EPA REGISTRATION DIVISION

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

EPA Registration Division contact: Kable Bo Davis (703)306

- 0415

B ASF Corporation

2E8045

EPA has received a pesticide petition ( 2E8045 ) from BASF Corporation

, 26 Davis Drive, Research Triangle Park, NC 27709 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 .490 by establishing a tolerance for residues of imazapyr 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- ] H

- imidazol

- 2

- y l]

- 3

- pyridinecarboxylic acid in or on the raw agricultural commodity on Crop subgroup 20A

- Rapeseed subgroup at 0.05 parts per million (ppm) , Crop subgroup 20B

– Sunflower subgroup at 0.05 parts per million (ppm) and lentils at 0. 2 parts per million (ppm). EPA has determined that the petition contains data or information regarding the el ements 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 1. Plant metabolism. The metabolic pathway of imazap yr is understood and is s imilar in a range of different crops including B ermuda grass, Imidazolinone

- Resistant Corn, Clover and soybean. Parent imazapyr w as identified as major component of the total residue. i. Bermuda grass. Radiolabelled imazapyr (pyridine

- 6

- 14 C

- imazapyr), was applied to established Bermuda grass. A single application was made at the nominal rate of 1.5 lbs a.i./A. Samples of Bermuda grass were collected for analysis at 0, 4, 10, 15, and 21 days after treatment. The majority of residues were extracted with acidified methanol (86

- 97% TRR). The pred ominant residue, accounting for 78 to 97% TRR, was the parent compound, imazapyr. M etabolites CL 240000 and CL 247087 each accounted for ≤ 10%TRR while CL 9140 was present at a maximum of 12% TRR. The study demonstrated that imazapyr is metabolised slowl y in Bermuda grass and the major residue in the foliage is imazapyr. ii. Imidazolinone

- Resistant Corn. Radiolabeled imazapyr was applied once to maize plants in two plots at 0.025 lb a.i./A and 0.071 lb a.i./A. Imazapyr was the only major residue found i n maize grains or in plants of different growth stages. Any metabolite observed was only present at insignificant concentrations in samples taken after the day of application. Thus, imazapyr is the only relevant residue in maize. Additionally, extractio n of maize oil with hexane showed that residues of imazapyr did not accumulate in that lipophilic matrix.2

iii. Clover. Radiolabeled imazapyr was applied once as an aqueous solution to established clover at 1.5 lb a.i./A (1680 g a.i./ha). Imazapyr was the major residue in clover plants, accounting for 68 to 99% TRR. Metabolites CL 9140, CL 240000 and CL 247087 each accounted for insignificant proportions of the residue below 10% TRR. Thus, the study demonstrates that imazapyr is the only relevant residue in clover. iv. Soybean. Radiolabeled imazapyr was applied once as an aqueous solution to established CV127

- 9 soybean at 0.096 lb ai/A (107 g ai /ha). Imazapyr underwent significant metabolism; however, the parent molecule was the most abundant component of the residue in all matrices except straw and pods. Imazapyr is significantly metabolized in soybean, but no metabolites occur that would be met abolites of concern. Thus, the study demonstrates that imazapyr is the only relevant residue in soybean. 2. Analytical method. i. Canola

. The proposed analytical method for detecting residues of imazapyr in Canola RAC and processed commodity samples is an LC/MS/MS method with LOQ of 0.05 ppm

. ii. Lentil s

. The proposed analytical method for detecting residues of imazapyr in lentil RAC samples is an LC/MS/MS method with LOQ of 0.05 ppm. iii. Sunflower

. The proposed analytical method for detecting residues of imazapyr in sunflower RAC and processed commodity samples is an LC/MS/MS method with LOQ of 0.05 ppm. Another proposed method for detecting residues of imazapyr in sunflower RAC and processed commodity samples is also an LC/MS/MS method with LO Q 0.01 ppm

. iv. Animals. Enforcement methods for analysis of residues of imazapyr in animal

c ommodities were included in prior submissions. M 3023 is a reliable capillary electrophoresis method with ultraviolet (CE/UV) detection for the determination of i mazapyr residues in grass forage and grass hay. M 3184 is a reliable CE/UV method for the determination of imazapyr residues in meat, kidney, other meat byproducts, and fat of cattle, sheep, goats, and horses. M 3075 is a reliable CE/UV method for the det ermination of imazapyr residues in milk. 3. Magnitude of residues. i

. Canola

. Field trial data were generated for imazapyr on imidazolinone

- tolerant ClearfieldTM canola with a total of 12 trials i n NAFTA g rowing regions during 2008. Following a single broadcast foliar application of BAS 723 00 H, to canola at 9

- 10 g ae/ha, imazapyr residues were <0.05 ppm (<LOQ) in/on 24 treated canola seed samples harvested at a 68

- 72 day PHI.

A processing study was conducted using a single a pplication of imazapyr at 45 g ae/ha

. Imazapyr residues were 0.10 ppm in the treated meal sample and non

quantifiable ( <0.05 ppm) in the treated refined oil sample, each derived from the seed RAC sample bearing residues at 0.07 ppm. A comparison of the res idues in the RAC with those in the processed fractions indicated that residues of imazapyr do not concentrate in canola refined oil, and do not concentrated appreciably in meal (processing factor, 1.4x). ii. Lentils. Field trial data were g enerated for ima zapyr on imidazolinone

- tolerant lentil with total of five trials in N AFTA g rowing r egion s d uring the 2008 season.3

Following a single broadcast foliar application of BAS 723 00 H, to lentil at 9 g

ae /ha, imazapyr residues ranged from 0.06 to 0.10 ppm in/on ten treated lentil seed samples harvested at a 58

- 60 day PHI. iii. Sunflower. Field trial data from 5 trials were generated for imazapyr on imidazolinone

- tolerant sunflower in Argentina during the 2001

- 2002 growing season. Following a single broadcast foliar application of BAS 693 05 H, to sunflower at rates of 80, 100 and 160 g ae/ha., imazapyr residues were <0.05 ppm (<LOQ) in/on 3 treated sunflower seed samples and 2 treated sunflower flower samp les harvested at a 90

- 100 day PHI. A total of six trials were conducted in USA during the 2001

- 2002 growing season. F ollowing a single broadcast foliar application of Arsenal 2AS, to sunflower at a rate of 0.02 lb ae/acre (22 g ae/ha), imazapyr residues ra nged from <0.05 ppm (<LOQ) to 0.09 ppm in/on 12 treated sunflower seed samples harvested at a 72

- 100 day PHI. A total of five trials were conducted on sunflower in NAFTA Growing Region s during 2008. Following a single broadcast foliar application of BAS 72 3 00 H, to sunflower at 9 g ae/ha, imazapyr residues ranged from <0.05 (<LOQ) to 0.06 ppm in/on ten treated sunflower seed samples harvested at a 58

- 60 day PHI. A total of six trials were conducted on sunflower in Argentina during 2007, 2008 and 2009. Foll owing a single broadcast foliar application of Clearsol DF, to sunflower at 60 and 120 g ae/ha, imazapyr residues ranged from <0.01 (<LOQ) to 0.03 ppm in/on eleven treated sunflower seed samples harvested at a 98

- 109 day PHI. A total of four trials were co nducted on sunflower in Argentina during 2011. Following a single broadcast foliar application of BAS 723 00 H, to sunflower at 30 and 60 g ae/ha, imazapyr residues ranged from <0.01 (<LOQ) to 0.03 ppm in/on eight treated sunflower seed samples harvested a t a 81

- 143 day PHI. A total of three trials were conducted on sunflower in Uruguay and Argentina during 2010. Following a single broadcast foliar application of BAS 723 00 H, to sunflower at 80 g ae/ha, imazapyr residues were all <0.01 (<LOQ) in/on eight treated sunflower seed samples harvested at a 102

- 111 day PHI.

A processing study was conducted using Sunflowers with imazapyr targeting 0.02 lb ae/A (22 g ai/ha, 1X) and 0.04 lb ae/A (44 g ai/ha, 2X) in North Dakota. Residues of imazapyr concentrated s lightly in meal (1.4X), but did not concentrate in refined oil. Another processing study was conducted using Sunflower from two trials in Canada

. Imazapyr residues after a single broadcast foliar application of imazapyr at 46 g ae/ha, were 0.16 and 0.27 pp m. Imazapyr residues were 0.54 and 0.61 ppm in two treated samples of meal and were non

quantifiable in two treated samples of refined oil, each derived from the seed RAC samples. The residues of imazapyr do not concentrate in sunflower refined oil, but do concentrate in meal (processing factors 3.4x and 2.3x, average, 2.8x). i v . Ruminants. Lactating dairy cows were dosed orally each day for 28 or 29 consecutive days at feed equivalents of 0, 58, 157, 607, and 1,680 mg imazapyr/kg dry matter consumed. At 5 8 mg/kg, imazapyr residues in milk were < 0.01 mg/kg; residues in muscle, fat, and liver were <0.05 mg/kg; and residues4

in kidney averaged 0.25 mg/kg. The estimated dietary burden under current guidance is 18 ppm in dairy cattle including canola and sunfl ower meal , which is lower than EPA’s 2005 dietary burden estimate of 24 mg/kg, which is the basis for the existing meat and milk tolerances. Therefore, the new import tolerance for canola, lentil and sunflower will not require any changes to the current meat and milk tolerances. Canola meal and sunflower meal are used as feed items for beef and dairy cattle. Due to the low levels of residue in canola meal and sunflower meal, there is only a slight increase in dietary burden for beef and dairy cattle. EPA ’s previous dietary burden of 24 mg/kg for beef and dairy cattle was estimated in 2005 using the now obsolete maximum theoretical dietary burden (MTDB) guidance. The current meat and milk tolerances are based on a dietary burden of 24 mg/kg.

v . Poultry. C anola meal and sunflower meal are used as feed items for poultry. Due to the low levels of residue in canola meal and sunflower meal, there is only a slight increase in dietary burden for laying hens. Based on the dietary burden of 0.068 mg/kg in laying h ens, no residues are expected in poultry commodities.

B. Toxicological Profile 1. Acute toxicity. Imazapyr has low toxicity via the oral, dermal and inhalation routes of exposure. It is not irritating to the skin and showed no dermal sensitization potential (Buehler Method). An eye irritation study demonstrated irreversible corneal opacity. 2. Genotoxicity

. Imazapyr showed no genotoxic potential in a battery of studies on gene mutation (Ames Assay, CHO/HGPRT Mutation Assay) and other genotoxic effects ( in vitro CHO cell chromosome aberration assay, dominant lethal assay, unscheduled DNA synthesis (UDS) in primary rat hepatocytes and mouse micronucleus). 3. Reproductive and developmental toxicity. i. For a rat developmental toxicity study at do ses of 0, 100, 300, or 1,000 mg/kg body weight/day (b.w./day), the only clinical sign of toxicity was salivation in gravid dams at 1,000 mg/kg b.w./day. The No

- Observed

- Adverse

- Effect Level (NOAEL) for maternal toxicity is 300 mg/kg b.w./day. There were n o developmental findings in this study up to the limit dose of 1,000 mg/kg b.w./day, the highest dose tested (HDT). ii. For a rabbit development toxicity study at doses of 0, 25, 100, and 400 mg/kg b.w./day, the maternal and developmental NOAEL is 400 mg/k g b.w./day, the HDT. Doses were based on pilot range

- finder study, which tested at 0, 250, 500, 1,000, and 2,000 mg/kg b.w./day. The only toxic effect observed was increased salivation at 1,000 and 2,000 mg/kg b.w./day. iii. A 2

– generation rat reproduction study at doses of 0, 1,000, 5,000, or 10,000 ppm yielded a NOAEL of 10,000 ppm highest concentration tested (HCT) (equivalent to 738 mg/kg b.w./day for males, 933.3 mg/kg b.w./day for females). 4. Subchronic toxicity. i . A 90

– day dietary study in rats at doses of 0, 15,000, or 20,000 ppm resulted in a NOAEL of 20,000 ppm, the HCT (approximately 1,695 mg/kg b.w./day for males, 1,785 mg/kg b.w./day for females).5

ii . A 21

– day rabbit dermal toxicity study at doses of 0, 100, 200, or 400 mg/ kg b.w./day resulted in the NOAEL of 400 mg/kg b.w./day, the HDT. 5. Chronic toxicity. i

. A 1

– year chronic toxicity study in dogs at doses of 0, 1,000, 5,000, or 10,000 ppm yielded a NOAEL of 10,000 ppm, the HCT (equivalent to 250 mg/kg b .w./day). ii . A 2

– year chronic toxicity/ carcinogenicity study in rats at doses of 0, 1,000, 5,000, or 10,000 ppm provided NOAELs for both systemic toxicity and oncogenicity of 10,000 ppm, the HCT (approximately 500 mg/kg b.w./day for males, 640 mg/kg b.w. /day for females). iii . An 18

– month oncogenicity study in mice at doses of 0, 1,000, 5,000, or 10,000 ppm provided NOAELs for both systemic toxicity and oncogenicity of 10,000 ppm, the HCT (equivalent to 1,500 mg/kg b.w./day). 6. Animal metabolism. The ra t, goat and hen metabolism studies indicate that the qualitative nature of the residues of imazapyr in animals is adequately understood. i. Rat. Results from a rat metabolism study indicated that imazapyr was rapidly absorbed and excreted by 7 days post

- dosing, with the majority (90%) of the administered 14 C

- label eliminated in the urine within 48 hours. Metabolite characterization studies showed that essentially all the test material was excreted unchanged. Two minor metabolites were detected in the urin e or feces of treated rats; however, their contribution combined was less than or equal to 0.5% of the administered dose. An additional 12 unidentified metabolites were isolated, but they contributed less than 3% of the total dose. ii. Ruminant . Goats were dosed with radiolabeled imazapyr at 17.7, 42.5, or 47 mg/kg dietary equivalents for 7 days. As assessed for goats receiving the 17.7 or 42.5 mg/kg doses, TRR in fat, liver, and leg and loin muscle were nondetectable (<0.05 mg/kg). The TRR in milk was a m aximum of 0.01, 0.02, and 0.02 mg/kg for the three goats, respectively, while the TRR in kidney was 0.08, 0.11, and 0.08 mg/kg, respectively. Of these residues, parent imazapyr accounted for 50

– 66% of the TRR in milk and 82

– 95% of the TRR in kidney. No met abolites were identified which require regulation. iii. Poultry. Hens were dosed with radiolabeled imazapyr at 0, 1.98 and 9.72 mg/kg. TRR in the egg samples was less than the validated detection limit of 0.01 mg/kg. Residues in blood, skin with adhering fat, muscle, liver and kidney tissues taken at 22 hours after the last dose were all less than the validated detection limit of 0.01 mg/kg. The results of this study clearly show that orally administered imazapyr was rapidly eliminated by the hen as unchanged parent compound and that imazapyr related residues do not accumulate in eggs or the edible tissues of poultry. Based on these metabolism results, and expected dietary burden in poultry, a poultry feeding study is not necessary. 7. Metabolite toxicology

. There were no metabolites identified in plant or animal c ommodities which require regulation. 8. Endocrine disruption

. The collective data from the 2

– generation rat reproduction study as well as from the subchronic (90

– day) rat feeding study and chronic feeding studies in the dog (1

– year), rat (24

– month), and m ouse (18

–6

month) studies, indicate that imazapyr is not associated with any treatment

related estrogenic or endocrine effects

.

C. Aggregate Exposure 1. Dietary exposure. i. Food. a. Acute Dietary Exposure. An acute dietary risk assessment is not required because no acute toxicological endpoint was identified by the EPA for imazapyr. b. Chronic Dietary Exposure. A Tier 1 assessment of potential chronic dietary exposure was performed using DEEMTM for the proposed import tolerance of imazapyr on Crop subgroup 20A

- Rapeseed subgroup (representative commodity rape seed canola, Crop subgroup 20B

– Sunflower subgroup (representative commodity sunflower seed) and lentils for weed control. This assessment included the current tolerances as listed in 40 C FR 180.500 on grass hay and forage, field corn commodities, fish, shellfish, tissues of cattle, sheep, goats, and horses, and milk. Drinking water was also included (see below). For this Tier 1 analysis, tolerance values were used for rapeseed subgroup a t 0.05 mg/kg; sunflower subgroup at 0.05 mg/kg; lentils at 0.2 mg/kg; corn grain at 0.05 mg/kg; fish at 1.0 mg/kg; shellfish at 0.1 mg/kg; kidney of cattle, sheep, goats, and horses at 0.2 mg/kg; liver, meat, fat and other meat byproducts of cattle, sheep , goats, and horses at 0.05 mg/kg; and milk at 0.01 mg/kg. Chronic dietary exposure analyses for the overall U.S. population and population subgroups, including infants and children, were compared to the chronic Reference Dose (RfD) of 2.5 mg/ kg b.w./day . Results of the chronic dietary analyses for all population subgroups examined were at or below 0.3% of the chronic RfD. Exposure estimates for non

- nursing infants, the most highly exposed subpopulation, were only 0.007152 mg/kg b.w./day (or 0.3% of the RfD). Therefore, the results of the chronic dietary assessment demonstrate a reasonable certainty of no harm from the proposed and existing uses of imazapyr. ii. Drinking water

. Drinking water residues were included in the dietary assessment at an estimated drinking water concentration (EDWC) of 79 μg/L, which is the maximum level estimated by EPA EFED in Tier 1 drinking water modeling conducted for the imazapyr RED. 2. Non

- dietary exposure

. A non

- dietary exposure assessment was conducted and this assessment included the updated chronic dietary exposure values for the proposed rapeseed subgroup , sunflower subgroup and lentil tolerance s . The incidental oral, dermal, and inhalation exposures were obtained from the EPA risk assessments conducted in 2005. Short

- term residential aggregate MOE’s are 400 for toddlers (children 1

- 2 years old) and 710 for adult females and the U.S. population. These MOE’s demonstrate that the p roposed import tolerance for rapeseed subgroup, sunflower subgroup and lentil will result in aggregate exposures with reasonable certainty of no harm.

D. Cumulative Effects

.7

Imazapyr belongs to the imidazolinone class of compounds, a class comprised of a number of registered herbicides. The herbicidal activity of the imidazolinones is due to the inhibition of acetohydroxyacid synthase (AHAS), an enzyme only found in plants. A HAS is part of the biosynthetic pathway leading to the formation of branched chain amino acids. Animals lack AHAS and this biosynthetic pathway. This lack of AHAS contributes to the low toxicity of the imidazolinone compounds in animals. We are aware of no information to indicate or suggest that imazapyr has any toxic effects on mammals that would be cumulative with those of any other chemical.

E. Safety Determination 1. U.S. population. Based on the chronic RfD of 2.5 mg/kg b.w./day, the proposed canola, lentil and sunflower application, in addition to the existing uses (tolerances), will utilize approximately 0.3% of this value. Exposure estimates for the general U.S. population were only 0.002006 mg/kg b.w./day or 0.1% of the RfD. Exposure estimates f or non

- nursing infants, the most highly exposed population group, were only 0.007152 mg/kg b.w./day or 0.3% of the RfD. EPA generally has no concern for exposure below 100% of the RfD which represents the level at or below which daily aggregate dietary ex posure over a lifetime will not pose appreciable risks to human health. The complete and reliable toxicity data, indicating low potential mammalian toxicity, and the conservative chronic exposure assumptions support the conclusion that there is a ‘‘reasona ble certainty of no harm’’ from aggregate exposure to imazapyr residues. 2. Infants and children

. No developmental, reproductive or fetotoxic effects were noted at the highest doses of imazapyr tested. The only maternal effect in the rat teratology study was increased salivation in the highest dose group. The NOAEL used to calculate the RfD for the general U.S. population is 250 mg/kg b.w./day derived from the 1

– year chronic toxicity study in dogs. That NOAEL is lower than the developmental NOAELs for the teratology studies in rabbits and rats (1.6 and 4 times, respectively), as well as lower than the NOAEL for the 2

– generation reproduction study in male and female rats (~3

- 3.7 times). EPA has found the database relative to prenatal and postnatal effects for children to be complete, valid and reliable. There were no effects observed in the offspring in the developmental studies in rats and rabbits. In the reproduction study, the lack of any pup effects observed at 10,000 ppm (the highest dose tested) in th eir growth and development from parturition through adulthood, suggests that there is no additional sensitivity for infants and children. Therefore, an additional safety (uncertainty) factor is not warranted and the RfD of 2.5 mg/kg b.w./day, which utilize s a 100

- fold safety factor, is appropriate to assure a reasonable certainty of no harm to infants and children. Therefore, the registrant believes that the results of the toxicology and metabolism studies support both the safety of imazapyr to humans based on the intended use as a herbicide for imported canola, lentils and sunflower and the granting of the requested tolerances.

F. International Tolerances8

PMRA has proposed Canadian MRL for Lentils at 0.2 ppm and Rape seed (Crop subgroup 20A) at 0.05 ppm for domestic crops treated with Imazap yr

. There are no Codex tolerances established for I mazap yr on Canola, Lentils and Sunflower

.