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, Princeton, NJ, 08540-6635, in 

cooperation with Bayer CropScience, Research Triangle Park, North Carolina 

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 180.473 by establishing a 

tolerance for residues of glufosinate-ammonium (butanoic acid, 2-amino-4-

(hydroxymethylphosphinyl)-monoammonium salt) and its metabolites, 2-acetamido4-methylphosphinico-butanoic acid and 3-methylphosphinico-propionic acid,

expressed as 2-amino-4-(hydroxymethylphosphinyl)butanoic acid 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 

other 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 

chromatography 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 currently 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 toxicity; 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. Genotoxicty. 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 chromosome 

aberration assays, in vivo mouse bone marrow micronucleus assays, and 

unscheduled 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 (LOAEL) 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 

Himalayan 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 level. 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 increased 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, glufosinateammonium 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. In a 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 140 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 levels 

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 diet 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) for 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 incidence of retinal atrophy.

6. Animal metabolism. Studies conducted in rats using 14C- glufosinateammonium 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 tissues.

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 099730) and 
2-methylohosphinico-acetic acid (Hoe 064619).

7. Metabolite toxicology. Additional 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. No special studies have been conducted 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 product 

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 metabolites 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 general 

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 FQPA 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 reproductive 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 effects, 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-ammonium 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 conducted 
using Exponent, Inc.’s DEEMTM software. Consumption data used in this program 

were taken from 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 becomes 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 NOAEL of 6.3 mg/kg bw/day with 

an uncertainty factor of 1000. 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 (95thpercentile) 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 NOAEL 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 nonfood 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-dietary exposure with dietary 

exposures in risk assessments because the end-points are different.

D. Cumulative Effects. EPA has indicated that, at this time, the Agency does not have 

available data to determine whether glufosinate-ammonium has a common 

mechanism 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, glufosinateammonium does not appear to produce a toxic metabolite produced by other 
substances. 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 glufosinateammonium 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 because 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 aggregate 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. There 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 glufosinateammonium derived 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 glufosinateammonium 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 certainty 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 established 
Maximum Residue Limits (Codex MRLs) for residues of glufosinate-ammonium 

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