Document ID: EPA-HQ-OPP-2008-0730-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILEING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

Docket ID No.:  EPA-HQ-OPP-2008-0730

EPA Registration Division Contact: Sidney Jackson (703-305-7610)

Pesticide Petition #: 8E7419  

ved pesticide petition (PP) 8E7419 from Interregional Research Project
No. 4 (IR-4), Rutgers University, Princeton, New Jersey 08540 and 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 180.293 by establishing tolerances for the residues of
the aquatic herbicide, Endothall, mono(N,N-dimethylalkylamine) salt of
endothall, and the dipotassium salt of endothall in or on the raw
agricultural commodities in Vegetable Root, and Tuber Group 1 at 2
ppm(parts per million); Vegetable, Leaves of Root and Tuber, Group 2 at
3.5 ppm; Vegetable, Bulb, Group 3-07 at 2 ppm; Vegetable, Leafy, except
Brassica, Group 4 at 3.5 ppm;  Vegetable, Brassica, Leafy, Group 5 at
0.1 ppm; Turnip, greens at 0.1 ppm; Vegetable, Legume, Group 6 at 3 ppm;
Vegetable, Fruiting, Group 8 at 0.05 ppm; Okra at 0.05 ppm; Vegetable,
Cucurbit, Group 9 at 1.1 ppm; Fruit, Citrus, Group 10 at 0.05 ppm;
Fruit, Pome, Group 11 at 0.05 ppm; Fruit, Stone, Group 12 at 0.25 ppm;
Berry and Small Fruit Group 13-07 at 0.6 ppm; Nut, Tree, Group 14, at
0.05 ppm; Pistachio at 0.05 ppm; Almond, hulls at 10 ppm; Grain, Cereal,
Group 15 at 2.5 ppm; Grain, Cereal, Forage, Fodder and Hay, Group 16,
forage at 3.5 ppm, Grain, Cereal, Forage, Fodder and Hay, Group 16, hay
at 5 ppm, Grain, Cereal, Forage, Fodder and Hay, Group 16, stover at 11
ppm, Grain, Cereal, Forage, Fodder and Hay, Group 16, straw at 6 ppm,
Grain, aspirated fractions at 24 ppm; Grass, Forage, Fodder, and Hay,
Group 17, forage at 3 ppm, Grass, Forage, Fodder and Hay, hay at 19 ppm;
Nongrass Animal Feed, Group 18 forage at 3.5 ppm, Nongrass Animal Feed,
Group 18 hay at 8 ppm; Grape at 0.9 ppm, Peppermint, tops at 7 ppm,
Spearmint, tops at 7 ppm; and Rice, grain at 1.7 ppm and Rice, straw at
4.5 ppm.   EPA has determined that the petitions contain data or
information regarding the elements set forth in section 408(d)(2) of the
FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data support granting of the
petitions.  Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry                                       

. 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%).

.

An adequate method for purposes of enforcement of the proposed endothall
tolerances is available.  The method uses an HPLC/MS/MS system. 
Separation is achieved using a reversed phase column.  The molecular
ions formed in negative ion mode were fragmented by collision with
neutral gas.  The method is capable of analyzing for residues of
endothall on different crop matricies.

.  Residue studies support the requested tolerances.  Six applications
were made to the following crops with fortified irrigation water, with
5ppm dipotassium salt of endothall.  The application rate was 1 acre
inch of irrigation water or 27,154 gallons per acre. The 6th application
was made at 0 days prior to harvest of the raw agricultural commodity. 

i.  Vegetable Root and Tuber Group: 

ii.  Vegetable, Leaves of Root and Tuber Group:

iii.  Vegetable, Bulb Group:

iv.  Vegetable, Leafy, except Brassica Group:

v.  Vegetable, Brassica, Leafy Group:

vi.  Vegetable, Legume Group:

vii.  Vegetable, Fruiting Group:

viii.  Vegetable, Cucurbit Group:

ix.  Fruit, Citrus Group:

x.  Fruit, Pome Group:

xi.  Fruit, Stone Group:

xii.  Berry Group:

xiii.  Nut, Tree Group:

xiv. Grain, Cereal Group:

xv.  Grain, Cereal, Forage, Fodder and Hay Group:

xvi. Grass, Forage, Fodder and Hay Group:

xvii.  Nongrass Animal Feed Group:

xviii. Grape:

xix.  Mint:

xx.   Rice:

B. Toxicological Profile



.  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. 

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

. 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.

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.

.  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.

.   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.

.   NA/REMOVE

. 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

.

.  Endothall exposure via the diet will occur from treated potatoes and
hops (adults).  Secondary residues are expected in meat, milk, and eggs,
as well as shellfish, fish, catfish, and crayfish.

.  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.  

. There are no registered and proposed uses for endothall products which
would result in non-occupational exposure.

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

.  For chronic dietary risk, two scenarios were used.  Scenario 1 used
tolerance values on all registered and proposed crops, as well as
secondary residues in meat, milk, and eggs, shellfish, fish, catfish,
and crayfish.  Under this scenario, less than 5% of the reference dose
(RfD) for the total U.S. population was utilized.  Because of the highy
milk consumption by children ages 1-6, this group represents the highest
exposed subgroup.  For children ages 1-6, approximatelt 12.4% of the RfD
is utilized.  In the second scenario, which included the above food
exposure from above plus tap water and non-food based water, 28.3% of
the RfD was utilized for the total U.S. population.  Because of high
water consumption likely from reconstituted formula, all infants
utilized 103.7% of the RfD and non-nursing infant utilized 130.7% of the
RfD.  This scenario, however, is not considered realistic estimate of
risk.  It is unlikely that endothall residues would be significant in
water considering its intermittent and seasonal use pattern, lack of
movement in surface water, rapid degradation and label restriction for
application within 600 feet of a potable water intake.  The acute
dietary risk analysis has been performed using TAS-Exposure software
which gives a distributional analysis of exposure.  For the total U.S.
population, children aged 7-12, women aged 13-50 all margins of exposure
(MOE) exceeded 1,000 at the 95th percentile of exposure for the first
scenario (excluding water).  Under this scenario, all infants,
non-nursing infants <1-year and children ages 1-6 had MOEs of 935, 852,
and 988 respectively.  When tap water and non-food based water are
included in the analysis at tolerance level (0.2 ppm), the highest
exposed subpopulation is again non-nursing infants with a MOE of 98 at
the 95th percentile of exposure. For the total U.S. population the 95th
percentile of exposure results in an MOE of 373.  This analysis included
all commodities, including water, at theoretical “worse case” levels
resulting in an extreme over estimation of acute risk from dietary
exposure to potential endothall residues.  This analysis has not
included estimates of anticipated residues, percent of crop treated, or
the likelihood of residues in water accounting for endothall’s use
pattern, movement and degradation.  Additionally, processing effects on
residue levels have not been considered.  Despite all of the worst case
assumptions, the dietary exposure analysis for the U.S. population, and
all population subgroups except all infants and non-nursing infants <1
year results in acceptable MOE, i.e., >100.  The MOE for all infants and
non-nursing infants <1 year were 99 and 98, respectively.  Clearly these
MOEs in this worst case assessment would exceed 100 if adjustments
described above were applied.

F. International Tolerances.

No international tolerances have been established for endothall.

	

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