Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: December 22, 1999 (Volume 64, Number 245)]
[Notices]
[Page 71774-71779]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22de99-89]

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

ENVIRONMENTAL PROTECTION AGENCY

[PF-906; FRL-6398-6]

Notice of Filing a Pesticide Petition to Establish a Tolerance
for Certain Pesticide Chemicals 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
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by docket control number PF-906, must be
received on or before January 21, 2000.
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-906 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT: By mail: James Tompkins, Registration
Support Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460; telephone number: (703) 305-5697; e-mail address:
tompkins.jim@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:

------------------------------------------------------------------------
Examples of
Categories NAICS 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-906. 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-906 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, 401 M St., SW., 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

[[Page 71775]]

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-904. 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 a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a
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 this petition contains 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 supports granting of the petition. Additional data
may be needed before EPA rules on the petition.

List of Subjects

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

Dated: December 10, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioners. EPA is publishing the petition summary verbatim without
editing it in any way. The petition summary 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.

Nippon Soda Co. LtD with, BASF Corporation as Agent

PP 8F4945

EPA has received a pesticide petition (8F4945) from BASF
Corporation , acting as Agent for Nippon Soda Company, LtD,
Agricultural Products, PO Box 13528, Research Triangle Park, NC 27709-
3528 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Costmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180
by establishing a tolerance for residues of tepraloxydim [(EZ)-(RS)-2-
1-[(2E)-3-chloroallyloxyimino]propyl-3-hydroxy-5-perhydropyran-4-
ylcylohex-2-en-1-one] and its metabolites containing the 3-
tetrahydroyrany-1-pentane-1,5-dione (GP) and/or 5-(4-
tetrahydropyranyl)-3-hydroxy-cyclohex-2-en-1-one (5-OH-DP) moiety
(calculated as the herbicide)] in or on the raw agricultural commodity
(RAC) in cotton seed at 0.2 parts per million (ppm), cotton meal at 0.2
ppm, cotton hulls at 0.2 ppm, cotton gin trash at 3.0 ppm, soybean seed
at 5.0 ppm, soybean meal at 5.0 ppm, soybean hulls, poultry meat at 0.5
ppm, poultry liver at 1.0 ppm, poultry fat at 0.5 ppm, and eggs at 0.2
ppm. EPA has determined that the petition contains 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 supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of the residues in
plants is adequately understood for the purposes of registration.
Analytical methods for detecting levels of tepraloxydim and its
metabolites in or on food with a limit of detection that allows
monitoring of food with residues at or above the levels set in these
tolerances was submitted to EPA.
2. Analytical method. The proposed analytical method involves
extraction, concentration, precipitation, centrifugation/filtration,
oxidation, partition, and clean-up. Samples are then analyzed by GC-MS
(selected ion monitoring). The limit of quantitation (LOQ) is 0.4 ppm
in soybean matrices and 0.1 ppm in cotton matrices.
3. Magnitude of residues. Soybean samples from 22 locations in 16
states were analyzed for residues of tepraloxydim. The highest average
total of tepraloxydim residues detected in soybean seed samples
collected 45 days after application was 4.93 ppm. The average total of
tepraloxydim residues in other soybean seed samples collected 45 days
after application for the remaining sites ranged from 0.65 to 4.81 ppm.
Forage and hay were not analyzed and these commodities will be
restricted from feeding to livestock. The tepraloxydim residues for 2
residue decline sites did not exhibit any clear trends from the range
of -10 days to +10 days around the 45-day harvest target.

[[Page 71776]]

In addition, soybeans were processed after treatment at the
proposed label rate into hulls, meal, and refined oil. There was little
or no concentration of tepraloxydim residues found in soybean meal or
refined oil. Residues in the meal were roughly equal to those found in
the seeds. Residues in the refined oil were less than 10% of the
residues observed in the seeds. Residues concentrated slightly in the
hull fractions. The average concentration factor in hulls was 1.45.
Cotton samples from 13 locations in 8 States were analyzed for residues
of tepraloxydim. The highest average total of tepraloxydim residues
detected in cotton seed samples collected 40 days after application was
0.19 ppm. The average total of tepraloxydim residues in cotton seed for
the remaining sites ranged from < 0.10 to 0.18 ppm. In gin trash, the
highest average total of tepraloxydim residues detected was 2.10 ppm.
The remaining sites contained tepraloxydim residues that ranged from <
0.10 to 1.34 ppm. The tepraloxydim residues for the residue decline
site in North Carolina exhibited no clear trends from the -11 day
harvest to the +10 day of the 41-day target. All 5-OH-DP residues were
< 0.05 ppm level of quanification. Only the 36 and 51 days after last
application (DALA) seed samples for tepraloxydim were at or above 0.05
ppm (0.054 and 0.05 ppm, respectively). The gin trash samples contained
tepraloxydim residues ranging from < 0.05 ppm to 0.178 ppm at 36 and 46
DALA, respectively.
Available data support the proposed tolerances of poultry meat and
fat at 0.5 ppm, poultry liver at 1.0 ppm, and eggs at 0.2 ppm.

B. Toxicological Profile

1. Acute toxicity. Based on available acute toxicity data
tepraloxydim does not pose any acute toxicity risks. Acute toxicity
studies place technical tepraloxydim in toxicity category III and for
acute oral, dermal, and inhalation and toxicity category IV for eye and
dermal irritation. The technical material is not a positive skin
sensitizer. Additionally, tepraloxydim was not found to have a
neurotoxic potential after acute exposure.
2. Genotoxicity. The following tests were conducted: An Ames Test
(1 study; point mutation): negative; in vitro CHO cells/hypoxanthine-
guanine phosphoribosyl transferase (CHO/HPRT) (1 study; point
mutation): negative; in vitro cytogenetics - CHO Cells (1 study;
chromosome aberrations): negative; in vitro unscheduled DNA synthesis
(UDS) test using rat hepatocytes (1 study; DNA damage and repair):
negative; mouse micronucleus - in vivo (1 study; chromosome
aberrations): negative based on the studies mentioned above,
tepraloxydim does not pose a mutagenic hazard to humans.
3. Reproductive and developmental toxicity. A 2-generation
reproduction study was conducted with rats being fed dosages of 0, 11,
53, and 268 milligrams/kilograms/day (mg/kg/day) with a reproductive no
observed adverse effect level (NOAEL) of 268 mg/kg/day, pup
developmental NOAEL of 53 mg/kg/day, and maternal NOAEL of 11 mg/kg/day
based on the following: (1) At the parental 268 mg/kg/day dose level,
decreased food consumption, reduced body weights (bwts) and/or gains,
increase in albumin and cholesterol, decrease in triglycerides and
increase in white blood cell count were observed; (2) at the parental
(F1 females) 53 mg/kg/day dose group only, increase in white blood cell
count was observed; and (3) the only pup toxicity was observed at the
268 mg/kg/day dose group which consisted of reduced bwts and/or gains
and delayed eye opening.
A developmental study in rats via oral gavage resulted in dosages
of 0, 40, 120, and 360 mg/kg/day highest dose tested (HDT) with a
developmental toxicity NOAEL of 40 mg/kg/day and a maternal toxicity of
120 mg/kg/day based on the following: (1) At the 360 mg/kg/day dose
group, distinct maternal toxicity consisting of reduced food
consumption, impairment in bwt gains, and reduced uterus weights; (2)
at the 360 mg/kg/day dose group, increased resorptions and post
implantation loss, lower mean percentage of live fetuses, and lower
mean placental weights were observed; and (3) at the 360 and 120 mg/kg/
day dose groups, slightly decreased mean fetal weights were observed
with a progression of severity to the upper dose group, and, at the 360
mg/kg/day dose group, slightly increased malformation rates were
observed.
A second developmental study was performed to clarify phenomenons
(skeletal retardations and variations) which were observed in the
preceding test also at the lowest dose level of 40 mg/kg/day, but which
were still within historical control data and, therefore, assessed as
not being substance-related. The dose levels in this study were 0, 10,
20, and 40 mg/kg/day HDT with a developmental toxicity NOAEL of 40 mg/
kg/day and a maternal NOAEL of 40 mg/kg/day. There were no substance-
related effects for all parameters measured in this study.
A developmental toxicity study in rabbits via oral gavage resulted
in dosages of 0, 20, 60, and 180 mg/kg/day HDT with a developmental
toxicity NOAEL of 180 mg/kg/day and a maternal toxicity NOAEL of 60 mg/
kg/day based on the following: (1) At the HDT, reduced food consumption
and impaired bwt gain were the only effects observed during the
treatment period; and (2) no other signs of maternal toxicity were
detected in this dose group or at the lower dose groups tested. No
developmental or teratogenic effects were observed in this study.
4. Subchronic toxicity. A subchronic neurotoxicity study in rats
fed dosages of 0, 28, 103, and 428 mg/kg/day (males) and 0, 33, 124,
and 513 mg/kg/day (females) with a neurotoxicity NOAEL of 428 mg/kg/day
(males) and 513 mg/kg/day (females) and a systemic NOAEL of
<difference>28 mg/kg/day based on the following effects: (1) At the
HDT, decreased food consumption and significantly reduced bwts and/or
bwt changes were observed in both male and females rats; and (2) in the
mid-dose level, reduced bwts and/or bwt changes were observed in female
rats only. No signs of neurotoxicity and gross and microscopic
pathology were observed at any dose level tested.
In an in vivo dermal absorption study, male Wistar rats were dosed
with [14C] - tepraloxydim. Dose levels of 0.005, 0.05, and
0.5 mg/cm2 diluted in Solvesso 200 were administered to rats
on a shaved area on the back. Groups of 4 rats per dose group were
sacrificed at 8, 24, or 72 hours following application of the dose.
Results indicated that after the 8-hour exposure, the total percent
absorbed at all dose levels was 3-5%. Additionally, with increasing
dose, the percentage of radioactivity absorbed tended to decrease
indicating that saturation of skin with increasing dose occurred under
the conditions tested. This effect was most striking at the high dose
level (HDL).
5. Chronic toxicity. Based on review of the available data, BASF
believes the reference dose (RfD) for tepraloxydim will be based on the
2-year feeding study in rats with a threshold NOAEL of 6 mg/kg/day in
male and female rats. Using an uncertainty factor of 100, the RfD is
calculated to be 0.06 mg/kg/day. The following are summaries of the
pertinent toxicity data supporting tepraloxydim tolerances
Two 1 year feeding study in dogs fed dosages of 0, 3.0, 12.0, 58.0
(first study) and 257.0 mg/kg/day (second study) with a NOAEL of 12 mg/
kg/day based on the following effects: (1) At the 257 mg/kg/day dose
level a slight anemia was detected; (2) clinical chemistry revealed
disturbances in lipid, protein, and carbohydrate metabolism in both
sexes of the 257 mg/kg/day dose level and, to a minor extent, in males
of the

[[Page 71777]]

58 mg/kg/day dose level; (3) the upper two dose levels caused reduced
function of the epididymides, and degeneration and atrophy of the
germinal epithelium in the testes were observed; (4) increased absolute
and/or relative weights for the liver, kidney, and thyroid, and
decreased absolute and or relative weights (males only) of the testes
and epididymides were observed in the 257 mg/kg/day dose group; (5)
increased absolute and/or relative weight for the liver and thyroid,
and decreased absolute and/or relative epididymides (males only)
weights were observed in the 58 mg/kg/day dose group (these increases
were not statistically significant); and (6) microscopic findings in
the urinary bladder, liver, gall bladder, spleen, bone marrow, thyroid,
testes (males), epididymides (male), and prostate (male) were seen in
the 257 mg/kg/day dose group and, in the 58 mg/kg/day dose group,
urinary bladder, epididymides (male), and prostate (male) microscopic
findings were seen at a lesser degree than the 258 mg/kg/day dose
group.
A chronic feeding study and carcinogenicity study resulted in rats
being fed dosages of 0, 6.0, 33, and 154 (males) and 273 (females) mg/
kg/day with a NOAEL of 6.0 mg/kg/day for males and females based on the
following effects: (1) Decreased bwt, bwt change, and food consumption
in both male and female rats at dose levels > 154 mg/kg/day; (2)
clinical chemical changes were observed in the mid- and high-dose
groups; and (3) in the 273 mg/kg/day dose group of the carcinogenicity
study, there was a trend towards a slightly elevated incidence for
hepatocellular adenomas and carcinomas. However, the incidence for
adenomas is within the range of historical control, the incidence for
carcinomas was slightly above the range of historical controls, and, in
the 154 mg/kg/day male dose group of the chronic study, a trend towards
a slightly elevated increase of carcinomas was observed which was not
considered to be statistically significant. The higher sensitivity of
females may possibly be due to the higher dose that was fed to that
sex, which clearly fulfilled the criteria for a Maximum Tolerated Dose
(MTD).
A carcinogenicity study in mice fed dosages of 0, 37, 332, and
1,035 mg/kg/day (males) and 0, 52, 490, and 1,456 mg/kg/day (females)
with a NOAEL of 37 mg/kg/day (males) and 52 mg/kg/day (females) based
on the following effects: (1) Significantly decreased bwts/bwt changes
were observed in both male and female mice at the mid-dose and high-
dose levels with a progression of severity to the top dose which
clearly fulfilled the criteria for a MTD for both dose levels; (2) in
the 1,456 mg/kg/day female dose group, a slight increase in lymphocytes
and decrease in polymorphonuclear neutrophils was seen; (3) relative
liver weights were increased in both sexes of the high-dose group and
in males of the 332 mg/kg/day dose group; (4) in females of the high-
dose and mid-dose levels, hyalinization (sclerosis) of the endometrial
stroma, muscularis, and/or perivascular areas were observed in the
uterus; and (5) a very slightly increased incidence of neoplasms
(adenomas and carcinomas) occurred at dose levels which fulfilled the
criteria for a maximum tolerated dose in the liver of female mice. No
substance-related neoplasms were observed in the top dose males or in
both sexes at dose levels below the MTD.
i. Mechanistic studies--a. Initiation potential study. In order to
determine if tepraloxydim will initiate the carcinogenic process,
tepraloxydim was tested for its foci initiating potential after single
oral administration of 2,000 mg/kg/day in 0.5% aqueous carboxymethyl-
cellulose (CMC) solution to partially hepatectomized female Wistar rats
according to a protocol of Prof. Schulte-Hermann, University of Vienna,
Austria. N-Nitrosomorpholine (NNM) is known to induce liver foci and
was used as a positive control for initiation at a dose of 25 mg/kg/
day. Phenobarbitone (PB) was used as a promoter. Three different groups
(test substance, negative and positive controls) were each divided into
two sub-groups, one being maintained for 8 weeks on basal diet, while
the other sub-group was treated with 500 ppm PB in the diet for the
same period. Each sub-group consisted of 15 male and 15 female animals.
The rats were subjected to an adaptation period of at least 17 days.
After this adaptation period, partial hepatectomy was performed.
Fourteen hours after partial hepatectomy, the test and control
substances were administered once by gavage to 2 groups each
(initiation period) and the animals were held on basal diet ad libitum
for a 14-day recovery period. Thereafter, the groups received either
500 ppm PB or basal diet for another 8 weeks (promotion period). The
state of health of the animals was checked at least once a day. Body
weight was determined in weekly intervals and food consumption was
measured in weekly intervals during the promotion period. At the end of
the study the animals were subjected to gross-pathological assessment,
giving special attention to the liver. Histopathologic evaluation of
the liver was performed on Hematoxylin and Eosin stained slides as well
as on slides stained for Glutathione-S-Transferase P (GST-P). GST-P
positive foci were evaluated quantitatively (foci/cm2 of
liver tissue). The initiating potential of a chemical is expressed in
the increased number of foci relative to control.
The mean numbers of GST-P positive foci per cm2, which
were detected in the different study groups, are given in the following
table.

Table 1: Mean number of GST-P positive foci per cm2
--------------------------------------------------------------------------------------------------------------------------------------------------------
Study group Initiation Promotion Mean number of foci per cm2
--------------------------------------------------------------------------------------------------------------------------------------------------------
0........................................... vehicle\1\ - 0.3
1........................................... vehicle\1\ 500 ppm PB\2\ 0.45
2........................................... 25 mg/kg/day NNM\3\ - 7.78
3........................................... 25 mg/kg/day NNM\3\ 500 ppm PB\2\ 11.86
4........................................... 2,000 mg/kg/day tepraloxydim - 0.08
5........................................... 2,000 mg/kg/day tepraloxydim 500 ppm PB\2\ 0.17
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\vehicle = 0.5% aqueous carboxymethyl cellulose
\2\PB = Phenobarbitone
\3\NNM = N-Nitrosomorpholine

The mean number of GST-P positive foci per cm2 liver
tissue was very low in groups 4 and 5 which were treated with the test
substance, and there were no significant differences to the
corresponding control groups 0 and 1.

[[Page 71778]]

As expected, the number of GST-P positive foci per cm2
was significantly increased in groups 2 and 3, when compared with the
corresponding control groups (group 0 or 1) demonstrating the known
initiating capacity of NNM.
Therefore, tepraloxydim does not have an initiating potential.
A possible non-genotoxic mechanism, which could account for the
increased incidence of liver tumors, is the induction of increased cell
proliferation (S-phase response).
b. S-Phase response. In order to determine if tepraloxydim causes
cell proliferation, tepraloxydim was administered to groups of 5 male
and 5 female Wistar rats at dietary levels of 0, 100, 600, 3,000 (males
only), and 4,000 (females only) ppm for different time periods: 1 week,
6 weeks, and 13 weeks. An additional group with a recovery period of 2
weeks was used after 1 week administration, and a 5-week recovery group
was additionally used after 13-week administration. The influence of
treatment on DNA-synthesis/cell proliferation (S-phase response) in the
liver was determined using bromodeoxyuridine (BrdU), which is
incorporated into the DNA if DNA-synthesis and cell proliferation is
induced. One week prior to necropsy, osmotic minipumps containing BrdU
were implanted subcutaneously. Food consumption and bwt were determined
weekly. The state of health was checked each day. All animals were
assessed by gross pathology. BrdU incorporated into the DNA of liver
cells was detected by immunohistochemistry and evaluated
microscopically.
Cell proliferation can be induced diffusely in all hepatocytes or
it can be localized in a specific region of the lobule. Therefore, in
each of the two liver lobes, five lobules were evaluated. In order to
assess whether a localized liver cell proliferation occurs in the liver
lobule, the lobule was subdivided into three zones (Rappaport)
containing the portal tract (zone 1), the central vein (zone 3), and
the zone in-between (zone 2). In total, more than 1,000 cells per zone
and more than 3,000 hepatocytes per animal were recorded and the BrdU
labeling index determined.
The results from the S-phase response study in the rat liver
demonstrate that tepraloxydim can induce a selective increase in cell
proliferation predominantly in zone 3 after 1, 6, and 13 weeks in
females at 4,000 ppm and, to a minor degree, at 600 ppm. In the males,
there was an increase in cell proliferation after 1 week treatment at
3,000 ppm and, to a minor degree, at 600 ppm. The enhanced cell
proliferation after 1 week of administration was reversible after 1
weeks of recovery in both sexes and appeared to be reversible in
females after 5 weeks of recovery following 13 weeks of administration.
The more pronounced S-phase response in female rats also explains why
liver neoplasia was predominantly found in the females. These studies
indicate that the mode of action by which an enhancement of liver
neoplasia was induced is a chronic increase in liver cell
proliferation. It is emphasized that this mechanism results in an
increased incidence of liver tumors only at dose levels at the MTD. It
is therefore concluded that tepraloxydim does not have an oncogenic
potential of biological relevance.
6. Animal metabolism. The qualitative nature of the residues in
animals is adequately understood for the purposes of registration.
Analytical methods for detecting levels of tepraloxydim and its
metabolites in or on food with a limit of detection that allows
monitoring of food with residues at or above the levels set in these
tolerances was submitted to EPA.
7. Metabolite toxicology. Available metabolism data indicate that
the metabolites containing the GP and 5-OH-DP moiety should be included
in the tolerance for expression for tepraloxydim.
8. Endocrine disruption. No specific tests have been performed with
tepraloxydim to determine whether the chemical may have an effect in
humans that is similar to an effect produced by naturally-occurring
estrogen or other endocrine effects.

C. Aggregate Exposure

1. Dietary exposure. For purposes of assessing the potential
dietary exposure, BASF has estimated aggregate exposure based on the
Theoretical Maximum Residue Contribution (TMRC) from the proposed
tolerances for tepraloxydim in or on the RAC cotton seed, meal, and
hulls at 0.2 ppm; cotton gin trash at 3.0 ppm; soybean seed, meal, and
hulls at 5.0 ppm; poultry meat and fat and 0.5 ppm; poultry liver at
1.0 ppm; and eggs at 0.2 ppm. The TMRC is a ``worst-case'' estimate of
dietary exposure since it is assumed that 100% of all crops for which
tolerances are established are treated and that pesticide residues are
at the tolerance levels. There are no established U.S. tolerances for
tepraloxydim, and there are no currently registered uses for
tepraloxydim on food or feed crops in the United States.
i. Food. Dietary exposure to residues of tepraloxydim in or on food
from these proposed tolerances would account for less than 4.0% of the
RfD (0.06 mg/kg/day) for the overall U. S. population. BASF estimates
indicate that dietary exposure will not exceed the RfD for any
population subgroup for which EPA has data. The most highly exposed
group in the subpopulation groups would be non-nursing infants < 1 year
old, which uses <difference>15.0% of the RfD. This exposure assessment
relies on very conservative assumptions--100% of crops will contain
tepraloxydim residues and those residues would be at the level of the
tolerance--which results in an overestimate of human exposure.
Tepraloxydim was evaluated for its potential mutagenicity and
genotoxicity in vitro using bacterial and mammalian cells as well as in
a cytogenetics assay. The results of these studies demonstrated the
absence of a mutagenic or genotoxic effect.
In vivo, the compound was assessed for the induction of micronuclei
in mice. The result of this study showed that tepraloxydim has no
chromosome-damaging potential.
It is therefore, concluded that tepraloxydim has no mutagenic or
genotoxic properties either in vitro or in vivo.
The results of a 24-month chronic toxicity study and a
carcinogenicity study in rats show that the HDL (154 mg/kg/day in males
and 273 mg/kg/day in females) clearly fulfilled the criteria for a MTD
based on distinctly reduced bwts or bwt changes and histopathological
alterations in the liver. The test substance induced changes in
clinico-chemical parameters, which are considered to be associated with
liver toxicity. Histopathologically, the liver was found to be
affected, therefore, this organ was identified as a target. In the
carcinogenicity study, in female animals of the top dose, a slight
trend towards an increased incidence of hepatocellular adenomas and
carcinomas was observed which was virtually within the historical
control range. In top dose males of the chronic toxicity study, a trend
towards a slightly elevated increase of carcinomas was detected. As
this increase was not evident in the carcinogenicity study, which
involves a far greater number of animals, it is likely that this
finding was incidental.
Additional mechanistical investigations have demonstrated that
tepraloxydim does not possess an initiating potential for a liver
carcinogenic process. Combined with the proven absence of a gene or
chromosome damaging effect, it can be concluded that the increased
incidence of rat liver neoplasia was not related to a genotoxic mode of
action.

[[Page 71779]]

The results from an S-phase response study in the rat liver
demonstrate that tepraloxydim can induce a selective increase in cell
proliferation predominantly in zone 3 after 1, 6, and 13 weeks in
females at 4,000 ppm and, to a minor degree, at 600 ppm. In the males,
there was an increase in cell proliferation after 1 week treatment at
3,000 ppm and, to a degree, at 600 ppm. The enhanced cell proliferation
after 1 week of administration was reversible after 2 weeks of recovery
in both sexes and appeared to be reversible in females after 5 weeks of
recovery following 13 weeks of administration. The more pronounced S-
phase response in female rats also explains why liver neoplasia was
predominantly found in the females. These studies indicate that the
mode of action, by which an enhancement of liver neoplasia was induced,
is a chronic increase in liver cell proliferation. It is emphasized
that this mechanism results in an increased incidence of liver tumors
only at dose levels at the MTD. It is therefore, concluded that
tepraloxydim does not have an oncogenic potential of biological
relevance. The result of the carcinogenicity study in mice demonstrates
that the HDL of 1,035 mg/kg/day (males) and 1,456 mg/kg/day (females)
by far exceeded the criteria of a MTD as evidenced by drastically
reduced bwts or bwt changes. A trend towards an increased incidence of
liver neoplasia occurred only in females exclusively at that dose level
and therefore cannot be extrapolated to dose levels below the MTD.
Relative liver weights were distinctly increased at the HDL associated
with foci of cellular alteration and hypertrophy of hepatocytes.
In female animals of the HDLs, hyalinization of the uterus was
found as well as reduced ovarian activity which may be a consequence of
the reduced terminal bwts.
In conclusion, in long-term feeding studies in rats and mice, there
was a slight trend towards increased incidences of liver neoplasia at
the HDLs. These dose levels were at or exceeded the MTD. As the liver
was shown to be the target organ, the increased cell proliferation,
resulting in neoplasia is considered to have been due to the toxicity
exerted on this organ.
The overall lowest NOAELs obtained in long-term feeding studies
were:
Rats: 6 mg/kg/day
Mice:
Males: 37 mg/kg/day
Females: 52 mg/kg/day
Dogs: 12 mg/kg/day.
These chronic NOAELs demonstrate that the rat is the most sensitive
species.
Tepraloxydim does not possess mutagenic or genotoxic properties. As
discussed above, it can be concluded that the compound has no
biologically relevant oncogenic potential.
Therefore, based on the results of the carcinogenicity study in
mice, the results of genotoxicity testing, the results of the 24-month
chronic feeding/oncogenicity study in rats, and auxiliary mechanistic
data showing that tepraloxydim is not an initiator of the carcinogenic
process, BASF believes that the threshold approach to regulating
tepraloxydim is appropriate.
ii. Drinking water. Based on the available studies, BASF does not
anticipate exposure to residues of tepraloxydim in drinking water.
There is no established Maximum Concentration Level (MCL) for residues
of tepraloxydim in drinking water under the Safe Drinking Water Act
(SDWA).
2. Non-dietary exposure. Tepraloxydim is not currently registered
for any nonagricultural use. The potential for non-occupational
exposure to the general population is therefore, not significant.

D. Cumulative Effects

BASF has considered the potential for cumulative effects of
tepraloxydim and other substances that have a common mechanism of
toxicity. No evidence or information exists to suggest that toxic
effects produced by tepraloxydim would be cumulative with those of any
other chemical compound.

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and the reliability of
the toxicity data, BASF has estimated that aggregate exposure to
tepraloxydim will utilize less than 4.0% of the RfD for the U.S.
population. BASF concludes that there is a reasonable certainty that no
harm will result from the aggregate exposure to residues of
tepraloxydim, including anticipated dietary exposure and non-
occupational exposures.
2. Infants and children--i. Developmental toxicity. The
teratogenicity studies in rats resulted in a developmental toxicity
NOAEL of 40 mg/kg/day and a maternal toxicity NOAEL of 40 mg/kg/day.
These NOAEL values are 7x higher than the NOAEL from the 2-year feeding
study in rats used to establish the RfD.
The teratogenicity study in rabbits resulted in a developmental
toxicity NOAEL of 180 mg/kg/day and a maternal toxicity NOAEL of 60 mg/
kg/day. These NOAEL values are 10x higher than the NOAEL from the 2-
year feeding study in rats used to establish the RfD.
ii. Reproductive toxicity. The 2-generation reproduction study with
rats resulted in a reproductive NOAEL of 268 mg/kg/day ppm and a
maternal NOAEL of 53 mg/kg/day. These NOAEL values are significantly
higher than the NOAEL from the 2-year feeding study in rats used to
establish the RfD.
iii. Reference dose. Since developmental and reproductive toxicity
occurs at levels at or above the levels shown to exhibit parental
toxicity and since these levels are significantly higher than those
used to calculate the RfD, BASF believes the RfD of 0.06 mg/kg/day is
an appropriate measure of safety for infants and children.
Using the conservative exposure assumptions described above, BASF
has concluded that the portion of the RfD that will be utilized by
aggregate exposure to residues of tepraloxydim resulting from the
proposed tolerances will be less than 15% for all populations of
infants and children. The most highly exposed group in the
subpopulation groups would be non-nursing infant < 1 year old, which
uses 15% of the RfD. Therefore, based on the completeness and
reliability of the toxicity data and the conservative exposure
assessment, BASF concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to the
residues of tepraloxydim, including all anticipated dietary exposure
and all other non-occupational exposures.

F. International Tolerances

A maximum residue level has not been established for tepraloxydim
by the Codex Alimentarius Commission.
[FR Doc. 99-33036 Filed 12-21-99; 8:45 am]
BILLING CODE 6560-50-F

Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food

Local Navigation