Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

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

PP No. 1F7822

EPA has received a pesticide petition (1F7822) from E.I. du Pont de Nemours & Company, 1007 Market Street, Wilmington, DE 19898, 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 a tolerance for the combined residues of the herbicide quizalofop-p-ethyl (ethyl - 2- [4-(6-chloroquinoxalin-2-yl oxy) phenoxy] propanoate), including its metabolites and degradates [DUPONTTM ASSURE® II], in or on the raw agricultural commodities: corn, grain at 0.01 ppm; corn, forage at 0.01 ppm; and corn, stover at 0.03 ppm.

The currently proposed aspirated grain fraction (AGF) tolerance of 1.0 ppm, based on sorghum AGF in PP# 0E7802, will not be changed by corn AGF residues.

This summary was prepared by the petitioner. EPA has determined that the petition contains data or information regarding the elements set fo rth 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, sugar

beets and corn.

The plant metabolism data show that quizalofop-p et hyl 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 aci d, 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, sugar beets and corn 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.Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

2. Analytical method.

An adequate analytical methodology (high-pr essure 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 twenty four trials show that the maximum total quizalofop P-ethyl - related residue expressed as parent equivalent was 0.004 ppm in corn, grain; <0.003 ppm (LOQ) in corn, forage; and 0.016 ppm in corn, 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 regul ar 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 maximizes the potential quizalofop exposure of 2.1 ppm. A theoretical dairy cattle diet consisting of pea and bean forage would maximize the potential quizalofop exposure at 2.4 ppm. Substitutions of othe r feed items (including corn residues) and varying their percentages in the diets w ould 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 f eeding 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.Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

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. Thes e include the following studies in Category III: acute oral toxicity (LD 50 s 1480 and 1670 for female and male rats, respectively) and eye irritation (mild effects; reversible within 4 days). 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 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. Th e maternal toxicity NOEL was 30 mg/kg/day and a developmental toxicity NOEL was greater than 300 mg/kg/day. The maternal NOEL wasPesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

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 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 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, respec tively). 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 we ights and reversible histopathological effects

in the liver at the LDT.

A 6-month feeding study in dogs was conducted w ith 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, 80Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

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, respec tively). 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. 14 C-Phenyl and 14 Cquinoxaline 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 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 significancePesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

8. Endocrine disruption.

No special studies investigating potential estrogenic or other endocrine effects of quizalofop pethyl have been conducted. However, the standa rd 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 lik ely 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 (DEEM TM -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 dos e (cRfD) of 0.009 mg/kg/day, based on a NOEL of 0.9 mg/kg/day from the chronic rat dietary st udy and a 100X uncertainty factor, was used.

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 0.001957 mg/kg/day, or 1% of the aRfD. The subpopulation with the highest estimated acute exposure was infants with exposure of 0.005311 mg/kg/day at the 95 th 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 0.000665 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 0.002224 mg/kg/day; this corresponds to 25% 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.Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

Current EPA water values (James Lin, “Drinking Water Exposure 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 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 th at 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.

Calculated hypothetical dietary risk 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 quizalofopethyl, data were considered from developmental toxicity studies in the rat and rabbit, and a multigeneration 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 fr om 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.Pesticide Petition for Toleran ces AGRICULTURAL COMMODITIES for Quizalofop-ethyl Corn – Grain, Forage and Stover

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.