hay........................................... 0.01
Barley, straw......................................... 0.01
Wheat, forage......................................... 0.50
Wheat, grain.......................................... 0.01
Wheat, hay............................................ 0.03
Wheat, straw.......................................... 0.015
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 2016-19118 Filed 8-10-16; 8:45 am]
BILLING CODE 6560-50-P