[Federal Register Volume 64, Number 245 (Wednesday, December 22, 1999)]
[Notices]
[Pages 71774-71779]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-33036]


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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.

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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: 
[email protected].

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: ``[email protected],'' 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 
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 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