Document ID: EPA-HQ-OPP-2016-0384-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-11-30T05:00Z

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

IR-4 Project Headquarters

PP #6E8488

	EPA has received a pesticide petition (PP 6E8488) from IR-4 Project
Headquarters, Rutgers, The State University of NJ, 500 College Road
East, Suite 201 W, Princeton, NJ 08540 proposing, 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 180.463 by establishing tolerances for the
combined residues of the herbicide quinclorac,
3,7-dichloro-8-quinolinecarboxylic acid in or on the following raw
agricultural commodities: the caneberry subgroup 13-07A at 0.06 parts
per million (ppm); the bushberry subgroup 13-07B, except lowbush
blueberry at 0.6 ppm; and asparagus at 0.06 ppm.  EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408(d)(2) of the FFDCA; 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 qualitative nature of the residues in
quinclorac in plants is adequately understood for currently registered
uses, based on metabolism studies on rice, grain sorghum, wheat and
canola.  In each of these studies, the major 14C residue was identified
as the parent compound.  The methyl ester of quinclorac was present as a
minor metabolite, but methyl ester is measured by the enforcement
method.  An additional metabolism study has been conducted on a fruit
(strawberry) and the parent quinclorac was the only residue of concern
in the fruit.  A minor polar metabolite was detected only in strawberry
foliage, but not in any fruit sample.

	2. Analytical method. Adequate analytical methods (GC/ECD) are
available for enforcing quinclorac tolerances on plant (BASF Method
A8902; MRID# 41063537) and livestock (BASF Method 268/1; MRID# 41063536)
commodities.  Both methods have undergone successful agency method
validation trials and have been submitted to FDA for publication in PAM
II as the tolerance enforcement methods.  The LOQ of both methods is
0.05 ppm for all matrices.  Updated enforcement analytical methods have
been submitted for determining residues of quinclorac, per se, in/on
plant parts, an LC/MS/MS method (BASF Method D9708/1).  The validated
LOQ for quinclorac is 0.05 ppm.  Quinclorac methyl ester can be
determined by an LC/MS/MS method (BASF method D9806/02).  Furthermore,
FDA has reported that quinclorac can be detected by Multiresidue
Protocol B.  

	3. Magnitude of residues. Field trials were carried out in order to
determine the magnitude of residues in blueberry, caneberry and
asparagus.  Seven blueberry field trials were conducted in blueberry
growing regions of the United States.  Blueberry is the representative
crop for Bushberry subgroup 13-07B.  Six caneberry field trials were
conducted in caneberry growing regions of the United States.  Caneberry
is the representative crop for Caneberry subgroup 13-07A.  Seven
asparagus field trials were conducted in asparagus growing regions of
the United States.  Field trials were carried out using the maximum
number of applications, the maximum label rate and shortest pre-harvest
interval (PHI).  Asparagus will be the representative for Stalk and stem
vegetable subgroup 22A, however, the use pattern proposed for quinclorac
on asparagus, is unlikely to be appropriate for other members of the
subgroup. 

B. Toxicological Profile

Acute toxicity. Quinclorac (technical grade material) has a low order of
acute toxicity as demonstrated by Toxicity Category III by the oral,
dermal, and inhalation routes. The chemical is a mild eye irritant, is
not a skin irritant, but was positive for dermal sensitization.

Genotoxicity. Quinclorac has been tested for its genotoxic potential in
a battery of six in vitro or in vivo studies covering the required
endpoints of point mutations, chromosomal damage and DNA damage and
repair.  Quinclorac did not demonstrate any genotoxic effects. 
Quinclorac was negative for inducing mutations in both an in vitro Ames
test and an in vitro forward mutation assay in mammalian cells (HGPRT
test with and without metabolic activation).  Both an in vitro and an in
vivo chromosome aberration assay (with and without metabolic activation)
showed no evidence of a clastogenic effect.  Unscheduled DNA synthesis
was not induced in the UDS assay.  A mutagenicity evaluation with
Bacillus subtilis (with and without metabolic activation) was also
negative.  These studies demonstrate that Quinclorac is not genotoxic.

3.	Reproductive and developmental toxicity. In a 2-generation
reproduction study (MRID # 41063526), Quinclorac (≥97.3% a.i.) was
administered to Wistar rats (24/sex/group) at dietary levels of 0,
1,000, 4,000 or 12,000 ppm (0, 40, 160 or 480 mg/kg/day, respectively). 
No effects on reproductive parameters were observed.  The reproductive
toxicity NOAEL is 12,000 ppm (480 mg/kg/day).  A reproductive toxicity
LOAEL was not established (>480 mg/kg/day).  This study was classified
as Acceptable/guideline and satisfied the guideline requirement for a
multigeneration reproductive toxicity study in the rodent (870.3800).

There was no increased qualitative or quantitative fetal or offspring
susceptibility in the prenatal developmental or postnatal reproduction
studies.  Developmental toxicity in rabbit consisted of increased
resorptions, post-implantation loss, decreased number of live fetuses,
and reduced fetal body weight.  These effects occurred at much higher
doses than the maternal effects of decreased food consumption and
increased water consumption and decreased body weight gain.  In rat no
developmental toxicity was observed at the highest dose tested (438
mg/kg/day).  In the 2-generation reproduction study, parental toxicity
and offspring toxicity occurred at the same dose.  Parental toxicity
consisted of reduced body weight in both sexes during premating and
lactation periods.  Offspring toxicity consisted of decreased pup
weight, developmental delays and possible marginal effect on pup
viability.

Subchronic toxicity. In a subchronic toxicity study (MRID 41063516),
Quinclorac (96.5% a.i.) was administered to 10 Wistar Chhb-THOM (SPF)
rats/sex/dose in diet, at dose levels of 0, 1000, 4000, or 12000 ppm (0,
76.8, 302.3 or 929.9 mg/kg/day for males and 0, 86.7, 358.0 or 1035.4
mg/kg/day for females).  No deaths occurred.  No compound related
clinical signs of toxicity were observed.  The LOAEL is 12,000 ppm
(males 929.9 and females 1035.4 mg/kg/day), based on decreases in body
weight gain, food consumption and an increase in water intake in males
and females, and decrease in monocytes in female, increases in SGOT and
SGPT in males, and pathological changes in kidneys of males (slight to
minimal focal chronic interstitial nephritis).  The NOAEL is 4000 ppm
(males 302.3 and females 358.0 mg/kg/day).  This subchronic toxicity
study was classified unacceptable/non-guideline due to lack of
information on the purity of the test material and information on
stability and homogeneity of the test substance in the diet.

In a subchronic toxicity study (MRID 41063518), Quinclorac (98.29% a.i.)
was administered to 10 B6C3F1/Crl BR mice/sex/dose in diet, at dose
levels of 0, 4000, 8000, or 16000 ppm (0, 1000, 2202 or 4555 mg/kg/day
for males and 0, 1467, 2735 or 5953 mg/kg/day for females).  No deaths
occurred.  No compound related clinical signs of toxicity were observed.
 At 8000 and 16000 ppm there was an increase in water intake in males
and females and BUN in males.  There was decreased kidney weight in
males and females and relative kidney weight in males in the 16,000 ppm
group.  At 4000 ppm there was decreased body weight gain in males and
females.  The LOAEL is 4,000 ppm (males 1,000 and females 1467
mg/kg/day), based on decreases in body weight.  The NOAEL was not
established.  This subchronic toxicity study was classified
Acceptable/non- guideline requirement for a subchronic oral study (82-1)
in mice.  However considered with MRID 41063519, it was acceptable/
guideline.

In another subchronic toxicity study (MRID 41063519), Quinclorac (98.29%
a.i.) was administered to 10 B6C3F1/Crl BR mice/sex/dose in diet, at
dose levels of 0 or 500 ppm (75 mg/kg/day, HDT).  No deaths occurred. 
No compound related clinical signs of toxicity were observed.  Females
in the 500 ppm group had slightly (although statistically significant)
reduced body weights when compared to controls on day 98.  This decrease
was minimal and is not believed to be compound related since body
weights were not significantly different at any other time intervals.
The NOAEL is 500 ppm (75 mg/kg/day).  This subchronic toxicity study was
classified Unacceptable because only one dose level was tested.  However
considered with MRID 41063518, it was acceptable /guideline.

5.	Chronic toxicity. A 1-year feeding study in dogs fed 0, 34, 142, and
513 (males) and 0, 35, 140, and 469 (females) milligrams/kilogram/day
(mg/kg/day) resulted in a no-observed-effect level (NOEL) of 140
mg/kg/day based on reduced body weight gains, adverse effect on food
efficiency, hematological and clinical chemistry values, increased liver
and kidney weights, and microscopic findings in liver and kidneys at 513
mg/kg/day (males) and 469 mg/kg/day.

6.	Animal metabolism A metabolism study with rats receiving dosages of
15, 100, 600 and 1200 mg/kg/day resulted in more than 90% of the
administered radioactivity eliminated in the urine within 5 days (most
within 24 hours) and 0.7%–3.7% in the feces. Radioactivity was mainly
associated with the unchanged parent compound. The glucuronic acid
conjugate of quinclorac was a minor (2%–5%) metabolite in urine.

7.	Metabolite toxicology. Quiclorac was the primary metabolite reported
in a rat metabolism study (MRID 41063533).  Elimination was primarily in
the urine (91-98%) with small amounts in the feces (1-4%) eliminated by
day 5 after dosing.

Endocrine disruption. No specific scientific studies have been conducted
to determine endocrine effects. Toxicity testing demonstrates no
apparent estrogenic effects or treatment-related effects of quinclorac
on the endocrine system.

Aggregate Exposure

Dietary exposure. Previous acute and chronic aggregate dietary (food and
drinking water) exposure and risk assessments have been conducted using
the Dietary Exposure Evaluation Model DEEM-FCID, Version 3.16 which uses
food consumption data from the U.S. Department of Agriculture's National
Health and Nutrition Examination Survey, What We Eat in America,
(NHANES/WWEIA).  This dietary survey was conducted from 2003 to 2008.
These analyses were performed to support the tolerance with no U.S.
registration for quinclorac in/on Rapeseed Subgroup 20A for the use of
the DMA salt of quinclorac in Canada. All registered, pending and
proposed uses of quinclorac and the DMA salt of quinclorac, were
included in assessments.  Both the acute and chronic assessments were
highly conservative and incorporated tolerance/maximum residue level
estimates based on field trial data for the residues of concern and
assume 100% crop treated. Default processing factors were used and,
based on empirical data, a processing factor of l .5x was used for oil
commodities of the Rapeseed Subgroup 20A.

Food. Acute Dietary Exposure Assessment:  In the most recent human
health risk assessment conducted by the EPA, the acute (food + water)
dietary risk estimate at the 95th percentile of exposure utilized 1.6%
of the acute population adjusted dose (aPAD) for females age 13 to 49.
This is the only population subgroup for which an acute endpoint was
selected.  The addition of caneberries, blueberries and asparagus may
result in an increase in dietary exposures but this additional exposure
will not result in unacceptable dietary risks and will be below 100% of
the aPAD.

Chronic Dietary Exposure Assessment: In the most recent human health
risk assessment conducted by the EPA, the chronic (food + water) dietary
risk estimates are less than or equal to 8.9% of the chronic population
adjusted dose (cPAD) for all population subgroups.  All Infants < I year
of age is the most highly-exposed subgroup, utilizing 8.9% of the cPAD,
while the general US population utilizes 3.6% of the cPAD.  The addition
of caneberries, blueberries and asparagus may result in an increase in
dietary exposures, but this additional exposure will not result in
unacceptable dietary risks and will be below 100% of the aPAD.

Drinking water. Water residues were previously incorporated in DEEM-FCID
via entry into the food categories “water, direct, all sources” and
“water, indirect, all sources.”  The estimated drinking water
concentrations (EDWCs) from existing and proposed uses of quinclorac for
both acute and chronic scenarios in ground and surface water are 0.029
ppm and 0.511 ppm, respectively.

	In the previous human health risk assessment conducted by the EPA, the
rice use (labeled for a single application of 0.5 lb a.i./A) was
identified as the use resulting in the highest estimated drinking water
concentrations (EDWCs) for surface water.  Because the use on rice
involves flooding (for which the current Tier II model is not
parameterized), the surface water EDWCs were assessed using a Tier I
Rice Model, Version 1.0 (May 8, 2007).  Turf grass was identified as the
use resulting in the highest EDWCs for ground water.  The EDWC in
ground water was assessed using the Tier I Screening Concentration in
Ground Water (SCI-GROW, Version 2.3) model.  Based on the rice and turf
modeling estimates the EDWCs for both acute and chronic scenarios in
ground and surface water are 0.029 ppm and 0.511 ppm, respectively.  The
proposed use on caneberries, blueberries and asparagus are for
applications to be made at 0.375 lb ai/acre with two applications and a
30 day PHI for blueberry and caneberry.  For asparagus, one application
at 0.375 lb ai/acre will be made after the last harvest and prior to the
first frost.  These uses are not expected to result in higher EDWCs than
turf and/or rice so the previous EDWCs are still appropriate for use in
risk assessment.

Non-dietary exposure. Quinclorac is currently registered for use in turf
and has been previously assessed by the EPA.  No dermal endpoint for
quinclorac has been identified because no dermal toxicity was observed
at the limit dose of 1000 mg/kg bw/day in the 21-day dermal toxicity
study.  For the turf use, oral exposure from hand-to-mouth and
object-to-mouth for toddlers is expected.  The addition of caneberries,
blueberry and asparagus will not impact non-dietary exposures so the
previously assessed non-dietary exposures are still appropriate for use
in risk assessment.

Cumulative Effects

Quinclorac has not been identified as having a common mechanism of
toxicity with any other active ingredient.

Safety Determination

U.S. population. The addition of caneberries, blueberries and asparagus
to the quinclorac risk cup will not result in unreasonable risks and
there is a reasonable certainty that no harm will result from the
aggregate exposure to quinclorac.

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caneberries, blueberries and asparagus to the quinclorac risk cup will
not result in unreasonable risks and there is a reasonable certainty
that no harm will result to infants or children from the aggregate
exposure to quinclorac.

International Tolerances

There are no CODEX maximum residue limits established for quinclorac on
blueberry, caneberry or asparagus.

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