[Federal Register Volume 67, Number 162 (Wednesday, August 21, 2002)]
[Notices]
[Pages 54188-54192]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-21294]


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

ENVIRONMENTAL PROTECTION AGENCY

[OPP-2002-0208; FRL-7195-2]


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

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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

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

DATES: Comments, identified by docket ID number OPP-2002-0208, must be 
received on or before September 20, 2002.

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 ID 
number OPP-2002-0208 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: By mail: Joanne Miller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 305-6224; 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 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,'' ``Regulations and Proposed Rules,'' 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 ID number OPP-2002-0208. 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 ID number OPP-2002-0208 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

[[Page 54189]]

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 ID number OPP-2002-0208. 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 
ID 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 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 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 support 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.

    Dated: August 12, 2002.
  Debra Edwards,
Acting 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 
petitioner. 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.

Bayer Corporation

PP 0F6094

    EPA has received a pesticide petition (0F6094) from Bayer 
Corporation, 8400 Hawthorn Road, Kansas City MO, 64120-0013, proposing, 
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing 
tolerances for residues of propoxycarbazone-sodium, methyl 2-[[[(4,5-
dihydro-4-methyl-5-oxo-3-propoxy-1H-1,2,4-triazol-1-
yl)carbonyl]amino]sulfonyl]benzoate, sodium salt and its metabolite, 
methyl 2-[[[(4,5-dihydro-4-methyl-5-oxo-3-(2'-hydroxy-propoxy)-1H-
1,2,4-triazol-1-yl)carbonyl]amino]sulfonyl]benzoate in or on the raw 
agricultural commodities (RACs) wheat forage, wheat hay, wheat straw, 
wheat grain, meat, and meat byproducts, (cattle, sheep, goats, horses, 
hogs), and milk at 1.5, 0.15, 0.05, 0.01, 0.05, and 0.002 parts per 
million (ppm); respectively. EPA has determined that the petition 
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 petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of MKH-6561 (propoxycarbazone-
sodium) in wheat was rapid, as only minor amounts of MKH-6561 were 
found in some of the wheat matrices. The primary metabolic pathway in 
wheat appeared to be hydroxylation of the propoxy side chain of MKH-
6561 to give Pr-2-OH MKH-6561 (methyl 2-[[[(4,5-dihydro-4-methyl-5-oxo-
3-(2'-hydroxy-propoxy)-1H-1,2,4-triazol-1-
yl)carbonyl]amino]sulfonyl]benzoate). Hydrolysis of Pr-2-OH MKH-6561 
then gave Pr-2-OH NMT and, probably the sulfonamide methyl ester which 
was not observed in any wheat matrices. Hydrolysis of the sulfonamide 
methyl ester gave sulfonamide acid, which was in equilibrium with 
saccharin. A minor metabolic pathway was demethylation of MKH-6561 to 
yield N-desmethyl MKH-6561.
    2. Analytical method--i. Plant. The proposed tolerance expression 
is MKH-6561 and Pr-2-OH MKH-6561. An analytical method was developed to 
measure these two analytes in plant matrices. The method was validated 
in wheat tissues. MKH-6561 and Pr-2-OH MKH-6561 were extracted from the 
wheat tissues with 0.05 M NH4OH using accelerated solvent 
extraction. Trifluoroacetic acid (0.5 milliliter (mL)) and an 
isotopically labeled internal standard were added to the extract. The 
whole extract was loaded onto a C-18 solid phase extraction (SPE) 
cartridge. The C-18 SPE cartridge was washed with aqueous 
trifluoroacetic acid (0.1%) and aqueous acetic acid (0.1%). A three to 
one mixture of acetonitrile and aqueous acetic acid (0.1%) was used to 
elute the analytes from the C-18 SPE cartridge. Water and acetic acid 
were added to the sample which was analyzed by LC/MS/MS.
    ii. Animal. The proposed tolerance expression is MKH-6561. An 
analytical method was developed to measure this analyte in animal 
tissues and milk. The method was validated in animal tissues and milk. 
MKH-6561 was extracted from the tissues with 0.05 M NH4OH

[[Page 54190]]

using accelerated solvent extraction. Trifluoroacetic acid (0.5 mL) and 
an isotopically labeled internal standard were added to the extract 
which was then centrifuged at 2,000 rpm for 10 minutes. Approximately 
half of the sample was loaded onto a C-18 SPE cartridge. The C-18 SPE 
cartridge was washed with aqueous trifluoroacetic acid (0.1%) and 
aqueous acetic acid (0.1%). A three to one mixture of acetonitrile and 
aqueous acetic acid (0.1%) was used to elute the analytes from the C-18 
SPE cartridge. Water and acetic acid were added to the sample which was 
analyzed by LC/MS/MS. Milk samples were analyzed by amending an aliquot 
of milk with trifluororacetic acid (0.5 mL) and isotopically labeled 
internal standard. The sample was purified by C-18 SPE as described 
above. The resultant sample was analyzed by LC/MS/MS.
    3. Magnitude of residues. Twenty-one field trials were conducted in 
19 locations to evaluate the quantity of MKH-6561 and Pr-2-OH MKH-6561 
in wheat forage, hay, straw, and grain following treatment with MKH-
6561, 70 water dispersible granule (WG) at an application rate of 45 
grams of active ingredient per hectare in the spring or at 30 grams 
active ingredient per hectare in the fall and 30 grams active 
ingredient per hectare in the spring. The highest average field trial 
(HAFT) residue in wheat forage, hay, straw, and grain were 1.21, 0.12, 
0.03, and <0.01 ppm respectively.

B. Toxicological Profile

    1. Acute toxicity. i. MKH-6561 is of very low acute toxicity to 
fasted rats following a single oral administration. The acute oral 
LD50 is >5,000 milligrams/kilogram/body weight (mg/kg/bwt) 
for males and females.
    ii. MKH-6561 is not toxic to rats following a single dermal 
application. The acute dermal LD50 is >5,000 mg/kg/bwt for 
males and females.
    iii. An acute inhalation study with rats showed low toxicity with a 
4-hour dust aerosol LC50 5,030 mg/m\3\ air for males and 
females.
    iv. An eye irritation study in rabbits showed minimal irritation 
completely reversible within 48 hours.
    v. A dermal irritation study in rabbits showed slight irritation 
completely reversible within 48 hours.
    vi. MKH-6561 has no skin sensitizing potential under the conditions 
of the maximization test in guinea pigs.
    2. Genotoxicity. The genotoxic action of MKH-6561 was studied in 
bacteria and mammalian cells with the aid of various in vitro test 
systems (Salmonella microsome test, hypoxanthine guanine phophoribosy 
transferase (HGPRT) test with chinese hamster V79 cells, cytogenetic 
study with chinese hamster V79 cells, and unscheduled DNA synthesis 
(UDS) test) and in one in vivo test (micronucleus test). None of the 
tests revealed any evidence of a mutagenic or genotoxic potential of 
MKH-6561. The compound did not induce point mutation, DNA damage or 
chromosome aberration (CA).
    3. Reproductive and developmental toxicity. i. In a 2-generation 
reproduction study, Wistar rats were administered MKH-6561 at levels of 
0, 1,000, 4,000, or 16,000 ppm in the diet. The no observe adverse 
effect level (NOAEL) for reproductive parameters was established at 
16,000 ppm (1,231 mg/kg bwt/day in males and 1,605 mg/kg bwt/day in 
females), the highest dose tested (HDT). The parental NOAEL was 1,000 
ppm (80 mg/kg bwt/day in F1 males and 93 mg/kg bwt/day in 
F0 females).
    ii. A developmental toxicity study was conducted with Wistar rats 
via oral gavage of MKH-6561 at levels of 0, 100, 300, and 1,000 mg/kg 
bwt/day on days 6 through 19 of gestation. There were no signs of 
maternal toxicity, embryotoxicity, fetotoxicity, or teratogenicity at 
the level of 1,000 mg/kg bwt/day. Therefore, the maternal and 
developmental NOAELs for rats were established at 1,000 mg/kg bwt/day, 
the limit dose for this study type. No teratogenic potential of MKH-
6561 was evident in rats.
    iii. Himalayan rabbits were administered MKH-6561 at levels of 0, 
20, 100, 500, or 1,000 mg/kg bwt/day by oral gavage on days 6 through 
28 post coitum in a test for developmental toxicity. A maternal NOAEL 
of 100 mg/kg bwt/day was established based on cold ears, alopecia, 
swelling of vulva, decreased feed, and water intake, body weight loss, 
gastrointestinal tract (GI) effects, liver effects, and thyroid hormone 
level effects. The gestation rate NOAEL of 100 mg/kg bwt/day was based 
on one abortion (assessed as secondary due to maternal toxicity) at 500 
mg/kg bwt/day. The NOAEL for fetal parameters of 500 mg/kg bwt/day was 
based on placental effects, increased post-implantation loss, decreased 
number of fetuses, decreased fetal weight, retarded fetal skeletal 
ossification, and possible increase in lobulation of liver in fetuses 
at 1,000 mg/kg bwt/day. No teratogenic potential of MKH-6561 was 
evident in rabbits.
    4. Subchronic toxicity. i. A 28-day dermal toxicity study in Wistar 
rats established a local and systemic NOAEL of 1,000 mg/kg bwt/day (the 
dermal limit dose) for males and females.
    ii. A 14-week feeding study was conducted with Wistar rats at 
dietary dose levels of 0, 250, 1,000, 4,000, or 20,000 ppm. The NOAEL 
was determined to be 4,000 ppm (286.4 mg/kg bwt/day in males and 350.6 
mg/kg bwt/day in females) based upon increased water consumption 
(reversible during the 4-week recovery period) and an irritative effect 
of the forestomach epithelium (reversible during the 4-week recovery 
period) in males and females dosed at 20,000 ppm as well as reduced 
glucose and triglyceride levels in females only dosed at 20,000 ppm.
    iii. A 91-day feeding study was conducted with B6C3F1 
mice at dietary dose levels of 0, 625, 2,500, or 10,000 ppm. The NOAELs 
determined for males and females were 625 ppm (205 mg/kg bwt/day) and 
2,500 ppm (1,159 mg/kg bwt/day), respectively, based on decreased body 
weights in 2,500 ppm males and 10,000 ppm females.
    iv. A 2-month range-finding feeding study in Beagle dogs, at levels 
of 0, 1,000, 5,000, 10,000, and 40,000 ppm in the diet established a 
NOAEL of 10,000 ppm ( 322.2 mg/kg bwt/day in males and 285.6 mg/kg bwt/
day in females) based on elevated hepatic biotransformation enzymes at 
40,000 ppm.
    5. Chronic toxicity. i. A 2-year chronic/oncogenicity study was 
conducted with male and female Fischer 344 rats at dietary levels of 0, 
50, 500, or 1,000 mg/kg bwt/day for approximately the first 7 months of 
the study (dose adjustment). From approximately 7 months to study 
termination, the doses were 0, 1,000, 10,000, and 20,000 ppm in the 
diet. A chronic toxicity NOAEL of 1,000 ppm (43 mg/kg bwt/day in males 
and 49 mg/kg bwt/day in females) was determined based on increased 
urine pH and decreased body weight gain at 1-year (but not 2 years) at 
10,000 ppm and 20,000 ppm. No carcinogenic potential was indicated.
    ii. B6C3F1 mice were administered MKH-6561 via the diet 
at levels of 0, 280, 1,400, and 7,000 ppm in a 2-year chronic feeding/
carcinogenicity study. The chronic toxicity NOAEL was established at 
1,400 ppm (369.0 mg/kg/day in males and 626.9 mg/kg bwt/day in females) 
based on retarded body weight development. No carcinogenic potential 
was indicated.
    iii. A 1-year feeding study in Beagle dogs was conducted at 0, 
2,000, 10,000, and 25,000 ppm in the diet. The NOAEL in males was 
determined to be 10,000 ppm (258.0 mg/kg bwt/day) based upon increased 
absolute adrenal gland weight without an increase in relative adrenal 
gland weight and slight enlargement of

[[Page 54191]]

zona fasciculata microscopically, without a correlation to adrenal 
gland weight in males dosed at 25,000 ppm. The NOAEL in females was 
determined to be 2,000 ppm (55.7 mg/kg bwt/day) based upon decreased 
food consumption and decreased relative heart weight in females dosed 
at 10,000 and 25,000 ppm.
    6. Animal metabolism. i. A single oral dose of 2 mg/kg/bwt 
[triazolinone-3-\14\C]MKH-6561 was administered to rats. Between 22% 
and 24% of the administered dose was absorbed. Maximum plasma radiation 
levels were observed 0.33 hours after dosing. Within 48 hours of 
dosing, between CA 88% and 97% of the radioactivity was excreted via 
urine and feces. Approximately 80-88% of the excreted radioactivity was 
unchanged parent compound. The highest single metabolite concentration 
was CA 3% of the administered dose. The terminal elimination half-live 
for total radioactivity was CA 12-13 hours, so no bioaccumulation of 
MKH-6561 or its metabolites will occur.
    ii. Single oral doses of 2 mg/kg/bwt and 200 mg/kg/bwt [phenyl-UL-
\14\C]MKH-6561 were administered to rats. Between CA 21-31% of the 
administered dose was absorbed. Maximum plasma radiation levels were 
observed after 0.33 hours (low dose) and 1-hour (high dose). Within 48 
hours of dosing, CA 97-104% of the administered dose was eliminated via 
urine and feces. Approximately 75-86% of the administered dose was 
eliminated as unchanged parent compound. The maximum single metabolite 
concentration was 8.8% of the administered dose. At the end of the 
study, less than 0.25% of the administered dose was found in organs and 
tissues. In a separate bile fistulation experiment, the predominantly 
fecal elimination was confirmed to be due to incomplete absorption of 
radioactivity from the GI tract. The terminal elimination half-live for 
total radioactivity was CA 9-11 hours, so no bioaccumulation of MKH-
6561 or its metabolites will occur.
    iii. Laying hens were given a daily dose of protonated MKH-6561 
[phenyl-UL-\14\C] at 3.12 mg/kg/bwt for 3 consecutive days. The residue 
levels were 1.343 ppm in liver, 0.017 ppm in muscle, 0.014 ppm in fat, 
0.006 ppm in the day-1 eggs, 0.009 ppm in the day-2 eggs, and 0.012 ppm 
in the day-3 eggs. The residue levels based on a theoretical 1x 
application rate, as determined from residue levels observed in the 
MKH-6561 wheat field trials would all be considerably less than 0.001 
ppm. The major residue identified in tissues and eggs were MKH-6561, 
Pr-2-OH MKH-6561, MKH-6561 sulfonamide methyl ester, and saccharin. The 
major metabolic pathway of MKH-6561 [phenyl-UL-\14\C] in poultry was 
hydrolysis of the parent compound producing N-methyl propyl 
triazolinone and sulfonamide methyl ester. The sulfonamide methyl ester 
was then converted to saccharin. A minor pathway involved hydoxylation 
at the 2-position of the triazolinone propoxy group. In the liver, the 
major metabolic pathway led to the formation of protein bound MKH-6561 
residue through conjugation with the amino acid serine.
    iv. Laying hens were given a daily dose of protonated MKH-6561 
[triazolinone-3-\14\C] at 2.91 mg/kg/bwt for 3 consecutive days. The 
residue levels were 0.184 ppm in liver, 0.044 ppm in muscle, 0.015 ppm 
in the fat, 0.011 ppm in the day-1 egg, 0.016 ppm in the day-2 egg, and 
0.022 ppm in the day-3 egg. The residue levels in tissues and eggs 
based on a theoretical 1x application, as determined from the residue 
levels observed in the MKH-6561 wheat field trials, would all be 
considerably less that 0.001 ppm. The metabolism of MKH-6561 
[triazolinone-3-\14\C] appeared to involve both hydroxylation at the 2-
position of the propoxy group and hydrolysis of the phenyl sulfonamide 
linkage.
    v. Goats were dosed with 1.0 mg/kg/bwt of MKH-6561 [phenyl-UL-
\14\C] for 3 consecutive days. Residue levels were 3.643 ppm in liver, 
0.486 ppm in kidney, 0.009 ppm in muscle, 0.004 ppm in fat, 0.015 ppm 
in day-1 milk and, 0.022 ppm in day-2 milk. The metabolic pathway was 
based on hydrolysis of the sulfonamide to yield MKH-6561 sulfonamide 
methyl ester and saccharin. The saccharin was then conjugated to 
proteins which were found mainly in the liver and kidney.
    vi. Goats were dosed with MKH-6561 [triazolinone-3-\14\C] at a dose 
of 0.98 mg/kg/bwt for 3 consecutive days. Residue levels were 0.171 ppm 
in liver, 0.425 ppm in kidney, 0.040 ppm in muscle, 0.007 ppm in fat, 
0.046 ppm in day-1 milk, and 0.057 ppm in day-2 milk. The metabolism of 
MKH-6561 involved the cleavage of the phenyl sulfonylurea side chain 
and the hydroxylation of the propyl side chain on the triazolinone ring 
system after the cleavage of the phenyl sulfonylurea side chain.
    7. Metabolite toxicology. i. 4-OH-saccharin is of low acute 
toxicity to fasted rats following a single oral administration. The 
acute oral LD50 is >5,000 mg/kg/bwt for males and females. 
4-OH-saccharin is considered non-mutagenic with and without S9 mix in 
the plate incorporation as well as in the preincubation modification of 
the Salmonella microsome test.
    ii. MKH-8394 is of very low acute toxicity to fasted rats following 
a single oral administration. The acute oral LD50 is>5,000 
mg/kg/bwt for males and females. MKH-8394 is considered non-mutagenic 
with and without S9 mix in the plate incorporation as well as in the 
preincubation modification of the Salmonella microsome test.
    iii. KTS-9061 (Pr-2-OH MKH-6561) is not toxic to fasted rats 
following a single oral administration. The acute oral LD50 
is>5,000 mg/kg/bwt for males and females. KTS-9061 is considered non-
mutagenic with and without S9 mix in the plate incorporation as well as 
in the preincubation modification of the Salmonella/microsome test. 
KTS-9061 is considered non-clastogenic with and without S9 mix CA test 
in vitro using chinese hamster V79 cells. Wistar rats were administered 
KTS-9061 via the diet at levels of 0, 800, 4,000, and 10,000 ppm for 
approximately 4 weeks. The NOAEL was determined to be 10,000 ppm (905.3 
mg/kg bwt/day in males and 880.0 mg/kg bwt/day in females), the HDT.
    iv. KTS-9304 has low to moderate acute toxicity to fasted rats 
following a single oral administration. The acute oral LD50 
was 263 mg/kg/bwt in males and 1,756 mg/kg/bwt in females. KTS-9304 is 
considered non-mutagenic with and without S9 mix in the plate 
incorporation as well as in the preincubation modification of the 
Salmonella/microsome test.
    8. Endocrine disruption. There is no evidence to suggest that MKH-
6561 has an effect on the endocrine system. Studies in this data base 
include evaluation of the potential effects on reproduction and 
development, and an evaluation of the pathology of the endocrine organs 
following short-term and long-term exposure. These studies revealed no 
endocrine effects due to MKH-6561.
    9. Other studies. i. An acute neurotoxicity screening study in 
Wistar rats established a NOAEL for males and females of 2,000 mg/kg/
bwt (HDT).
    ii. A 13-week neurotoxicity screening study in Wistar rats 
established a NOAEL of 20,000 ppm (1,321 mg/kg bwt/day in males and 
1,651 mg/kg/day in females) (HDT). No neurotoxic potential was 
observed..
    iii. A Plaque-Forming-Cell Assay to investigate immunotoxicological 
potential was performed on male Wistar rats after an approximate 4-week 
exposure of 0, 4,000, 10,000, or 20,000 ppm in the diet. The Plaque-
Forming-Cell Assay NOAEL was 20,000 ppm (2,144 mg/kg bwt/day; HDT). The

[[Page 54192]]

overall study NOAEL was 10,000 ppm (986 mg/kg bwt/day) based upon 
increased water intake at 20,000 ppm.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Estimates of chronic dietary exposure 
to residues of MKH-6561 utilized the proposed tolerances in wheat 
forage, wheat hay, wheat straw, wheat grain, meat, and meat byproducts 
(cattle, sheep, goats, horses, hogs), and milk of 1.5, 0.15, 0.05, 
0.01, 0.05, and 0.002 ppm respectively. Other assumptions were that 
100% of the target crop would be treated with MKH-6561 and that no loss 
of residue would occur due to processing or cooking. For chronic 
exposures, a reference dose (RfD) of 0.43 mg/kg/day was assumed based 
on and NOAEL of 43 mg/kg bwt/day from the combined chronic toxicity/
oncogenicity study in the rat. A safety factor of 100 was used based on 
interspecies extrapolation (10x) and intraspecies variability (10x). 
Using these conservative assumptions, dietary residues of MKH-6561 
contribute 0.000219 mg/kg/day (0.1% of the RfD) for children 1 to 6 
years old, the most sensitive sub-population. For the U.S. population, 
the exposure was 0.000098 mg/kg/day (0.02% of the RfD). For acute 
dietary exposure, the same conservative assumptions were made. A NOAEL 
of 100 mg/kg bwt/day from the developmental toxicity study in rabbits 
and an safety factor of 100 were used in the acute dietary assessment. 
The safety factor of 100 was based on interspecies extrapolation (10x) 
and intraspecies variability (10x). Acute dietary exposure at the 
95\th\ percentile was negligible for all population subgroups. For 
children 1 to 6 years old (the most sensitive sub-population,) and for 
the U.S. population, <0.1% of the acute RfD was consumed at the 95\th\ 
percentile.
    ii. Drinking water. Estimates of chronic dietary exposure to 
residues of MKH-6561 utilized the proposed tolerances in wheat forage, 
wheat hay, wheat straw, wheat grain, meat, and meat byproducts (cattle, 
sheep, goats, horses, hogs), and milk of 1.5, 0.15, 0.05, 0.01, 0.05, 
and 0.002 ppm respectively. Other assumptions were that 100% of the 
target crop would be treated with MKH-6561 and that no loss of residue 
would occur due to processing or cooking. For chronic exposures, an RfD 
of 0.43 mg/kg/day was assumed based on and NOAEL of 43 mg/kg bwt/day 
from the combined chronic toxicity/oncogenicity study in the rat. A 
safety factor of 100 was used based on interspecies extrapolation (10x) 
and intraspecies variability (10x). Using these conservative 
assumptions, dietary residues of MKH-6561 contribute 0.000219 mg/kg/day 
(0.1% of the RfD) for children 1 to 6 years old, the most sensitive 
sub-population. For the U.S. population, the exposure was 0.000098 mg/
kg/day (0.02% of the RfD). For acute dietary exposure, the same 
conservative assumptions were made. A NOAEL of 100 mg/kg bwt/day from 
the developmental toxicity study in rabbits and an safety factor of 100 
were used in the acute dietary assessment. The safety factor of 100 was 
based on interspecies extrapolation (10x) and intraspecies variability 
(10x). Acute dietary exposure at the 95\th\ percentile was negligible 
for all population subgroups. For children 1 to 6 years old (the most 
sensitive sub-population,) and for the U.S. population, <0.1% of the 
acute RfD was consumed at the 95\th\ percentile.
    2. Non-dietary exposure. There are no current non-food uses for BAY 
MKH-6561 registered under the Federal Insecticide, Fungicide, and 
Rodenticide Act, as amended. No non-food uses are proposed for BAY 
MKH6561 and no non-dietary exposures are expected for the general 
population.

D. Cumulative Effects

    BAY MKH-6561 is a sulfonamide herbicide. There is no information to 
suggest that any chemical in this class of herbicides has a common 
mechanism of mammalian toxicity or that chemicals in this class produce 
similar effects so it is not appropriate to combine exposures of BAY 
MKH-6561 with other herbicides. Bayer Corporation is considering only 
the potential risk of BAY MKH-6561.

E. Safety Determination

    1. U.S. population. As presented previously, the exposure of the 
U.S. general population to MKH-6561 is low, and the risks, based on 
comparisons to the RFD, are minimal. The margins of safety from the use 
of MKH-6561 are well within EPA's acceptable limits. Bayer Corporation 
concludes that there is a reasonable certainty that no harm will result 
to the U.S. population from aggregate exposure to MKH-6561 residues.
    2. Infants and children. The complete toxicological data base 
including the developmental toxicity and 2-generation reproduction 
studies were considered in assessing the potential for additional 
sensitivity of infants and children to residues of BAY MKH-6561. The 
developmental toxicity studies in rats and rabbits revealed no 
increased sensitivity of rats or rabbits to in-utero exposure to BAY 
MKH-6561. The 2-generation reproduction study did not reveal any 
increased sensitivity of rats to in-utero or postnatal exposure to BAY 
MKH-6561. Furthermore, none of the other toxicology studies revealed 
any data demonstrating that young animals were more sensitive to BAY 
MKH-6561 than adult animals. The data taken collectively clearly 
demonstrate that application of a FQPA uncertainty factor for increased 
sensitivity of infants and children is not necessary for BAY MKH-6561.

F. International Tolerances

    There are currently no international Codex tolerances established 
for BAY MKH-6561. It is not currently registered in any other 
countries. There are no harmonized maximum residue levels at the 
European Union level at present.
[FR Doc. 02-21294 Filed 8-20-02; 8:45 am]
BILLING CODE 6560-50-S