Document ID: EPA-HQ-OPP-2008-0362-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-04T04:00Z

<EPA Registration Division contact: Sidney Jackson, 703-305-7610>

<Interregional Research Project #4/Dow AgroSciences LLC

>

<8E7325>

<	EPA has received a pesticide petition (PP) 8E7325 from the
Interregional Research Project No. 4 (IR-4), 500 College Road East,
Suite 201W, 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, by establishing a tolerance for residues of
quinoxyfen in or on the raw agricultural commodity globe artichoke at
1.4 parts per million (ppm); stone fruits crop group 12 at 0.70 ppm;
winter squash at 0.20 ppm; pumpkin at 0.20 ppm; edible gourd at 0.20
ppm;. 

Upon approval of the aforementioned tolerances, it is proposed that 40
CFR 180 be amended to remove the established tolerances for the residues
of quinoxyfen in or on the raw agricultural commodity sweet cherry at
0.3 ppm and tart cherry at 0.3 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>

ues (> 0.003 μg/g) to succeeding crops.>

<	2. Analytical method. A practical analytical method is available to
monitor and enforce the tolerances of quinoxyfen residues in crops.  The
analytical method uses a capillary gas chromatography and mass selective
detection (GC-MSD) with limits of quantitation (LOQ) of <0.01.  The
method is adequate for collecting data and enforcing tolerances for
quinoxyfen residues in/on the subject crops.>

<	3. Magnitude of residues. The residue data in support of the proposed
tolerances was generated from the magnitude of residue studies on
artichoke, stone fruits (peach, plum), and winter squash. 

Artichoke: Three artichoke trials were conducted in California to
collect data on the residues of quinoxyfen.  At each trial, four foliar
applications of quinoxyfen at a rate of approximately 0.13 lb ai/A were
applied, for a total of approximately 0.52 lb ai/A quinoxyfen.  The
applications were made 6-7 days apart and mature artichoke buds were
harvested with a PHI of 0 days.  The limit of detection (LOD) and limit
of quantitation (LOQ) were calculated as 0.0033 ppm and 0.0099 ppm,
respectively, for quinoxyfen.  Residues from treated field samples with
a PHI of 0 days ranged from 0.63 to 1.09 ppm for quinoxyfen.  The
results from the trials show that the maximum residue in artichokes
following a total application of approximately 0.52 lb ai/A quinoxyfen
and a pre-harvest interval (PHI) of 0 days was 1.09 ppm quinoxyfen. 
Data from this study may be used to support a tolerance proposal for
quinoxyfen on artichokes.  

Stone Fruits, Peach:  Eleven peach trials were conducted in New York,
North Carolina, New Jersey, Michigan, Texas and California.  At each
trial, four foliar applications of quinoxyfen at a rate of approximately
0.13 lb ai/A were applied, for a total of approximately 0.52 lb ai/A
quinoxyfen.  The applications were made 6-8 days apart and mature
peaches were harvested with a PHI of 7+1 days.  Based on recoveries of
samples fortified at the LLMV, the limit of detection (LOD) and limit of
quantitation (LOQ) were calculated as 0.0012 ppm and 0.0037 ppm,
respectively, for quinoxyfen.  Residues from treated field samples with
a PHI of 7 (+ 1) days ranged from 0.057 to 0.55 ppm for quinoxyfen.  The
results from the trials show that the maximum residue in peaches
following a total application of approximately 0.52 lb ai/A quinoxyfen
and a pre-harvest interval (PHI) of 7+1 days was 0.55 ppm quinoxyfen.

Stone Fruits, Plum:  Six residue trials were conducted with four foliar
applications of Quintec EF 1295 to plum trees at nominally 0.13 lb.
a.i./A for a total application rate of nominally 0.52 lb a.i./A with
retreatment intervals of 6-8 days and a pre-harvest interval of 7 days. 
The lowest level of method validation (LLMV) in this study was 0.010 ppm
for both plums and dried plums.  Based on recoveries of fresh plum
samples fortified at the LLMV, the limit of detection (LOD) and limit of
quantitation (LOQ) were calculated as 0.002 ppm and 0.005 ppm
respectively.  For dried pitted plums, the limit of detection (LOD) and
limit of quantitation (LOQ) were calculated as 0.001 ppm and 0.004 ppm
respectively based on recoveries of dried pitted plum samples fortified
at the LLMV.  The maximum residue of quinoxyfen in plum fruit was 0.095
ppm after four foliar applications of 0.129- 0.131 lb a.i./A for a total
application rate of 0.518 lb a.i./A during fruiting with a PHI of 7
days.  The residue of quinoxyfen in dried pitted plum fruit (one sample)
was 0.030 ppm after four foliar applications of 0.128 to 0.133 lb a.i./A
for a total application rate of 0.522 lb a.i./A during fruiting with a
PHI of 7 days.  No residues were detected in any of the control samples
analyzed. 

Winter Squash:  Five winter squash trials were conducted with trials in
California, Florida, Maryland, New Jersey and Ohio.  At each trial, four
foliar applications of quinoxyfen at a rate of approximately 52 lb ai/A
quinoxyfen.  The applications were made 6-9 days apart and mature winter
squash were harvested with a PHI of 3-4 days.  Based on recoveries of
samples fortified at the LLMV, the limit of detection (LOD) and limit of
quantitation (LOQ) were calculated as 0.0014 ppm and 0.0041 ppm,
respectively, for quinoxyfen.  The results from the trials show that the
maximum residue in winter squash following a total application of
approximately 0.52 lb ai/A quinoxyfen and a pre-harvest interval (PHI)
of 3-4 days was 0.106 ppm quinoxyfen.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  No appropriate toxicological endpoint attributable
to a single exposure of quinoxyfen was identified based on the available
toxicity studies including the acute neurotoxicity study in rats, the
developmental toxicity studies in rats and in rabbits.  Therefore, acute
risk assessment is not required.>

<	2. Genotoxicty.  Quinoxyfen was negative for genotoxicity when tested
in 

in vitro and in vivo systems.>

<	3. Reproductive and developmental toxicity   There was no evidence of
increased> susceptibility in the oral rat or rabbit developmental
studies.  There 

was an increased quantitative susceptibility of young animals following 

pre/postnatal exposure to rats in the reproduction study.  No maternal
effects were observed up to the highest dose tested (100
milligrams/kilograms/day (mg/kg/day); however, minimally reduced F1a pup
weights were noted at 100 mg/kg/day.

<	4. Subchronic toxicity.  Quinoxyfen caused increased liver weights and
microscopic hepatocellular hypertrophy when given at sufficiently high
dose levels in rats and mice for 13 weeks; no effects were observed in
the subchronic dog study 

at the highest dose tested.  Very high dietary levels were associated
with slight 

hepatocellular necrosis.  Similar increases in liver weights were seen
in chronic studies.  In addition, increased kidney weights, and an
increase in the incidence of chronic progressive glomerulonephropathy,
were seen after 24 months in female rats given high dose levels of
quinoxyfen.>

<	5. Chronic toxicity.  Combined chronic/carcinogenicity (rat) NOAEL =
20 mg/kg/day.  LOAEL = 80 mg/kg/day based on increases in severity of
chronic progressive glomerulonephropathy in the males and minimal
decreases in body weight and body weight gain in the males and females. 
No evidence of carcinogenicity existed in an 18-month mouse feeding
study and a 24-month rat feeding study at any dosage tested.>

<	6. Animal metabolism.  Quinoxyfen is rapidly absorbed, extensively
metabolized and rapidly eliminated in the urine and feces.  Studies
conducted with 14C-quinoxyfen, labeled in either the phenyl ring or the
quinoline ring, indicated extensive cleavage of the diaryl ether
linkage.  There were no substantive differences in the metabolism and
disposition of quinoxyfen between males and females, or between single
or repeated exposure.  Parent quinoxyfen was not found in the urine,
though it was identified in the feces.  The major metabolites found in
urine and/or feces included (1) acid-labile conjugates of the phenyl
ring moiety (4-FP) and quinoline ring moiety (DCHQ); (2) lesser
quantities of free 4-FP and DCHQ; and, (3) isomers of fluorophenyl-ring
hydroxy-quinoxyfen, both free and glucuronide and/or sulfate conjugates.
 Trace quantity of the 3-OH metabolite was also identified in the urine
and feces of rats.>

<7. Metabolite toxicology.  The nature of residue studies (NOR) of
quinoxyfen in plants indicated that the majority of applied radiolabeled
material remained as the parent compound.  Analyses from NOR studies in
a number of crops revealed low residues of metabolites (<10% TRR)
identified as (1) a quinoline-ring hydroxylated metabolite, most likely
3-OH; (2) a cyclized deschloro photoproduct (CFBPQ); (3) 4-FP; and, (4)
a metabolite in which the fluorine was replaced by a hydroxyl group.  

Of these metabolites, 4-FP (formed by ether bridge cleavage), and DCHQ
(corresponding to the other half of the molecule), as well as trace
quantities of 3-OH, have been identified in rat urine and/or feces. 
These data suggest that most metabolites formed in plants are similarly
formed in mammals and are of little toxicologic concern, based on the
existing data for quinoxyfen.>

<	8. Endocrine disruption.  There is no evidence from any studies to
suggest that quinoxyfen has an effect on any endocrine system.>

<C. Aggregate Exposure>

<	1. Dietary exposure.  Risk assessments were conducted to assess
dietary exposures from quinoxyfen in food as follows:>

<	i. Food.  No appropriate toxicological endpoint attributable to a
single exposure was identified in the available toxicological studies on
quinoxyfen.  Thus, the risk from acute exposure is considered
negligible. 

Based on the conservative assumptions used and using a cPAD of 0.20
mg/kg/day, the chronic dietary exposure to quinoxyfen from all
registered and proposed uses without drinking water, to all population
subgroups is approximately 2% of the cPAD.  Children 1-2 years old have
been identified as the most highly exposed population subgroup utilizing
only 2.1% of the cPAD.>

<	ii. Drinking water.  Calculation of potential acute aggregate dietary
exposure from food and drinking water was not necessary.  Risk
assessment for short-term and chronic exposure to quinoxyfen indicates
that drinking water is not a significant exposure pathway.  

Based on the FIRST and SCI-GROW models, the estimated environmental 

concentrations (EECs) of quinoxyfen for chronic exposures are estimated 

to be 0.84 ppb for surface water and 0.006 ppb for ground water.  For
the purpose of these assessments, 8.4 ppb was used for the chronic
exposure estimate for water, and this value was incorporated as a single
point estimate for both “water, direct, all sources,” and “water,
indirect, all sources” within DEEM-FCID( food categories exposure
modeling.  Based on the conservative assumptions used and using a cPAD
of 0.20 mg/kg/day, the chronic dietary exposure to quinoxyfen from all
registered and proposed uses and drinking water, to all population
subgroups is approximately 2% of the cPAD.  Children 1-2 years old have
been identified as the most highly exposed population subgroup utilizing
only 2.1% of the cPAD.>

<	2. Non-dietary exposure. Quinoxyfen is not registered for use on any
sites that would result in residential exposure.  Thus, the risk from
non-dietary exposure is considered negligible.>

<D. Cumulative Effects>

<	At this time, EPA does not have available data to determine whether
quinoxyfen has a common mechanism of toxicity with other substances. 
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, quinoxyfen does not
appear to produce a toxic metabolite generated by other substances.  For
purposes of this assessment, therefore, it is assumed that quinoxyfen
does not have a mechanism of toxicity common with other substances and
no cumulative risk assessment is required.>

<E. Safety Determination>

<	1. U.S. population.  Using conservative exposure assumptions (Tier 1)
and taking into account the completeness and reliability of the toxicity
data, chronic dietary food exposure to quinoxyfen from registered uses
as well as from proposed uses will utilize 1.3% of the cRfD for the
general U.S. population.  The major identifiable subgroup with the
highest chronic food exposure is children (1-2 years old) utilizing only
2.1% of the cRfD.  Generally, EPA has no concern for exposures below
100% of the cRfD because the chronic RfD represents the level at or
below which daily dietary exposures over a lifetime will not pose
appreciable risks to human health.  Additionally, the potential
contribution of quinoxyfen residues in drinking water to aggregate
exposure is expected to be minimal.  

Short-term and intermediate-term risks are considered to be negligible
because of lack of significant toxicological effects.  Therefore, based
on these risk assessments, Dow AgroSciences concludes that there is
reasonable certainty that no harm will result to the U.S. population
from aggregate exposure to quinoxyfen residues from registered and
proposed uses.>

<	2. Infants and children. EPA uses a weight of evidence approach in
determining what safety factor is appropriate for assessing risks to
infants and children.  This approach takes into account the nature and
severity of the effects observed in pre- and post-natal studies and
other information such as epidemiological data.  The completeness and
adequacy of the toxicity database is also considered.

The toxicity database and exposure data for quinoxyfen are complete.  No
indication of increased susceptibility of rats or rabbits to in utero
and/or postnatal exposure was noted in the acceptable developmental
toxicity studies in rats and rabbits as well as in a 2-generation
reproductive toxicity study in rats.  EPA has previously determined that
no additional safety factor to protect infants and children is necessary
for quinoxyfen and that the RfD at 0.20 mg/kg/day is appropriate for
assessing risk to infants and children.

Using the conservative assumptions (Tier 1) described above, the chronic
dietary exposure to quinoxyfen from (food + water) will utilize 1.3% of
the cPAD for the U.S. population, <1% of the cPAD for infants (< 1year
old), and 2.1% of the cPAD for children (1-2 years old) the population
at greatest exposure.  Even when considering the potential exposure to
drinking water, the aggregate exposure is not expected to exceed 100% of
the cRfD.  There are no residential uses for quinoxyfen that result in
chronic residential exposure to quinoxyfen.  Therefore, based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, Dow AgroSciences concludes with reasonable
certainty that no harm will result to infants and children from the
aggregate exposure to quinoxyfen residues from registered and proposed
uses.>

<F. International Tolerances>

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There are no Mexican, Canadian or Codex maximum residue limits 

(MRLs) established for quinoxyfen in/on any food or feed crop. 
Therefore, no compatibility issues exist for these tolerances. 
International harmonization is therefore not an issue for this
notification.>

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