[Federal Register Volume 66, Number 241 (Friday, December 14, 2001)]
[Notices]
[Pages 64823-64828]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-30914]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-1060; FRL-6813-2]


Notice of Filing Pesticide Petitions to Establish a Tolerance for 
a 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 pesticide 
petitions proposing the establishment of regulations for residues of a 
certain pesticide chemical in or on various food commodities.

DATES:  Comments, identified by docket control number PF-1060, must be 
received on or before January 14, 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-1060 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Shaja R. Brothers, 
Registration Division (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460; telephone number: (703) 308-3194; 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 control number PF-1060. 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

[[Page 64824]]

imperative that you identify docket control number PF-1060 in the 
subject line on the first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: [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-1060. 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 29, 2001.
  Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

Interregional Research Project Number 4 (IR-4) and Uniroyal 
Chemical Company

PP 0E6167, 1E6347, and 1F6235

    EPA has received pesticide petitions (0E6167, 1E6347 and 1F6235) 
from the Interregional Research Project Number 4 (IR-4), 681 US Highway 
#1 South, North Brunswick, NJ 08902 and Uniroyal Chemical Company Inc., 
Middlebury, CT 06749 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 180.377 by establishing tolerances for residues of 
diflubenzuron, (N-(4-chlorophenyl)amino]carbonyl-2,6-difluorobenzamide) 
in or on the following raw agricultural commodities:
     PP 0E6167 proposes the establishment of a tolerance for 
pear at 0.5 part per million (ppm).
     PP 1E6347 proposes the establishment of a tolerance for 
the grass, forage, fodder, and hay group at 6.0 ppm.
     PP 1F6235 proposes the establishment of tolerances for 
stonefruit (except cherries) at 0.05 ppm, tree nuts and pistachios at 
0.05 ppm, almond hulls at 5.0 ppm, peppers at 1.0 ppm, and meat-by-
products at 0.15 ppm.
    EPA has determined that the petitions contain data or information 
regarding the elements set forth in section 408(d)(2) of the FFDCA; 
however, EPA has not fully evaluated the sufficiency of the submitted 
data at this time or whether the data support granting of the 
petitions. Additional data may be needed before EPA rules on the 
petitions. This notice of filing contains a summary of the petition 
provided by Uniroyal Chemical Company, Inc., the registrant.

A. Residue Chemistry

    1. Plant metabolism. The nature of the residue in plants is 
adequately understood. The metabolism of diflubenzuron was investigated 
in soybeans, oranges, and rice. The main component of residues in rice 
was p-chlorophenylurea (CPU); levels of p-chloroaniline (PCA) were 
negligible to non-detectable. The main component of the residues in 
soybeans and oranges was the parent diflubenzuron (DFB). A considerable 
portion of the residues were bound. DFB showed very limited absorption 
and translocation in plants

[[Page 64825]]

with most of the residues remaining on the surface.
    2. Analytical method. Practical analytical methods for detecting 
levels of DFB, CPU and PCA, in or on food with a limit of detection 
that allows monitoring of the residue at or above the level set in the 
tolerance was used to determine residues in the proposed commodities. 
Residues of the individual analytes are detectable and quantifiable 
using three separate analytical methods. Residues of DFB are extracted 
from the proposed commodities with dichloromethane. Extracts are 
purified with deactivated florisil. An aliquot of the extract is 
hydrolyzed with phosphoric acid and the DFB is partitioned into hexane. 
The resulting extract is derivatized in heptafluorobutyric anhydride 
(HFBA). Quantification of DFB is accompanied by gas chromatography 
using an electron capture detector.
    The analytical method for quantitation of the 4-chlorophenylurea 
requires ethyl acetate extraction of the residue from the matrix. 
Column chromatography is utilized for clean-up of the extract 
immediately prior to derivitization with HFBA. Derivatized extracts are 
analyzed by gas chromatography equipped with an electron capture 
detector.
    The analysis for the determination of PCA residues from the 
proposed commodities utilize an internal standard method. Samples of 
matrix to be analyzed are fortified with the internal standard. 
Residues of 12C-PCA and the internal standard are subjected to acid and 
base hydrolysis. The final extract is passed through florisil column 
for clean-up and derivatized with HFBA in hexane. An aliquot of the 
derivatized extract is analyzed by gas chromatography using a mass 
spectrometry detector in the selective ion monitoring mode. Recovery of 
PCA is determined by the combined peak areas for the two mass spectral 
ions obtained from the derivatized 12C-PCA relative to the response 
factor derived from the combined areas of the corresponding two mass 
spectral ions from the internal standard.
    3. Magnitude of residues. Individual residue trials have been 
conducted with diflubenzuron on the proposed commodities. Analyses of 
these trials show that the maximum total residue for diflubenzuron and 
its conversion products PCA and CPU will be at or below the proposed 
tolerance levels.

B. Toxicological Profile

    1. Acute toxicity. Studies for diflubenzuron technical indicate the 
acute oral toxicity in rats and mice is >4,640milligram per kilogram 
(mg/kg), and the acute dermal toxicity in rats is >10,000 mg/kg. The 
acute inhalation lethal concentration (LC)50 in rats is >35 
mg/L (6 hours). Diflubenzuron technical is not an eye or skin irritant 
to rabbits, and is not a dermal sensitizer in guinea pigs.
    2. Genotoxicity. Diflubenzuron did not show any mutagenic activity 
in point mutation assays employing S. typhimurium, S. cerevisiae, or 
L5178Y Mouse Lymphoma cells. Diflubenzuron did not induce chromosomal 
aberrations in chinese hamster ovary (CHO) cells and it did not induce 
unscheduled DNA synthesis (UDS) in human WI-38 cells. Diflubenzuron was 
also negative in mouse micronucleus and mouse dominant lethal assays 
and it did not induce cell transformation in Balb/3T3 cells.
    3. Developmental and reproductive. In a rat developmental toxicity 
study, diflubenzuron was administered by oral gavage to pregnant female 
rats at dosage levels of 0, 1, 2, and 4 mg/kg/day. No treatment-related 
effects were seen. A subsequent study was conducted in pregnant Sprague 
Dawley rats at a dose of 0 and 1,000 mg/kg/day. No maternal toxicity 
was observed. The incidence of fetuses with skeletal abnormalities was 
slightly increased in the treated group, but was within historical 
background range. The no observed adverse effect level (NOAEL) for 
maternal and developmental toxicity in rats was greater than 1,000 mg/
kg/day.
    Diflubenzuron was also administered by oral gavage to pregnant New 
Zealand white rabbits at dosage levels of 0, 1, 2, and 4 mg/kg/day. No 
treatment-related effects were seen. A subsequent study was conducted 
in pregnant rabbits at a dose of 0 and 1,000 mg/kg/day. No maternal or 
developmental toxicity was seen. The NOAEL for maternal and 
developmental toxicity in rabbits was greater than 1,000 mg/kg/day.
    In a rat reproduction study, diflubenzuron was fed to 2-generations 
of male and female rats at dietary concentrations of 0, 10, 20, 40, and 
160 ppm. No effects were seen on parental body weight gain and there 
were no reproductive effects. A subsequent study was conducted on one 
generation (1 litter) of rats at dietary concentrations of 0, 1,000, 
and 100,000 ppm. Systemic effects were seen in adults at these doses 
but there was no effect on reproductive parameters. The NOAEL for 
reproductive toxicity was greater than 100,000 ppm (5 g/kg/day).
    4. Subchronic toxicity. To assess subchronic toxicity, a 4-week 
inhalation study and a 3-week dermal study were conducted. In the 
inhalation study rats were exposed nose only to 10, 30, or 100 
milligram per cubic meters (mg/m\3\) for 6 hours per day, 5 days per 
week for 4 weeks. Treatment-related findings were a slight reduction in 
erythrocytes, hemoglobin and hematocrit in male and female rats at a 
concentration of 100 mg/m\3\ and an increase in total bilirubin in high 
dose female rats. There was no effect on methemoglobin concentration at 
any dose level. The NOAEL for subchronic inhalation toxicity was 30 mg/
m\3\.
    To assess subacute dermal toxicity, diflubenzuron was applied to 
the backs of male and female CD rats for 3 weeks at dose levels of 20, 
500, and 1,000 mg/kg/day. Hematology evaluation showed reductions in 
red blood cell (RBC), hemoglobin (Hgb) and hematocrit values at 500 and 
1,000 mg/kg/day. An increased incidence of polychromasia, 
hypochromasia, and anisocytosis was seen at 500 and 1,000 mg/kg/day. An 
increase in methemoglobin and sulfhemoglobin values was seen at 1,000 
mg/kg/day. The NOAEL for systemic toxicity was 20 mg/kg/day. Also, a 
dermal absorption factor of 0.5%, for systemic absorption, was derived 
from a study where rats were dosed with either 0.005 or 0.05 mg/cm\2\ 
of (\14\C) diflubenzuron technical. This value can be used for 
converting dermal exposure to oral equivalents.
    5. Chronic toxicity. Diflubenzuron was given by capsule to male and 
female Beagle dogs for 1 year at dose levels of 0, 2, 10, 50, and 250 
mg/kg/day. Body weight (bwt) gain was slightly reduced in females at 
250 mg/kg/day. Absolute liver and spleen weights were increased in 
males given 50 and 250 mg/kg/day. A reduction in hemoglobin and mean 
corpuscular hemoglobin concentration, with an elevation in reticulocyte 
count, was seen at 50 and 250 mg/kg/day. Methemoglobin and 
sulfhemoglobin values were increased at doses of 10 mg/kg/day and 
greater. Histopathological findings were limited to pigmented 
macrophages and Kupffer cells in the liver at doses of 50 and 250 mg/
kg/day. The NOAEL for chronic toxicity in dogs was 2 mg/kg/day.
    Diflubenzuron was fed to male and female Sprague Dawley rats for 2 
years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm. 
Methemoglobin values were elevated in female rats at all dose levels 
and in male rats at the two highest dose levels. Sulfhemoglobin was 
elevated in females, only, at dose levels of 2,500 and 10,000 ppm. Mean 
corpuscular volume (MCV) and reticulocyte counts were increased in high 
dose females. Spleen and liver weights were elevated at the two highest 
doses. Histopathological examination

[[Page 64826]]

demonstrated an increase in hemosiderosis of the liver and spleen, bone 
marrow and erythroid hyperplasia and areas of cellular alteration in 
the liver. In another study diflubenzuron was administered to male and 
female CD rats for 2 years at dose levels of 0, 10, 20, 40, and 160 
ppm. Elevated methemoglobin levels were seen in high dose males and 
females. No additional effects, including carcinogenic findings, were 
observed. The NOAEL for chronic toxicity in rats was 40 ppm (2 mg/kg/
day).
    A 91-week carcinogenicity study in CFLP mice was conducted at doses 
of 0, 16, 80, 400, 2,000, and 10,000 ppm. There was no increase in 
tumor incidence as a result of diflubenzuron administration. Target 
organ effects included: Increased methemoglobin and sulfhemoglobin 
values, Heinz bodies, increased liver and spleen weight, hepatocyte 
enlargement, and vacuolation, extramedullary hemopoiesis in the liver 
and spleen, siderocytosis in the spleen and pigmented Kupffer cells. A 
NOAEL for these effects was 16 ppm (2 mg/kg/day).
    Diflubenzuron was fed to male and female Sprague Dawley rats for 2 
years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm. 
Methemoglobin values were elevated in female rats at all dose levels 
and in male rats at the two highest dose levels. Blood sulfhemoglobin 
was elevated in females, only, at dose levels of 2,500, and 10,000 ppm. 
MCV and reticulocyte counts were increased in high dose females. Spleen 
and liver weights were elevated at the two highest doses. 
Histopathological examination demonstrated an increase in hemosiderosis 
of the liver and spleen, bone marrow and erythroid hyperplasia, and 
areas of cellular alteration in the liver. There was no increase in 
tumor formation. In another study, diflubenzuron was administered to 
male and female CD rats for 2 years at dose levels of 0, 10, 20, 40, 
and 160 ppm. Elevated methemoglobin levels were seen in high dose males 
and females. No additional effects, including carcinogenic findings, 
were observed.
    6. Animal metabolism. DFB in rats at a single dose of 100 mg/kg and 
5 mg/kg single and multiple oral doses depicted limited absorption from 
the gastrointestinal tract. No major difference was observed between 
the single and multiple doses. In single dose treatments, after 7 days, 
20% and 3% of the applied dose 5 and 100 mg/kg, respectively, were 
excreted in urine, while 79% and 98% of the applied dose 5 and 100 mg/
kg, respectively, were eliminated in the feces. Very little 
bioaccumulation in the tissues was observed. In the feces, only 
unchanged parent compound was detected. Several metabolites were 
observed in the urine which are, among others, 2,6-diflurobenzoic acid 
(DFBA), 2,6-difluorophippuric acid, 2,6-difluorobenzamide (DFBAM), and 
2-hydroxydiflubenzuron (2-HDFB). An unresolved peak that was 
characterized as p-chloroaniline (PCA) and/or p-chlorophenylurea (CPU) 
was found. This latter peak accounted for about 2% of the administered 
dose (5 mg/kg). To resolve if PCA and CPU are indeed metabolites of 
DFB, rats were administered a single oral dose, 100 mg/kg of 14C DFB. 
The major metabolites identified in rat urine were 4-chloroaniline-2-
sulfate, accounting for almost 50% of the total radioactive residue 
(TRR) in the urine and N-(4-chlorophenyl)oxamic acid which accounted 
for about 15% of the (TRR). Neither CPU, PCA nor their N-hydroxyl 
derivatives were found in rat urine at a limit of detection of 23 parts 
per billion (ppb). As in the previous study, DFB was the only residue 
found in the feces.
    7. Metabolite toxicology. NCI/NTP conducted chronic feeding and 
gavage studies with p-chloroaniline (PCA), a minor potential metabolite 
of diflubenzuron, in Fischer 344 rats and B6C3F1 mice.
    PCA was administered in the diet to Fischer 344 rats at dietary 
concentrations of 250 and 500 ppm for 78 weeks, followed by a 24-week 
observation period. A slight body weight depression was seen in high 
dose females rats, compared to controls. Survival was reduced in high 
dose males compared to controls. In male rats there was a slight 
increase in uncommon fibromas or fibrosarcomas of the spleen, which was 
not statistically significant. Non-neoplastic proliferative and chronic 
inflammatory lesions were found in spleens of treated rats. It was 
concluded that, under the conditions of the assay, sufficient evidence 
was not found to establish the carcinogenicity of PCA for Fischer 344 
rats.
    PCA was administered 5 days/week by oral gavage, as a hydrochloride 
salt in water, to male and female F344/N rats at doses of 0, 2, 6, or 
18 mg/kg/day. Mean body weights of dosed rats were generally within 5% 
of those of controls throughout the study. High dose animals generally 
showed mild hemolytic anemia and dose-related methemoglobinemia. Non-
neoplastic lesions seen were bone marrow hyperplasia, hepatic 
hemosiderosis, and splenic fibrosis, suggesting treatment-related 
effects on the hematopoietic system. Adrenal medullary hyperplasia was 
observed in high dose female rats. The incidence of uncommon sarcomas 
of the spleen was significantly increased in high dose male rats. A 
marginal increase in pheochromocytomas of the adrenal gland was seen in 
high dose male and female rats. It was concluded that, under the 
conditions of this 2-year gavage study, there was clear evidence of 
carcinogenic activity of PCA hydrochloride for male F344/N rats and 
equivocal evidence of carcinogenic activity of PCA hydrochloride for 
female F344/N rats.
    PCA was administered in the diet to B6C3F6 mice at dietary 
concentrations of 2,500 and 5,000 ppm for 78 weeks followed by a 13-
week observation period. A body weight depression was seen in treated 
mice of both sexes, compared to controls. An increased incidence of 
hemangiomas and hemangiosarcomas in spleen, kidney, liver, and other 
sites was seen in treated mice of both sexes; however this increase was 
not statistically significant compared to controls. Non-neoplastic 
proliferative and chronic inflammatory lesions were found in spleens of 
treated mice. The evidence was considered insufficient to conclusively 
relate the hemangiomatous tumors in mice to compound administration. It 
was concluded that, under the conditions of the assay, sufficient 
evidence was not found to establish the carcinogenicity of PCA for 
B6C3F1 mice.
    PCA hydrochloride was administered 5 days/week by oral gavage to 
male and female B6C3F1 mice at doses of 0, 3, 10, or 30 mg/kg/day. Mean 
body weights of high dose male and female mice were generally within 5% 
of those of controls throughout the study. The incidence of 
hepatocellular adenomas or carcinomas (combined) was increased in a 
non-dose-dependent manner in treated male mice. Metastasis of carcinoma 
to the lung was seen in the high dose group. An increased incidence of 
hemangiosarcomas of the liver or spleen was seen in high dose male 
mice. It was concluded that, under the conditions of this 2-year gavage 
study, there was some evidence of carcinogenic activity of PCA 
hydrochloride for male B6C3F1 mice and no evidence of carcinogenic 
activity of PCA hydrochloride for female B6C3F1 mice.
    In addition to PCA, 4-chlorophenylurea (CPU) is also a potential 
minor metabolite of diflubenzuron. By association with PCA, EPA has 
concluded that CPU has carcinogenic potential and the same carcinogenic 
potency (q\1\*) as PCA. In the NTP report of the PCA bioassay, it is 
proposed that PCA undergoes N-hydroxylation to form the corresponding 
N-hydroxylamine

[[Page 64827]]

metabolites; N-hydroxylation of aromatic amines is a well know 
mechanism of aromatic amine carcinogenicity. This metabolite, or 
proximate carcinogen, is then conjugated to form the ultimate 
carcinogen capable of ionizing and reacting with DNA to form adducts 
which result in splenic tumor formation. An alternate mechanism 
involving toxicity resulting in erythrocyte damage, splenic scavenging, 
hemorrhage, hyperplasia and fibrosis and ultimately splenic tumor 
formation is also proposed, but both mechanisms are based on the 
formation of N-hydroxy PCA.
    This metabolite also causes methemoglobinemia in animals. 
Therefore, methemoglobin formation can be used as an indicator of the 
presence of PCA and N-hydroxy metabolite. However, in recent CPU rat 
toxicity studies, both dietary (7-day) and gavage, and a CPU rat 
metabolism study, it has been demonstrated that CPU does not induce 
methemoglobin formation and it is neither metabolized to PCA nor forms 
an N-hydroxylamine derivative. Since N-hydroxylation is the required 
first step in the mechanism of action of PCA's carcinogenicity, it can 
be concluded that CPU's mechanism of action and toxicity is different 
from that of PCA's.
    8. Endocrine disruption. The standard battery of required studies 
has been completed and evaluated to determine potential estrogenic or 
endocrine effects of diflubenzuron. These studies include an evaluation 
of the potential effects on reproduction and development, and an 
evaluation of the pathology of the endocrine organs following repeated 
or long-term exposure. These studies are generally considered to be 
sufficient to detect any endocrine effects. No such effects were noted 
in any of the studies with diflubenzuron.

C. Aggregate Exposure

    1. Dietary exposure. Since 1-day single dose oral studies in rats 
and mice indicated only marginal effects, an acute exposure risk 
assessment is not needed, as there were no significant acute effects 
observed.
    i. Food--a. Diflubenzuron. The chronic dietary exposure from 
diflubenzuron was estimated based on the average residue values from 
the various currently labeled raw agricultural commodities (RACs) and 
the proposed pear use. Percent of crop treated was also factored into 
the estimate. Residues in meat, milk, and egg products were obtained 
from extrapolation of metabolism study data to anticipated livestock 
dietary burdens. The dietary exposure analysis was estimated based on 
1989-1992 USDA food consumption data.
    For the U.S. population (total), the dietary exposure of 
diflubenzuron was estimated as 0.000027 mg/kg/day. For nursing and non-
nursing infants, the exposure was estimated as and 0.000110 and 
0.000304 mg/kg/day, respectively. For children, the exposure was 
0.000046 and 0.000033 mg/kg/day for 1-6 year olds and 7-12 year olds, 
respectively.
    b. p-Chloroaniline. The chronic dietary exposure from p-
chloroaniline (PCA) which has been detected in some food products was 
also determined. Average residues from field trials for mushrooms, 
rice, pears, nut crops, and pistachios, stonefruit (except cherries), 
and peppers were used. Residues in liver were obtained from 
extrapolation of metabolism data to anticipated livestock dietary 
burdens. EPA has previously used a 2% in vivo conversion factor of DFB 
to PCA for foods derived from plant products. However, based on results 
of a recent rat metabolism study showing that no PCA is formed, this is 
no longer appropriate. The percent treated of each crop was also 
factored into the exposure estimate.
    For the U.S. population (total), the dietary exposure of PCA was 
estimated as <0.000001 mg/kg/day. For nursing and non-nursing infants, 
the exposure was estimated as 0.000002 and 0.000007 mg/kg/day, 
respectively. For children 1 to 6 years old and 7 to 12 years old, the 
exposure was 0.000001 mg/kg/day.
    ii. Drinking water. Diflubenzuron degrades in soil relatively 
quickly with an aerobic half-life ranging from 3 to 7 days. Major 
degradates include difluorobenzoic acid (DFBA) and CPU. DFBA is further 
metabolized through decarboxylation and ring cleavage by soil microbes 
whereas CPU is slowly degraded to soil-bound entities. Under anaerobic 
aquatic conditions, diflubenzuron has a half-life of 34 days with the 
main degradates being DFBA and CPU. In surface water, diflubenzuron is 
degraded by microbes with a half-life of 5 to 10 days. The soil 
mobility of diflubenzuron is considered quite limited based on a number 
of experimental studies as well as by computer modeling. CPU has also 
been shown to be relatively immobile in soil. Although DFBA shows 
mobility in soil, it is rapidly degraded. Therefore, based on results 
of laboratory and field studies, it is not likely that diflubenzuron or 
its degradates will impact ground water quality to any significant 
extent.
    Based on EPA's PRZM/EXAMS modeling, the average annual mean 
concentration of diflubenzuron in surface water sources is not expected 
to exceed 0.05 ppb. These values were determined using the maximum 
concentrations for any diflubenzuron crop uses including the proposed 
commodities. The drinking water level of concern (DWLOC) for chronic 
(non-cancer) exposure to diflubenzuron in drinking water was determined 
as 700 ppb for the U.S. population (total) and approximately 200 ppb 
for infants and children. The estimated maximum concentration of 
diflubenzuron in surface and ground water (0.05 ppb) is much less than 
the DWLOCs as a contribution to chronic (non-cancer) aggregate 
exposure.
    2. Non-dietary exposure. Diflubenzuron is a restricted use 
pesticide based on its toxicity to aquatic invertebrates. This 
restricted use classification makes it unavailable for use by 
homeowners. Occupational uses of diflubenzuron may expose people in 
residential locations, parks, or forests treated with diflubenzuron. 
However, diflubenzuron has very low residues detected in forestry 
dissipation studies, low dermal absorption rate (0.05%), and extremely 
low dermal and inhalation toxicity.

D. Cumulative Effects

    Uniroyal Chemical Co. has considered the potential for cumulative 
effects of diflubenzuron and other substances with a common mechanism 
of toxicity. The mammalian toxicity of diflubenzuron is well defined. 
We are not aware of any other pesticide product registered in the 
United States that could be metabolized to p-chloroaniline. For this 
reason, consideration of potential cumulative effects of residues from 
pesticidal substances with a common mechanism of action as 
diflubenzuron is not appropriate. Thus only the potential exposures to 
diflubenzuron were considered in the total exposure assessment.

E. Safety Determination

    1. U.S. population. Based on the available toxicology and exposure 
data base for diflubenzuron, Uniroyal has determined that the total 
possible non-occupational aggregate exposure from diflubenzuron would 
occur from the dietary route. Dietary exposure to the U.S. population 
(total) from diflubenzuron was estimated at 0.000027 mg/kg/day. Based 
on the 0.02 mg/kg/day RfD (reference dose) derived from the dog chronic 
NOAEL of 2 mg/kg/day and a 100-fold safety factor, this dietary 
exposure is 0.1% of the RfD. Despite the potential for exposure to 
diflubenzuron in drinking water,

[[Page 64828]]

aggregate exposure is not expected to exceed 100% of the RfD.
    For PCA, Uniroyal has also determined that the total possible non-
occupational aggregate exposure would occur from the dietary route. 
Dietary exposure to the U.S. population (total) from PCA was estimated 
as less than 0.000001 mg/kg/day. The risk from diflubenzuron-derived 
PCA can be estimated using a linear extrapolation of the dose-response 
from the rat chronic study conducted by the National Toxicology Program 
in which rats were dosed via gavage with p-chloroaniline 
(hydrochloride) for 24 months. EPA has determined the q\1\* as 0.0638 
based on the combined sarcoma incidence in the spleen of male rats.
    In view of the results of recent CPU rat mechanistic and metabolism 
studies, and the DFB rat metabolism study, the dietary risk assessment 
included here considers only actual residues of PCA found in food and 
animal by-products. This is consistent with a parent compound, such as 
diflubenzuron, which is negative (category E) for carcinogenicity.
    Using the q\1\* of 0.0638, the risk to the U.S. population (total) 
from dietary exposure to diflubenzuron-derived PCA is 3.09 x 
10-8.
    2. Infants and children. The same assumptions as for the U.S. 
population were used for the dietary exposure risk determination in 
infants and children. The dietary exposure of diflubenzuron was 
calculated as 0.000110 and 0.000304 mg/kg/day, respectively for nursing 
and non-nursing infants. These values are 0.6% and 1.5%, respectively 
of the RfD for diflubenzuron. The dietary exposure from diflubenzuron 
in children 1 to 6 years and 7 to 12 years old was determined as 
0.000046 mg/kg/day and 0.000033 mg/kg/day, respectively. These values 
are 0.2% of the RfD.
    As previously discussed, the NOAELs for maternal and developmental 
toxicity in rats and rabbits were greater than 1,000 mg/kg/day, and the 
NOAEL for reproductive toxicity was greater than 5,000 mg/kg/day. 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative exposure assessment, Uniroyal concludes that 
there is reasonable certainty that no harm will result in infants and 
children from aggregate exposure to residues of diflubenzuron and its 
conversion products containing the p-chloroaniline moiety.

F. International Tolerances

    There is a Codex maximum residue limit (MRL) for pears at 1.0 mg/
kg, a Mexican MRL at 1.0 mg/kg, and no limits set for Canada for pears. 
A Codex MRL has also been established for plums (including prunes) at 
1.0 mg/kg. There are no Codex maximum residue limits established for 
other stonefruit, tree nuts or peppers.
[FR Doc. 01-30914 Filed 12-13-01; 8:45 am]
BILLING CODE 6560-50-S