[Federal Register: August 27, 2004 (Volume 69, Number 166)]
[Notices]
[Page 52688-52693]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27au04-39]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2004-0288; FRL-7676-3]
Clofentezine; Notice of Filing a Pesticide Petition to Establish
a Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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 identification (ID)number OPP-
2004-0288, must be received on or before September 27, 2004.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Sidney Jackson, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 305-7610; e-mail address: jackson.sidney@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
Crop production (NAICS 111)
Animal production (NAICS 112)
Food manufacturing (NAICS 311)
Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. Other types of
entities not listed in this unit could also be affected. If you have
any 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 Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket ID number OPP-2004-0288. The official public docket
consists of the documents specifically referenced in this action, any
public comments received, and other information related to this action.
Although a part of the official docket, the public docket does not
include Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. The official public docket
is the collection of materials that is available for public viewing at
the Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket
facility is open from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The docket telephone number is (703) 305-
5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket
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facility identified in Unit I.B.1. Once in the system, select
``search,'' then key in the appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B. EPA intends to work towards
providing electronic access to all of the publicly available docket
materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or in paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and To Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket/
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2004-0288. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID Number OPP-2004-0288. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2004-0288.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
2, 1801 S. Bell St., Arlington, VA, Attention: Docket ID
Number OPP-2004-0288. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is 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 docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
[[Page 52690]]
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in section 408(d)(2) 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.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: August 20, 2004.
Betty Shackleford
Acting Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioner. 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 4E6824
EPA has received a pesticide petition (PP 4E6824) 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 180.446 by
establishing a tolerance for residues of the miticide, clofentezine,
(3,6-bis (2-chlorophenyl)-1,2,4,5-tetrazine) in or on the raw
agricultural commodity persimmon at 0.05 parts per million (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. The
registrant, Makhteshim-Agan of North America, Inc., New York, NY 10176
has prepared this summary in support of the pesticide petition. This
summary does not necessarily reflect the findings of EPA. Additional
data may be needed before EPA rules on the petition.
Clofentezine is marketed in the U.S. under tradenames including
APOLLO SC. APOLLO[reg]SC Ovicide/Miticide (42% active
ingredient (a.i.)) is registered for use on apples, pears, almonds,
walnuts, apricots, cherries, nectarines, and peaches to control
European red mites and several spider mite species (tolerance for
grapes is pending, petition 0F6119). APOLLO SC is an environmentally
friendly, IPM-compatible product used at low dose rates, and only once
per season. The product has been shown to be relatively non-toxic in
studies conducted on mammals, fish, birds, aquatic invertebrates,
predacious and other beneficial mites, bees, algae, and plants.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of clofentezine
residues in plants is adequately understood. The metabolism of
clofentezine has been studied in three crops representative of the use
pattern for APOLLO SC: Apples (pome fruit), peaches (stone fruit), and
grapes (vines/small fruit). In each case, unchanged clofentezine was
the major extractable residue present. Non-extractable residues (fiber-
bound) were negligible. Minor amounts of 2-chlorobenzonitrile, the
major photo-degradation product, were detected, predominantly on the
fruit surface. Dissipation of this component may be a significant route
in the degradation of clofentezine on the surface of these crops. The
nature of the residue in grapes, and in all the other registered crops,
is therefore adequately understood. The residue of concern is the
parent, clofentezine.
2. Analytical method. An adequate method for purposes of
enforcement of the proposed clofentezine tolerance is available. An
independent method validation was successfully completed, and the
method was found acceptable. An extensive database of method validation
data using this method on various crop commodities is available. The
Limit of Quantitation (LOQ) and Minimum Detection Limit (MDL) were
determined to be 0.01 ppm and 0.003 ppm, respectively. The method was
forwarded to FDA for inclusion in PAM-II.
3. Magnitude of residues. Residue data covering the major growing
area for persimmon has been submitted in support of the requested
tolerance. The magnitude of residues for the proposed tolerance is
adequately understood. The results demonstrate that the maximum residue
of clofentezine in or on persimmon was 0.0305 ppm, measured 133 to 140
days after application (0.25 pounds active ingredient (lb a.i.)/acre).
B. Toxicological Profile
The toxicology of clofentezine has been thoroughly evaluated by EPA
as part of previous regulatory actions. The studies are considered to
be valid, reliable and adequate for the purposes of evaluating
potential health risks and for establishing tolerances. The primary
studies submitted in support of the registration of clofentezine are
summarized below.
1. Acute toxicity. Clofentezine has a relatively low degree of
acute toxicity and irritation potential. It is classified as toxicity
category III for oral, dermal and inhalation toxicity, and toxicity
category IV for eye and skin irritation. The acute oral lethal dose
(LD50) of clofentezine was determined to be >5,200
milligrams/kilograms (mg/kg) in rats and mice, >3,200 mg/kg in
hamsters, and >2,000 mg/kg in beagle dogs. The acute rat dermal
LD50 was >2,100 mg/kg. Clofentezine is considered to be
practically non-irritating to eyes and skin but is considered to be a
week skin sensitizer in the guinea pig maximization assay.
APOLLO SC is classified as toxicity category IV for oral toxicity
and skin irritation, and as toxicity category III for dermal toxicity
and eye irritation. The
[[Page 52691]]
acute oral LD50 of APOLLO SC was determined to be >5,000 mg/
kg in rats; the acute dermal LD50 in rats was >2,400 mg/kg.
APOLLO SC is considered slightly irritating to eyes and skin.
2. Genotoxicity. No evidence of genotoxicity was noted in a battery
of in vitro and in vivo studies. Studies submitted included Ames
Salmonella and mouse lymphoma gene mutation assay, a mouse micronucleus
assay, a rat dominant lethal assay, and a gene conversion and mitotic
recombination assay in yeast. Therefore, the registrant concludes that
clofentezine has no potential to induce genotoxicity.
3. Reproductive and developmental toxicity. A multigeneration rate
reproduction study was conducted at dietary concentrations of 0, 4, 40,
and 400 ppm. The parental no observed adverse effect level (NOAEL) was
40 ppm based on slightly reduced body weights, increased liver weights
and hepatocellular hypertrophy at 400 ppm. No treatment-related
reproductive effects were noted at any dose level.
In a rat developmental toxicity study, clofentezine was
administered by gavage at dose levels of 0, 320, 1, 280 and 3,200 mg/
kg/day during gestation days 6 to 20. Evidence of maternal toxicity was
noted at 3,200 mg/kg/day and consisted of decreased weight gain,
increased liver weights and centrilobular hepatocellular enlargement.
No developmental effects were observed at any dose level.
In a rabbit developmental toxicity study, clofentezine was
administered by gavage at dose levels of 0, 250, 1,000 and 3,000 mg/kg/
day during gestation days 7 to 28. Slight maternal toxicity (decreased
maternal food consumption and weight gain) and a slight decrease in
fetal weight were noted at 3,000 mg/kg/day. Thus, the NOAEL was
considered to be 1,000 mg/kg/day for both maternal and developmental
effects.
4. Subchronic toxicity. In a preliminary 90-day feeding study
designed to select a suitable high dose level for a subsequent chronic
rate study, clofentezine was administered to rats at dietary
concentrations of 0, 3,000, 9,000 and 27,000 ppm. A significant
reduction in weight gain was noted at 9,000 and 27,000 ppm. In
addition, a marked, dose-related hepatomegaly and centrilobular
hepatocyte enlargement was noted in all treatment groups.
In a subsequent 90-day feeding study, clofentezine was administered
to rats at dietary concentrations of 0, 40, 400, and 4,000 ppm.
Slightly reduced weight gain, alterations in several clinical pathology
parameters, increased liver, kidney and spleen weights, and
centrilobular hepatocyte enlargement were noted at 400 and/or 4,000
ppm. Thus, 40 ppm (2.8 mg/kg/day) was considered to be the NOAEL for
this study.
Clofentezine was administered to beagle dogs for 90 days at dietary
concentrations of 0, 3,200, 8,000 and 20,000 ppm. Increased liver
weights were noted at all dose levels but no histopathological changes
nor any other treatment-related effects were observed.
5. Chronic toxicity. In a 12-month feeding study, clofentezine was
administered to beagle dogs at dietary concentrations of 0, 50, 1,000,
and 20,000 ppm. An increase in adrenal and thyroid weights, as well as
moderate hepatotoxicity consisting of minimal periportal hepatocyte
enlargement with cytoplasmic eosinophilia, hepatomegaly and increased
plasma cholesterol, triglycerides and alkaline phosphatase levels, were
noted at 20,000 ppm. Evidence of slight hepatotoxicity was also noted
at 1,000 ppm. Thus, the NOAEL for this study was considered to be 50
ppm (1.25 mg/kg/day).
In a 27-month feeding study, clofentezine was administered to rats
at dietary concentrations of 0, 10, 40, and 400 ppm. Effects noted at
400 ppm were limited to the liver and thyroid, primarily of males, and
consisted of increased liver weights, a variety of microscopic liver
lesions (centrilobular hepatocyte hypertrophy and vacuolation, focal
cystic hepatocellular degeneration and diffuse distribution of fat
deposits), increased serum thyroxine levels, and a slight but
statistically significant increase in the incidence of thyroid
follicular cell tumors. The NOAEL was considered to be 40 ppm (2 mg/kg/
day).
Clofentezine was not oncogenic to mice when administered for 2
years at dietary concentrations of 0, 50, 500, and 5,000 ppm. Decreased
weight gain, increased liver weights, and increased mortality were
noted at 5,000 ppm. An increased incidence of eosinophilic or
basophilic hepatocytes was noted at 5,000 ppm, and possibly 500 ppm.
Numerous studies were conducted to investigate the mechanism for
the increased incidence of male thyroid follicular tumors that was
observed in the chronic rat study. These studies suggest that the
tumors may have been caused by increased thyroid stimulating hormone
(TSH) levels, which, in turn, resulted from clofentezine's liver
toxicity, and were not attributable to a genotoxic mode of action.
6. Animal metabolism. The metabolism, tissue distribution and
excretion of clofentezine have been evaluated in a number of species.
In all species, almost all of the administered dose was recovered
within 24 to 48 hours after treatment, primarily via the feces. The
major route of metabolism was found to be ring hydroxylation, sometimes
preceded by the replacement of a chlorine atom with a methyl-thio
group. Blood and tissue levels in the fetuses of pregnant rats that had
been treated with clofentezine were much lower than the levels found in
the mother, indicating that clofentezine does not readily pass across
the placenta. In addition, less than 1% of the administered dose was
absorbed through the skin of rats following a 10-hour exposure to the
end use formulation of clofentezine, APOLLO SC.
Following oral dosing of a cow and three goats with 14C-labeled
clofentezine, the residue in milk was identified as a single
metabolite, 4-hydroxyclofentezine. Similarly, 4-hydroxyclofentezine has
been shown to be the only metabolite present in fat, liver, and kidney.
No unchanged clofentezine or other metabolites were found. Therefore,
the nature of the residue in animals is adequately understood. The
residues of concern in ruminant commodities and milk are the combined
residues of the parent, clofentezine, and the 4-hydroxyclofentezine
metabolite.
7. Metabolite toxicology. There are no metabolites of toxicological
concern and therefore, no metabolites need to be included in the
tolerance expression and require regulation.
8. Endocrine disruption. Except for the thyroid mechanistic studies
mentioned above, no special studies have been conducted to investigate
the potential of clofentezine to induce estrogenic or other endocrine
effects. However, the standard battery of required toxicity studies has
been completed. 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. Repeated dose studies are generally considered to be of
substantial value as a means for detection of any endocrine effects.
However, with the exception of a slightly increased incidence of
thyroid tumors in male rats, no such effects were noted in any of the
repeated dose toxicity studies with clofentezine. The male rat is known
to be much more susceptible than humans to the carcinogenic effects
resulting from thyroid hormone imbalance and/or increased levels of
TSH. Therefore, the alterations in thyroid hormone and subsequent
thyroid pathological
[[Page 52692]]
changes, which have been noted following administration of high doses
of clofentezine, are considered to be of minimal relevance to human
risk assessment, particularly considering the low levels of
clofentezine to which humans are likely to be exposed.
C. Aggregate Exposure
1. Dietary exposure. Current tolerances (40 CFR 180.446) have been
established for almonds (hulls, nutmeat), apples (fruit, pomace),
apricots, cherries, nectarines, peaches, pears, walnuts, ruminant
commodities, and milk. There is also a proposed tolerance for grapes
pending (PP OF6119). A notice of filing for grapes was published in the
Federal Register of July 12, 2000 (65 FR 43004; FRL-6591-8). In
addition to the registered and pending uses, this notice of filing
includes exposure assessments for potential residues of clofentezine in
or on persimmon. Presently and in the future, clofentezine is not
considered for residential uses. Thus, potential sources of non-
occupational exposure to clofentezine would consist only of any
potential residues in food and drinking water. No acute dietary
assessments were conducted since no appropriate toxicological endpoint
attributable to a single exposure was identified in the available
toxicology studies. Therefore, only chronic exposure calculations were
compared against the chronic RfD of 0.0125 mg/kg/day.
i. Food. A conservative dietary exposure assessment was performed
for clofentezine using Exponent's Dietary Exposure Evaluation Model
(DEEM) software, and consumption data derived from the 1994-1996 USDA
Continuing Surveys of Food Intake by Individuals (CSFII). This
assessment used all existing and proposed tolerances, residue levels at
current and proposed tolerance levels, and percent crop treated (PCT)
data based on the following assumptions: 24% apples, 0% apricots, 6%
cherries, 30% nectarines, 12.2% peaches, 16% pears, 1.4% plums and
prunes, 9.2% almonds, 7.4% walnuts, and 25% for grapes and 25%
persimmon. The PCT data for current uses are in agreement with USEPA
earlier assessment for clofentezine (April 19, 1999, 64 FR 19042; FRL-
6075-6).
Based on these assumptions, the chronic dietary exposure estimates
(DEEM) from the existing and proposed tolerances are well below the
chronic RfD, ranging from 2.7% to 10.3% of the cRfD for the U.S. and
its subpopulations.
ii. Drinking water. Sufficient ground or surface water monitoring
data are not available to perform a quantitative risk assessment for
clofentezine at this time. However, in the final rule published in the
Federal Register on April 19, 1999 (see cite above), EPA previously
determined estimated drinking water environmental concentrations
(DWECs) for clofentezine in ground and surface water using available
environmental fate data and the screening model for ground water (SCI-
GROW) and the generic expected environmental concentration (GENEEC)
model for surface water. The DWEC of clofentezine in groundwater was
estimated to be 0.04 parts per billion (ppb) using SCI-GROW, and the
chronic DWEC for surface water was estimated to be 0.3 ppb using
GENEEC. EPA's policy allows the 90/56-day GENEEC value to be divided by
3 to obtain a value for chronic risk assessment calculations.
Therefore, a surface water estimate of 0.1 ppb was used in the chronic
risk assessment.
2. Non-dietary exposure. Not applicable.
3. Chronic exposure (diet plus water). EPA uses the Drinking Water
Level Of Comparison (DWLOC) as a theoretical upper limit on a
pesticide's concentration in drinking water when considering total
aggregate exposure to a pesticide in food, drinking water, and
residential uses (not applicable for this assessment). DWLOCs are not
regulatory standards for drinking water. However, EPA uses these values
in the risk assessment process as a point of comparison against
conservative model estimates of a pesticide's concentration in water.
To calculate the DWLOC for chronic exposure relative to a chronic
toxicity endpoint, the chronic dietary exposure analysis (DEEM) was
subtracted from the RfD to obtain the acceptable chronic exposure to
clofentezine in drinking water. DWLOCs were then calculated using
default body weights and drinking water consumption factors. If the
DWLOC exceeds the DWEC value then there is reasonable certainty that no
harm will result from the aggregate exposure.
The estimated average concentration of clofentezine in surface
drinking water (0.1 ppb) is far below the range of calculated DWLOCs:
442 ppb (U.S. population), 233 ppb (children 1-6 years) and 117 ppb
(All infants < 1 year, and Non-nursing infants). Therefore, Makhteshim-
Agan believes there is reasonable certainty that no harm will result
from aggregate exposure to residues arising from all current and
proposed clofentezine uses.
D. Cumulative Effects
To our knowledge there are currently no available data or other
reliable information indicating that any toxic effects produced by
clofentezine would be cumulative with those of other chemical
compounds; thus only the potential risks of clofentezine have been
considered in this assessment of its aggregate exposure.
E. Safety Determination
1. U.S. population. The toxicity and residue databases for
clofentezine are considered to be valid, reliable, and essentially
complete. No acute dietary assessment was conducted because there is no
toxicological endpoint attributable to a single exposure. Although
clofentezine has been classified by EPA as category C for oncogenicity
(April 3, 1990), quantitative oncogenic risk assessment was considered
inappropriate given the weight of the evidence presently supported by
the Agency's position that human health risk associated with long-term
exposure to clofentezine is most appropriately evaluated by a chronic
RfD value derived from the 1-year dog feeding study (NOAEL of 1.25 mg/
kg/day), and using a 100-fold uncertainty factor. No effect on the
thyroid, including the induction of thyroid follicular cell tumors
would be expected at exposure levels that did not affect the liver.
Furthermore, male rats are believed to be much more susceptible than
humans to this type of effect. Therefore, the registrant concludes that
quantification of carcinogenic risk based on thyroid follicular cell
tumors in male rats is not appropriate.
Using worst-case assumptions of 100% percent crop treated, and that
all crops and animal commodities contain residues of clofentezine at
the current tolerance levels data maximum percent crop treated data,
the aggregate exposure of the general population to clofentezine from
the established and proposed tolerances utilizes about 8.7% of the
chronic RfD or 2.7% if more realistic estimates of percent crop treated
data have been used. The theoretical maximum residue contribution
(TMRC) for the proposed use on persimmon is negligible. There is
generally no concern for exposures, which utilize less than 100% of the
RfD because the RfD represents the level at or below which daily
aggregate exposure over a lifetime would not pose significant risks to
human health. Therefore, Makhteshim-Agan concludes that there is a
reasonable certainty that no harm will result to the general population
from aggregate exposure to clofentezine residues.
2. Infants and children. The toxicology database for clofentezine
regarding potential prenatal and
[[Page 52693]]
postnatal effects in children is complete according to existing Agency
data requirements and does not indicate any developmental or
reproductive concerns.
No indication of increased sensitivity to infants and children was
noted in any of the studies with clofentezine. No developmental effects
were noted in rats, even at a dose level (3,200 mg/kg/day) that
exceeded the 1,000 mg/kg/day limit dose and produced maternal toxicity.
In addition, no evidence of reproductive toxicity was noted in the rat
multigeneration reproduction study. Slight developmental toxicity
(decreased fetal weights) was noted in rabbits, but only at a dose
level (3,000 mg/kg/day) that exceeded the EPA limit dose and also
produced maternaltoxicity.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children to account for prenatal and postnatal
toxicity and the completeness of the database. The toxicology database
for clofentezine regarding potential prenatal and postnatal effects in
children is complete according to existing Agency data requirements and
does not indicate any developmental or reproductive concerns.
Furthermore, the existing RfD is based on a NOAEL of 1.25 mg/kg/day
(from the 1-year dog study), which is already more than 800-fold lower
than the NOAEL in the rabbit developmental toxicity study. Thus, the
registrant believes that the existing RfD of 0.0125 mg/kg/day is
considered to be appropriate for assessing potential risks to infants
and children and an additional uncertainty factor is not warranted.
Using the conservative exposure assumptions described above
(proposed and current tolerances, 100% crop treated, and no adjustments
for percent contribution from livestock diet), aggregate exposure to
residues of clofentezine are expected to utilize about 48% of the RfD
in non-nursing infants, 20% of the RfD in nursing infants, and 36% of
the RfD in children aged 1 to 6 years old. Using more realistic
estimates of percent crop treated, the percent of RfD utilized is less
than or equal to 10% for these population subgroups. These numbers
would be lowered further if anticipated residues and/or an adjustment
for percent contribution from livestock diet were utilized rather than
tolerance values. The residue contribution for the proposed use on
persimmon is negligible. Therefore, Makhteshim-Agan concludes that
there is reasonable certainty that no harm will result to infants or
children from aggregate exposure to clofentezine residues.
F. International Tolerances
There are no international maximum residue levels (MRL) established
for clofentezine in or on the raw agricultural commodity, persimmon.
[FR Doc. 04-19616 Filed 8-26-04; 8:45 am]
BILLING CODE 6560-50-S