EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division C ontact: James Tompkin s ; 703

- 305

- 5697

BASF Corporation

0E7793

EPA has received a pesticide petition ( 0E7793 ) 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. 500 by establishing a tolerance for residues of imazapyr 2

- [4,5

- dih ydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- ] H

- imidazol

- 2

- yl]

- 3

- pyridinecarboxylic acid ] in or on the raw agricultural commodity soybean at 4 .0 parts per million (ppm) and in or on the processed commodity soybean meal at 4.5 parts per million (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 d a ta at this time or whether the data supports granting o f the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism

. i. Bermuda grass

. Radiolabelled imazapyr (pyridine

- 6

- 14 C

imazapyr), was applied to established Bermuda grass. A single appli cation 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 predominant re sidue, 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 slowly in Bermu da 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 in maize g rains or in plants of different growth stages. Any metabolite

observed wa s only present at insignificant concentrations in samples taken after the day of application. Thus, i mazapyr is the only relevant residue in maize. Additionally,

extraction of maiz e oil with hexane showed that residues of i mazapyr did not accumulate in that lipophilic matrix.

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 re sidue in clover plants, accounting for 68 to 99% TRR. Metabolites CL 9140, CL 240000 and CL 247087 each2

accounted for insignificant proportions of the residue below 10% TRR. Thus, the study demonstrates that imazapyr is the only relevant residue in clove r

.

2. Analytical method. The proposed analytical method for detecting residues of imazapyr in soybean seed and processed fractions is an LC

- MS/MS method. This validated method has an LOQ of 0.01 mg/kg.

M 3023 is a reliable capillary electrophoresis method with ultraviolet (CE/UV) detection for the determination of imazapyr 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, she ep, goats, and horses. M 3075 is a reliable CE/UV method for the determination of imazapyr residues in milk

.

3. Magnitude of residues. i. Soybeans. I mazapyr was applied at the proposed

labeled rate in 8 field trials in Brazil. Residues of imazapyr ranged from <0.05 to 2.0 mg/kg in samples taken 60 days after treatment. Three of the trials also incorporated residue decline samples taken at 40, 60, 80, 100, and 120 days after treatment. No residues were determined 120 days after treatment.

T he for mulation BAS 714 01 H, containing the active ingredients imazapyr and imazapic, was applied according to labeled rates in 8 field trials in Brazil

. Residues of imazapyr ranged from <0.05 to 3.0 mg/kg in samples taken 60 days after treatment. Three of the trials also incorporated residue decline samples taken at 40, 60, 80, 100, and 120 days after treatment. No residues were determined 120 days after treatment.

A processing study was conducted using soybeans from two trials in Brazil , applied at

two time s and three times the proposed application rate . The soybean samples were taken 60 days after treatment and processed into fractions (flake soybean, oil, meal, and toasted meal). The mean transfer factors for soybean commodities demonstrate that

i mazapyr residues do not result in the soybean oil, but concentrate into flaked soybean,

meal and toasted meal.

Another processing study was conducted using soybeans from two trials in Brazil. A single treatment of BAS 714 01 H, containing imazapyr and imazapic was applied at two times and three times the proposed application rate . The soybean samples were taken 60 days after treatment and processed into fractions (flake soybean, oil, meal, and toasted meal). The mean transfer factors for soybean commodities we re 0.75, <0.04, 1.34 and 1.15 for flake soybean, oil, meal, and toasted meal, respectively.

Soybean hulls and aspirated grain fractions were not analyzed in either processing study. However, it is not anticipated that a significant amount of soybean hull s or aspirated grain fractions from genetically modified soybeans would be used as animal feed items. Additionally, soybean hulls and aspirated grain fractions are blended commodities and therefore any imazapyr treated soybean hulls and aspirated grain fr actions would be blended with other untreated soybean hulls and aspirated grain fractions before being fed

to cattle. Based on the limited import of genetically modified soybeans from Brazil and the blended nature of these commodities, any potential imaza pyr residues would be3

diluted and can be considered de minimus.

Furthermore, inclusion of potential imazapyr residues in the blended commodities of soybean hulls and aspirated grain fractions would not significantly add to the estimated dietary burden for cattle. The new estimated dietary burden for dairy cattle, under the maximally reasonably balanced diet (MRDB) guidance (updated in 2008) and including soybean seeds and meal at tolerance

- level residues results, is 18.5 mg/kg imazapyr.

EPA’s previous di etary burden of 24 m g/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 b ased on a dietary burden of 24 m g/kg

. Soybean hull residues woul d have to be higher than 65 mg/kg in order to resul t in a dietary burden of 24 m g/kg for dairy cattle under the MRDB guidance. Aspirated grain fractions are not used in the dairy cattle diet (i.e., the basis for the existing meat and milk tolerances), and they constitute only 5% of the beef cattle diet. The updated dietary burden for beef cattle is 0.8 mg/kg using the MRDB guidance, in comparison to the new dietary burden of 18.5 mg/kg for dairy cattle and, therefore, it is exceedingly unlikely that

resid ues in aspirated grain fractions would lead to a beef cattle diet with higher imazapyr residues than the dairy cattle diet. Consequently, soybean hulls and/or soybean aspirated grain fractions containing imazapyr residues are unlikely to result in potenti al beef and dairy cattle dietary burdens in excess of the 24 mg/kg basis for the existing meat and milk

tolerances.

ii. 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 58 mg/kg, imazapyr residues in milk were < 0.01 mg/kg; residues in muscle, fat, and liver were <0.05 mg/kg; and residues in kidney averaged 0.25 mg/kg. The estimated dietary burden under current guidance is 18. 5 ppm in dairy cattle including soybean seeds and 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 soybeans will not require any changes to the current meat and milk

tolerances.

B. Toxicological Profile

1. Acute toxicity. Based on a battery of acute toxicity studies, imazapyr has been placed in toxicity category I for eye irritation, category IV for oral LD 50 and primary dermal irritation, and category III for dermal LD 50 and inhalation LC 50 . Imazapyr was a

non

- sensitizer when tested for dermal sensitization (Buehler Method).

2. Genotoxicty. Studies on gene mutation and other genotoxic effects, Ames Salmonella Assay, CHO/HGPRT Point Mutation Assay, in vitro CHO cell chromosome aberration assay, dominant lethal assay, and unscheduled DNA synthesis (UDS) in primary rat hepatocytes yielded negative results.

3. Reproductive and developmental toxicity. i. For a rat d evelopmental toxicity study at doses of 0, 100, 300, or 1,000 mg/kg 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 effect4

level (NOAEL) for maternal toxicity is 300 mg/kg b.w./day . There were no 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/kg b.w./day 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) (738 mg/kg b.w./day for males, 933.3 mg/kg b.w./day for females, as based on food consumption data).

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 HCT (approximately 1,695 mg/kg b.w./day for males, 1,785 mg/kg b.w./day for females, as based on food consumption data).

ii. A 21

– day rabbit dermal toxicity study at doses of 0, 100, 200, or 400 mg/ kg b.w./day resulted with the NOAEL of 400 mg/kg b.w./day 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 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 HCT (approximately 500 mg/kg b.w./da y for males, 640 mg/kg b.w./day for females, as based on food consumption data).

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 HCT (equivale nt to 1,500 mg/kg b.w./day).

6. Animal metabolism. The rat

, goat and hen metabolism studies indicate that the qualitative nature of the residues of imazap yr in animals is adequately understood.

i. R esults from a rat metabolism study indicated that imazapyr was rapidly absorbed and excreted by 7 days post

- dosing, with the majority of the administered 14 C

- label (90%)

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 urine or feces of treated rats; however, their contribution combined was less than or equal to 0.5% of the administered dose. An additional 1 2 unidentified

metabolites were isolated, but they contribute d less than 3% of the total dose.5

i i

. 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 maximum 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 metabolites 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 detecti on 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 a dministered 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, a poultry feeding study is not necessary.

7. Metabolite toxicology

. There were no metabolites identified in plant or animal commodities which require regulation.

8. Endocrine disruption

. The collective data from the 2

– generation rat reproduction study as well as from the subchronic (9 0

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

– year), rat (24

– month), and mouse (18

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

- related estrogenic or

endocrine effects

.

C. Aggregate Exposure

1. Di etary exposure.

i. Food. a. Acute Dietary Exposure.

An acute dietary risk assessment is not required because no acute toxicological endpoint

w as 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 soybeans for weed control. This assessment included the current tolerances as listed in 40 CFR 180.500 on grass hay and forage, field corn com modities, fish, shellfish, tissues of cattle, sheep, goats, and horses, and milk. For this Tier 1 analysis, tolerance values were used for soybean at 4.0 mg/kg ; grass, hay at 30 mg/kg ; grass, forage at 100 mg/kg , field 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 ; other meat byproducts of cattle, sheep, goats, and horses at 0.05 mg/kg ; meat of cattle, sheep, goats, and horses 0.05 mg/kg ; fat of cattle, sheep, goats, and horses a t 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 to6

the chronic Reference Dose (RfD) of 2.5 mg/ kg b.w./day. Results of the chro nic dietary analyses for all population subgroups examined were at or below 0.4% of the chronic RfD. Exposure estimates for infants, the most highly exposed subpopulation, were only 0.011012 mg/kg b.w./ day (or 0.4% of the RfD). Therefore, the results of t he chronic dietary assessment demonstrate a reasonable expectation 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 concentr ation (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

t his assessment include d the upda ted chronic dietary exposure values for the proposed soybean tolerance. The incidental oral, dermal, and inhalation exposures were obtained

from the EPA risk assessments conducted in 2005. S hort

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

- 2 years old) and 710 for adult females and the U.S. population. These MOE’s demonstrate that the proposed import tolerance for soybeans will result in aggregate exposures with reasonable certainty of no harm.

D. Cumulative Effects Imazapyr be longs 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. AHAS 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 informatio n 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 soybean ap plication will utilize approximately 0.4% of this value. Exposure estimates for the general U.S. population were only 0.003891 mg/kg b.w./day or 0.16% of the RfD

. Exposure estimates for infants, the most highly exposed population group, were only

0.011012 mg/kg b.w./day or 0.4% 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 exposure 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 ‘‘reasonable certainty of no harm’’ from aggregate exposure to imazapyr

residues.

2. Inf ants 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 to7

calculate the RfD for the general U.S. populati on 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

– gen eration reproduction study in male and

female rats ( ~3

- 3.7 times ). EPA has found the data base relative to prenatal and postnatal effects for children to be complete, valid and reliable. There were no effects observed in the offspring in the developmenta l 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 their 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 utilizes a

100

- fold safety factor, is appropriate to assure a reasonable certainty of no harm to

infants and children. Ther efore, 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 soybeans and the granting of the requested

tolerances.

F. Inter national Tolerances

There are no Codex tolerances established for imazapyr on soybeans

.