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Diflufenzopyr (IR-4; BASF). December 12, 2001. Pesticide Tolerance Petition. Federal Register.


http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-12/p30595.htm


[Federal Register: December 12, 2001 (Volume 66, Number 239)]
[Notices]
[Page 64257-64262]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12de01-121]

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ENVIRONMENTAL PROTECTION AGENCY
[PF-1058; FRL-6812-7]
 
Notice of Filing a Pesticide Petition to Establish a Tolerance 
fora Certain Pesticide Chemical in or on Food

AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.

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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 control number PF-1058, must be 
received on or before January 11, 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 
control number PF-1058 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: By mail: Hoyt Jamerson, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 308-9368; e-mail address: 
jamerson.hoyt@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 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 control number PF-1058. 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-1058 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

[[Page 64258]]

(OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-1058. 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 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, Reporting and recordkeeping 
requirements.

    Dated: November 27, 2001.
Peter Caulkins,
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 BASF Corporation, Agricultural Products, 26 
Davis Drive, Research Triangle Park, NC 27709 and represents the view 
of BASF Corporation. 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.

Interregional Research Project Number 4

PP 0E6185

    EPA has received a pesticide petition (0E6185) from the 
Interregional Research Project Number 4 (IR-4), 681 U.S. Highway #1 
South, North Brunswick, NJ 08902-3390 proposing, pursuant to section 
408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of diflufenzopyr, 2-(1-(3,5-
difluorophenylamino]carbonyl)-hydrazono]ethyl)-3-pyridinecarboxylic 
acid, and its metabolites convertible to M1 (8-methylpyrido[2,3-
d]pyridazin-5(6H)-one) in or on crop group 17 (grass forage, fodder, 
and hay group) including: Forage at 3.0 parts per million (ppm); hay at 
1.5 ppm; and corn, sweet, fresh at 0.05 ppm; corn, sweet, forage at 
0.05 ppm; corn, sweet, stover at 0.05 ppm, and corn, pop, stover at 
0.05 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 support granting of the 
petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. The nature of the residue in plants (field 
corn) is understood. In field corn, no diflufenzopyr was detected in 
any of the corn matrices; metabolites comprising approximately 10% 
total radioactive residue (TRR) include M1 (8-methylpyrido[2,3-
d]pyridazin-5(6H)-one), M10 (8-hydroxymethyl-5(6H)-pyrido[2,3-
d]pyridazone) and its glucose conjugate, and M9 (8-methylpyrido[2,3-
d]pyridazine-2,5(1H,6H)-dione in forage and fodder, and 6-14% TRR 
lignin was found in fodder. Corn grain contained 3-4 discrete unknowns, 
all at less than 10% TRR or less than 0.05 ppm each. The residues of 
concern in plants are diflufenzopyr, 2-(1-[([3,5-
difluorophenylamino]carbonyl)-hydrazono]ethyl)-3-pyridinecarboxylic 
acid, and its metabolites convertible to M1 (8-methylpyrido [2,3-
d]pyridazin-5(6H)-one).
    2. Analytical method. BASF Corporation has provided suitable 
independently validated analytical methods for detecting and measuring 
levels of diflufenzopyr and its metabolites in or on food with a limit 
of detection that allows monitoring of food with residues at or above 
the levels described in these and the existing tolerances. Adequate 
enforcement

[[Page 64259]]

methodology (gas chromatography) is available to enforce the tolerance 
expression. The method may be requested from Calvin Furlow, PIRIB, IRSD 
(7502C), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Avenue, NW., Washington, DC 20460. Office location 
and telephone number: Rm 101FF, Crystal Mall #2, 1921 Jefferson Davis 
Hwy., Arlington, VA 22202, (703) 305-5229.
    3. Magnitude of residues. Residue trials have been conducted with 
dicamba/diflufenzopyr end use product distinct on pasture and rangeland 
grasses and the sweet corn crop for expanded use requested in the 
subject petition. The tolerances listed below are based on the maximum 
expected residue from geographically representative field trial data. 
Crop group 17 (grass, forage, fodder, and hay group) including: Forage 
at 3.0 ppm; hay at 1.5 ppm; and corn, sweet, fresh at 0.05 ppm; corn, 
sweet, forage at 0.05 ppm; corn, sweet, stover at 0.05 ppm, and corn, 
pop, stover at 0.05 ppm.
    4. Animal residue. Data from metabolism studies in goat and poultry 
have established that the expected dietary burden from crops treated 
with diflufenzopyr will not result in quantifiable residues above the 
limits of the standard analytical method.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicology studies place technical-grade 
diflufenzopyr in Toxicity Category III or IV for all routes of 
exposure. It is not a dermal sensitizer.
    i. Acute oral toxicity (rat). LD50 = >5,000 milligrams/
kilogram (mg/kg) in males and females.Toxicity Category IV.
    ii. Acute dermal toxicity (rabbit). LD50 = >5,000 mg/kg 
in males and females. Toxicity Category IV.
    iii. Acute inhalation toxicity (rat). LC50 = >3.14 mg/L 
in males and females. Toxicity Category IV.
    iv. Primary eye irritation (rabbit). Diflufenzopyr is minimally 
irritating. Toxicity Category III.
    v. Primary dermal irritation (rabbit). Diflufenzopyr is not a 
dermal irritant. Toxicity Category IV.
    vi. Dermal sensitization (guinea pig). Diflufenzopyr is not a 
dermal sensitizer.
    2. Genotoxicty. Diflufenzopyr shows no signs of being genotoxic--i. 
In a microbial mutagenicity assay, Salmonella typhimurium strains TA98, 
TA100, TA1,535, TA1,537, and TA1,538 were exposed to diflufenzopyr 
(97.1%) in DMSO at concentrations of 333, 667, 1,000, 3,330, 6,670, and 
10,000 microgram/plate in the presence and absence of mammalian 
metabolic activation. Diflufenzopyr (97.1%) was tested to twice the 
limit concentration of 5,000 microgram/plate and cytotoxicity was 
observed at 6,670 and 10,000 microgram/plate in the absence of 
activation (-S9) but not in its presence (+S9). The positive controls 
induced the appropriate responses in the corresponding strains. There 
was no evidence that the test article induced mutant colonies over 
background.
    ii. In a mammalian cell gene mutation assay at the thymidine kinase 
locus, heterozygous L5178Y (TK +/-) mouse lymphoma cells cultured in 
vitro were exposed in independent repeat assays to diflufenzopyr 
technical (97.1% active ingredient) in dimethyl sulfoxide at dose 
levels ranging from 0.05 to 3.0 mg/mL (50 to 3,000 microgram/mL) in the 
presence and absence of S9 mammalian metabolic activation in the first 
trial, and 0.05 to 2.0 mg/mL (50 to 2,000 microgram/mL) in the second. 
Diflufenzopyr was tested up to cytotoxic dose levels and mutation 
frequencies were determined for dose levels selected on the basis of 
relative growth. Although initially declared positive by the then study 
director, application of more recent criteria for mutagenic responses 
has rendered the test article negative for forward gene mutation at the 
thymidine kinase locus in mouse L5178Y cells in the presence and 
absence of S9 activation. The positive controls induced the appropriate 
responses.
    iii. In an in vivo mouse bone marrow micronucleus assay, groups of 
15 male and female ICR mice were dosed by oral gavage with 
diflufenzopyr (technical, 97.1%) in corn oil at 500, 1,667, and 5,000 
mg/kg. Bone marrow cells were harvested at 24, 48, or 72 hours and 
scored for micronucleated polychromatic erythrocytes (MPCEs). No 
mortalities or adverse clinical signs were observed at any dose 
including the limit dose of 5,000 mg/kg, and there were no changes in 
the PCE/NCE ratios (an indirect measure of cytotoxicity). The positive 
control induced significant increases in MPCEs, also in the absence of 
any target cell cytotoxicity. No significant increase in the frequency 
of MPCEs in bone marrow cells after any treatment time were recorded; 
therefore, the test article is considered negative in this micronucleus 
assay.
    iv. In an unscheduled DNA synthesis (UDS) assay, primary rat 
hepatocyte cultures were exposed to diflufenzopyr (97.1% active 
ingredient) in dimethylsulfoxide (DMSO) at 15 concentrations ranging 
from 0.0250 to 1,000 microgram/mL in the presence of 10 microCi/mL (42 
Ci/mmole) for approximately 19 hours. Mutagenicity, as measured by UDS, 
was determined for 6 concentrations selected on the basis of 
cytotoxicity. The concentrations selected were 5.00, 10.0, 25.0, 50.0, 
100, and 250 microgram/mL. The highest concentration selected for UDS 
evaluation, 250 microgram/mL, was moderately toxic (50.8% survival). 
There was no evidence that unscheduled DNA synthesis, as determined by 
radioactive tracer procedures (nuclear silver grain counts) was 
induced. The positive control induced the appropriate response.
    3. Reproductive and developmental toxicity--i. In a rat 
developmental toxicity study, technical diflufenzopyr (98.1% active 
ingredient) in 0.5% aqueous methyl cellulose was administered by gavage 
to 25 female Crl: CD BR VAF/Plus (Sprague Dawley) rats/dose at dose 
levels of 0, 100, 300, or 1,000 mg/kg/day from days 6 through 15 of 
gestation. The maternal no observed adverse effect level (NOAEL) is 300 
mg/kg/day and the maternal lowest observed adverse effect level (LOAEL) 
is 1,000 mg/kg/day based on decreases in food consumption and weight 
gain. Developmental effects, characterized as significantly lower fetal 
body weights (bwts) in males (5%) and skeletal variations, exhibited as 
incompletely ossified and unossified sternal centra and reduced fetal 
ossification sites for caudal vertebrae, were observed at 1,000 mg/kg/
day. The developmental LOAEL is 1,000 mg/kg/day, based on decreased 
fetal body weights and skeletal variations. The developmental NOAEL is 
300 mg/kg/day.
    ii. In a rabbit developmental toxicity study, technical 
diflufenzopyr (98.1% active ingredient) in 0.5% aqueous methyl 
cellulose was administered by gavage to 20 female New Zealand White 
Hra: (NZW)SPF rabbits/dose at dose levels of 0, 30, 100, or 300 mg/kg/
day from days 6 through 19 of gestation. The maternal LOAEL is 100 mg/
kg/day, based on minimal reductions in body weight gain with no 
reduction in food consumption and clinical signs of toxicity (abnormal 
feces). The maternal NOAEL is 30 mg/kg/day. Developmental effects, 
characterized as significant increases (p 0.01) in the 
incidence of supernumerary thoracic rib pair ossification sites (12.74 
vs. 12.54 for controls) occurred at the 300 mg/kg/day dose. No 
treatment-related developmental effects were noted at the low- or mid-
doses. The developmental LOAEL is 300 mg/kg/day based on increased 
skeletal variations (supernumerary rib ossification sites). The 
developmental NOAEL is 100 mg/kg/day.

[[Page 64260]]

    iii. In a 2-generation rat reproduction study, technical 
diflufenzopyr (98.1% active ingredient) was administered continuously 
in the diet to 26 Wistar rats/sex/dose at dose levels of 0, 500, 2,000 
or 8,000 ppm in the diet (0, 27.3-42.2, 113.1-175.9, or 466.2-742.0 mg/
kg/day). The systemic LOAEL is 2,000 ppm (113.1-175.9 mg/kg/day) based 
on reduced body weight gain, increased food consumption, and increased 
seminal vesicle weights. The systemic NOAEL is 500 ppm (27.3-42.2 mg/
kg/day). The reproductive LOAEL is 8,000 ppm (466.2-742.0 mg/kg/day) 
based on lower live birth and viability indices, total pre-perinatal 
loss, reduced body weights and body weight gain during lactation, a 
higher proportion of runts, and a higher percentage of offspring with 
no milk in the stomach. The reproductive NOAEL is 2,000 ppm (113.1-
175.9 mg/kg/day).
    iv. In an acute rat neurotoxicity study, diflufenzopyr (96.4% 
active ingredient) was administered by gavage to Crl:CD BRR rats (10/
sex/group) at dose levels of 0, 125, 500 or 2,000 mg/kg. The rats were 
evaluated for reactions in functional observations and motor activity 
measurements at 3 hours, 7 days, and 14 days postdosing. 
Histopathological evaluation on the brain and peripheral nerves was 
assessed after day 14. Diflufenzopyr had no definite impact on 
neurotoxic responses, although a few abnormalities were observed in the 
functional battery on the day of dosing. A decrease in immediate 
righting responses that was observed in several males in all treatment 
groups was not concentration-dependent. Nasal staining was observed in 
more rats in the 2,000 mg/kg treatment groups (6 males, 3 females), but 
was not considered a definite or significant response to treatment. 
Lower mean brain weights in all female treatment groups lacked 
associated macroscopic and microscopic histopathological changes, and 
were only 4-5% lower than the control brain weight. There were no 
definite treatment-related differences in body weights or food 
consumption in any of the treatment groups. There was no evidence of 
treatment-related neuropathology in the 2,000 mg/kg treatment group. A 
LOAEL was not established. The NOAEL for acute neurotoxicity is 2,000 
mg/kg (the limit dose).
    v. In a subchronic rat neurotoxicity study, diflufenzopyr (96.4% 
active ingredient) was administered in the diet to Crl: CD BR rats (10/
sex/group) at dose levels of 0, 25, 75, or 1,000 mg/kg/day for 13 
weeks. The rats were evaluated for reactions in functional observations 
and motor activity testing at 4 hours and during weeks 4, 8, and 13 of 
treatment. No treatment-related neurotoxicological effects were 
observed at any treatment level. A LOAEL for neurotoxicological effects 
was not established; the NOAEL was 1,000 mg/kg/day for both sexes. 
Treatment-related toxic effects were observed at the 1,000 mg/kg/day 
treatment level. The toxicological LOAEL for this study is 1,000 mg/kg/
day, based on decreased body weight gains for both sexes. The 
toxicological NOAEL is 75 milligram/kilogram/day (mg/kg/day).
    4. Subchronic toxicity--i. In a subchronic feeding study in rats, 
male and female Wistar rats were fed test diets containing technical 
diflufenzopyr, purity 96%, at dose levels of 0, 1,000, 5,000, 10,000, 
and 20,000 ppm (equal to 0, 60.8, 352, 725, and 1,513 mg/kg body 
weight/day (mg/kg bw/day) for males, and 0, 72.8, 431, 890, and 1,750 
mg/kg bwt/day for females) for a period of 13 weeks, 10 rats per sex 
per group. An additional 10 rats per sex were assigned to the 0 and 
20,000 ppm groups for a 4-week recovery period following treatment. The 
NOAEL was set at 5,000 ppm (equal to 352 mg/kg bwt/day for males, and 
431 mg/kg bwt/day for females) based on lower mean body weight gain and 
decreased food efficiency in the 10,000 and 20,000 ppm groups, both 
sexes. Additional findings were decreased food intake (20,000 ppm, 
males only); slight increases in cholesterol (20,000 ppm, both sexes, 
and 10,000 ppm, males only) and ALAT (10,000 and 20,000 ppm, both 
sexes); and slightly lower chloride (20,000 ppm, both sexes). 
Histopathological findings were an increased incidence of foamy 
macrophages in the lungs in the 10,000 and 20,000 ppm groups, both 
sexes, and testicular atrophy in the 20,000 ppm group. Following the 
47-week recovery period, the only treatment-related effects which 
showed partial or no evidence of recovery were foamy macrophages in the 
lungs and testicular atrophy.
    ii. In a 13-week feeding study, male and female CD-1 mice were fed 
test diets containing technical diflufenzopyr, purity 97.1%, at dietary 
concentrations of 0, 350, 1,750, 3,500, and 7,000 ppm (equal to 0, 58, 
287, 613 and 1,225 mg/kg bwt/day for males, and 0, 84, 369, 787 and 
1,605 mg/kg bwt/day for females) for a period of 13 weeks, 10 mice per 
sex per group. The NOAEL was determined to be 7,000 ppm (equal to 1,225 
mg/kg bw/day for males and 1,605 mg/kg bw/day for females) since there 
were no treatment-related effects observed in male or female mice at 
any dose level tested.
    iii. In a subchronic toxicity study in dogs, diflufenzopyr (98% 
active ingredient) was administered to beagle dogs (4/sex/dose) by 
feeding at dose levels of 0, 1,500, 10,000, or 30,000 ppm (0, 58, 403, 
or 1,131 mg/kg/day for males; 0, 59, 424, or 1,172 mg/kg/day for 
females) for 13 weeks. The lowest adverse effect level LOAEL for this 
study is 10,000 ppm (403 mg/kg/day in males and 424 mg/kg/day in 
females), based on the occurrence of erythroid hyperplasia in the bone 
marrow, extramedullary hemopoiesis in the liver, and hemosiderin 
deposits in Kupffer cells. The NOAEL is 1,500 ppm (58 mg/kg/day in 
males and 59 mg/kg/day in females).
    iv. In the subchronic rabbit dermal toxicity study, technical 
diflufenzopyr, purity 96.4%, was moistened with distilled water and 
administered by dermal application to male and female New Zealand white 
rabbits, 5/sex/dose, at dose levels of 0, 100, 300, and 1,000 mg/kg bwt 
per application. Duration of application was 6 hours a day, daily for 
21 to 24 consecutive days. The NOAEL for systemic toxicity was 
determined to be 1,000 mg/kg bwt/day, since there were no apparent 
signs of treatment-related systemic effects observed in male or female 
rabbits at any dose level tested. A NOAEL for dermal effects could not 
be determined since local dermal irritation was observed at all dose 
levels tested (there were no corresponding findings upon 
histopathological examination).
    5. Chronic toxicity--i. In a chronic toxicity study in dogs, 
diflufenzopyr (98.1% active ingredient) was administered to Beagle dogs 
(4/sex/dose) by feeding at dose levels of 0, 750, 7,500, or 15,000 ppm 
(0, 26, 299, or 529 mg/kg/day for males; 0, 28, 301, or 538 mg/kg/day 
for females) for 52 weeks. The LOAEL for this study is 7,500 ppm (299 
mg/kg/day for males and 301 mg/kg/day for females), based on erythroid 
hyperplasia in the bone marrow in bone sections, reticulocytosis, and 
increased hemosiderin deposits in the liver, kidneys, and spleen. The 
NOAEL is 750 ppm (26 mg/kg/day for males and 28 mg/kg/day for females).
    ii. In a mouse carcinogenicity study, male and female CD-1 mice 
were fed test diets containing technical diflufenzopyr, purity 98.1%, 
at dietary concentrations of 0, 700, 3,500 and 7,000 ppm (equal to 0, 
100, 517, and 1,037 mg/kg bwt/day for males, and 0, 98, 500, and 1,004 
mg/kg bwt/day for females), 60 mice per sex per group, for a period of 
78 weeks. The NOAEL for systemic toxicity was determined to be

[[Page 64261]]

7,000 ppm (equal to 1,037 mg/kg bwt/day for males and 1,004 mg/kg bwt/
day for females). There were no treatment-related effects observed at 
any dose level tested in male rats. There was a slight, but 
statistically significantly lower mean overall body weight gain for 
females in the 7,000 ppm group, due primarily to decreased gain/
increased weight loss during the second year of the study. In the 
absence of any other treatment-related findings, this was not 
considered to be an adverse, toxicologically significant finding. There 
was no evidence of carcinogenic potential of diflufenzopyr for male or 
female mice at any dose level tested.
    iii. In a combined chronic toxicity/carcinogenicity study, male and 
female Wistar rats were fed test diets containing technical 
diflufenzopyr, purity 97.1% to 99.6%, at dietary concentrations of 0, 
500, 1,500, 5,000, and 10,000 ppm (equal to 0, 22, 69, 236, and 518 mg/
kg bwt/day for males, and 0, 29, 93, 323, and 697 mg/kg bwt/day for 
females), 72 rats per sex per group, for a period of 104 weeks. The 
NOAEL for systemic toxicity was set at 5,000 ppm (equal to 236 mg/kg 
bwt/day for males and 323 mg/kg bwt/day for females). Treatment-related 
effects in the 10,000 ppm group were significantly lower body weight 
and body weight gains throughout the study period and decreased food 
efficiency. There was no evidence of carcinogenic potential of 
diflufenzopyr at any dose level tested. The incidences of benign and 
malignant tumors were comparable between control and treated groups.
    6. Animal metabolism. In rats, goats, and hens the majority 
(greater than 90%) of diflufenzopyr was excreted. In the ruminant, 
major metabolites include M1, M5 (6-((3,5-difluorophenylcarbamoyl-8-
methyl-pyrido[2,3-d]-5-pyridazinone) and M19 (8-
hydroxymethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione. In poultry, 
diflufenzopyr was not detected, and M1 was the only significant 
metabolite identified, and in egg white only. Transfer of secondary 
residues to livestock is not expected.
    7. Metabolite toxicology. Toxicity of the metabolites of 
diflufenzopyr to humans is concurrently evaluated during toxicity 
testing because both plant and animal metabolites are formed during the 
course of toxicity tests. Both plant and animal major metabolites are 
considered not of toxicological concern and have been identified in the 
rat metabolism study.
    8. Endocrine disruption. No specific tests have been conducted with 
diflufenzopyr to determine whether this active ingredient may have an 
effect in humans that is similar to an effect produced by a naturally 
occurring estrogen or other endocrine effects. However, chronic, 
lifespan, and multigenerational bioassays in mammals and acute aquatic 
organisms and wildlife did not reveal endocrine effects. It is expected 
that these studies would reveal endocrine disrupting activity of this 
active ingredient if it existed.

C. Aggregate Exposure

    1. Dietary exposure. EPA has established the reference dose (RfD) 
for diflufenzopyr at 0.26 milligrams/kilogram/day (mg/kg/day). This RfD 
is based on bone marrow compensated hemolytic anemia observed in the 1-
year dog feeding study with a NOAEL of 26 mg/kg/day and an uncertainty 
factor of 100.
    Cancer classification and risk assessment. Based on the lack of 
evidence of carcinogenicity in mice and rats at doses that were judged 
to be adequate to assess the carcinogenic potential, diflufenzopyr has 
been characterized as ``not likely'' to be a human carcinogen.
    i. Food--chronic dietary exposure. A chronic dietary risk 
assessment was performed for diflufenzopyr and its metabolites 
characterized as M1. The analysis used the RfD of 0.26 mg/kg bwt/day 
and assumed that 100% of corn-derived foods contain residues at the 
tolerance level (0.05 ppm). These assumptions result in a theoretical 
maximum residue contribution (TMRC) that is less than or equal to 0.1% 
of the RfD for the overall U.S. population (48 states) and all 
population subgroups.
    ii. Drinking water. There are no established maximum contaminant 
levels or health advisory levels for residues of diflufenzopyr or its 
metabolites in drinking water. EPA used the screening concentration in 
ground water (SCI-GROW) model to estimate residues of diflufenzopyr in 
ground water and the generic expected environmental concentration 
(GENEEC) model to estimate diflufenzopyr residue levels in surface 
water. Estimated maximum concentrations of diflufenzopyr in surface and 
ground water are 3.80 parts per billion (ppb) and 0.006 ppb, 
respectively. The estimated maximum concentrations in water are less 
than EPA's level of comparison (29,970 ppb) for diflufenzopyr residues 
in drinking water as a contribution to acute aggregate exposure. 
Therefore, taking into account the uses proposed in this action, BASF 
Corporation concludes with reasonable certainty that residues of 
diflufenzopyr in drinking water (when considered along with other 
sources of exposure for which EPA has reliable data) would not result 
in unacceptable levels of aggregate human health risk at this time.
    iii. Acute exposure and risk. An acute dietary risk assessment was 
performed for diflufenzopyr and its metabolites. The analysis was 
conducted using the acute RfD of 1.0 mg/kg/day, based on developmental 
findings (increased skeletal variations) observed in the rabbit 
developmental study. For the population subgroup of concern, females 13 
years and older, the estimated 95\th\ percentile of exposure is equal 
to 0.01% of the acute RfD. The analysis is conservative since it 
assumes that 100% of corn-derived foods contain residues at the 
tolerance level (0.05 ppm).
    iv. Chronic exposure and risk. Using TMRC exposure assumptions, EPA 
has concluded that aggregate exposure to diflufenzopyr from food will 
utilize less than 0.1% of the RfD for the U.S. population. Despite the 
potential for exposure to diflufenzopyr in drinking water and from non-
dietary, non-occupational exposure, EPA does not expect the aggregate 
exposure to exceed 100% of the RfD. BASF Corporation concludes that 
there is a reasonable certainty that no harm will result from aggregate 
exposure to diflufenzopyr residues.
    2. Non-dietary exposure. There are no registered or proposed 
residential uses for diflufenzopyr.

D. Cumulative Effects

    EPA does not have, at this time, available data to determine 
whether diflufenzopyr has a common mechanism of toxicity with other 
substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
diflufenzopyr does not appear to produce a toxic metabolite produced by 
other substances. For the purposes of this tolerance action, therefore, 
BASF Corporation has not assumed that diflufenzopyr has a common 
mechanism of toxicity with other substances.

E. Safety Determination

    1. U.S. population. Using TMRC exposure assumptions EPA has 
concluded that aggregate exposure to diflufenzopyr from food will 
utilize less than 0.1% of the RfD for the U.S. population.
    2. Infants and children. There is a complete toxicity data base for 
diflufenzopyr and exposure data are

[[Page 64262]]

complete or are estimated based on data that reasonably account for 
potential exposures. Taking into account the completeness of the data 
base and the toxicity data regarding prenatal and postnatal 
sensitivity, BASF Corporation concludes, based on reliable data, that 
use of the standard margin of safety will be safe for infants and 
children without addition of another ten-fold factor. Using the 
standard exposure assumptions EPA has concluded that aggregate exposure 
to diflufenzopyr from food will utilize 0.1% of the RfD for infants and 
children. EPA generally has no concern for exposures below 100% of the 
RfD because the RfD represents the level at or below which daily 
aggregate dietary exposure over a lifetime will not pose appreciable 
risks to human health. Despite the potential for exposure to 
diflufenzopyr in drinking water, BASF Corporation does not expect the 
aggregate exposure to exceed 100% of the RfD. Based on these risk 
assessments, BASF Corporation concludes that there is a reasonable 
certainty that no harm will result to infants and children from 
aggregate exposure to diflufenzopyr residues.

F. International Tolerances

    There are no CODEX or Mexican residue limits established for 
diflufenzopyr or its metabolites.
[FR Doc. 01-30595 Filed 12-11-01; 8:45 am]
BILLING CODE 6560-50-S

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Last Updated: Dec 12 15:24:20 2001
URL: http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-12/p30595.htm