Document ID: EPA-HQ-OPP-2010-0031-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-19T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

<EPA Registration Division contact: [Joanne Miller (PM 23).
(703-305-6224)]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Bayer CropScience]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Bayer CropScience], [2 Alexander Drive, Research Triangle Park, NC]
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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

	the herbicide chemical glufosinate ammonium and its metabolites
expressed as butanoic acid, 2-amino-4-(hydroxymethylphosphinyl)-,
monoammonium salt, 2-acetamido-4-methylphosphinico-butanoic acid (Hoe
099730 or N-Acetyl Glufosinate)   and 3-methylphosphinico-propionic acid
(Hoe 061517 or MPP) expressed as glufosinate free acid equivalents,  in
or on the raw agricultural commodity citrus fruit, CG-10, including
Calamondin, Citrus citron, Citrus hybrids (Citrus spp. and Fortunella
spp.), Grapefruit (including Japanese summer), Kumquat, Lemon, Lime
(sweet, Australian desert, Australian finger, Australian round, Brown
River finger, Mount White, New Guinea wild, Russell River, Tahiti),
Mandarin (Mediterranean, Satsuma), Orange (sour, sweet, Tachibana,
Trifoliate), Pummelo, Tangelo, Tangerine (Mandarin), Tangor (Citrus
reticulate and Citrus sinensis) and varieties and/or hybrids of these,
and all associated processed fractions at 0.05 ppm; pome fruits, CG-11,
including Apple, Crabapple, Loquat, Mayhaw, Pear, Oriental Pear and
Quinnce, and all associated processed fractions at 0.10 ppm, stone
fruit, CG-12, including Apricot, Cherry (sweet and tart), Nectarine,
Peach, Plum (including Chicksaw, Damson and Japanese), Plumcot and Prune
(fresh) at 0.10 ppm and Dried Plums (dried prunes) at 0.2 ppm, and
olives and the processed fraction olive oil at 0.05 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 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 uptake and metabolism of glufosinate in
primary crops is adequately understood. Radiolabeled studies have been
conducted in various plants all showing similar results. The relevant
residues are parent glufosinate and MPP (3-methylphosphinico-propionic
acid) in conventional plants and additionally N-acetyl-L-glufosinate 
(2-amino-4-(hydroxymethylphosphinyl)-, monoammonium salt,
2-acetamido-4-methylphosphinico-butanoic acid) in modified plants.>

<	2. Analytical method. [  SEQ CHAPTER \h \r 1 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. [Residue trials (12 orange, 6 grapefruit and
5 lemon) were conducted in citrus orchards with RELY 200SL (EPA Reg. No.
264-660) applied to soil at a rate of 1.5 lb a.i./A three times at 14
day intervals with a 14 day PHI. All residue measurements in fruit were
less than the LOD. An exaggerated 5X rate was applied in the orange
processing trial; residues in fresh fruit and oil were less than the
LOD, therefore no residue is expected in any processed commodity. The
overall results support a proposed tolerance of 0.05 pm for citrus fruit
(Crop Group 10) and all processed commodities.

Residue trials (6) were conducted in pear orchards with RELY 200SL (EPA
Reg. No. 264-660) applied to soil at a rate of 1.5 lb a.i./A three times
at 14 day intervals with a 14 day PHI, the same use pattern previously
registered for apples. All glufosinate and NAG residues in fruit were
less than the LOD; MPP residues were quantified in one sample at an
average of 0.08 ppm. The proposed MRL for pears is 0.10 ppm.  Since the
previously established tolerance for apples and associated processed
fractions is 0.05 ppm, which is within 3X of the proposed pear MRL, the
overall results support a proposed tolerance of  0.10 ppm for pome fruit
(Crop Group 11) and all processed commodities.

On stone fruit,  Bayer CropScience conducted residue trials in cherry
(6) and plum (6) orchards and IR-4 conducted 9 trials in peach orchards
with RELY 200SL (EPA Reg. No. 264-660) applied to soil at a rate of 1.5
lb a.i./A two times at 28 day intervals with a 14 day PHI. Residues were
also investigated in dried plums (prunes) that had been treated at a 5X
exaggerated rate. Overall results support a tolerance of 0.10 ppm for
stone fruit (Crop Group 12) and 0.20 ppm for dried plums (prunes).

Residue trials (3)  were conducted in olive orchards with RELY 200SL
(EPA Reg. No. 264-660) applied to soil at a rate of 1.5 lb a.i./A three
times at 14 day intervals with a 14 day PHI. All residue measurements in
olives were less than the LOD. An exaggerated 5X rate was applied in the
processing trial; residues were not found to concentrate in oil. The
overall results support a proposed tolerance of 0.05 pm for olives,
fresh fruit and olive oil.

>

<B. Toxicological Profile>

<	1. Acute toxicity.  [  SEQ CHAPTER \h \r 1 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 LD50 is 4010 mg/kg in male rats and 3030 mg/kg in
female rats.]>

<	2. Genotoxicity. [  SEQ CHAPTER \h \r 1 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. [  SEQ CHAPTER \h \r 1 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
NOAEL for maternal toxicity is 10 mg/kg/day; the 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.

  SEQ CHAPTER \h \r 1 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. [  SEQ CHAPTER \h \r 1 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 mg/kg bw/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 no observed adverse effect
level (NOAEL) is 12 mg/kg/day, the lowest observed adverse effect level
(LOAEL) is 48 mg/kg/day based on the changes in clinical biochemistry
and liver weights.]

>

<	5. Chronic toxicity. [In a dog 1 year 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.

  SEQ CHAPTER \h \r 1 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 in females and 140 ppm in males.  No treatment-related oncogenic
response was noted.]

Additionally, a rat oncogenicity study was performed in which
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,
based on increased incidences of retinal atrophy; the NOAEL is 1000 ppm
(equivalent to 45.4 mg/kg/day for male rats and 57.1 mg/kg/day for
females.  Under the conditions of this study, there was no evidence of
carcinogenic potential.  

In a mouse 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.>

<	6. Animal metabolism. [  SEQ CHAPTER \h \r 1 Studies 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 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. [  SEQ CHAPTER \h \r 1 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, similar to
lower toxicity was observed for the metabolites as compared to the
parent compound, glufosinate-ammonium.]>

<	8. Endocrine disruption. [  SEQ CHAPTER \h \r 1 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. [  SEQ CHAPTER \h \r 1 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 (aRfD) 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 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. 

Chronic dietary risk is expressed as a percentage of the chronic
Population Adjusted Dose (cPAD) of 0.006 mg/kg bw/day. A weight of
evidence approach considering chronic rat and dog studies concluded the
chronic NOAEL to be 6.0 mg/kg bw/day, and the cRfD was derived by
applying an uncertainty factor of 1000; because the FQPA SF was
determined to be 1X, the cRfD and the cPAD are equivalent. 

>

ed subpopulations to glufosinate-ammonium residues. The analyses were
conducted using Exponent, Inc.’s DEEM™ 2.16 software. Consumption
data used in this program were taken from USDA’s CSFII,
1994-1996.1998. Assessments were conducted to evaluate the potential
risks due to acute dietary exposure for females 13+ years and chronic
dietary exposure of the entire U.S. population and selected population
subgroups to residues of glufosinate ammonium and its metabolites MPP
and N-acetyl glufosinate.  These assessments cover all established and
proposed uses of glufosinate. These assessments also include secondary
residues in animal tissues resulting from registered and proposed uses. 

Acute dietary risk was expressed as a percentage of the acute Population
Adjusted Dose (aPAD) of 0.0063 mg/kg bw/day The estimated risk from
acute dietary exposure (99.9 th percentile) for women 13-49 years of age
was 34.2% of the aPAD. Potato tubers with and without peel 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.  Chronic exposure
for the most exposed subpopulation, children 1-2 years, equated to 7.9%
of the cPAD.  The exposure to the U.S. population equated to 2.4% of the
cPAD. These Tier 3 chronic dietary exposure estimates, incorporating
Bayer CropScience estimates of  percent crop treated, are well below
EPA’s level of concern for the overall U.S. population as well as the
various population subgroups.]

>

<	ii. Drinking water. [The guidelines for conducting drinking water
exposure assessment have been revised since the last glufosinate
drinking water report issued by US EPA in 2006. Therefore, DWECs have
been updated to reflect the latest guidelines.   

The revised surface drinking water exposure assessment for glufosinate
ammonium was conducted with the PE5 modeling shell for the major uses on
the label. Results from the PE5 modeling system were adjusted by the PCA
factors listed in a July 2003 EPA-EFED document (  HYPERLINK
"http://www.epa.gov/oppefed1/models/water/regional_pca.htm" 
http://www.epa.gov/oppefed1/models/water/regional_pca.htm ). 
Environmental value inputs were the same as used in the 2003 EPA report
(Table 2 in DP Barcode: 289227 dated April 22, 2003).  

The estimated acute and chronic glufosinate DWECs for surface water were
calculated for three apple scenarios (North Carolina, Oregon and
Pennsylvania), Georgia peach scenario, Mississippi cotton scenario and
California almond and grape scenarios. Acute DWECs ranged from 13.6 ppb
to 38.9 ppb.  The highest acute DWEC was for the North Carolina apple
scenario.  As such, the daily DWECs from the North Carolina apple
scenario were used in the aggregate dietary risk assessment.  The
Chronic DWECs ranged from 2.9 ppb to 17.8 ppb.  For the chronic
aggregate assessment, a DWEC of 17.8 ppb from the Pennsylvania apple
scenario was used.  

Acute risk from aggregate dietary exposure (food and water) was
expressed as a percentage of the acute Population Adjusted Dose (aPAD)
of 0.0063 mg/kg bw/day for women 13-49 years of age. The estimated risk
from acute exposure (99.9 th percentile) was 47.3% of the aPAD 

For the most highly exposed population subgroup, non-nursing infants,
chronic aggregate dietary exposure (food and water) calculated using
DEEM-FCID Version 2.14 was 31.6% of the cPAD. For the overall U.S.
population, chronic aggregate dietary exposure was 8.8% of the cPAD.]>

<	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 available residential exposure and risk assessment for homeowner
handlers/applicators combined the short-term inhalation and short-term
dermal exposure estimates since the same toxicological endpoint was
selected for both routes of exposure. An ARI approach was used to
estimate risk to account for the different target MOEs for residential
dermal (>1000) and inhalation (>3000) exposures. These calculations
showed spot treatments to result in exposure levels below HED’s level
of concern (ie ARIs >1). In accordance with the HED Exposure Science
Advisory Committee (ExpoSAC) guidance, the registered spot treatment use
is not expected to result in significant post application exposure and
thus no residential post application risk assessment is necessary.]

>

<<D. Cumulative Effects> [The Agency has not determined whether
glufosinate

ammonium shares a common mechanism of toxicity with other chemical
substances, and whether a cumulative assessment is warranted. If
glufosinate ammonium is determined to share a common mechanism of
toxicity with other substances, then methods for aggregating exposures
and risks will be developed. Until glufosinate ammonium is scheduled for
a common mechanism determination and a decision is made, the Agency
would not a priori assume a common mechanism of toxicityexists for
glufosinate ammonium and 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 (food and water) to the
registered and proposed uses of glufosinate-ammonium will utilize at
most 8.8% of the chronic reference dose for the US Population. 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 47.3% 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 since 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, the 2-generation reproduction study and the DNT.  EPA
determined that retaining a data uncertainty factor of 10X at this point
is appropriate for assessing the risk of glufosinate-ammonium derived
residues.

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 31.6% for
non-nursing infants, 25.7% for all infants <1 year and 17.2% for
children aged 1 to 2 years. Of this, water comprises 80% of the total
calculated exposure for all infants and 43% for children 1 to 2.  

EPA generally has no concerns for exposures below 100 percent of the
RfD, because the RfD represents the level at or below which daily
aggregate exposure over a lifetime will not pose appreciable risks to
human health.  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>

<[CODEX MRLs for glufosinate ammonium exist for the following
commodities. ]

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	Maize	0.1

Maize fodder	10

Meat (from mammals other than marine mammals)	0.05

Milks	0.02

Onion, Bulb	0.05

Peas (dry)	3

Pome fruits	0.05

Potato	0.5

Poultry meat	0.05

Poultry, Edible offal of	0.1

Rape seed	5

Rape seed oil, Crude	0.05

Soya bean (dry)	2

Stone fruits	0.05

Sugar beet	0.05

Sunflower seed	5

Sunflower seed oil, crude	0.05

Tree nuts	0.1

]>

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