Docket #: EPA - HQ - OPP - 2009 - 0813

COMPANY NOTICE OF FILING EPA Registration Division contact: Sidney Jackson (703) 305- 7610 Interregional Research Project No. 4 PP9E7604 EPA has received a pesticide petition PP9E7604 from Interregional Research Project No. 4 , 500 College Road East, Suite 201W, Princ eton, NJ, 08540 - 6635 , in cooperation with Bayer CropScience, Research Triangle Park, North Carolina 27709 proposing, pursuant to sec tion 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 . 473 by establishing a tolerance for residues of glufosinate - ammonium (butanoic acid, 2 - amino - 4 - (hydroxymethylphosphinyl) - monoammonium salt) and its metabolites, 2 - acetamido 4 - methylphosphinico - butanoic acid and 3 - methylphosphinico - propionic acid , expressed as 2 - amino - 4 - (hydroxymethylphosphinyl)butanoic a cid equivalents in or on the raw agricultural commodities corn , sweet, kernel plus cob with husks removed at 0.2 parts per million (ppm), corn , sweet, forage at 4.0 ppm , and corn , sweet, stover at 6.0 ppm . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of the FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. A confined rotational crop study has been submitted and reviewed by the Agency. Based on the previously submitted and reviewed confined and field rotational crop studies, the EPA has determined that the residues of concern in rotational crops, for the purpose of risk assessments and tolerance expression are glufosinate ammonium (HOE 061517) and 2 methylphosphinicoacetic acid (HOE 064619). The results of these studies are consistent with other metabolism studies conducted with glufosinate - ammonium on o ther crops and support the contention that the nature of residues found in plants as a result of a treatment of glufosinate - ammonium is well understood. 2. Analytical method. The enforcement analytical method utilizes gas chromatogr aphy for detecting and measuring levels of glufosinate - ammonium and metabolites with a general limit of quantification of 0.05 ppm. This method allows detection of residues at or above the proposed tolerances. 3. Magnitude of residues. Tolerances are cu rrently listed in 40 CFR §180.473 (a) for field corn grain, forage and stover .B. Toxicological Profile 1. Acute toxicity. Glufosinate - ammonium has been classified as toxicity category III for acute oral, dermal, and inhalation toxi city; and for eye irritation. Glufosinate - ammonium is not a dermal irritant (toxicity category IV) nor is it a dermal sensitizer. The oral lethal dose (LD ) 50 is 4010 milligrams per kilogram ( mg/kg) in male rats and 3030 mg/kg in female rats. 2. Genotox icty. Based on results of a complete genotoxicity database, there is no evidence of mutagenic activity in a battery of studies, including: Salmonella spp., E. coli, in vitro mammalian cell gene mutation assays, mammalian cell chromos om e aberration assays, in vivo mouse bone marrow micronucleus assays, and un scheduled DNA synthesis assays. 3. Reproductive and developmental toxicity. In a developmental toxicity study, groups of 20 pregnant female Wistar rats were administered glufosinate - ammonium by gavage at doses of 0, 0.5, 2.24 10, 50 and 250 mg/kg/day from days 7 to 16 of pregnancy. The no - observed adverse effect level (NOAEL ) for maternal toxicity is 10 mg/kg/day; the lowest- observed adverse effect level (LO AEL ) is 50 mg/kg/day based on vaginal bleeding and hyperactivity in dams. In the fetus, the NOAEL is 50 mg/kg/day, based on dilated renal pelvis observations at the LOAEL of 250 mg/kg/day. In a developmental toxicity study, groups of 15 pregnant female H imalayan rabbits were administered glufosinate - ammonium by gavage at doses of 0, 2.0, 6.3, or 20.0 mg/kg/day from days 7 to 19 of pregnancy. In maternal animals, decreases in food consumption and body weight gain were observed at the 20 mg/kg/day dose lev el. The NOAEL for maternal toxicity was 6.3 mg/kg/day and that for developmental toxicity was 20 mg/kg/day. In a multi- generation reproduction study, glufosinate - ammonium was administered to groups of 30 male and 30 female Wistar/Han rats in the diet at concentrations of 0, 40, 120, or 360 ppm. The LOAEL for systemic toxicity is 120 ppm based on increased kidney weights in both sexes and generations. The systemic toxicity NOAEL is 40 ppm. The LOAEL for reproductive/developmental toxicity is 360 ppm based on decreased numbers of viable pups in all generations. The NOAEL is 120 ppm. In a developmental neurotoxicity study, groups of 25 bred female rats were fed glufosinate ammonium at doses of 0, 200, 1000 or 4500 ppm in the diet. Body weights and food consumption were decreased at 1000 and 4500 ppm. No effects were seen in treated animals for the functional observation battery, developmental landmarks, grip strength, startle response or learning and memory. Motor activity was increase d at the mid and high dose. The NOAEL for developmental neurotoxicity was determined to be 200 ppm. 4. Subchronic toxicity

. In a sub - chronic oral toxicity study, glufosinate ammonium was administered to 10 NMRI mice/sex/ dose in the diet at levels of 0, 80, 320 or 1,280 ppm (equivalent to 0, 12, 48 or 192 millgrams/kilogram/day(mg/kg/day)) for 13 weeks. Significant (p< 0.05) increases were observed in serum

aspartate aminotransferase and in alkaline phosphatase in high - dose (192 mg/kg/ day) males. Also observed were increases in absolute and relative liver weights in mid - (48 mg/kg/day) and high - dose males. The NOAEL is 12 mg/kg/day, the LOAEL is 48 mg/kg/day based on the changes in clinical biochemistry and liver weights. 5. Chronic toxicity. Ina combined chronic toxicity/oncogenicity study, glufosinate - ammonium was administered to 50 Wistar rats/sex/dose in the diet for 130 weeks at dose levels of 0, 40, 140, or 500 ppm (mean compound intake in males was 0 , 1.9, 6.8, and 24.4 mg/kg/day and for females was 0, 2.4, 8.2 and 28.7 mg/kg/day, respectively). A dose - related increase in mortality was noted in females at 140 and 500 ppm, whereas in males increased absolute and relative kidney weights were noted at 1 40 ppm and 500 ppm. The NOAEL was considered to be 40 ppm. No treatment- related oncogenic response was noted. In an oncogenicity study, glufosinate - ammonium was administered to 50 NMRI mice/sex/dose in the diet at dose levels of 0, 80, 160 (males only) or 320 (females only) ppm for 104 weeks. The NOAEL for systemic toxicity is 80 ppm (10.82/16.19 mg/kg/day in males/females (M/F)), and the LOAEL is 160/320 ppm (22.60/ 63.96 mg/kg/day in M/F), based on increased mortality in males, increased glucose level s in males and females, and changes in glutathione levels in males. No increase in tumor incidence was found in any treatment group. In a chronic feeding study, technical glufosinate - ammonium was fed to male and female beagle dogs for 12 months in the die t at levels of 2.0, 5.0, or 8.5 mg/kg/day. The NOAEL is 5.0 mg/kg/day based on clinical signs of toxicity, reduced weight gain and mortality 8.5 mg/kg/day. In a rat oncogenicity study, glufosinate - ammonium was administered to Wistar rats (60/sex/group) fo r up to 24 months at 0, 1,000, 5,000, or 10,000 ppm (equivalent to 0, 45.4, 228.9, or 466.3 mg/kg/day in males and 0, 57.1, 281.5, or 579.3 mg/kg/day in females). The LOAEL for chronic toxicity is 5,000 ppm (equivalent to 228.9 mg/kg/day for male rats and 281.5 mg/kg/day for females), based on increased incidences of retinal atrophy. The chronic NOAEL is 1,000 ppm. Under the conditions of this study, there was no evidence of carcinogenic potential. Dosing was considered adequate based on the increased i ncidence of retinal atrophy. 6. Animal metabolism. S tudies conducted in rats using 14C - glufosinate ammonium have shown that the compound is poorly absorbed (5 - 10%) after oral administration and is rapidly eliminated primarily as the parent compound. The highest residue levels were found in liver and kidney tissu es. The metabolic profile and the quantitative distribution of metabolites were very similar in both goat and hen. The vast majority of the dose was excreted, primarily as parent compound. The very limited residues found in edible tissues, milk and eggs were comprised principally of glufosinate and 3 - methylphosphinico - propionic acid (Hoe 061517), with lesser amounts of N - acetyl- L - glufosinate (Hoe 0997 30) and2 - methylohosphinico - acetic acid (Hoe 064619). 7. Metabolite toxicology

. A dditional testing has been conducted with the major metabolites, 3 - methylphosphinico - propionic acid, and N - acetyl- L - glufosinate. Based on sub - chronic and developmental toxicity study results, a profile of similar or less toxicity was observed for the metabolites as compared to the parent compound, glufosinate - ammonium. 8. Endocrine disruption

. N o special studies have been conduct ed to investigate the potential of glufosinate - ammonium to induce estrogenic or other endocrine effects. However, no evidence of estrogenic or other endocrine effects have been noted in any of the toxicology studies that have been conducted with this prod uct and there is no reason to suspect that any such effects would be likely. C. Aggregate Exposure 1. Dietary exposure. Tolerances have been established (40CFR part 180.473) for the combined residues of glufosinate - ammonium and met abolites in or on a variety of raw agricultural commodities. No appropriate toxicological endpoint attributable to a single exposure was identified in the available toxicity studies. EPA did not, therefore, establish an acute reference dose (RfD) for the g eneral population. An acute RfD of 0.0063 mg/kg/day was established, however, for the females 13+ subgroup, based on a developmental NOAEL of 6.3 mg/kg/day in the rabbit and a 100x uncertainty factor (10x inter - 10x intra - species extrapolation) and a 10x F QPA data uncertainty factor. EPA determined that the Special FQPA uncertainty factor would be 1X for the acute dietary risk assessment based on conclusions of the HIARC and the complete residue and environmental fate data bases. The developmental LOAEL (20 mg/kg/day) was based on increased fetal death in the presence of maternal toxicity. There was no qualitative or quantitative indication of increased susceptibility in the prenatal developmental toxicities in rats and rabbits or in the 2 - generation reprodu ctive study in rats with parent compound or metabolites of concern. Toxicological studies showed clinical signs in short term studies described as aggressive behavior, piloerection and a high startle response at dosages of 300 mg/kg/day. Based on these eff ects, EPA determined that a 10x FQPA data uncertainty factor was appropriate for the risk assessment for the food and feed use of glufosinate - ammonium. Using the 10x FQPA data uncertainty factor, the acute population adjusted dose (aPAD) for glufosinate - am monium is 0.0063 mg/kg/day. 2. Food & water

. The assessment of the dietary exposures and risks associated with use of this product included the commodities with tolerances as listed above. Tier 2 acute and tier 3 chronic dietary assessments were recently conducted by Bayer CropScience to evaluate the dietary exposure of the U.S. population and selected subpopulations to glufosinate - ammonium residues. These analyses cover the current glufosinate - ammonium registrations which include broadcast application to apple, grape, banana, tree nut orchards, potato (harvest aid desiccant); and the bushberry crop subgroup. The analyses were conductedusing Exponent, Inc.’s DEEMTM software. Consumption data used in this program

were taken fr om USDA’s CSFII, 1994 - 1996 and 1998 . An updated water estimate was added to EPA Assessment (D289227. 2 August 2003. Author: D. Young). A retreat interval of 28 days was used for apples as opposed to a 14 day retreat interval. Under this scenario, the acute estimated environmental concentration (EEC ) from use in apples for sucker control drops to 67 ppb, and the next highest exposure level b ecomes that associated with weed control in tree nut crops at 74 ppb. Acute dietary risk was expressed as a percentage of the acute Population Adjusted Dose (aPAD) of 0.0063 mg/kg bw/day based on a NO AEL of 6.3 mg/kg bw/day with an uncertainty factor of 1 000. The EPA identified an acute endpoint of concern for females of childbearing age. No endpoint attributed to a single exposure was identified for the general population, including infants and children. The estimated risk from acute dietary exposure (95 t h percentile) for women 13 - 50 years of age was 85.6% of the aPAD. Beef liver (31%), water (40%) and potato (22%) were the major contributors to the acute exposure for this subgroup. Chronic dietary risk was expressed as a percentage of the chronic Population Adjusted Dose (cPAD) of 0.006 mg/kg bw/day based on a NO AEL of 6.0 mg/kg bw/day with an uncertainty factor of 1000. The most highly exposed subpopulation was infants (<1 year) at 57.0% of the cPAD. The chronic value for the the U.S Population was 20.9% of the cPAD. A major contributor to the overall dietary exposure for the <1 year old subgroup was water at 86% and water at 72% for the U.S. Population. 2. Non

- dietary exposure

. Glufosinate - ammonium is currently registered for use on the following non - food sites: areas around ornamentals, shade trees, Christmas trees, shrubs, walks, driveways, flower beds, farmstead buildings, in shelter belts, and along fences. It is also registered for use as a post- emergent herbicide on farmsteads, areas associated with airports, commercial plants, storage and lumber yards, highways, educational facilities, fence lines, ditch banks, dry ditches, schools, parking lots, tank farms, pumping stations, parks, utility rights - of - way, roadsides, railroads, and other public areas and similar industrial and non food crop areas. The EPA has determined that there are no acute or chronic non - dietary exposure scenarios. Further, the Agency has determined that it is not appropriate to aggregate short- and intermediate - term non - d ietary exposure with dietary exposures in risk assessments because the end - points are different. D. Cumulative Effect

s . EPA has indicated that, at this time, the Agency does not have available data to determine whether glufosinate - ammonium has a common m echanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, glufosinate ammonium does n ot appear to produce a toxic metabolite produced by othersubstances. For the purposes of this tolerance petition, therefore, it has not been

assumed that glufosinate - ammonium has a common mechanism of toxicity with other substances. E. Safety Determination 1. U.S. population. Using the conservative assumptions described above, based on the completeness and reliability of the toxicity data, it is concluded that chronic dietary exposure to the registered and proposed uses of glufosinate ammonium will utilize at most 20.9% of the chronic reference dose for the US Population. The actual exposure is likely to be much less as more realistic data and models are developed. Exposures below 100% of the reference dose are generally assumed to be of no concern becau se the reference dose represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risk to human health. The acute population of concern, female 13 - 50 yrs. utilizes ~85.6% of the aPAD and the actual exposure is likely to be far less. It is not appropriate to aggregate non - dietary exposures with dietary exposures uses because the toxicity end - points are different. Therefore, there is a reasonable certainty that no harm will occur to the US Population from agg regate exposure (food, drinking water and nonresidential) to residues of glufosinate - ammonium and metabolites. 2. Infants and children

. The toxicological data base is sufficient for evaluating prenatal and postnatal toxicity for glufosinate - ammonium. Th ere are no prenatal or postnatal susceptibility concerns for infants and children, based on the results of the rat and rabbit developmental toxicity studies and the 2 - generation reproduction study. Based on clinical signs of neurological toxicity in short and intermediate dermal toxicity studies with rats, and due to the lack of a DNT (study submitted January 2005

– MRID 48455701) EPA determined that an added FQPA data uncertainty factor of 10x is appropriate for assessing the risk of glufosinate ammonium d erived residues in crop commodities. Using the conservative assumptions described in the exposure section above, the percent of the cPAD that will be used for exposure to residues of glufosinate ammonium in food and water is 57.0 percent for infants less than on year of age. Of this, water composes 86% of the total. As in the adult situation, drinking water levels of comparison are higher than the worst case drinking water estimated concentrations, if they occur at all. Therefore, there is a reasonable ce rtainty that no harm will occur to infants and children from aggregate exposure to residues of glufosinate - ammonium. F. International Tolerances

. The Codex Alimentarius Commission has establishedMaximum Residue Limits (Codex MRLs) for residues of glufosinate - ammonium

and metabolites in or on field corn kernels (i.e., maize) at 0.1 ppm.