[Federal Register Volume 68, Number 31 (Friday, February 14, 2003)]
[Notices]
[Pages 7548-7554]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-3695]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2003-0007; FRL-7289-1]


Pyrimethanil; 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 
pyrimethanil in or on various food commodities.

DATES: Comments, identified by docket ID number OPP-2002-0007, must be 
received on or before March 17, 2003.

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: Mary Waller, Registration Division 
(7505C), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 308-9354; 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:
    [sbull] Crop production (NAICS 111)
    [sbull] Animal production (NAICS 112)
    [sbull] Food manufacturing (NAICS 311)
    [sbull] 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. 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 Copies of this Document and Other Related Information?

    1. Docket. EPA has established an official public docket for this 
action under docket identification (ID) number OPP-2003-0007. 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, 
1921 Jefferson Davis Hwy., 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 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

[[Page 7549]]

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-2003-0007. 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 [email protected], 
Attention: Docket ID Number OPP-2003-0007. 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-2003-0007.
    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, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket 
ID Number OPP-2003-0007. 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.

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.

[[Page 7550]]

    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 FFDCA 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: February 3, 2003.
Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by FFDCA section 408(d)(3). 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.

Janssen Pharmaceutica Inc.

PP 2F6480

    EPA has received a pesticide petition (2F6480) from Janssen 
Pharmaceutica Inc., Plant and Material Protection Division, 1125 
Trenton-Harbourton Road, Titusville, NJ 08560 proposing, pursuant to 
section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing tolerances for 
residues of the fungicide, pyrimethanil (4,6-dimethyl-N-phenyl-2-
pyrimidinamine) in or on the raw agricultural commodities citrus fruits 
(calamondin, citrus citron, citrus hybrids, grapefruit, kumquat, lemon, 
lime, mandarin, sour and sweet oranges, pummelo and Satsuma mandarin) 
at 6 parts per million (ppm), pome fruit (apples, pears, oriental 
pears, crabapples, loquats, mayhaws, and quince) wet pomace at 12 ppm, 
and pome fruit (apples, pears, oriental pears, crabapples, loquats, 
mayhaws, and quince) at 3 ppm. EPA has determined that the petition 
contains data or information regarding the elements set forth in 
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated 
the sufficiency of the submitted data at this time or whether the data 
support granting of the petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolic profile of pyrimethanil has been 
investigated following application to five different crops (apple, 
carrots, grapes, lettuce and tomatoes) and is well understood. In 
plants, pyrimethanil is the only significant residue ranging from 
essentially all of the Total Radioactive Residues (TRR) in carrots and 
tomatoes to 44% in lettuce. Limited metabolism of pyrimethanil occurs 
with minor amounts (less than 10%) of the phenyl and pyrimidyl 
hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE 
C621312) being released after acid hydrolysis. Analysis of the foliage 
from apples and carrots confirmed that the metabolism of pyrimethanil 
in plants proceeded primarily via hydroxylation of the aromatic ring 
structures as well as the methyl groups.
    2. Analytical method. The plant metabolism studies indicated that 
analysis for the parent compound, pyrimethanil was sufficient to enable 
the assessment of the relevant residues in crop commodities. For 
citrus, the pyrimethanil was extracted with acetone, the extract 
acidified and washed with isohexane and basified to enable solvent 
partition. After solvent exchange to ethyl acetate, the residue is 
determined using GC-MS. For pome fruits, the pyrimethanil was extracted 
directly with ethyl acetate/isohexane (1:1), dried, and analyzed for 
residues with GC-MS. The limit of quantitation is 0.05 ppm. These 
methods allow detection and measurement of residues in or on 
agricultural commodities at or above the proposed tolerance level.
    3. Magnitude of residues. Magnitude of residue trials were 
conducted for pyrimethanil on apples, pears, and citrus (lemons, 
oranges (navels and valencias), tangerines, tangelos, and grapefruit). 
Trials were conducted in the major producing states which together 
represent 97%, 70%, and 75% of the citrus, apple and pear domestic 
production, respectively. Samples were collected according to good 
agricultural practices at harvest and/or following a postharvest 
treatment. The pre-harvest interval (PHI) for pome fruit was 7 days 
following application of the fungicide at the proposed label rate, to 
approximate maximum field residues. The proposed PHI for pome fruit is 
72 days. Samples were harvested at maturity and analyzed with a method 
having an level of quantitation (LOQ) of 0.05 ppm pyrimethanil. 
Residues in the raw agricultural commodity (RAC) samples (range, 
maximum and average) are discussed per crop grouping below.
    i. Citrus fruits (calamondin, citrus citron, citrus hybrids, 
grapefruit, kumquat, lemon, lime, mandarin, sour and sweet oranges, 
pummelo and Satsuma mandarin). Nine trials were conducted on citrus 
during 2001. An end use formulation containing 400 gram/liter or 3.34 
lbs/active ingredient/gallon of pyrimethanil was applied by drench, dip 
and/or line spray in water, storage wax or shipping wax. Multiple 
treatments (single, double and triple applications) were investigated. 
A maximum of ten different multiple treatment scenarios were 
investigated for lemons, seven for oranges, and five for grapefruit. 
Fruit were washed between treatments only when this was typical of 
commercial packinghouse operations. The maximum rates applied were 
1,000 ppm in drench and dip tanks, and 2,000 ppm in any type of line 
spray. The maximum proposed use recommendations are for a 4 minute 
drench at 500 ppm, 2 minute dip at 1,000 ppm, and/or 2,000 ppm line 
spray for water or storage and shipping wax, with a maximum of three 
applications. Whole fruit and edible pulp were analyzed separately for 
pyrimethanil residues. In the whole fruit samples, maximum residues 
were 6.0 ppm for the proposed applications, and 0.76 ppm for edible 
pulp. Mean pyrimethanil residues ranged from 1.1 ppm for an single 
aqueous line spray applied with a 20,000 ppm treating solution to 5.45 
ppm for a triple treatment that included a drench (1,000 ppm), dip 
(1,000 ppm), and 2,000 ppm wax line spray. A single orange trial was 
established in Florida as a processing study. Pyrimethanil was

[[Page 7551]]

applied as a dual application at rates of 2,000 and 4,000 ppm active 
ingredient (a.i.) in aqueous and wax line sprays, respectively. This 
rate is the maximum for the aqueous treatment and two times the 
proposed label rate for wax incorporation. Mean pyrimethanil residue 
levels found in/on the samples were: Whole citrus fruits 7.46 ppm, 
dried pulp 2.93, orange juice 0.05 ppm and citrus oil 131 ppm. No 
pyrimethanil-derived residue concentrated from the whole fruit into the 
orange juice or dried pulp. However, the pyrimethanil residues 
concentrated from the whole oranges into the citrus oil by a factor of 
17.5. Citrus oil is not considered as a ready-to-eat food commodity and 
since none of the of the processed food products are likely to contain 
pyrimethanil residues above the proposed citrus tolerance of 6.0 ppm in 
the raw agricultural commodity of whole fruit utilizing dilution 
factors, tolerances are not necessary for citrus oil.
    ii. Pome fruit (apples, pears, Oriental pears, crabapples, loquats, 
mayhew, and quince). Ten trials were established for this study, four 
in Washington, four in California, and two in New York. Of the 10 
trials, 4 were conducted on pears and 6 on apples. A pre-harvest 
formulation of pyrimethanil was applied to the apple or pear trees 
during a single application, at a nominal rate of 0.40 lb of a.i., 7 
days prior to harvest. Mean pyrimethanil residue levels found in or on 
the apple fruit following both preharvest and postharvest applications 
ranged from 0.49 ppm for a single aqueous line spray at 1,000 ppm a.i. 
to 1.44 ppm for the dual treatment consisting of a drench (1,000 ppm) 
followed by an aqueous line spray (1,000 ppm). Individual sample 
residues ranged from a low of 0.11 ppm for the 1,000 ppm aqueous line 
spray to 2.84 ppm for the dual treatment of a 1,000 ppm drench followed 
by a 2,000 ppm wax application. The limit of quantitation of the 
analytical method was 0.05 ppm. A single trial was established in 
Washington as a processing study. Pyrimethanil was applied to apple 
trees four times prior to harvest. Applications were made at a nominal 
rate of 2.0 lb a.i./Acre, with 7 days between applications. This rate 
is approximately five times the proposed label application rate. Mean 
pyrimethanil residue levels found in or on the samples were: Whole 
apple fruit 0.17 ppm, wet pomace 0.69 ppm, and juice 0.06 ppm. No 
pyrimethanil-derived residue concentrated from the whole fruit into the 
apple juice. However, the pyrimethanil residues concentrated from the 
whole apples into the wet pomace by a factor of 4.

B. Toxicological Profile

    1. Acute toxicity. Pyrimethanil is of low acute toxicity placing 
the active ingredient in Toxicity Category II, III and IV. Pyrimethanil 
is non-irritating to the eyes and skin and is not a skin sensitizer.
    Acute neurotoxicity. Groups of 10 rats/sex/group were dosed once by 
oral gavage at dose levels of 0, 30, 100, 1,000 milligrams/kilogram 
(mg/kg) of pyrimethanil bodyweight. On the day of dosing, high dose 
animals experienced transient behavioral effects attributable to 
receipt of a substantial bolus dose of test substance. No 
histopathological lesions accompanied these transient behavioral 
changes. The no observed adverse effect level (NOAEL) was 100 mg/kg due 
to reduced body temperature for males. The NOAEL was 30 mg/kg.
    2. Genotoxicity. Pyrimethanil is not mutagenic or genotoxic in any 
assay in either the presence or absence of metabolic activation.
    3. Reproductive and developmental toxicity. Pyrimethanil is not a 
developmental or reproductive toxicant.
    i. Teratology - rat. Thirty Sprague Dawley rats/group received 
doses of 0, 7, 85, 1,000 mg/kg of pyrimethanil by gavage from gestation 
days (GD) 6-15. At the highest dose tested, reduced maternal body 
weight gain was observed during GD6-15, along with a slight but 
statistically significant decrease in food consumption, hair loss, 
hunched posture, slight emaciation, and slightly reduced mean fetal 
body weight. The maternal and developmental NOAEL was 85 mg/kg.
    ii. Teratology - rabbit. Groups of at least 18 time-mated New 
Zealand White rabbits received oral gavage doses of 0, 7, 45, or 300 
mg/kg/day pyrimethanil over gestation days (GD) 7-19. At the highest 
dose tested, there was a decrease in body weight gain, production of 
feces and food consumption. Three females were euthanized due to severe 
emaciation. The highest dose, 300 mg/kg/day exceeded the maternal 
maximum tolerated dose (MTD). The maternal NOAEL was 45 mg/kg/day due 
to reduced fecal production in 1/3 of the animals. The high dose 
resulted in reduced mean fetal body weight, increased incidence of 
runts, delayed skeletal ossification and incidence of fetuses with 13 
thoracic vertebrae and ribs. The maternal NOAEL was 7 mg/kg/day. The 
developmental NOAEL was 45 mg/kg/day.
    iii. Two-generation reproduction - rat. Three groups of 30 Sprague-
Dawley rats per sex received dietary exposure to pyrimethanil at levels 
of 0, 1.7, 20.9, or 266.7 mg/kg/day. In the parental generation at the 
highest dose tested there was a statistically significant decrease in 
mean body weight gain in both sexes. Mean pup weights, observed on PND1 
through weaning, were reduced, though were within the range of 
historical controls. In the F1 generation at the highest dose tested, 
mean body weights and mean food consumption were reduced. Though the 
mean score for the combined sexes was the same as the controls, a 
marginally different air-righting reflex at PND11 associated with 
reduced body weight was seen in high dose male pups. The NOAEL for 
maternal and developmental toxicity was 20.9 mg/kg/day. The 
reproductive NOAEL was 266.7 mg/kg/day.
    4. Subchronic toxicity--i. 28-Day dietary rat. Five Sprague-Dawley 
rats/sex/group received dietary exposure to pyrimethanil for 28 days at 
0, 844, 1,161, 1,500, and 2,710 mg/kg/day. All doses exceeded the 
maximum tolerated dose. Severe emaciation was observed at all dose 
levels. Body weight gains and food consumption were reduced. Liver and 
thyroid histopathology were observed, along with reduced hemoglobin, 
MCV and MCH. Kidney, adrenal and liver weights were altered. No NOEL or 
NOAEL was achieved.
    ii. 90-Day dietary rat. Ten Sprague-Dawley rats/sex/group received 
pyrimethanil in the diet at dose levels of 0, 5.4-6.8, 54.5-66.7, and 
545-667 mg/kg/day (males and females, respectively). High dose animals 
had reduced body weight gain and food consumption, increased urinary 
protein in males, colored urine (not blood or bilirubin) and minimal 
hepatocellular hypertrophy. The NOAEL in males was 54.5-66.7 (males and 
females, respectively) due to colored urine and a low incidence of 
minimal centrilobular hepatocellular hypertrophy. The NOAEL was 5.4 mg/
kg/day (males) -6.8 mg/kg/day (females).
    iii. 28-Day dietary-mouse. Five CD-1 mice/sex/group received 
dietary doses of 0, 167-236, 567-667, 1960-2357 mg/kg/day, males and 
females respectively, for 28 days (all the mice in one additional high 
dose group, 30,000 ppm, died within the first week of the study). At 
1960-2357 mg/kg/day, animals experienced: body weight loss (females), 
decreased body weight gain during the first 2 weeks (males), a 
statistically significant decrease in cholesterol, statistically 
significant decreases in relative liver weights (females), pigmentation 
of thyroid follicles, urolithiasis, moderate urothelial hyperplasia in 
urinary bladder, and

[[Page 7552]]

slight kidney tubular degeneration (females). The NOAEL was 167-236 mg/
kg/day.
    iv. 90-Day dietary-mouse. Twenty CD-1 mice/sex/group received 
pyrimethanil diet exposure at dose levels of 0, 12-18, 139-203, 1,864-
2,545 mg/kg/day males-females for 90 days. At the high dose, animals 
had decreased body weight and increased food consumption, cholesterol 
and total bilirubin. High dose females had increased relative liver 
weights. Histopathology in the high dose animals was found in the 
kidneys, liver, thyroid, and urinary bladder. High dose males had 
slight urinary tract tubular dilation and slight to moderate 
hyperplasia of bladder epithelium. The NOAEL was determined to be 12 
mg/kg/day (males) -18 mg/kg/day (females). Based on mild hepatic 
glycogen depletion, the NOAEL was 139-203 mg/kg/day (males and females, 
respectively).
    v. 90-Day dietary-dog. Four beagle dogs/sex/group received 
pyrimethanil by gavage for 90 days at doses of 0, 6, 80, 1,000 mg/kg/
day. The high dose was lowered to 800 mg/kg/day on day 7 due to 
frequent and consistent vomiting. Decreased body weight, food, and 
water consumption were observed. Males had a significant reduction in 
phosphate, while females experienced a slight reduction in sodium, 
anion gap and total protein. At 80 mg/kg/day, infrequent vomiting after 
dosing and decreased water consumption were observed. After 4 weeks of 
dosing at 80 mg/kg/day, males had significantly reduced phosphate. The 
NOAEL was 80 mg/kg/day. The NOEL was 6 mg/kg/day.
    vi. Subchronic neurotoxicity. Groups of 12 Sprague-Dawley rats per 
sex were treated for 13 weeks with pyrimethanil via the diet at 0, 4, 
38.7-44.3, 391.9-429.9 mg/kg/day (males and females, respectively). 
There were no treatment-related findings in behavioral assessments, 
neuropathology or brain morphometrics. The NOAEL for this study is 
38.7-44.3 mg/kg/day (males and females, respectively) based upon 
decreased body weight and food consumption in the high dose group.
    vii. Dermal toxicity evaluation. No dermal studies have been 
conducted for pyrimethanil.
    5. Chronic toxicity--i. Chronic toxicity - dog. Four beagle dogs/
sex/group received pyrimethanil by gavage at levels of 0, 2, 30, or 250 
mg/kg/day for 12 months. The high dose was reduced from 400 to 250 mg/
kg/day on day 8 of treatment due to excessive vomiting during the first 
week of treatment. At the high dose, there was a decrease in mean body 
weight gain and mean consumption of food and water. The NOAEL for the 
study was 30 mg/kg/day, with the high dose of 250 mg/kg/day being the 
NOAEL.
    ii. Combined chronic toxicity/oncogenicity - rat. Seventy Sprague-
Dawley rats/sex/group received pyrimethanil by diet at levels of 0, 
1.3-1.8, 17-22, and 221-291 mg/kg/day (males and females, respectively) 
for 2 years. At the highest dose tested, body weight gain and food 
consumption were decreased. Absolute liver weights were increased. 
Histopathology revealed centrilobular hepatocyte hypertrophy, increased 
incidence of eosinophilic foci (males), thyroid follicular hyperplasia, 
hypertrophy and colloid depletion, and the presence of a brown pigment, 
identified as lipofuscin in thyroid follicular cell epithelium. There 
was a statistically significant, dose-dependent increase in the 
incidence of benign thyroid follicular cell adenomas. There was no 
increased incidence in any malignant tumor or increase in tumor 
multiplicity as a result of daily dietary ingestion of pyrimethanil at 
any dose level. The results of special studies, discussed below, 
demonstrate that the benign thyroid tumors are likely a secondary 
result of a disruption of thyroid-pituitary homeostasis, a well-known, 
threshold-mediated mechanism. The NOAEL was 17 mg/kg/day (males) and 22 
mg/kg/day (females).
    iii. Oncogenicity - mouse. Fifty-one CD-1 mice/sex/group received 
pyrimethanil by diet at 0, 16, 160, and 1,600 ppm (corresponding to 0, 
2-2.5, 20-24.9, and 210.9-253.8 mg/kg/day in males and females, 
respectively). There was an increase in the number of high dose male 
deaths caused by urogenital tract lesions. Urinary bladder 
histopathology on those dying during the course of the study indicates 
an increase in the incidence of male urinary bladder distension, 
cystitis, urothelial hyperplasia and inflammation of the penis. These 
findings are consistent with the findings of both the 28- and 90-day 
studies indicating that high dose administration of pyrimethanil 
resulted in urolith formation leading to irritation, distension and 
hyperplasia of the urinary bladder and urinary tract. Chronic dietary 
treatment with pyrimethanil produced no increased incidence of tumor-
bearing mice nor of any specific tumor type suggestive of a 
carcinogenic effect. The NOAEL for both sexes was 20-24.9 mg/kg/day 
(males and females, respectively).
    iv. Special studies. Since rodent thyroid tumors are fairly common, 
and since the EPA has established that five lines of evidence are 
required to prove the thyroid-pituitary disruption mode of action for 
rodent thyroid tumors, special studies were undertaken
    a. Thyroid mechanistic study (14-Day). Sprague Dawley rats received 
378.5 mg/kg/day of pyrimethanil for 14 days to study the effects of 
pyrimethanil on the thyroid and liver microsomal enzymes. An increase 
in the levels of UDPGT and a corresponding statistically significant 
increase in liver weight were observed. Thyroid hormones T4 and T3 were 
decreased, while TSH levels were significantly increased. All effects 
were shown to be reversible.
    b. Dietary thyroid function test using perchlorate discharge (7-
Day). Sprague Dawley rats received 509 mg/kg/day pyrimethanil or 177 
mg/kg/day propylthiouracil, or 109 mg/kg/day phenobarbital in order to 
study the function of the thyroid gland. The animals fed pyrimethanil 
had 43% decreased body weight gain, 21% decreased food consumption and 
a 150% increase in uptake of iodine-125. There was no significant 
discharge of radioactive iodine from the thyroid after administration 
of perchlorate.
    The required five lines of evidence to support the threshold mode 
of action for thyroid pituitary disruption and rat thyroid tumors are 
satisfied in the pyrimethanil studies.
    EPA's final rule establishing a tolerance for pyrimethanil in wine 
stated that ``The Agency's Carcinogenicity Peer Review Committee (CPRC) 
chose a non-linear approach Margin of Exposure (MOE) based on a NOAEL 
of 17 mg/kg/day for increased incidences of thyroid tumors in rats. The 
MOE methodology was selected because of thyroid tumors associated with 
administration of pyrimethanil in the rat, which may be due to a 
disruption in the thyroid-pituitary status. This chemical has been 
classified as a Group C chemical (possible human carcinogen) and a non-
linear methodology (MOE) was applied for the estimation of human cancer 
risk. The estimated MOE does not exceed the Agency's level of concern 
and therefore, EPA has a reasonable certainty that no harm will result 
from exposures to residues of pyrimethanil.''
    6. Animal metabolism. Pyrimethanil is rapidly metabolized and 
excreted from lactating dairy cows. The observed total radioactive 
residues in edible tissues and milk were as follows: Milk - maximum 
residue of 0.069 ppm; liver - 0.363 ppm; kidney 0.249 ppm and muscle 
0.017 ppm. The metabolic pathway is similar to that of plants involving 
hydroxylation of the phenyl and pyrimidine rings as well as 
hydroxylation of the methyl

[[Page 7553]]

substituents. Further metabolic reactions occur including cleavage of 
the phenyl ring to produce substituted pyrimidines. The major 
metabolite was AE C614276 (46% of the kidney residues, 63% of the milk 
residues) resulting from hydroxylation of the phenyl ring. 
Hydroxylation of the pyrimidinyl ring of pyrimethanil resulted in 
formation of minor amounts of AE C614277. Hydroxylation of the methyl 
groups of pyrimethanil resulted in formation of minor amounts of AE 
C614278. Hydroxylation of the methyl groups of AE C614276 resulted in 
formation of minor amounts of AE C614800.
    7. Metabolite toxicology. The primary residue of concern in both 
crop and animal commodities is pyrimethanil. In the animal metabolism, 
since major metabolites are produced following the oral administration 
of pyrimethanil, toxicology data for metabolites are completely 
supported by data obtained for pyrimethanil.
    8. Endocrine disruption. Chronic, life span, and multi-generational 
bioassays in mammals and acute and subchronic studies on aquatic 
organisms and wildlife did not reveal endocrine effects. Any endocrine 
related effects would have been detected in this definitive array of 
required tests. The probability of any such effect due to agricultural 
uses of pyrimethanil is negligible.

C. Aggregate Exposure

    1. Dietary exposure. Tolerances are proposed under 40 CFR part 180 
for pyrimethanil in or on citrus fruits and pome fruits following 
postharvest application. An import tolerance for wine grapes has been 
approved by the EPA. A petition for registration of pyrimethanil on 
bananas is pending at EPA. In March 2002, registration applications and 
tolerance petitions were filed for tree nuts, bulb vegetables, grapes, 
stone fruits (except cherries), pome fruit (preharvest application), 
tuberous and corm vegetables, strawberries, and tomatoes. There are no 
residential uses proposed for pyrimethanil. Therefore, potential human 
risk scenarios cover aggregate exposure from food residues and drinking 
water.
    i. Food. Refined estimates of acute dietary exposure from potential 
pyrimethanil residues with the addition of postharvest uses on citrus 
and pome fruits are all well under 100% of the acute reference dose 
(RfD) at the 99.9th percentile. The most highly exposed sub population 
of non-nursing infants utilizes 13.35% of the RfD, while the U.S. 
population utilizes 6.1%. These potential dietary exposures were 
estimated in a Tier 3 Monte Carlo risk assessment using the Dietary 
Exposure Evaluation Model (DEEM) software (Novigen 2001). The 1994-96, 
1998 Continuing Surveys of Food Intake by Individuals (CSFII) 
consumption data from USDA was used which includes the Supplemental 
Children's Survey (1998). Residue values included in the assessment 
were distributions of the field trail values incorporating percent crop 
treated (PCT) as zeroes for all non-blended and partially blended 
items. Blended items were included as the average residue and adjusted 
for PCT. These PCT values are the anticipated market share of 
pyrimethanil for the crops at market maturity (5 years). Concentration 
factors derived from processing studies were included where 
appropriate. Secondary residues for meat and milk were included in the 
assessment. These were calculated using theoretical dietary burdens 
from sensible diets for beef and dairy cattle and tissue to feed ratios 
from the ruminant feeding study.
    Refined chronic dietary exposure estimates resulting from the 
proposed uses of pyrimethanil are well within acceptable limits for all 
population subgroups examined. The most highly exposed group of non-
nursing infants utilized 0.9% of the reference dose with the U.S. 
population utilizing 0.2% of the reference dose. A Tier 3 chronic 
analysis was done using the DEEM software, (Novigen 2001). The 1994-96, 
1998 CSFII consumption data from USDA were used. Average anticipated 
residue values were calculated from the appropriate field trial studies 
conducted for pyrimethanil. The average residue values were adjusted by 
the projected PCT at product maturity. Concentration factors derived 
from processing studies were included where appropriate. Secondary 
residues were calculated using theoretical dietary burdens derived from 
sensible diets for beef and dairy cattle and tissue to feed ratios from 
the ruminant feeding study.
    ii. Drinking water. EPA's Standard Operating Procedure (SOP) for 
Drinking Water Exposure and Risk Assessments was followed to perform 
the Tier One drinking water assessment. This SOP uses a variety of 
tools to conduct drinking water assessments, including water models 
such as Screening Concentrations in Ground Water (SCI-GROW), First 
Index Reservoir Screening Tool (FIRST), Pesticide Root Zone Model/
Exposure Analysis Modeling System (PRZMS/EXAMS), and monitoring data. 
If monitoring data are not available then the models are used to 
predict potential residues in surface and ground water and the highest 
levels (whether ground or surface) are assumed to be the drinking water 
residue. In the case of pyrimethanil, monitoring data are not 
available. SCI-GROW and FIRST were used to estimate a drinking water 
residue. Calculation of the Drinking Water Estimated Concentration 
(DWEC) for surface water for the worst case pyrimethnail use scenario 
results in a acute DWEC of 122 ppb and a chronic DWEC of 37 ppb. 
Drinking Water Levels of Comparison (DWLOCs) calculated based on the 
acute and chronic risk assessments described above are many fold higher 
than these conservative DWECs. The adult acute and chronic DWLOCs are 
9,860 ppb and 5,936 ppb respectively. Children's acute and chronic 
DWLOCs are 2,641ppb and 1,686 ppb respectively.
    2. Non-dietary exposure. Pyrimethanil products are not labeled for 
residential uses (food or non-food), thereby eliminating the potential 
for residential exposure or non-occupational exposure.

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that, when considering whether to 
establish, modify, or revoke a tolerance, the Agency consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' There are no available data to 
determine whether pyrimethanil has a common mechanism of toxicity with 
other substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
pyrimethanil does not appear to form a toxic metabolite produced by 
other substances. For the purposes of the tolerance petition, it has 
been assumed that pyrimethanil does not have a common mechanism of 
toxicity with other substances.

E. Safety Determination

    1. U.S. population. Using the assumptions and data described above, 
based on the completeness and reliability of the toxicity data, it is 
concluded that dietary risk from the proposed uses of pyrimethanil are 
acceptable for all populations examined. Chronic exposure for the U.S. 
population utilizes 0.2% (0.000392 mg/kg bw/day) of the chronic 
reference dose. Acute exposure for the U.S. population utilizes 6.1% 
(0.018287 mg/kg bw/day) of the acute reference dose. The most highly 
exposed population of non-nursing infants utilizes only 0.9% of the 
chronic reference dose and

[[Page 7554]]

13.35% of the acute reference dose. The actual exposures are likely to 
be much less as more realistic data and models are developed. EPA 
generally has no concern for exposures below 100% of the RfD (acute or 
chronic), because the RfD represents the level at or below which 
exposure will not pose appreciable risk to human health. DWLOC for 
adults both acute (9,860 ppb) and chronic (5,936 ppb) are several 
orders of magnitude above the conservative DWEC for acute (122 ppb) and 
chronic (37 ppb) worst case scenarios. Therefore, there is a reasonable 
certainty that no harm will occur to the U.S. population from aggregate 
exposure (food and drinking water) to residues of pyrimethanil.
    2. Infants and children. The relevant toxicity studies as discussed 
in the toxicology section above show no extra sensitivity of infants 
and children to pyrimethanil, therefore, the FQPA safety factor can be 
removed. Using the assumptions and data described in the exposure 
section above, it is concluded that dietary risk from the proposed uses 
of pyrimethanil are acceptable for all infant and children sub-
populations examined. The most highly exposed sub-population was non-
nursing infants for both the chronic and acute analyses. The sub-
population non-nursing infants utilizes 0.9% (0.001563 mg/kg bw/day) of 
the chronic reference dose and 13.35% (0.040040 mg/kg bw/day) of the 
acute reference dose. All other infant and children populations have 
less exposure. The chronic and acute drinking water levels of concern 
for children (1,684 ppb and 2,600 ppb respectively) are well above the 
conservative drinking water estimated concentrations for chronic and 
acute scenarios. The chronic DWEC is 37 ppb and the acute DWEC is 122 
ppb. Therefore, there is a reasonable certainty that no harm will occur 
to infants and children from aggregate exposure to residues of 
pyrimethanil.

F. International Tolerances

    Maximum Residue Limits for pyrimethanil have not been established 
by the Codex Alimentarius Commission.
[FR Doc. 03-3695 Filed 2-13-03; 8:45 am]
BILLING CODE 6560-50-S