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 I nterregion al 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 ) b y establishing tolerance s for residues of the herbicide quizal ofop ethyl (ethyl
- 2
- [4
- (6
- chloroquinoxalin
- 2
- yl oxy )phenoxy ]propanoate) , including its metabolites and degradates, in or on the following commodities : r apeseed subgroup 20A, e xcept 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 amen d 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the table in paragraph (a)(3) upon the approval of the aforementioned tolerances, as the individual tolerance will be superseded by inclusion in rapeseed subgroup 20A , except flax, seed .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. T he 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 e thy l , 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 ethy l residues convertible to 2
- methoxy
- 6
- chloroquinox aline, expressed as the stoichiometric equivalent of quizalo fop 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 ethy l residues convertible to qu izalofop (2
- [4
- (6
- chloroquinoxalin
- 2
- yl
- oxy )phenoxy ]propanoic acid), expressed as quizalo fop, in or on the commodity .” Finally , the petition proposes to revise the tolerance expression under section (c) to read as follows: " Tolerances with regional regis trations
. 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 ethy l residues convertible to 2
- methoxy
- 6
- chloroquinoxaline, expressed as the stoichiometric equivalent of quizalo fop 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 soy beans, 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 hy droly zed to the quizalofop acid. The acid is then cleaved to form a number of phenols and conjugates with natural plant sugars. Metabolism studies in soy beans using quizalofop
- p ethyl ester (the resolved D+ isomer) and quizalofop ethyl ester (racemic mixture) show consistent pathway s with nearly

identical results
. Insummary , qu izalofop
- p ethyl ester is metabolized by cleavage at three sites as follows: 1) Primary

pathway is hy droly sis of the ethyl ester to form the quizalofop
- p acid 2) Cleavage of the enol ether linkage in the acid, between the phenyl and quinoxaliny l rings, t o form phenols, and 3) Cleavage of the ether linkage between the isopropy l group and the phenyl ring to form a phenol. The nature of the quizalofop
- p ethyl ester residue in cottonseed, potatoes, tomatoes, soy beans, and sugar beets is adequately understoo d. 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. Analy tical method. An adequate analy

tical methodology

(hi gh
- pressure liquid chromatography using either ultraviolet or fluorescence detection) is available for enforcement purposes in Vol. I I of the Food and Drug Administration Pesticide Analy tical Method (PAM I I, Method I ). 3. Magnitude of residues.
a . Magn itude of the residue in p lants: The results from thirteen sorghum trials showed that all samples contained only quizalofop acid residue above the lowest level of method validation (L LM V) 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
- ethy l to be <0.05 ppm (LLM V). Therefore. the total quizalofop P
- ethy l
- 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 contro l group) were fed 0.1, 0.5, and 5.0 ppm quizalofop ethy l ester (encapsulated) for 28 consecutive day s. Milk was collected daily and a sub
- sample was divided into skim milk and cream. Two cows were sacrificed after 28 day s with samples of fat, skeletal mu scle, liver, and kidney being collected and analy zed. The remaining cow in each test group was fed a regular diet without encapsulated quizalofop ethy l ester for seven additional day s 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 partit ioned 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 ethy l 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 i tems 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 e thy l ester treated RACS or their processed feed items when Assure® I I is used as directed. The established quizalofop and quizalofop ethy l 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 day s. Eggs were collected daily , and after 28 day s 3/4 of the hens in each test group were sacrificed, and samples of fat, liver, kidney , breast and thigh muscles were collected and analy

zed. Tissues from each test group were poo led prior to analy sis. The remaining five hens were fed a regular poultry diet without quizalofop ethy l ester for an additional seven day s before sacrifice. No quizalofop residues were detected in the liver to <0.05 ppm, and in breast and thigh muscles t o <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 fee ding 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® I I is used as direc ted, 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
- productsof 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 ethy l in toxicity Category I II. These include the following studies in Category I II: acute oral to xicity

(LD 50 s 1480 and 1670 for female and male rats, respectively ) and ey e irritation (mild effects; reversible within 4 day s). Dermal toxicity (LD 50 > 5,000 mg/kg; rabbit), inhalation toxicity (LC 50 > 5.8 mg/L; rat) and dermal irritation were classified within Category I V. Technical quizalofop ethyl was not a dermal sensitizer. 2. Genotoxicty
. Technical quizalofop ethyl was negative in the following genotoxicity tests: bacterial gene mutation assay s with E. coli and S. typhimurium ; gene mutation ass ay s in Chinese hamster ovary (CHO) cells; in vitro DNA damage assay s with B. subtillis and in rat hepatocy tes; and an in vitro chromosomal aberration test in CHO cells. 3. Reproductive and developmental toxicity
. Studies supporting the registration incl ude: A developmental toxicity study in rats administered dosage levels of 0, 30, 100, and 300 mg/kg/day

on day s 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 mater nal 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 g roup 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 day s 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 (sy stemic effects) NOEL of 1.25 mg/kg/day for F 2B 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 phy siological 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
- day s of age. Consumption could no t be quantified; therefore, the maternal consumption was assumed as the NOEL (ifnormalized 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 wei ght 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 i ncreased 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 live r weights and reversible histopathological effects in the liver at the L DT. 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

w as 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
- ye ar 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 e ffects observed under the conditions of the study at levels up to and including 18.6 g/kg/day (HDT). The sy stemic NOELwas 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
- ye ar 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 C ategory D ( not c lassifiable as to human cancer potential). 6. Animal metabolism.The metabolism of quizalofop
- ethyl in animals is well understood. 14 C
- Pheny l and 14 C
quinoxaline quizalofop ethy l ester metabolism studies have been conducted in the laboratory rat, lact ating goat and laying hen. Overall, the metabolism in these three species was consistent. Q uizalofop ethy l is rapidly and extensively

metabolized and rapidly

excreted by

rats. The principal metabolites were quizalofop acid and two dechlorinated hydroxy l ated forms of the acid. Tissue residues were minimal and there was no evidence of accumulation of quizalofop ethy l or its metabolites in the rat. The primary

metabolic step in ruminants and poultry is hy droly sis of the ethyl ester to form the quizalofop a cid. I n poultry , quizalofop acid is esterified to form the quizalofop methy l 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 ethy l. 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. Endocr ine disruption. No special studies investigating potential estrogenic or other endocrine effects of quizalofop p ethyl have been conducted. H owever, the standard battery o f required toxicology

s tudies has been completed. T hese include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology o f the endocrine organs following repeated or long
- term exposure to doses that far exceed likely h uman exposures. B ased on these studies there is no evidence to sugg est that quizalofop p - ethyl has an adverse effect on the endocrine sy stem. 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 (DEEM TM

- FCI D) Version 2.03 software from Exponent, I nc. An acute reference dose (aRfD) of 0.3 mg/kg/day , based on a maternal NOEL of 30 mg/kg/day

and a 10 0X 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 re vised 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 95 th percentile since a Tier 1 assessment was performed. The acute exposure at the 95 th 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 95 th percentile, or 2% of the aRfD. Based on the risk estimates arrived at in this analy sis, 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/d ay ; this corresponds to 24% of the cRfD. Based on the risk estimates arrived at in this analy sis, chronic dietary risk from the current and proposed uses of Assure  II is minimal. b . Drinking water. Current EPA water values (James L in, “Drinking Water Ex posure for Quiazolfop
- P
- Ethyl Based on the Proposed and Registered Uses According to TARGA TM Label”, Oct . 25, 2005) are used
. Since surface water values were higher than gro und water they will be used . I n the EPA work a Tier I I 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 u se that could result in non - occupational, non - dietary exposure to the general population. D. Cumu lative Effects There is no evidence to indicate or suggest that quizalofop p - ethyl has any t oxic 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 95 th 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 95 th percentile, or 2% of the aRf D. 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 childr en 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 . I nfants and children. Inassessing 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 phy siological effects were observ ed 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
- ye ar rat study with quiza lofop 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 ethy l. As indicated above, infants and children have a low potential f or 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 ethy l, 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 qu izalofop ethy l. F. I nternational Tolerances Harmonization of Tolerances: Since there are no Mexican or Codex MRL s/tolerances, compatibility

is not a problem at this time.