Document ID: EPA-HQ-OPP-2010-1018-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-25T05:00Z

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

E. I. du Pont de Nemours and Company (DuPont) 

 

Petition Number 0E7802

EPA has received a pesticide petition, PP 0E7802, from the Interregional
Research Project No. 4 (IR-4), Rutgers, The State University of New
Jersey, 500 College Road East, Suite 201W. Princeton, NJ 08540,
proposing pursuant to section 408 (d) of the Federal Food, Drug, and
Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR Part 180.441 (a)(1) by
establishing tolerances for residues of the herbicide quizalofop ethyl
(ethyl-2-[4-(6-chloroquinoxalin-2-yl oxy)phenoxy]propanoate), including
its metabolites and degradates, in or on the following commodities:
rapeseed subgroup 20A, except flax, seed at 1.0 ppm; gold of pleasure,
meal at 1.5 ppm; crambe, meal at 1.5 ppm; sorghum, grain at 0.2 ppm;
sorghum, forage at 0.2 ppm; sorghum, stover at 0.35 ppm; and sorghum,
aspirated grain at 1.0 ppm. 

Additionally, PP 0E7802 proposes to amend 40 CFR Part 180.441 by
removing the established tolerance for canola, seed at 1.0 ppm from the
table in paragraph (a)(3) upon the approval of the aforementioned
tolerances, as the individual tolerance will be superseded by inclusion
in rapeseed subgroup 20A, except flax, seed. The petition also proposes
to remove section (a)(4), as these tolerances expired on June 14, 1999. 

The petition, PP 0E7802, also proposes to amend the tolerances in 40 CFR
part 180.441 by combining the tables for sections (a)(1) and (a)(3) into
one table under section (a)(1), and by removing section (a)(3). The
petition further proposes to revise the tolerance expression under
section (a)(1) to read as follows: "Tolerances are established for
residues of the herbicide quizalofop ethyl, 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 those quizalofop ethyl residues convertible to
2-methoxy-6-chloroquinoxaline, expressed as the stoichiometric
equivalent of quizalofop ethyl, in or on the commodity."  The petition
additionally proposes to revise the tolerance expression under section
(a)(2) to read as follows: “Tolerances are established for residues of
the herbicide quizalofop ethyl, 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 those quizalofop ethyl residues convertible to quizalofop
(2-[4-(6-chloroquinoxalin-2-yl-oxy)phenoxy]propanoic acid),  expressed
as quizalofop, in or on the commodity.”  Finally, the petition
proposes to revise the tolerance expression under section (c) to read as
follows: "Tolerances with regional registrations. Tolerances with
regional registration are established for residues of the herbicide
quizalofop ethyl, 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 those quizalofop
ethyl residues convertible to 2-methoxy-6-chloroquinoxaline, expressed
as the stoichiometric equivalent of quizalofop ethyl, in or on the
commodity."

This summary was prepared by the petitioner. 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 the petition. Additional data may be needed before EPA
rules in the petition.

A. Residue Chemistry                                        

1. Plant metabolism.    

The registrant has provided plant metabolism studies for soybeans,
cotton, tomatoes, potatoes, and sugar beets.  These studies have been
previously reviewed in PP# 3F4268. 

The plant metabolism data show that quizalofop-p ethyl ester does not
translocate, but is rapidly hydrolyzed to the quizalofop acid. The acid
is then cleaved to form a number of phenols and conjugates with natural
plant sugars.  Metabolism studies in soybeans using quizalofop-p ethyl
ester (the resolved D+ isomer) and quizalofop ethyl ester (racemic
mixture) show consistent pathways with nearly identical results. In
summary, quizalofop-p ethyl ester is metabolized by cleavage at three
sites as follows:

1)  Primary pathway is hydrolysis of the ethyl ester to form the
quizalofop-p acid

2)  Cleavage of the enol ether linkage in the acid, between the phenyl
and quinoxalinyl rings, to form phenols, and

3)  Cleavage of the ether linkage between the isopropyl group and the
phenyl ring to form a phenol.

The nature of the quizalofop-p ethyl ester residue in cottonseed,
potatoes, tomatoes, soybeans, and sugar beets is adequately understood.
The residues of concern are quizalofop-p ethyl ester and its acid
metabolite, quizalofop-p, and the S enantiomers of both the ester and
the acid, all expressed as quizalofop-p ethyl ester. 

2. Analytical method. 

An adequate analytical methodology (high-pressure liquid chromatography
using either ultraviolet or fluorescence detection) is available for
enforcement purposes in Vol. II of the Food and Drug Administration
Pesticide Analytical Method (PAM II, Method I).  

3. Magnitude of residues.

a. Magnitude of the residue in plants: 

The results from thirteen sorghum trials showed that all samples
contained only quizalofop acid residue above the lowest level of method
validation (LLMV) of 0.05 ppm. The maximum quizalofop acid residues were
0.12 ppm in forage (KS03 site), 0.10 ppm in grain (KS02 site) and 0.20
ppm in stover (KS03 site). All samples showed residues of quizalofop
P-ethyl to be <0.05 ppm (LLMV).  Therefore. the total quizalofop P-ethyl
- related residue expressed as parent equivalent was 0.208 ppm grain,
0.266 ppm forage and 0.266 ppm stover.  

b. Magnitude of the residue in animals: 

A ruminant feeding study has been submitted and reviewed in PP Nos.
5F3252 and 1F3951.  In summary, three groups of three lactating dairy
cows (plus a control group) were fed 0.1, 0.5, and 5.0 ppm quizalofop
ethyl ester (encapsulated) for 28 consecutive days.  Milk was collected
daily and a sub-sample was divided into skim milk and cream.  Two cows
were sacrificed after 28 days with samples of fat, skeletal muscle,
liver, and kidney being collected and analyzed.  The remaining cow in
each test group was fed a regular diet without encapsulated quizalofop
ethyl ester for seven additional days before sacrifice.  Whole milk,
skim milk, and cream from the control, and the 0.1 and 0.5 ppm dose
groups showed no quizalofop to <0.02 ppm (0.05 ppm in cream).  From the
5 ppm dose, quizalofop residues ranged from 0.01 to 0.02 ppm in whole,
and when these samples were separated into cream and skim milk, the
quizalofop partitioned into the cream with residues plateauing at 0.26
to 0.31 ppm.  No quizalofop to <0.02 ppm was detected in skeletal
muscle, and to <0.05 ppm was detected in any liver or fat sample from
any of the three doses.  Quizalofop was detected in one kidney sample as
0.05 ppm from the 5 ppm dose.

From the feed items in this petition, all of the feed items in cattle
diets can be treated with quizalofop ethyl ester. A theoretical beef
cattle diet consisting of canola meal, bean and pea forage, pea hay, and
sugar beet tops which none-the-less maximizes the potential quizalofop
exposure of 2.1 ppm. A theoretical dairy cattle diet consisting of pea
and bean forage would none-the-less maximize the potential quizalofop
exposure at 2.4 ppm. Substitutions of other feed items and varying their
percentages in the diets would give a lower dietary quizalofop burden.

The results of the quizalofop ethyl ester bovine feeding study show that
finite residues will actually occur in milk and tissues from the feeding
of quizalofop ethyl ester treated RACS or their processed feed items
when Assure® II is used as directed. The established quizalofop and
quizalofop ethyl ester tolerance in milk, and in fat, meat, and meat
by-products of cattle, goats, hogs, horse, and sheep are adequate and
need not be increased from these additional uses. 

A poultry feeding study has been submitted and reviewed (ibid). In
summary, three groups of 20 hens (plus one control group) were dosed
with encapsulated quizalofop ethyl ester at 0.1, 0.5, and 5 ppm daily
for 28 consecutive days.  Eggs were collected daily, and after 28 days
3/4 of the hens in each test group were sacrificed, and samples of fat,
liver, kidney, breast and thigh muscles were collected and analyzed. 
Tissues from each test group were pooled prior to analysis.  The
remaining five hens were fed a regular poultry diet without quizalofop
ethyl ester for an additional seven days before sacrifice.  No
quizalofop residues were detected in the liver to <0.05 ppm, and in
breast and thigh muscles to <0.02 ppm for any dose administered.  From
the 5 ppm dose, one kidney sample showed 0.09 ppm quizalofop, two fat
samples were 0.05 and 0.06 ppm quizalofop, and one egg sample was 0.02
ppm quizalofop.

The results of the quizalofop ethyl ester poultry feeding study show
that while it is not possible to establish with certainty whether finite
residues will actually occur in eggs and tissues from the feeding of
quizalofop ethyl ester treated RACS or their processed feed items when
Assure® II is used as directed, there is a reasonable expectation for
such residues to occur. The established tolerance of quizalofop and
quizalofop ethyl ester in eggs, and in fat, meat, and meat by-products
of poultry are adequate and need not be changed from these additional
uses.

B. Toxicological Profile 

1. Acute toxicity. 

Several acute toxicology studies were conducted and the overall results
placed technical grade quizalofop ethyl in toxicity Category III.  These
include the following studies in Category III: acute oral toxicity
(LD50s 1480 and 1670 for female and male rats, respectively) and eye
irritation (mild effects; reversible within 4 days).  Dermal toxicity
(LD50 > 5,000 mg/kg; rabbit), inhalation toxicity (LC50 > 5.8 mg/L; rat)
and dermal irritation were classified within Category IV.  Technical
quizalofop ethyl was not a dermal sensitizer.

2. Genotoxicty. 

Technical quizalofop ethyl was negative in the following genotoxicity
tests: bacterial gene mutation assays with E. coli and S. typhimurium;
gene mutation assays in Chinese hamster ovary (CHO) cells; in vitro DNA
damage assays with B. subtillis and in rat hepatocytes; and an in vitro
chromosomal aberration test in CHO cells.

3. Reproductive and developmental toxicity. 

Studies supporting the registration include:

A developmental toxicity study in rats administered dosage levels of 0,
30, 100, and 300 mg/kg/day on days 6 to 15 of gestation.  The maternal
toxicity NOEL was 30 mg/kg/day and a developmental toxicity NOEL was
greater than 300 mg/kg/day.  The maternal NOEL was based on reduced food
consumption and increased liver weights at 100 and 300 mg/kg/day and
reduced maternal weight gain at 300 mg/kg/day.  There was an equivocal
effect on maternal weight/ gain in the 100 mg/kg/day group (body weight
in this group was lower before the outset of dosing, so unclear if
subsequent effects were compound related).

A developmental toxicity study in rabbits administered dosage levels of
0, 7, 20, and 60 mg/kg/day on days 7-19 of gestation with no
developmental effects noted at 60 mg/kg/day.  The maternal toxicity NOEL
was 20 mg/kg/day based on decreases in food consumption at 60/mg/kg/day.

A two-generation reproduction study in rats fed diets containing 0, 25,
100 or 400 ppm (or approximately 1, 1.25, 5, and 20 mg/kg/day,
respectively) with a developmental (systemic effects) NOEL of 1.25
mg/kg/day for F2B weanlings based on increased liver weights and
increased incidence of eosinophilic changes in the livers at 5.0
mg/kg/day.  These liver changes were considered to be physiological or
adaptive changes to compound exposure among weanlings.  When access to
the mother’s feed is available, it is a common observation that young
rats will begin consuming chow prior to complete weaning at 21-days of
age.  Consumption could not be quantified; therefore, the maternal
consumption was assumed as the NOEL (if normalized on a body weight
basis, exposures to the weanling rats were likely higher).  The parental
NOEL of 5.0 mg/kg/day was based on decreased body weight and premating
weight gain in males at 20 mg/kg/day (HDT).

4. Subchronic toxicity. 

A 90-day study was conducted in rats fed diets containing 0, 40, 128,
1,280 ppm (or approximately 0, 2, 6.4 and 64 mg/kg/day, respectively). 
The NOEL was 2 mg/kg/day.  This was based on increased liver weights at
6.4 mg/kg.

A 90-day feeding study in mice was conducted with diets that contained
0, 100, 316 or 1,000 ppm (or approximately 0, 15, 47.4, and 150
mg/kg/day, respectively).  The NOEL was <15 mg/kg/day (LDT) based on
increased liver weights and reversible histopathological effects in the
liver at the LDT. 

A 6-month feeding study in dogs was conducted with diets that contained
0, 25, 100 or 400 ppm (or approximately 0, 0.625, 2.5, and 10 mg/kg/day,
respectively).  The NOEL was 2.5 mg/kg/day based on increased blood urea
nitrogen at 10 mg/kg/day.

A 21-day dermal study was conducted in rabbits at doses of 0, 125, 500
or 2,000 mg/kg/day. The NOEL was 2,000 mg/kg/day (HDT).

5. Chronic toxicity. 

An 18-month carcinogenicity study was conducted in CD-1 mice fed diets
containing 0, 2, 10, 80 or 320 ppm (or approximately 0, 0.3, 1.5, 12,
and 48 mg/kg/day, respectively).  There were no carcinogenic effects
observed under the conditions of the study at levels up to and including
12 mg/kg/day.  A marginal increase in the incidence of hepatocellular
tumors was observed at 48 mg/kg/day, the highest dose tested (HDT),
which exceeded the maximum tolerated dose (MTD).  (Please see the
discussion by the EPA HED Carcinogenicity Peer Review Committee.)

A 2-year chronic toxicity/carcinogenicity study was conducted in rats
fed diets containing 0, 25, 100 or 400 ppm (or 0, 0.9, 3.7, and 15.5
mg/kg/day for males and 0, 1.1, 4.6, and 18.6 mg/kg/day for females,
respectively).  There were no carcinogenic effects observed under the
conditions of the study at levels up to and including 18.6 g/kg/day
(HDT).  The systemic NOEL was 0.9 mg/kg/day based on altered red cell
parameters and slight/minimal centrilobuler enlargement of the liver at
3.7 mg/kg/day.

A 1-year feeding study was conducted in dogs fed diets containing 0, 25,
100 or 400 ppm (or approximately 0, 0.625, 2.5, and 10 mg/kg/day,
respectively). The NOEL was 10 mg/kg/day (HDT).

EPA has classified quizalofop ethyl as carcinogenicity Category D (not
classifiable as to human cancer potential). 

6. Animal metabolism. 

The metabolism of quizalofop-ethyl in animals is well understood. 
14C-Phenyl and 14C-quinoxaline quizalofop ethyl ester metabolism studies
have been conducted in the laboratory rat, lactating goat and laying
hen. Overall, the metabolism in these three species was consistent. 

Quizalofop ethyl is rapidly and extensively metabolized and rapidly
excreted by rats.  The principal metabolites were quizalofop acid and
two dechlorinated hydroxylated forms of the acid. Tissue residues were
minimal and there was no evidence of accumulation of quizalofop ethyl or
its metabolites in the rat.

The primary metabolic step in ruminants and poultry is hydrolysis of the
ethyl ester to form the quizalofop acid.  In poultry, quizalofop acid is
esterified to form the quizalofop methyl ester as a minor pathway.

The nature of the quizalofop ethyl ester residue in livestock is
adequately understood.  The residues of concern are quizalofop ethyl,
quizalofop methyl, and quizalofop, all expressed as quizalofop ethyl.

7. Metabolite toxicology. 

There is no evidence that the metabolites of quizalofop ethyl as
identified as either the plant or animal metabolism studies are of any
toxicological significance

8. Endocrine disruption. 

No special studies investigating potential estrogenic or other endocrine
effects of quizalofop p-ethyl have been conducted.  However, the
standard battery of required toxicology studies has been completed. 
These include an evaluation of the potential effects on reproduction and
development, and an evaluation of the pathology of the endocrine organs
following repeated or long-term exposure to doses that far exceed likely
human exposures.  Based on these studies there is no evidence to suggest
that quizalofop p-ethyl has an adverse effect on the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. 

Acute and chronic dietary risk assessments were conducted for
quizalofop-p-ethyl.  Tolerance values and 100% crop treated were used in
the assessments. The dietary risk assessments were conducted with
Dietary Exposure Evaluation Model (DEEMTM-FCID) Version 2.03 software
from Exponent, Inc.  An acute reference dose (aRfD) of 0.3 mg/kg/day,
based on a maternal NOEL of 30 mg/kg/day and a 100X uncertainty factor,
was used; the NOEL is from a rat developmental toxicity study in which
an effect on maternal body weight may have occurred at the outset of
dosing.  A chronic reference dose (cRfD) of 0.009 mg/kg/day, based on a
NOEL of 0.9 mg/kg/day from the chronic rat dietary study and a 100X
uncertainty factor, was used.

Current published tolerances including meat and poultry were used for
the residue values in both the chronic and acute (Tier 1) assessments. 
Milk and milk fat tolerances were revised upwards to 0.02 and 0.5 ppm,
respectively, based on recalculated dietary burdens due to the new crops
and new US Table 1 guidelines.  Sorghum grain was added at 0.2 ppm.  The
canola seed tolerance of 1.0 ppm was used for the residue value for
mustard seed.

a. Food. 

i. Acute

Acute exposure was determined at the 95th percentile since a Tier 1
assessment was performed.  The acute exposure at the 95th percentile for
the US population was 0.001928 mg/kg/day, or 1% of the aRfD.  The
subpopulation with the highest estimated acute exposure was infants with
exposure of 0.005280 mg/kg/day at the 95th percentile, or 2% of the
aRfD.  Based on the risk estimates arrived at in this analysis, acute
dietary risk from the current and proposed uses of Assure( II is
minimal.

ii. Chronic

Chronic exposure for the US population was determined to be 0.000652
mg/kg/day, which corresponds to 7% of the cRfD.  The subpopulation with
the highest estimated chronic exposure was children 1-2 with an exposure
of 0.002197 mg/kg/day; this corresponds to 24% of the cRfD. Based on the
risk estimates arrived at in this analysis, chronic dietary risk from
the current and proposed uses of Assure( II is minimal.

b. Drinking water.

Current EPA water values (James Lin, “Drinking Water Exposure for
Quiazolfop-P-Ethyl Based on the Proposed and Registered Uses According
to TARGATM Label”, Oct. 25, 2005) are used.  Since surface water
values were higher than ground water they will be used.  In the EPA work
a Tier II drinking water assessment of surface water was performed based
on Index Reservoir settings.  The simulation produced estimated drinking
water concentrations (EDWC) of 5.25 ppb for acute exposure, 1.99 ppb for
chronic exposure. The surface water values reported above, 5.25 ppb and
1.99 ppb, were put into the acute and chronic, respectively, dietary
risk assessments.

2. Non-dietary exposure. 

Quizalofop ethyl is not registered for any use that could result in
non-occupational, non-dietary exposure to the general population.

D. Cumulative Effects

There is no evidence to indicate or suggest that quizalofop p-ethyl has
any toxic effects on mammals that would be cumulative with those of any
other chemicals.

E. Safety Determination

1. U.S. population. 

The acute exposure due to food and drinking water at the 95th percentile
for the US population was 0.002088 mg/kg/day, or 1% of the aRfD.  The
subpopulation with the highest estimated acute exposure was infants with
exposure of 0.005820 mg/kg/day at the 95th percentile, or 2% of the
aRfD.  Chronic exposure due to food and drinking water for the US
population was determined to be 0.000694 mg/kg/day, which corresponds to
8% of the cRfD.  The subpopulation with the highest estimated chronic
exposure due to food and drinking water was children 1-2 with an
exposure of 0.002259 mg/kg/day; this corresponds to 25% of the cRfD.

These results fall below HED’s level of concern (>100% RfD) and
indicate that there is reasonable certainty that no chronic or acute
effects would result from exposure to quizalofop p-ethyl with the
recommended agricultural uses. 

 

2. Infants and children. 

In assessing the potential for additional sensitivity of infants and
children to residues of quizalofop ethyl, data were considered from
developmental toxicity studies in the rat and rabbit, and a
multi-generation reproduction study in rats.  There were no
developmental effects observed in the absence of maternal toxicity in
the rat and rabbit developmental studies.  Minimal adaptive or
physiological effects were observed in livers of weanlings in the
two-generation rat reproduction study described earlier. However, this
effect was only observed at a dose that far exceeds any expected human
exposure. Further, the NOEL of 0.9 mg/kg/day from the 2-year rat study
with quizalofop ethyl which was used to calculate the RfD (discussed
above), is already lower than any of the NOELs defined in the
developmental and reproductive toxicity studies with quizalofop ethyl.

As indicated above, infants and children have a low potential for
quizalofop ethyl exposure. The toxicology profile of quizalofop ethyl
demonstrates low mammalian toxicity. Because there was no evidence that
offspring were uniquely susceptible to the toxic effects of quizalofop
ethyl, an additional 10-fold uncertainty factor should not be required
to protect infants and children. Therefore, the RfD of 0.009 mg/kg/day,
which utilizes a 100-fold safety factor, is appropriate to assure a
reasonable certainty of no harm to infants and children from aggregate
exposure to quizalofop ethyl.

F. International Tolerances

Harmonization of Tolerances:  Since there are no Mexican or Codex
MRLs/tolerances, compatibility is not a problem at this time.