Document ID: EPA-HQ-OPP-2016-0650-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-04-10T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

Interregional Research Project No. 4 (IR-4)

6E8516

EPA has received a pesticide petition (6E8516) from Interregional
Research Project No. 4, Rutgers, The State University of New Jersey, 500
College Road East, Suite 201 W, Princeton, NJ 08540 requesting, pursuant
to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA),
21 U.S.C. 346a(d), to amend 40 CFR part 180.650 by establishing
tolerances for residues of isoxaben
N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2, 6-dimethoxybenzamide in
or on the raw agricultural commodities apple at 0.01 parts per million
(ppm), the bushberry subgroup 13-07B at 0.01 ppm, the fruit, small, vine
climbing, except fuzzy kiwifruit, subgroup 13-07F at 0.01 ppm and the
nut, tree, group 14-12 at 0.02 ppm.  In addition, upon establishment of
the aforementioned tolerances, IR-4 proposes to remove the established
tolerances for residues of isoxaben
N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2, 6-dimethoxybenzamide in
or on raw agricultural commodities grape at 0.01 ppm; nut, tree, group
14 at 0.02 ppm; and pistachio at 0.02 ppm.

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of FDDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The nature of the residue in plants (grapes and
cereals) has been determined using radiolabeled isoxaben and is
adequately understood for the purposes of these tolerances. The results
of the plant and animal metabolism studies and toxicity testing indicate
that the total toxic residue to be regulated is isoxaben.

	2. Analytical method. An acceptable analytical method is available for
enforcement purposes. The apple and blueberry samples in the respective
MOR studies were analyzed using a working method very similar to the
reference method, Determination of Residues of lsoxaben in Cereals,
Chicory and Endives by Liquid Chromatography with Tandem Mass
Spectrometry; Authors: M. J. Hastings and D. A. Lindsay; Dow
AgroSciences Method: GRM: 02.26; Dated: February 9, 2003.

	3. Magnitude of residues. The proposed tolerances for isoxaben are
supported by MOR trials conducted in apple (12 trials) and blueberry (7
trials). The magnitude of residues of isoxaben were determined following
a single application per trial that ranged between 0.98 - 1.03 and 1.00
- 1.09 lbs a.i./A for apple and blueberry respectively.

The results from the trials show the residues of isoxaben in both apples
and blueberries following a total application of approximately 1.0 lb
ai/A to be less than 0.01 ppm. 

B. Toxicological Profile

The toxicological profile for isoxaben, which supports the petition to
add new tolerances and revise existing tolerances, was reviewed in the
2014 Preliminary Human Health Risk Assessment for registration review
(D414154). EPA considers the toxicology dataset complete for the
purposes of characterizing the hazard associated with isoxaben and for
conducting a human health risk assessment. EPA has not established an
acute reference dose for isoxaben and the chronic RfD is equivalent to
the chronic PAD = 0.05 mg/kg/day, because the FQPA SF has been reduced
to 1X. 

	1. Acute toxicity.  Per the 2014 Preliminary Human Health Risk
Assessment for registration review (D414154) no significant acute
hazards were attributable to a single exposure in the available
toxicology studies on isoxaben. Since no acute toxicological endpoints
were established, no acute assessment is required.

	2. Genotoxicty. Isoxaben yielded negative results in a battery of in
vitro and in vivo tests for mutagenicity and other forms of
genotoxicity. Initially, the micronucleus assays in mice gave a weakly
positive result but findings were not deemed to be dose-related and were
of questionable biological significance. A more recent mouse bone marrow
micronucleus test gave negative results and isoxaben showed no genotoxic
potential.

	3. Reproductive and developmental toxicity. No maternal or
developmental effects were observed in the rat or rabbit developmental
studies. In the rat reproductive toxicity study increased liver weights
and decreased bodyweight or weight gain particularly during gestation
for females dosed at 200 or 1000 mg/kg bw/day were observed.  Maternal
toxicity was also indicated in the high dose group by reduced litter
size and reduced ovulation.  Fetal effects, limited to the high dose
group, included retarded progeny growth and increased incidence of
microphthalmia and associated craniofacial anomalies which appeared to
have been related to genetic factors, traced back to the original
litters from which the adult animals were derived.

	4. Subchronic toxicity. Repeated dietary exposure to isoxaben
identified the liver and kidneys as target organs of toxicity in rats,
mice and dogs, with effects judged to be adverse observed only in the
chronic mouse study. These effects included histopathology and increased
blood alkaline phosphatase and alanine aminotransferase activities at
high doses. No adverse renal effects were reported in the mouse or dog.
There was increased incidence and severity of nephropathy in the chronic
rat study.

	5. Chronic toxicity. EPA has established the reference dose (RfD) for
isoxaben at 0.05 mg/kg/day for chronic risk assessment. Studies in dogs,
rats and mice were reviewed and the resulting cRfD is conservatively
based on the 2-year rat feeding study in rats with a NOEL of 5 mg/kg/day
and applied uncertainty factor of 100 for both interspecies
extrapolation (10x) and intraspecies variability (10x). The critical
effects associated with the threshold were increased BUN, decreased
serum AP (alkyl phosphatase) and AST (aspartate aminotransferase);
decreased food consumption efficiency; increased

heart/body weight.

	6. Animal metabolism. Isoxaben has been shown to be readily and rapidly
absorbed when orally administered, but also rapidly excreted from
tissues: total urinary and fecal excretion ranging from 70 to 100% has
been observed in series of studies and timeframes. Two tissue
distribution studies in rats with single doses of 14C labelled isoxaben
investigated the distribution of the absorbed dose; both found the
highest levels in the GI tract congruent with the understanding of the
rapid faecal excretion. About 10% of absorbed dose converted to 15 or
more metabolites excreted in the urine. For dermal exposure: a dermal
absorption value of 11% has been observed. Supplemental data from bovine
NOR work demonstrates any meat or fat residues of isoxaben in cattle
would be constituted primarily of degradates and <10% of the parent
isoxaben. Based on the understanding of metabolism in both rats and the
cow, the low potential dietary burden to cattle from almond hulls should
result in residues below the current limit of

detection in milk and fat.

	7. Metabolite toxicology. The residue of concern for tolerance purposes
has already been established as the parent material isoxaben. Thus,
there is no need to address metabolite toxicity

	8. Endocrine disruption. The available mammalian toxicity and
toxicokinetic studies on isoxaben, including a 2-generation reproduction
study, developmental toxicity studies in two species, and repeat dose
toxicity studies ranging from 28 days to 2 year studies in three species
(rat, mouse, and dog), do not demonstrate that isoxaben possesses
endocrine disrupting properties that are relevant to humans.

C. Aggregate Exposure

	1. Dietary exposure. The dietary assessment model DEEM-FCIDTM software
version 3.18, which contains food consumption data based on NHANES 2-day
food Consumption data for 2003 to 2008 was employed to assess chronic
dietary risk. A DEEM residue file for a Tier I Dietary assessment was
prepared using proposed tolerance values plus water values from the Tier
I screening models. The resulting exposures were assessed against the
cRfD / cPAD for isoxaben of 0.05 mg/kg bw/day. An acute endpoint was not
identified for acute dietary exposure and risk assessment, therefore, an
acute dietary exposure assessment was not performed

	i. Food. A chronic assessment was conducted to evaluate potential
chronic dietary exposure of the U.S. population subgroups to residues of
isoxaben.  These analyses cover all registered crops, as well as the
proposed tolerances.  The current dietary assessment is a conservative
unrefined Tier I assessment using tolerance values and 100% crop-treated
assumption to estimate dietary exposure to isoxaben. The use of these
parameters clearly results in an overestimate of human exposure and
results in a conservative dietary assessment. 

	ii. Drinking water. There are no water-related exposure data from
monitoring to complete a quantitative drinking water exposure analysis
and risk assessment for isoxaben. The current estimated drinking water
concentrations (EDWCs) for the herbicide isoxaben are based on modeling
results generated by EFED (2014) and used in the most recent EPA human
health risk assessment. Groundwater EDWCs were substantially higher than
surface water EDWCs with the recommended concentration for use in
HED’s dietary assessment being 909 ppb. The value of 909 ppb has also
been incorporated as a single point estimate for both “water, direct,
all sources” and water, indirect, all sources” within DEEM-FCIDTM
food categories exposure modeling for the purposes of this current
submission. The use of this highly conservative tier 1 assessment
results in an overestimate of human exposure.

Per the 2014 Preliminary Human Health Risk Assessment for registration
review (D414154) the established chronic endpoints are cRfD = cPAD =
0.05 mg/kg bw/day. The Tier 1 DEEM exposure for food and water using the
newly proposed tolerances and existing tolerances resulted in an
estimated exposure of 0.019055 mg/kg bw/day for the US general
population, which is 38% of the cPAD. For the most highly exposed
population subgroup, All Infants (< 1 year old), the estimated exposure
is 0.049153 mg/kg bw/day at 98% of the cPAD. These results are
conservative (health protective) risk estimates.  Refinements such as
use of percent crop-treated information and/or anticipated residue
values would yield lower estimates of chronic dietary exposure.

	2. Non-dietary exposure. The proposed new uses of isoxaben on apples
and bushberry, subgroup 13-07F will not alter the residential assessment
conducted in 2014 by HED, which was based on two previous assessments
(M. Crowley, D0405265, 6/6/2013; and S. Oonithan, D374750 and D368834,
26 Jul 2010). EPA conducted a conservative assessment of potential
intermediate-term oral risk from soil ingestion and found the resulting
MOE of 1,500,000 (children 1-2 years old), based on the residential
post-application total exposure of 0.00014 mg/kg bw/day to far exceed
the LOC. The total MOE for residential handlers, based on inhalation
exposures were calculated to be 19,000 (residential handler total
exposure is 0.011 mg/kg bw/day), which far exceeds level of concern
(LOC) for all formulation types and application equipment used.

D. Cumulative Effects

	Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency considers
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.”  EPA does not have, at this time,
available data to determine whether isoxaben has a common mechanism of
toxicity with other substances or how to include this pesticide in a
cumulative risk assessment.  Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, isoxaben does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, it is assumed that isoxaben does not have a common
mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Using the highly conservative exposure assumptions
described above, and based on the completeness and reliability of the
toxicity data, the aggregate exposure to isoxaben, as determined under
the guidance of the FQPA, will utilize less than 39% of the cPAD from
the dietary exposure for the general U.S. population.  Generally and
under the FQPA, the U.S. EPA has no concern for exposures below 100% of
the cPAD because the cPAD represents the level at or below which daily
dietary exposure over a lifetime will not pose appreciable risks to
human health.  Short-term post application risks were estimated for the
most conservative or worst case residential adult scenario (females
13-49).  When the food, water and residential exposures were aggregated
for this subpopulation, it resulted in an MOE of 6700, which is well
above the LOC of 100; values above the LOC are typically not of a
concern for the EPA.

	2. Infants and children. Per the 2014 Preliminary Human Health Risk
Assessment for registration review (D414154), September 11, EPA has
previously determined that an additional safety factor was not needed
for the protection of infants and children (FQPA SF = 1x).  Using the
DEEM exposure assumptions described above for the dietary and water
exposure to isoxaben with the current and proposed new tolerances, the
highest exposed subpopulation is All Infants (< 1 year old) at 98.3% of
the cPAD.  EPA generally has no concern for exposures below 100% of the
cPAD because the cPAD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. In the case of isoxaben the EPA acknowledged that
the value of 98.3% was generated using highly conservative drinking
water models. Therefore with refinements the actual % cPAD for the
subpopulation All Infants (< 1 year old) is likely to be far lower than
the current value suggests.  The residential uses are not anticipated to
result in exposure to this subpopulation, so the aggregate exposure is
equivalent to the dietary exposure, and therefore is not of concern.
Intermediate term (children) post application risks were estimated for
the subpopulation likely to be most highly exposed (children 1-2 years).
When the food, water and residential exposures were aggregated for this
subpopulation, it resulted in an MOE of 7,200, which is well above the
LOC of 100; values above the LOC are typically not of a concern for the
EPA.

F. International Tolerances

	Governing bodies have established Maximum Residue Levels (MRLs) for
isoxaben in a variety of crops.  The related international MRLs are
found in the following table based on a review of MRLs compiled by
searches in the Global MRL database (  HYPERLINK
"http://www.globalmrl.com"  http://www.globalmrl.com ), Homologa ( 
HYPERLINK "http://www.homologa.com/"  http://www.homologa.com/ ) the EU
SANCO website (  HYPERLINK
"http://ec.europa.eu/sanco_pesticides/public/index.cfm" 
http://ec.europa.eu/sanco_pesticides/public/index.cfm ) the Australian
MRL website (  HYPERLINK
"http://www.comlaw.gov.au/Details/F2014C00164/Download" 
http://www.comlaw.gov.au/Details/F2014C00164/Download ), Japan MRL
website (  HYPERLINK
"http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700
" 
http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700
) and Codex MRL (  HYPERLINK
"http://www.codexalimentarius.net/pestres/data/pesticides/details.html?i
d=209" 
http://www.codexalimentarius.net/pestres/data/pesticides/details.html?id
=209 ).  Homologa is a third party database used as the source for this
table; Dow AgroSciences makes no claim regarding the verification of
these values relative to the individual national authoritative sources.
There is no MRL for isoxaben in apple and blueberry at the time of this
submission on Global MRL database, Japan MRL website and Codex MRL. 

Commoditya	Existing MRLa

(ppm)	Regulatory Authority

Apple	0.01; 0.05	Australia; EU SANCO

Blueberry	0.05	EU SANCO

a as listed on regulatory authority websites

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