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Endothall - Pesticide Petition Filing 1/01

ENVIRONMENTAL PROTECTION AGENCY

[PF-994; FRL-6764-8]

Notice of Filing Pesticide Petitions to Establish Tolerances for
a Certain Pesticide Chemical in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.

DATES: Comments, identified by docket control number PF-994, must be
received on or before March 9, 2001.

ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-994 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT: By mail: Cynthia Giles-Parker,
Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (703) 305-7740; e-mail address:
giles-parker.cynthia@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

[[Page 9324]]

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                                                          Examples of
           Categories                 NAICS codes         potentially
                                                      affected  entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select "Laws and
Regulations" and then look up the entry for this document under the
"Federal Register--Environmental Documents." You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for
this action under docket control number PF-994. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-994 in the subject line on the
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-994. Electronic comments may
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under FOR FURTHER INFORMATION
CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used
that support your views.
    4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.

II. What Action is the Agency Taking?

    EPA has received pesticide petitions as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that these petitions contain data or information
regarding the elements set forth in section 408(d)(2); however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of these petitions. Additional
data may be needed before EPA rules on the petitions.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.

    Dated: January 25, 2001.
  James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    The petitioner summaries of the pesticide petitions are printed
below as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioner and represent the view of the
petitioner. EPA is publishing the petitioner's summaries verbatim
without editing it in any way. The petitioner's summaries announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.

Elf Atochem North America

PP 7F4867 and 7F4868

    EPA has received pesticide petitions PP 7F4867 and PP 7F4868 from
Elf Atochem North America, 2000 Market Street, Philadelphia, PA 19103
proposing pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d),
to amend 40 CFR part 180 by establishing tolerances for residues of
endothall in or on the raw agricultural commodities cottonseed ((RAC)
seed and processed seed) at 2.0 parts per million (ppm) and apples at
0.05 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
petitions.

1. PP 7F4867

A. Residue Chemistry

    1. Plant metabolism. Acala cotton was treated by a single foliar
application with 14C-endothall formulated as the dipotassium
salt. The study identified 84- >100% of the radioactivity in/on cotton
calyx, forage, and lint. Endothall accounted for ca. 94% and 83% of
total radioactive residue (TRR) in calyx and lint, respectively,
harvested 4 days following application at 1x, and for ca. 99%, 102%,
and 95% of TRR in calyx, forage and lint, respectively, harvested 14
days post-treatment. No other metabolites were identified in calyx and
forage. The monomethyl and dimethyl ester of endothall were minor (<
10% TRR) metabolites in lint. No metabolites were identified in seed.
    2.  Analytical method. The analytical method for endothall in water
is EPA/ORD method 548, "Determination of Endothall in Drinking Water
by Aqueous Derivatization, Liquid-Solid Extraction and Gas
Chromatography with Electron-Capture Detection." The limit of
detection (LOD) for this method is 0.015 ppm.
    3. Magnitude of residues. Endothall was applied to cotton at a rate
of 0.85 lb./acre with a 3-day pre-harvest interval (PHI). Residues in
RAC seed were 0.46 ppm (0.071 to 1.1 ppm) and residues in RAC gin trash
were 21 ppm (6.6 to 59 ppm).

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. Genotoxicity. 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 dose 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 30 mg/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 to 16 of gestation. The NOAEL for maternal toxicity was 5
mg/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 dose 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 58.8
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 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 signs 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 male
and 50 female 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 shows that the maximum
tolerance dose (MTD) was exceeded. At 750 ppm, compound-related effects
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 the urine, feces, cecum, and large intestine of both male
and female rats gave a single radioactive component corresponding to
unchanged endothall.
    7. Endocrine disruption. Evaluation of the results from the 2-
generation reproduction studies do 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--i. Food. Endothall exposure via the diet will
occur from treated apples, sugar beets, potatoes, cotton, and hops
(adults). Secondary residues are expected in meat, milk, and eggs as
well as shellfish, fish, catfish, and crayfish.
    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. There are no registered and proposed uses
for endothall products which would result in non-occupational exposure.

D. Cumulative Effects

    Elf Atochem 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. 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 high milk consumption by children ages 1-6,
this group represents the highest exposed subgroup. For children ages
1-6, approximately 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 infants
utilized 130.7% of the RfD. This scenario, however, is not considered a
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, and women aged 13 to
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 "worst 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.
    2. Infants and children. The exposure to infants and children has
been calculated in both the acute and chronic dietary assessments. In
all cases, and all age groups of infants and children, the MOE is
sufficient to protect the health of infants and children.

F. International Tolerances

    No international tolerances have been established for endothall.

2. PP 7F4868

A. Residue Chemistry

    1. Plant metabolism. The metabolism of endothall was examined in
three crops 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%),

with the monomethyl and dimethyl esters of endothall present as minor
metabolites (<10%).
     2. Analytical method. The analytical method for endothall in water
is EPA/ORD method 548, "Determination of Endothall in Drinking Water
by Aqueous Derivatization, Liquid-Solid Extraction and Gas
Chromatography with Electron-Capture Detection." The limit of
detection LOD for this method is 0.015 ppm.
    3. Magnitude of residues. Residue trials in apples showed residue
levels in the RAC of 0.0086 ppm (residue range of 0.005-0.023 ppm),
0.015 ppm (0.012-0.020 ppm) for the processed RAC, 0.019 ppm (0.012-
0.026 ppm) for apple pomace, and 0.019 ppm (0.071-1.1 ppm) for apple
juice.

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. Genotoxicity. 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 dose via
oral gavage on gestation days 6 through 15 with endothall doses of 0,
10, 20, or 30 mg/kg/day. The maternal NOAEL was 20 mg/kg/day due to
mortality seen at 30 mg/kg/day. The developmental NOAEL was 30 mg/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 to 16 of gestation. The NOAEL for maternal toxicity was 5
mg/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 58.8
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 F1animals).
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
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
female 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 signs 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 and 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 male
and 50 female 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 shows that the MTD was
exceeded. At 750 ppm, compound-related effects 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 the urine, feces, cecum and large intestine of both male
and female rats gave a single radioactive component corresponding to
unchanged endothall.
    7. Endocrine disruption. Evaluation of the results from the 2-
generation reproduction studies do 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-- i. Food. Endothall exposure via the diet will
occur from treated apples, sugar beets, potatoes, cotton, and hops
(adults). Secondary residues are expected in meat, milk, and eggs as
well as shellfish, fish, catfish,and crayfish.
    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. There are no registered and proposed uses
for endothall products which would result in non-occupational exposure.

D. Cumulative Effects

    Elf Atochem 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. 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 RfD for the total U.S. population was utilized. Because of
the high milk consumption by children ages 1-6, this group represents
the highest exposed subgroup. For children ages 1-6, approximately
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 infants utilized 130.7% of
the RfD. This scenario, however, is not considered a 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 ages 7-12, and women ages 13 to 50 all MOEs
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 an 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 "worst 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.
    2. Infants and children. The exposure to infants and children has
been calculated in both the acute and chronic dietary assessments. In
all cases and all age groups of infants and children, the margins of
exposure are sufficient to protect the health of infants and children.

F. International Tolerances

    No international tolerances have been established for endothall.

[FR Doc. 01-3092 Filed 2-6-01; 8:45 am]