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Diflubenzuron
(IR-4 and Uniroyal). December 14, 2001. Three
Pesticide Tolerance Petitions for residues in or on pear
at 0.5 ppm; grass, forage, fodder, and hay group
at 6 ppm; stonefruit (except cherries), tree nuts,
and pistachios at 0.05 ppm; almond hulls at 5 ppm;
peppers at 1 ppm; and meat-by-products
at 0.15 ppm.
Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-14/p30914.htm
[Federal Register: December 14, 2001 (Volume 66, Number 241)]
[Notices]
[Page 64823-64828]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14de01-47]
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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:
brothers.shaja@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-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: 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-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,
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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