Document ID: EPA-HQ-OPP-2008-0322-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-04T04:00Z

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

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

<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], [P. O. Box 12014, 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.by establishing a tolerance for residues of
[tebupirimphos; [O-[2-(1,1-dimethylethyl)-5-pyrimidinyl] O-ethyl
O-(1-methylethyl) phosphorothioate], in or on the raw agricultural
commodity [Corn, field, forage] at [0.01] parts per million (ppm),
[Corn, field, stover] at [0.01] parts per million (ppm), [Corn, pop,
forage] at [0.01] parts per million (ppm),  [Corn, pop, stover] at
[0.01] parts per million (ppm),  [Corn, sweet, forage] at [0.01] parts
per million (ppm),  [Corn, sweet, stover] at [0.01] parts per million
(ppm),  [Corn, field, grain] at [0.01] parts per million (ppm),  [Corn,
pop, grain] at [0.01] parts per million (ppm) and [Corn, sweet, kernel
plus cob with husks removed] at [0.01] 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 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. [No residues (<0.01 ppm) in corn commodities have
been detected in the corn metabolism studies, even at exaggerated rates
of application.]>

<	2. Analytical method. [Adequate validated analytical methodology is
available for enforcement purposes.]>

<	3. Magnitude of residues. [Magnitude of the residue studies support
establishing the requested tolerances. No residues (<0.01 ppm) in corn
commodities have been detected in crop field trials or processing
studies even at exaggerated rates of application. The results of the OP
Market Basket Survey specific to tebupirimphos showed that no residues
(LOQ of 0.001 ppm) were detected in any of the four hundred fifty-two
(452) samples analyzed.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Tebupirimphos is an organophosphate inhibitor of
cholinesterase which is the most sensitive endpoint identified for risk
assessment. Based on acceptable acute oral, dermal and inhalation
studies, tebupirimphos is considered Toxicity Category 1 by all three
routes of exposure, although the granular formulated products of Aztec
(formulation of tebupirimphos and cyfluthrin) are less toxic. An NOAEL
was not achieved in the acute neurotoxicity study in the rat but based
on plasma and red blood cell cholinesterase inhibition the LOAEL was
0.5mg/kg.]>

<	2. Genotoxicty. [Several genotoxicity tests were conducted to test for
point-mutagenic activity, chromosome aberration in vitro and in vivo,
and for DNA repair.  All tests conducted were negative, indicating no
evidence of mutagenic or genotoxic potential.]>

<	3. Reproductive and developmental toxicity. [In a two-generation
reproduction study in rats the developmental NOAEL was approximately
0.25 mg/kg. A decrease in fertility indices and an increase in number of
dead pups were observed at the LOAEL. There were no teratogenic effects
observed under conditions of the study. The maternal NOAEL for
cholinesterase and systemic effects was approximately 0.25 mg/kg. In a
rat developmental study no developmental effects were observed under
conditions of the study. The maternal NOAEL was 0.50 mg/kg based
cholinesterase and systemic effects at the LOAEL. In a rabbit
developmental study the NOAEL was 0.1 mg/kg for developmental effects
based on cholinesterase inhibition, a decreased number of live
fetuses/litter, a higher number of resorptions per group, and a greater
number of litters with at least one resorption at the LOAEL. The FQPA
Safety Factor was reduced to 1X based on a complete database and no
indication of increased susceptibility of rats or rabbits to
tebupirimphos.]>

<	4. Subchronic toxicity. [A subchronic toxicity feeding study with rats
over 86 days demonstrated a cholinesterase NOAEL of 0.3 mg/kg/day for
males and 0.4 mg/kg/day for females. In a subchronic toxicity feeding
study with dogs over 13 weeks the cholinesterase NOAEL was approximately
0.018 mg/kg/day and the LOAEL was approximately 0.15 mg/kg/day based on
plasma, erythrocyte and brain cholinesterase inhibition.]>

<	5. Chronic toxicity. [Three studies fulfill the rat
chronic/oncogenicity study requirement. Two multiple dose studies were
conducted:  a 2-year rat-feeding carcinogenicity study with a NOAEL of
0.05 mg/kg/day for cholinesterase inhibition and a 6-month
cholinesterase study in rats with a NOAEL 0.02 mg/kg/day for erythrocyte
cholinesterase inhibition.  Systemic NOAELs were higher than the NOAELs
for cholinesterase inhibition. Tebupirimphos was negative for
carcinogenic effects.  A 12-month sacrifice study in rats was conducted
at 0 and 1.25 mg/kg/day in which a decrease in body weight gain, an
increase in food consumption, and an inhibition of brain cholinesterase
activity were observed. Two studies fulfill the mouse
chronic/oncogenicity requirement.  A 2-year mouse carcinogenicity study
was negative for carcinogenic effects under the conditions of the study.
The cholinesterase NOAEL was 0.52 mg/kg/day for males and 0.58 mg/kg/day
for females for erythrocyte, plasma and brain.  In a 12-month mouse
cholinesterase study the NOAEL for cholinesterase inhibition was 0.13
mg/kg/day in males and less than 0.16 mg/kg/day in females. The NOAELs
for systemic effects were higher.  In a 1-year dog-feeding study the
NOAEL was 0.02 mg/kg/day based on plasma, red blood cell, and brain
cholinesterase inhibition effects. No systemic effects were observed
under the conditions of the study.]>

<	6. Animal metabolism. [A rat metabolism study demonstrated that
tebupirimphos was readily absorbed, distributed, metabolized, and
excreted and that bioaccumulation and retention of the compound and/or
its metabolites are low in rats. In vivo and in vitro metabolism studies
indicate that the insecticide is metabolized by mixed function oxidases
to O-[2-(1,1- dimethylethyl)-5-pyrimidinyl]
O-ethyl-O-(1-methylethyl)phosphorothioate (OMAT), an oxygen analog,
which is rapidly hydrolyzed to 2-(1,1-dimethylethyl)-5-hydroxypyrimidine
(TPHP) and excreted as the glucuronide conjugate of TBHP, a major
metabolite representing 60 to 74 percent of the administered
radioactivity.]>

<	7. Metabolite toxicology. [In crops the compound of concern is parent
tebupirimphos. Regulation of residues in animal commodities is not
required as there is reasonable expectation of no residues in these
commodities. Metabolite toxicity information is, therefore not
required.]>

<	8. Endocrine disruption. [There is no evidence to suggest that
tebupirimphos has any primary endocrine disruptive potential.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [The FQPA Safety Factor for tebupirimphos has
been reduced to 1X based on a complete database and no indication of
increased susceptibility of rats or rabbits to the compound. For the
acute dietary analysis, the acute reference dose (aRfD) of 0.002
mg/kg/day was derived from the LOAEL of 0.5 mg/kg for plasma and red
blood cell cholinesterase inhibition in the acute neurotoxicity study in
rats. An uncertainty factor of 300X has been applied to account for
inter- and intraspecies variation (100X) and lack of NOAEL (3X). Since
the FQPA Safety Factor has been reduced to 1X, the aRfD is identical to
the cute population adjusted dose (aPAD). For the chronic dietary
analysis, the chronic reference dose (cRfD) of 0.0002 mg/kg/day was
derived from a NOAEL of 0.02 mg/kg/day based on plasma red blood cell
and brain cholinesterase inhibition in the 2-year dog feeding study. An
uncertainty factor of 100X has been applied to account for inter- and
intraspecies variation. Since the FQPA Safety Factor has been reduced to
1X, the cRfD is identical to the chronic population adjusted dose
(cPAD).]>

<	i. Food. [A Tier 1, or upper-end,  estimate of acute dietary exposure
was determined using all residues at tolerance level and 100 percent of
the commodities assumed to be treated with tebupirimphos. The analysis
was conducted using DEEMTM Software using consumption data  from the
USDA Continuing Survey of Food Intake by Individuals (CSFII) from 1989
– 1992. The chronic analysis was also a Tier 1 assessment
incorporating the same assumptions.  Acute exposure at the 95th
percentile for the most exposed subpopulation, Children 1-6 years,
equated to 4.79% of the aPAD.  The exposure to the U.S. population
equated to 2.33% of the aPAD. Chronic exposure at the 95th percentile
for the most exposed subpopulation, Children 1-6 years, equated to 17.6%
of the cPAD.  The chronic exposure to the U.S. population equated to
7.4% of the cPAD. These Tier 1 estimates of dietary are well below
EPA’s level of concern for the overall U.S. population as well as the
various population subgroups.]>

<	ii. Drinking water. [A Tier 1 drinking water assessment for
tebupirimphos has been conducted based on The Generic Expected
Environmental Concentration Program (GenEEC) to  calculate the surface
water estimated drinking water concentrations (EDWCs) and on the
Screening Concentration in Ground Water (SCI-GROW) model to calculate
corresponding ground water EDWCs. Drinking water levels of comparison
(DWLOC) were calculated for acute exposure of tebupirimphos in surface
and ground water for the U.S. general population (68.335 ppb) and
children ages 1-6 (19.04 ppb). For chronic exposure the DWLOC for the
U.S. general population was 6.475 ppb and for children ages 1-6, 1.65
ppb. EDWCs for surface and ground water for acute exposure (estimated
maximum concentrations) are 1.89 ppb and 0.3 ppb, respectively. EDWCs
for surface and ground water for chronic exposure (estimated average
concentrations) are 0.86 ppb and 0.3 ppb, respectively. Note that the
average concentration for tebupirimphos in surface can be divided by a
factor of 3 prior to comparison with the chronic DWLOC i.e. 0.287 ppb. 
All Tier 1 EDWCs values are well below the DWLOC values.  Therefore it
can be concluded with reasonable certainty that residues in drinking
water will not pose an unacceptable level of risk.]>

<	2. Non-dietary exposure. [There are no indoor or outdoor residential
uses associated with this product.]>

<D. Cumulative Effects>

<	[EPA concluded the organophosphate (OP) cumulative risk assessment in
July 2006. At that time all tolerance reassessment and reregistration
eligibility decisions for individual OP pesticides, including
tebupirimphos, were considered complete. The risk of cumulative effects
from tebupirimphos use has therefore been evaluated and can be
considered as posing reasonable certainty of no harm.]>

<E. Safety Determination>

<	1. U.S. population. [Based on the Tier 1 exposure assessments
described above and on the completeness and reliability of the toxicity
data, it can be concluded that total aggregate exposure to tebupirimphos
from all label uses will utilize less than the RfD for acute and chronic
dietary exposures to the U.S. population and all population subgroups.
EPA generally has no concerns for exposures below 100 percent of the
RfD, because the RfD represents the level at or below which acute daily
aggregate exposure  or chronic aggregate exposure over a lifetime will
not pose appreciable risks to human health.  Thus, it can be concluded
that there is a reasonable certainty that no harm will result to the
U.S. population from aggregate exposure to tebupirimphos residues.]>

<	2. Infants and children. [The Agency has previously concluded that the
toxicology database is adequate for Food Quality Protection Act (FQPA)
purposes and that there are no concerns or residual uncertainties for
pre-/post-natal toxicity. Acceptable acute and subchronic neurotoxicity
studies are available and no treatment-related neuropathology was seen
in studies conducted in hen and rat. Therefore, a FQPA factor of 1X was
selected. Based on the Tier 1 assessments above aggregate exposures were
below the acute and chronic population adjusted dose for the most highly
exposed population subgroup, children 1-6.   EPA generally has no
concerns for exposures below 100 percent of the PAD, because the RfD
represents the level at or below which acute daily aggregate exposure 
or chronic aggregate exposure over a lifetime will not pose appreciable
risks to human health.  Thus, it can be concluded that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to tebupirimphos residues.>

<F. International Tolerances>

<	[Due to the limited use of tebupirimphos outside the United States and
the absence of residues in corn grain, international tolerances have not
been established and tebupirimphos has not been submitted to Codex for
review.]>

 PAGE   

 PAGE   2