iprovalicarb Pesticide Petition Filing 9/00
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[Federal Register: September 22, 2000 (Volume 65, Number 185)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing Pesticide Petitions to Establish Tolerances for
Certain Pesticide Chemicals in or on Food
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by docket control number PF-961, must be
received on or before October 23, 2000.
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-961 in the subject line on the first page of your
FOR FURTHER INFORMATION CONTACT: By mail: Mary L. Waller, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (703) 308-9354; e-mail address: firstname.lastname@example.org.
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:
Categories NAICS codes potentially
Industry 111............... Crop production
.............................. 112............... Animal production
311 Food manufacturing
.............................. 32532............. Pesticide
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
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
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'' 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-961. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-961 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to:``email@example.com'', 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-961. 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
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
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
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
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 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
Dated: September 6, 2000.
Director, Registration Division, Office of Pesticide Programs.
II. Tomen Agro, Inc.
EPA has received a pesticide petition 9E06020 from the TM-210 (SZX
0722) Fungicide Task Force, comprised of Tomen Agro, Inc., 100 First
Street, Suite 1700, San Francisco, CA 94105, and Bayer Corporation,
8400 Hawthorn Road, Kansas City, MO 64120 proposing, pursuant to
section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR part
180 by establishing a tolerance for residues of iprovalicarb: (1S)-2-
methyl-1-[[[1-(4-methylphenyl)ethyl] amino] carbonyl] propyl] carbamic
acid 1-methylethyl ester in or on the raw agricultural commodity
imported grapes at 2 ppm and on the processed commodity imported
raisins 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
A. Residue Chemistry
1. Plant metabolism. The metabolism of iprovalicarb was
investigated in grapes, potatoes and tomatoes, and the metabolic
pathway is similar in the three crops. The rate of degradation on
plants is quite low, and the parent compound was always the major
component, with quantitatively relevant metabolites formed only in
potatoes. The metabolites observed in the potato were also observed in
the rat. Therefore, iprovalicarb is the only residue of concern. Plant
metabolism proceeds along three pathways:
i. Hydroxylation/glycosylation of parent at the 4-methyl group on
the phenyl ring, followed by further conjugations.
ii. Cleavage of the amide group between the L-valine and p-methyl-
iii. Hydroxylation/glycosylation of parent at the phenyl-ring 3
2. Analytical method. The proposed enforcement residue analytical
method is an HPLC method with ultra violet (UV) detection. The limit of
determination is 0.05 ppm in grapes, wine, juice and raisins, and the
mean recovery is 94%. DFG multiresidue method S19 has been evaluated as
analytical method for the determination of iprovalicarb residues in
grapes and other commodities. The limit of quantitation (LOQ) of
iprovalicarb in/on grapes is 0.01 ppm. Recoveries in spiked samples
ranged from 79% to 119%, with the standard deviations ranging from 0.06
ppm to 0.16 ppm. DFG multiresidue method S 19 (with modified
extraction) was successfully validated as an analytical method for the
determination of residues in/on grapes and other commodities.
3. Magnitude of residues. The maximum measured residue resulting
from treatment according to the proposed labels and representative
viticulture practices was 1.40 ppm in grapes and 2.55 ppm in raisins.
Measured residues in juice and wine were lower than the measured
residues in grapes.
B. Toxicological Profile
1. Acute toxicity. The acute oral LD50 in Wistar rats is
greater than 5,000 mg/kg body weight.
2. Genotoxicty. Iprovalicarb was non-mutagenic or non-clastogenic
in six of six assays:
i. Salmonella/microsome test, with and without S9 mix.
ii. V79-HPRT forward mutation assay, with and without metabolic
iii. CHO cell assay, with and without metabolic activation in
iv. In vitro rat primary hepatocyte unscheduled DNA synthesis UDS
v. Mouse micronucleus test.
vi. \32\P-postlabelling assay of the uterus and urinary bladder of
rats. Based upon these studies, iprovalicarb is non-mutagenic and non-
genotoxic both in vitro and in vivo.
3. Reproductive and developmental toxicity-- i. In a 2-generation
reproduction study in Wistar rats receiving 0, 100, 2,000 or 20,000 ppm
iprovalicarb in the diet, the parental NOAEL was 2,000 ppm based upon
reduced body weight development and increased liver weight at 20,000
ppm. The reproductive toxicity NOAEL was 2,000 ppm (100 mg/kg bwt/day)
based upon delayed body weight development in F1 and F2 pups during
lactation, slightly reduced mean litter weight at birth and at day 28,
increased relative liver weights and a reduced lactation index in F1
pups at 20,000 ppm.
ii. In a developmental toxicity study in Wistar rats, the maternal
and developmental NOAEL was 1,000 mg/kg bwt/day (limit dose for study
and highest dose tested (LD/HDT)).
iii. In a developmental toxicity study in Russian rabbits, the
maternal and developmental NOAEL was 1,000 mg/kg bwt/day LD/HDT.
4. Subchronic toxicity-- i. In the 13-week feeding study in Wistar
rats, the doses were 0, 1,250, 5,000 and 20,000 ppm. The NOAEL was
5,000 ppm (372.7 mg/kg bwt/day in males; 561.4 mg/kg bwt/day in
females) based upon reduced body weight gain, increased feed intake
(females only), changed clinical chemistry parameters (including liver
enzyme induction) and elevated absolute liver weights at 20,000 ppm.)
ii. In the 13-week feeding study in B6C3F1 mice, the doses were 0,
280, 1,400, 7,000, and 14,000 ppm in the diet. The NOAEL in males was
1,400 ppm (325.0 mg/kg bwt/day) based upon elevated water intake and a
changed hematological parameter (MCV) at 7,000 ppm (1,724.6 mg/kg bwt/
day). The NOAEL in females was 7,000 ppm (3,599.5 mg/kg bwt/day) based
upon elevated water intake, changed parameter in the red blood count,
and increased liver weights at 14,000 ppm (6,869.0 mg/kg bwt/day).
iii. In the 13-week feeding study in Beagle dogs, the doses were 0,
250, 2,500 and 50,000 ppm iprovalicarb in the diet (0, 9.1, 62.5 and
1,250 mg/kg bwt/day). The NOAEL was 250 ppm (9.1 mg/kg bwt/day) for
males and females based upon liver effects (increased activity of
alkaline phosphatase and hepatocellular hypertrophy in one animal) at
5. Chronic toxicity-- i. Wistar rats received 0, 500, 5,000 or
20,000 ppm iprovalicarb in the diet for 24 months. The NOAEL in females
was 500 ppm (31.7 mg/kg bwt/day) based upon decreased body weights,
changed clinical chemistry parameters (increased cholesterol
concentration and decreased total bilirubin concentration), increased
relative liver weights and histopathological findings (increased
incidences of hepatocellular hypertrophy) at 5,000 ppm. The NOAEL in
males was 5,000 ppm (262.5 mg/kg bwt/day) based upon decreased body
weights, increased APh-activity, and slight increase of tumor
incidences at 20,000 ppm. The histopathological NOAEL was 5,000 ppm
(262.5 mg/kg bwt/day in males and 326.3 mg/kg bwt/day in females).
To further evaluate the results of the chronic feeding study in
a. A special 2-day/13-week metabolism study was conducted in Wistar
rats at 500 ppm and 20,000 ppm in the diet. Some quantitative
differences (shift in diastereomer ratio in favor of S,R; relative
higher amounts of p-methyl-phenethylamine, higher proportions of
unchanged parent compound in feces) after administration of 20,000 ppm
compared to the low dose of 500 ppm were observed.
b. Plasma concentrations were investigated in a special 12-week
feeding study in HsdCpb:WU rats. The plasma concentrations of parent
compound increased to a measurable level at a dose of 20,000 ppm in the
diet. The concentration of parent in plasma was very low due to
extensive metabolism during the first pass in the liver. At a dose of
20,000 ppm, the iprovalicarb-carboxylic acid (S,R) diastereomer
increased in relation to the corresponding (S,S) diastereomer when
compared to the low dose.
c. A bioavailability study was conducted in Wistar rats.
Administration of thermodynamically stable and thermodynamically labile
modifications of iprovalicarb to Wistar rats at concentrations of 2,000
and 20,000 ppm for 2 weeks resulted in no toxicologically relevant
differences based upon the concentration of the main metabolite,
iprovalicarb-carboxylic acid, in plasma. Therefore, the
thermodynamically stable and thermodynamically labile modifications of
iprovalicarb demonstrated no significant differences in intestinal
absorption and bioavailability.
d. An in vivo \32\P-postlabelling assay of uterus and urinary
bladder epithelium was conducted in female Wistar rats dosed at 10,000
or 20,000 ppm in the diet for 7 days. Iprovalicarb was determined to be
inactive in the assay.
e. A liver foci test was conducted in male Bor: WISW (SPF-Cpb) rats
that were dosed by oral gavage with 0 or 1,000 mg/kg iprovalicarb for
28 days, followed by a promotion treatment with phenobarbital over a
period of 8 weeks. Iprovalicarb was determined to not have a tumor
Based upon the 24-month chronic feeding study in rats, plus the
special studies, a dose of 20,000 ppm exerts a continuous stress on the
xenobiotic metabolizing capacity of the liver that is not observed at
lower doses. Moreover, iprovalicarb has no genotoxic potential and no
tumor initiation potential. Therefore, iprovalicarb is not carcinogenic
ii. B6C3F1 mice received 0, 280, 1,400, or 7,000 ppm
iprovalicarb in the diet for up to 105 weeks. The NOAEL in males was
1,400 ppm (283.4 mg/kg bwt/day) based upon slightly higher food and
water intake and slightly lower body weights at 7,000 ppm (1,566.8 mg/
kg bwt/day). The NOAEL in females was 7,000 ppm (2,544 mg/kg bwt/day),
the HDT. No oncogenic potential was observed in mice.
iii. Beagle dogs received 0, 80, 800 or 8,000 ppm iprovalicarb in
the diet for 53 weeks. The NOAEL was 80 ppm (2.62
mg/kg bwt/day in males and 2.68 mg/kg bwt/day in females) based upon
liver effects (increased serum activities of ALT and APh, cellular
hypertrophy and periportal fatty change) at 800 ppm (24.69 mg/kg bwt/
day in males and 28.10 mg/kg bwt/day in females). A follow-up study was
conducted in Beagle dogs that received 0, 10, 20, 40, or 80 ppm
iprovalicarb in their diet for 28 days. The NOAEL for microsomal liver
enzyme induction was determined to be 20 ppm (0.77 mg/kg bwt/day).
Microsomal liver enzyme induction was observed at the higher doses, and
reversal of induction was observed within a 4-week recovery period in
the 80 ppm dose group (2.93 mg/kg bwt/day).
6. Animal metabolism. Iprovalicarb is readily absorbed, and greater
than 97.8% of the total radioactivity was eliminated in urine and feces
within 48 hours of dosing. Iprovalicarb is extensively metabolized in
the rat. The primary metabolites (>58% of the administered dose) were
diastereomers of iprovalicarb-carboxylic acid. Eight minor metabolites,
each representing less than 2% of the administered dose, were
7. Metabolite toxicology. The toxicity of p-methyl-phenethylamine,
a rat, plant and soil metabolite, was investigated in 2 studies:
i. The acute oral LD 50 in Wistar rats was determined to
be in the range of 300 to 500 mg/kg bw.
ii. No mutagenic activity was observed in the Salmonella/microsome
test. p-Methyl-phenethylamine was found at concentrations of 0.2% and
has been determined to not be toxicologically significant.
8. Endocrine disruption. No endocrine disruption potential was
observed in the 2-generation reproduction study, developmental toxicity
studies, subchronic feeding studies, and chronic feeding studies.
C. Aggregate Exposure
1. Dietary exposure. There are no registered uses of iprovalicarb
in the U.S., and no registrations or other tolerances are pending.
Dietary exposure to iprovalicarb in the U.S. is limited to residues in/
on imported grapes, grape juice, wine, and raisins.
i. Food. The anticipated residue in/on fresh grapes based upon the
field studies is 0.50 ppm, and 35.71% of the fresh grapes consumed in
the U.S. are imported. The anticipated residue in grape juice based
upon the field and processing studies is 0.050 ppm, and 37.05% of the
grape juice consumed in the U.S. is imported. The anticipated residue
in wine based upon the field and processing studies is 0.32 ppm, and
17.38% of the wine consumed in the U.S. is imported. The anticipated
residue in raisins based upon the field and processing studies is 0.91
ppm, and 8.165% of the raisins consumed in the U.S. are imported.
Assuming 100% of the imported commodities are treated and have the
average residue resulting from the maximum international use of
iprovalicarb, the total anticipated residue is 0.000021 mg/kg bwt/day
in the U.S. diet and 0.000056 mg/kg bwt/day for the most exposed sub-
population, children 1 to 6 years old.
ii. Drinking water. Iprovalicarb is not registered for use in the
United States. Therefore, there is no exposure to iprovalicarb through
drinking water in the United States.
2. Non-dietary exposure. Iprovalicarb is not used in the United
States. Therefore, there is no non-dietary exposure to iprovalicarb in
the United States.
D. Cumulative Effects
Iprovalicarb is a member of a new class of chemistry and does not
have a mode of action that is common with other registered pesticides.
Therefore, there are no cumulative effects.
E. Safety Determination
1. U.S. population. The reference dose (RfD) is 0.03 mg/kg bwt/day.
Based upon anticipated residues in imported commodities and assuming
100% of the imported commodities contain residue resulting from the
proposed European use of iprovalicarb, the estimated chronic dietary
margin of exposure of the U.S. population is 0.07% of the RfD.
Therefore, there is a reasonable certainty of no harm to the U.S.
population resulting from exposure to iprovalicarb residues in/on
2. Infants and children. The population subgroup with the maximum
estimated dietary exposure is children age 1 to 6 years old. For this
subgroup, and using the same assumptions as listed for the U.S.
population, the estimated chronic dietary margin of exposure is 0.18%
of the RfD. Therefore, there is a reasonable certainty of no harm to
infants and children in the U.S. resulting from exposure to
iprovalicarb residues in/on imported commodities.
F. International Tolerances
The following maximum residue levels are pending in the European
Union: 2.0 mg/kg in/on grapes; 0.5 mg/kg in animal fat; 0.05 mg/kg in
potatoes, animal meat, animal edible offal and eggs; and 0.01 mg/kg in
[FR Doc. 00-24436 Filed 9-21-00; 8:45 a.m.]
BILLING CODE 6560-50-S