Document ID: EPA-HQ-OPP-2012-0431-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-07-25T04:00Z

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

<EPA Registration Division contact: [Kathryn Montague (703) 305-1243]>

<TEMPLATE:>

<United Phosphorus, Inc. >

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
United Phosphorus, Inc., 630 Freedom Business Center, Suite 402, King of
Prussia, Pennsylvania 19406 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 the
herbicide Endothall, mono (N,N-dimethylalkylamine) salt of endothall,
and the dipotassium salt of endothall in or on apples at 0.05 ppm under
40 CFR Part 180.293 and apple pomace at 0.15 ppm under 40 CFR Part
180.293.   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 metabolism of endothall was examined in
three crop types: alfalfa, cotton, and sugarbeet.  All three studies
were conducted using C-2 and C-3-(14C) endothall and showed the same
pattern of metabolic breakdown.  The parent compound endothall accounted
for the majority of the total radioactive residue (85 - 110%).

>

<	2. Analytical method. The samples were analyzed using GC/ECD with a
DB-1701 column.  In summary, the endothall residues in apples were
extracted with acidified acetonitrile, purified on an HPLC column,
derivatized with heptaflouro-p-tolylhydrazine (HFTH), cleaned up, then
analyzed using GC/ECD.  The validated LOQ is 0.01 ppm.  Additionally, an
adequate method for purposes of enforcement of the proposed endothall
tolerances is available.  The method uses an HPLC/MSD system.  The
samples are extracted with water, derivatized, cleaned-up, then analyzed
for endothall (as endothall acid) by HPLC.  An alternative enforcement
method is listed as Method I in the Pesticide Analytical manual (PAM,
Volume II) for the determination of endothall in plant commodities.  The
commodities are extracted, derivatized, and analyzed with a GC with a
nitrogen-specific detector.  

>

<	3. Magnitude of residues.  In controlled field trials, endothall (0.4
lb ae (where ae is endothall acid equivalents)/gal SC/L; dipotassium
salt) was applied twice to apple trees at about 0.30 lb
ae/A/application, for a total of about 0.60 lb ae/A/season.  This is
1.3X the proposed maximum label rate.  Residues ranged from <0.01-0.023
ppm in or on 26 apple samples harvested 91-152 days posttreatment. 
Based on processing studies, residues concentrated in wet apple pomace,
with a factor of 2.8 X.>

<B. Toxicological Profile>

<	1. Acute toxicity.  Endothall acid and the dipotassium salt of
endothall are moderately toxic by oral ingestion and inhalation
(Toxicity Category II), slightly toxic by dermal exposure (Toxicity
Category III) and severely irritating to the eye.  The diamine salt of
endothall is moderately toxic by oral, dermal, and inhalation routes of
exposure (Toxicity Category II) and is severely irritating to the eyes
and skin.> 

<	2. Genotoxicty.  A full battery of genetic toxicology studies were
conducted for endothall.  Endothall was not mutagenic.>

<	3. Reproductive and developmental toxicity.   In a teratology and
postnatal behavioral study, pregnant Sprague Dawley rats were dosed via
oral gavage on gestation days 6 through 15 with endothall doses of 0,
10, 20, or 30 milligram/kilogram (mg/kg) /day.  The maternal no observed
adverse effect level (NOAEL) was 20 mg/kg/day due to mortality seen at
30 mg/kg/day.  The developmental NOAEL was 30mg/kg/day.  In a subsequent
developmental toxicity study, pregnant Sprague Dawley rats were orally
dosed with 0, 6.25, 12.5, or 25.0 mg/kg/day from gestation day 6 through
15.  The NOAEL for maternal toxicity was 12.5 mg/kg/day.  The
developmental NOAEL was 25.0 mg/kg/day.>

	A developmental toxicity study was conducted in female CD-1 mice. 
Groups of pregnant mice were orally dosed with 0,5,20, or 40 mg/kg/day
on days 6 through 16 of gestation.  The NOAEL for maternal toxicity was
5mg/kg/day based on mortality seen at 20 mg/kg/day.  The developmental
NOAEL was 20 mg/kg/day.  Developmental changes seen at 40 mg/kg/day were
related to the severe maternal toxicity at that dose.  A developmental
toxicity study was conducted in New Zealand white rabbits by oral
exposure.  Preliminary studies indicated that the rabbit was extremely
sensitive to endothall.  Groups of pregnant rabbits were dosed with 0,
0.3, 1.0, or 3.0 mg/kg/day on gestation days 6 through 19.  The fetal
and maternal toxicity NOAELs were 1.0 mg/kg/day.  A 2-generation
reproduction study was conducted in rats.  In this study, groups of rats
received dietary doses of 0, 30, 150 and 900 ppm (0, 1.9, 9.5, or 58.9
mg/kg/day for male and 0, 1.9-3.4, 9.6-18.5, or 59.0-106.5 mg/kg/day for
female F0 animals; 0, 2.1, 10.9, or 77.1 for male and 0,1.8-3.1,
9.5-17.3, or 63.5-107.7 for female F1 animals).  The NOAEL for parental
effects was 30 ppm based on dose related body weight effects.  The NOAEL
for reproductive toxicity was 900 ppm.

  

<	4. Subchronic toxicity. Male and female Sprague Dawley rats were
exposed dermally to 0, 30, 100, and 300 mg/kg/day for 21 days.  The
lowest observed adverse effect level (LOAEL) was 30 mg/kg/day based on
decreased body weight gain and dermal irritation.  A NOAEL was not
established.  Male and female Sprague Dawley rats were exposed to oral
concentrations of 0, 150, 600, or 1,800 ppm (0, 10, 39, or 118 mg/kg/day
for males; 0,12,51,or 153 mg/kg/day for females respectively) for 13
weeks.  The LOAEL was 1,800 ppm based on decreases in body weight gain
and food intake.  The NOAEL was 600 ppm.  Male and female Beagle dogs
were exposed to oral concentrations of 0, 100, 400, or 1,000 ppm (0,
3.2, 11.7, or 27.5 mg/kg/day for males and 0, 3.2, 13.0, or 28.9
mg/kg/day for females respectively) for 13 weeks.  The LOAEL was 1,000
ppm based on decreases in body weight gain and food intake.  The NOAEL
was 400 ppm.

 >

<	5. Chronic toxicity. [In a combined chronic toxicity and oncogenicity
study, male and female Sprague Dawley rats were fed endothall dietary
concentrations of 0, 150, 300, 900, and 1,800 ppm for 104 weeks.  No
evidence of carcinogenicity was seen in this study.  The NOAEL was 150
ppm.  The incidence of acanthosis and hyperkeratosis of the stomach was
slightly higher than control for the 150 ppm males.  This finding was
not considered an adverse effect since the incidence of this finding in
the 300 ppm males was similar to control.  Beagle dogs were fed diets
containing 0, 100, 300, or 800 ppm disodium endothall (equivalent to 0,
2, 6, or 16 mg/kg/day endothall) for 24 months.  No clinical sign of
toxicity were seen at any dose level.  The 100 ppm dietary concentration
(2 mg/kg/day) was the NOAEL.

	In a 52-week oral toxicity study, groups of 4 male and 4 female Beagle
dogs were fed diets containing 0, 150, 450, or 1,350/1,000 ppm (0, 5.7,
17.1, and 35.8 mg/kg/day for males; 0, 6.4, 18.8 and 36 mg/kg/day for
females).  The 1,350 ppm dietary level had to be 1,000 ppm after 6 weeks
of treatment due to marked reductions in body weight, food consumption,
and subsequent sacrifice of 5 animals from this group. Minimal to very
mild gastric epithelial effects were seen in some of the dogs receiving
150 ppm.  This effect was considered as a low grade reaction to chronic
epithelial irritation and 150 ppm is considered a NOAEL.  IN an 18-month
oncogenicity study, Swiss Albino mice were fed in the diet at
concentrations of 0, 50, 100, and 300 ppm (0, 8.1, 16.7, and 50
mg/kg/day for males; 0, 10.8, 22.4, and 68 mg/kg/day for females) for 92
weeks.  The systemic NOAEL was 100 ppm based on decreased mean body
weight in 300 ppm males.  No evidence of carcinogenicity was seen in
this study.

	In a second 18-month dietary oncogenicity study, groups of 50 males and
50 females Swiss Albino mice were fed the disodium salt of endothall at
dietary concentrations of 0, 750, and 1,500 ppm (0, 122, and 258
mg/kg/day for males; 0, 152, and 319 mg/kg/day for females).  Toxicity
results for the 1,500 ppm dietary level clearly show that the maximum
tolerance dose (MTD) was exceeded.  At 750 ppm, compound-related effect
consisted of decreased body weight gain, rectal prolapse and an increase
in the incidence and severity of mucosal hyperplasia of the glandular
stomach.  Endothall was not considered carcinogenic in this study.

>

<	6. Animal metabolism. Following a single oral administration of
14C-endothall to males and female rats, the majority of the
radioactivity was excreted within 24 hours.  The majority of the
radioactivity was found in the feces.  Chromatographic analysis of
extracts of urine, feces, cecum, and large intestine of both male and
female rats gave a single radioactive component corresponding to
unchanged endothall.  The nature of the residue in goat and poultry
studies has been determined in metabolism studies.  The residues of
concern are parent endothall and its monomethyl ester.  

 >

<	7. Metabolite toxicology.  NA/REMOVE

>

<	8. Endocrine disruption. Evaluation of the results from 2-generation
reproduction studies does not demonstrate any effects suggestive of
disruption of hormonal stasis in the rat.  Further, histopathologic
evaluation of hormone sensitive tissues from chronically exposed rats,
mice, and dogs did not reveal any changes suggestive of an
endocrine-related effect.

 >

<C. Aggregate Exposure>

<	1. Dietary exposure. EPA conducted a chronic, aggregate dietary
exposure for food and water using the dietary model DEEM-FCID™,
Version 2.03.    >

<	i. Food. The food exposure was based on residue results from 18 field
trials on numerous crops and 9 associated processing studies conducted
by IR-4.  The exposures assumed that the maximum labeled rate of
endothall was applied to irrigation canals. The average residues from
the field trials were used for all crops.  The exposure assessment
assumed that all livestock consumed both water and feeds containing
maximum endothall residues.   >

<	ii. Drinking water. Drinking water exposure to endothall may be
expected.  However this exposure is not considered to be significant due
to the seasonal intermittent use of the product for aquatic weed
control, its low mobility in surface waters and rapid degradation.  

 	2. Non-dietary exposure. NA/REMOVE>

<D. Cumulative Effects>

<	United Phosphorus has reviewed chemical structure data to determine if
any other pesticide products are chemically similar to endothall and
produce gastrointestinal changes specific to endothall.  Endothall
appears to be chemically and toxicologically dissimilar to existing
chemical substances.  Therefore, cumulative risk should not be an issue
for this chemical.

 >

<E. Safety Determination>

<	1. U.S. population. The chronic RfD is 0.007 mg/kg/day, with a chronic
population adjusted dose (cPAD) also of 0.007 mg/kg/day based on the
2-generation reproduction study in rats.  The 2-generation rat
reproduction study has a LOAEL of 2 mg/kg/day (UFtotal = 300).   The
cPAD for the general U.S. population is 33%.  This level is below
EPA’s level of concern.  An acute endpoint was not identified for
endothall, therefore an acute dietary risk assessment is not
appropriate.  Endothall is not likely to be carcinogenic in humans.   

 

 >

<	2. Infants and children. The % CPAD for the most sensitive subgroup is
children 1-2 years old, with 85% cPAD.  This level is below EPA’s
level of concern.  >

<F. International Tolerances>

<	No international tolerances have been established for endothall.  >

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