 

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (19 March 2007)>

<EPA Registration Division contact: [  SEQ CHAPTER \h \r 1 Joanne I.
Miller: (703) 305-6224]>

 

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<[Bayer Crop Science]>

<[Revised - PP 6F7161]>

<	EPA has received a revised pesticide petition ([PP 6F7161])   SEQ
CHAPTER \h \r 1 Bayer CropScience, 2 T.W. Alexander 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 180.473(a) General, and eliminate the reference to
180.473(2) transgenic crops tolerant to glufosinate ammonium such that
the crop tolerances listed under subsection (a) General., support uses
in all of the crops listed to include both conventional and transgenic
crops. The same inclusive tolerances for glufosinate-ammonium and its
metabolites expressed as butanoic acid,
2-amino-4-(hydroxymethylphosphinyl)-, monoammonium salt,
2-acetamido-4-methylphosphinico-butanoic acid and
3-methylphosphinico-propionic acid expressed as glufosinate free acid
equivalents are already listed for the commodities printed under both
subsections (1) and (2) under (a) General.

 <(Options (pick one)>

<	1. by listing the established tolerances for residues of>

<<glufosinate-ammonium and its metabolites expressed as butanoic acid,
2-amino-4-(hydroxymethylphosphinyl)-, monoammonium salt,
2-acetamido-4-methylphosphinico-butanoic acid and
3-methylphosphinico-propionic acid expressed as glufosinate free acid
equivalents in or on the raw agricultural commodity aspirated grain
fractions at [25.0] parts per million (ppm), beet, sugar, molasses at
[5.0] parts per million (ppm), beet, sugar, roots at [0.9] parts per
million (ppm) beet, sugar, tops (leaves) at [1.5] parts per million
(ppm) canola, meal at [1.1] parts per million (ppm), canola, seed at
[0.4 ] at parts per million (ppm), field corn, forage at [4.0] parts per
million (ppm), field corn, grain at [0.2] parts per million (ppm), field
corn, stover at [6.0] parts per million (ppm), rice, grain at [1.0]
parts per million (ppm), rice, hull at [2.0] parts per million (ppm)
rice, straw at [2.0] parts per million (ppm), soybean, at [2.0] parts
per million (ppm) and soybean, hulls at [5.0] parts per million (ppm)
under Section (a) General (1) of 40 CFR part 180.473 in addition to the
commodities already listed under this section . 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 supports granting of the petition. Additional data may be
needed before EPA rules on the petition.>

<A. Residue Chemistry>

<	1. Plant metabolism.   SEQ CHAPTER \h \r 1 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.   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 existing tolerances.

<	3. Magnitude of residues. Tolerances are currently listed in 40 CFR
§180.473(2) for transgenic canola, transgenic field corn and transgenic
soybean.

<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. Genotoxicty.   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 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
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.   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.  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   SEQ
CHAPTER \h \r 1 retinal atrophy.

<	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, a profile of similar or less
toxicity was observed for the metabolites as compared to the parent
compound, glufosinate-ammonium.

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

using Exponent, Inc.’s DEEM™ software. Consumption data used in this
program were taken from USDA’s CSFII, 1994-1996.1998. A retreat
interval of 28 days was used for apples as opposed to a 14 day retreat
interval. Under this scenario, the acute EEC estimates 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 NOEL 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 (95th 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 NOEL 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-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, glufosinate-ammonium 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 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 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 glufosinate-ammonium 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 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 certainty that no harm will occur to
infants and children from aggregate exposure to residues of
glufosinate-ammonium.

<F. International Tolerances>

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at 10.0 ppm, soya bean (dry), at 2.0 ppm, rape seed, at 5.0 ppm, rape
seed oil (crude) at 0.05 ppm, sugar beet at 0.05 ppm and sugar beet
leaves or tops at 0.1 ppm.

