[Federal Register Volume 65, Number 185 (Friday, September 22, 2000)]
[Notices]
[Pages 57338-57344]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-24436]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-961; FRL-6737-8]
Notice of Filing Pesticide Petitions to Establish Tolerances for
Certain Pesticide Chemicals in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
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
response.
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: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS codes potentially
affected entities
------------------------------------------------------------------------
Industry 111............... Crop production
.............................. 112............... Animal production
311 Food manufacturing
.............................. 32532............. Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and
[[Page 57339]]
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 protected]'', or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-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
CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in section 408(d)(2); however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: September 6, 2000.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
I. BASF Corporation Agricultural Products
7E4885
EPA has received a pesticide petition 7E4885 from BASF Corporation,
Agricultural Products, P.O. Box 13528, Research Triangle Park, NC 27709
proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d),
to amend 40 CFR part 180 by establishing tolerances for residues of
epoxiconazole, (2RS,3SR)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-(1H-
1,2,4-triazol-1-yl)methyl oxirane in or on bananas at 0.5 parts per
million (ppm) and in or on banana pulp at 0.2 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 metabolism in bananas was investigated
using 14C labeled epoxiconazole. On average 70% of the total residue
could be identified as parent. This corresponds to approximately 80% of
the residue extractable from the peel and
[[Page 57340]]
approximately 90% of the residue extractable from the edible portion,
pulp. Based on this result, a parent only method was developed to
analyze residues from the magnitude of the residue trials.
Under worst case practices (unbagged bananas) residue in the whole
fruit ranged from the limit of quantitation (LOQ) (0.025 milligrams/
kilograms (mg/kg) to a maximum of 0.41 mg/kg. Banana pulp residues from
bagged bananas ranged from < the LOQ (0.025 mg/kg) to 0.17 mg/kg and
averaged 0.036 mg/kg. The average value was calculated by assuming all
values below the LOQ were equal to one half the LOQ or 0.0125 mg/kg.
2. Analytical method. The method of analysis includes extraction,
liquid/liquid partition, column clean-up quantitation by gas
chromatography/electron capture detection. Forty-three whole banana
samples were fortified with epoxiconazole at levels ranging from 0.025
mg/kg to 0.5 mg/kg. Recovery averaged 89.3% +/- 12.4%. Forty-one banana
pulp samples were fortified with epoxiconazole at levels ranging from
0.025 mg/kg to 0.25 mg/kg. Recovery averaged 88.8% +/- 9.2.%.
3. Magnitude of residues. Fifteen crop residue trials were
conducted in the banana growing regions of Mexico, South and Central
America including three sites in Colombia, four sites in Costa Rica,
four sites in Ecuador, one site in Guataemala, two sites in Hondouras,
and one site in Mexico. Four sequential applications were made at the
90 g/ha, slightly higher than the maximum use rate 75 g/ha to both
bagged and unbagged bananas at each site. Fruit from both the bagged
and unbagged treatments were harvested at 0 days following the last
application.
Whole fruit (peel and pulp) samples and pulp only samples were
analyzed from all treatments at all sites. Under typical practices
(bagged bananas) residue in the whole fruit ranged from < the LOQ
(0.025 mg/kg) to a maximum of 0.082 mg/kg. Banana pulp residues from
bagged bananas ranged from < the LOQ (0.025 mg/kg) to 0.05 mg/kg and
averaged 0.013 mg/kg. The average value was calculated by assuming all
values below the LOQ were equal to one half the LOQ or 0.0125 mg/kg.
B. Toxicological Profile
1. Acute toxicity. The acute toxicity studies place technical
epoxiconazole in acute toxicity category III for acute oral, dermal,
and inhalation; and in acute toxicity category IV for skin and eye
irritation; and the technical material is not a skin sensitizer.
2. Genotoxicty. A modified Ames test (3 studies; point mutation):
Negative; E. coli reverse mutation assay (1 study; point mutation):
Negative; in vitro chinese hampster ovary/hypoxanthine guanine
phophoribosyl transferase (CHO/HGPRT) mammalian cell mutation assay (1
study; point mutation): Negative; in vitro Cytogentics--CHO cells (1
study; chromosome aberrations): Negative; mouse micronucleus assay (1
study; chromosome aberrations): Negative; in vitro unscheduled DNA
synthesis (UDS) test using rat hepatocytes (1 study; DNA damage and
repair): Negative; in vivo DNA binding in rats and mice (1 study; DNA
binding): Negative.
3. Reproductive and developmental toxicity. i. A developmental
study via oral gavage in rabbits resulted in dosages of 0, 20, 50, and
80 mg/kg/day highest dose tested (HDT) with a developmental toxicity no
observed adverse effect level (NOAEL) of 80 mg/kg/day and a maternal
toxicity of 20 mg/kg/day based on the following:
a. Decreased body weight (bwt), food consumption, uterus weight,
and increased resorption rate and post-implantation losses in the 80
mg/kg/day dose level.
b. Slight decreases of body weight and food consumption was seen in
the 50 mg/kg/day dose level.
c. No substance-related findings were observed in any fetus at all
dose levels.
ii. A developmental study was conducted via oral gavage in rats
resulted in dosages of 0, 5, 15, and 45 mg/kg/day HDT with a
developmental toxicity NOAEL of 5 mg/kg/day and a maternal toxicity of
5 mg/kg/day based on the following:
a. Signs of maternal toxicity, in the form of decreased body
weights, food consumption, and increased placental weights observed at
the highest dose tested.
b. Maternal animals in the 45 mg/kg/day showed an increase in the
number of late resorptions as compared to controls.
c. Increased placental weights in the 15 mg/kg/day dose level.
d. A significant number of fetuses with skeletal variations
(especially rudimentary cervical and/or accessory 14th rib(s)) in the
high dose group tested were observed. However, no malformations were
observed in any pups in this study.
iii. In a second developmental study in rats via dermal exposure
for 6 hours/day on intact skin with dosages of 0, 100, 400, and 1,000
mg/kg/day (HDT) with a development toxicity NOAEL of 400 mg/kg/day and
a maternal toxicity of 400 mg/kg/day based on increased placental
weights and a slight increase in the number of fetuses with skeletal
variations was observed at the highest dose tested.
iv. A combination of two multi-generation rat reproduction studies
(study A dose levels were 0, 3.0, 30, and 145 mg/kg/day and study B
dose levels were 0, 0.9, 2.3, and 23 mg/kg/day). Study A was
discontinued after extreme systemic toxicity was observed at 145 mg/kg/
day. The following discussion summarizes the results from both studies.
A reproductive NOAEL of 2.3 mg/kg/day and with a parental NOAEL of 2.3
mg/kg/day were determined based on:
a. Dose levels 23 mg/kg/day resulted in maternal death,
clinical signs, clinical chemical effects, liver effects (i.e.,
damage), histopathology, and limited number of pregnancy and pups with
reduced body weights which increased in severity to the upper dose
levels, this also indicated that doses above 23 mg/kg/day were
considered to be beyond the maximum tolerated dose (MTD) for pregnant
rats.
b. Questionable effects were observed in the 3.0 mg/kg/day dose
level.
c. No treatment-related clinical signs, body weight changes,
parameters of fertility and gestation, or macro- or histopathological
changes were observed for the parental F0, F1, and F2 at dose levels
equal to and below 2.3 mg/kg/day.
4. Chronic toxicity. i. A series of two 1-year dog studies (study A
dose levels were 0, 1.6, 15, and 49 mg/kg/day for which a NOAEL was
established in females, and study B dose levels were 0, 0.3, 0.6, 0.9,
and 1.1 mg/kg/day to determine a NOAEL in males. The NOAEL was
established as 1.1 mg/kg/day based on the following effects:
a. Mortality in the 49.0 mg/kg/day dose group with severe clinical
signs and evidence of liver damage in those dogs which were sacrificed
for humane reasons.
b. Hematological examinations demonstrated effects in either male
or female dogs at dose levels 1.6 mg/kg/day.
c. Clinical chemical effects of varying types were seen in either
male and female dogs at dose levels 15.0 mg/kg/day.
d. No effects were observed in male animals at levels of
1.1 or female dogs at dose levels of 1.6 mg/kg/
day.
ii. Separate chronic feeding and oncogenicity studies in rats were
performed to assess the chronic toxicity and oncogenic potential of
epoxiconazole. The chronic toxicity study was conducted at dose levels
of 0 and approximately 2, 8, 38, and 78 mg/
[[Page 57341]]
kg/day. The oncogenicity study was conducted at dose levels of 0 and
approximately 2, 7, 40, and 80 mg/kg/day.
The results from the 2 studies are combined and summarized as
follows:
The NOAEL was determined to be 2.0 mg/kg/day based on the following
effects:
a. Decreases in body weights and food consumption were observed in
both male and female rats at dose levels 38 mg/kg/day dose
groups with a very slight progression of severity to the upper level.
b. Varying clinical chemical and hematological effects were
observed in either male and/or female rats at dose levels
8mg/kg/day with a very slight progression of severity to the
upper levels.
c. Increased absolute and relative liver weights were seen for
males and/or females at dose levels 38 mg/kg/day.
d. Microscopic findings were observed in the liver for male and/or
female rats at dose levels 38 mg/kg/day, in female adrenals
at the highest dose test, and in the ovaries at dose levels
38 mg/kg/day.
e. An increased incidence of neoplasms occurred at dose levels
greater than the MTD of 8 mg/kg/day in the females for the adrenals and
ovaries. No increased number of neoplasms were seen in male rats due to
the fact that the MTD in male rats was the HDT as opposed to the female
rat which was significantly lower. Taking into account the results
obtained in these studies, it is concluded that the reduction in body
weight gain at 38 and 78 mg/kg/day levels met the criteria for a
maximum tolerated dose. It has been determined that effects observed at
the 10 mg/kg/day dose level achieved or approximated the MTD.
The effects on the ovaries were as follows:
Decreasing aromatase enzyme activity which, is a response
from converting both testosterone and adrostendione (male sex-steroids)
into female sex steroids (e.g., estradiol). This action would result in
decreased estradiol (i.e., estrogen and prolactin) and increased
androgen levels (i.e., testosterone). As a consequence of reduced
estradiol levels, measured LH and FSH concentrations are slightly
altered.
The increased incidences of neoplasms in the ovaries are
considered to be the result of a continuous cell proliferation by these
stimulating hormones of the pituitary-gonadal axis (LH and FSH).
The effects on the adrenals were as follows:
Decreasing adrenal-cortical enzyme activity. This action
would result in decreased adrenal hormones such as corticosterone
levels. As a consequence of reduced corticosterone levels, pronounced
ACTH concentrations are found.
The increased incidences of neoplasms in the adrenals are
considered to be the result of a continuous cell proliferation by these
stimulating hormones of the pituitary-adrenal axis (ACTH).
For risk assessment purposes the results obtained at 38 and 78 mg/
kg/day dose levels should not be used because an extrapolation to lower
dose levels is not justified due to the unphysiological conditions in
animals treated at dose levels near or at the MTD. Under these
circumstances neoplastic and non-neoplastic mechanisms may be induced
which will not occur at dose levels in which the animals are able to
maintain their normal physiological homeostasis.
The increases in tumor incidence in endocrine organs due to
hormonal imbalance are considered to have a threshold value, because at
dose levels which do not induce cellular alterations via hormone levels
in these organs, a subsequent proliferation and hence tumor formation
cannot occur.
iii. An oncogenicity study in mice fed dosages of 0, 0.17, 0.81,
35.3, and 70.4 (males) or 205.4 (females) mg/kg/day with a NOAEL of
0.81 mg/kg/day for male and female mice based on the following effects:
a. Highly significant decreased body weights were observed in both
male and/or female mice at the mid-high and highest dose tested.
b. Clinical sign of deteriorated state of general health were
observed in high dose female mice.
c. Increased liver weights and microscopic findings were observed
for male and female mice at dose the highest dose tested.
d. An increased incidence of neoplasms occurred at dose levels
(70.4/205.4 mg/kg/day) greater than the MTD of 35.3 mg/kg/day in the
male and female mice for the liver.
Taking into account the results obtained in this study, the
following conclusions are drawn: The severe reduction in body weight
and body weight gain at dose levels 35.3 mg/kg/day indicates
that these dose levels exceeded the criteria for a MTD. It has been
determined that liver tumor effects observed at the 70.4 and 205.4 mg/
kg/day dose levels clearly exceeded the MTD. The liver necrosis
observed in the male and female mice, further support the finding that
the MTD was exceeded in the 70.4 and 205.4 mg/kg/day dose levels.
A series of mechanistic studies were performed to elucidate and
define the liver promotion properties of epoxiconazole. The following
conclusions can be drawn from the data:
The material is a potent inducer of the hepatic cytocrome
P-450 enzyme system, similar to the drug-phenobarbital.
The material induced proliferation of the smooth
endoplasmatic reticulum in the liver centrolobular hypertrophy and
induction of phase 1 and phase 2 enzymes of the xenobiotic metabolism.
The material was determined not to be an initiator of the
carcinogenic process, but a promoter of initiated cells in the
tumorgenesis as has been similarly shown with drug--phenobarbital.
As stated above, for risk assessment purposes the results obtained
at 70.4 and 205.4 mg/kg/day dose levels should not be used because an
extrapolation to lower dose levels is not justified due to the
unphysiological conditions in animals treated at dose levels exceeding
the MTD. Under these circumstances, neoplastic and non-neoplastic
mechanisms may be induced which will not occur at dose levels in which
the animals are able to maintain their normal physiological
homeostasis.
5. Animal metabolism. Since there are no animal feed items
associated with bananas, there is no likelihood of secondary residues
in meat, milk, poultry or eggs. Therefore, data concerning metabolism
in livestock is not required.
6. Metabolite toxicology. Residues of the parent molecule,
epoxiconazole are the only residues of concern.
7. Endocrine disruption. A series of mechanistic studies were
performed to elucidate and define the aromatase enzyme inhibition
properties of epoxiconazole. The following conclusions can be drawn
from the in vivo data: The effects on the ovaries are assessed to be
the result of the following:
Decreasing aromatase enzyme activity which is responsible
for converting both testosterone and adrostendione (male sex-steroids)
into female sex steroids (e.g., estradiol). This action would result in
decreased estradiol (i.e., estrogen) and increased androgen. As a
consequence of reduced estradiol levels, measured LH and FSH
concentrations are slightly altered.
The increased incidences of neoplasms in the ovaries are
considered to be the result of a continuous cell proliferation by these
stimulating
[[Page 57342]]
hormones of the regulating hormones of the pituitary-gonadal axis (LH
and FSH).
The changes adrenals are assessed to be the result of the
following:
Decreasing adrenal-cortical enzyme activity. This action
would result in decreased adrenal hormones such as corticosterone
levels. As a consequence of reduced corticosterone levels, pronounce
ACTH concentrations are found.
The increased incidences of neoplasms in the adrenals are
considered to be the result of a continuos cell proliferation by these
stimulating hormones of the pituitary-adrenal axis ACTH.
C. Aggregate Exposure
1. Dietary exposure. For the purpose of assessing the potential
chronic dietary exposure, BASF has estimated aggregate exposure based
on theoretical maximum residue contribution (TMRC) from the tolerance
of epoxiconazole in or on bananas at 0.2 ppm the maximum residue found
in banana pulp. The TMRC is a ``worst case'' estimate of dietary
exposure since it is assumed that 100% of all the crops for which the
tolerances are established are treated and that pesticide residues are
always found at tolerance levels. Based on the expected reference dose
(RfD) of 0.011 mg/kg/day (from the NOAEL determined in the chronic dog
study and a 100-fold safety factor) and the tolerance level residue
chronic dietary exposure of the general population is less than 1% of
the RfD.
i. Food. This is a new chemical and there are no other food uses
except for the proposed use on bananas.
ii. Drinking water. No exposure is expected from drinking water as
this is an import tolerance and no U.S. registrations are expected.
2. Non-dietary exposure. There are no non-occupational sources of
exposure to epoxiconazole for the general population due to fact the
action being requested is to establish a tolerance for import purposes
only.
D. Cumulative Effects
BASF has considered the potential for cumulative effects of
epoxiconazole and other substances which may have a common mechanism of
toxicity. BASF is aware of other triazole fungicides but has no
reliable toxicology information concerning those other materials which
would allow a determination regarding similarity of toxicity
mechanisms. Therefore, BASF has considered only the potential risks of
epoxiconazole in its exposure assessment.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above,
based on the completeness and the reliability of the toxicity data,
BASF has estimated that aggregate exposure to epoxiconazole will
utilize less than 1% of the RfD for the U.S. population. EPA generally
has no concern for exposure below 100% of the RfD. Therefore, based on
the completeness and reliability of the toxicity data, and the exposure
assessment discussed above, BASF concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to residues
of epoxiconazole, including all anticipated dietary exposure and all
other non-occupational exposures.
2. Infants and children. The findings in the rat and rabbit are
most likely as a result of excessive maternal toxicity, treatment of
pregnant rats and rabbits with epoxiconazole induced embryotoxic
effects which manifested themselves in the form of early resorptions
and structural anomalies in the offspring. In both the rat and rabbit,
the dose-effect relationship was rather steep and showed clear
threshold levels. At dose levels below the threshold of maternal
toxicity, reproductive parameters as well as the offsprings remained
entirely unaffected.
This data demonstrate that the rat and rabbit are similarly
sensitive to epoxiconazole. Additionally, the NOAEL of 1.1 mg/kg/day
from the chronic dog study used to set the RfD is 4.5x and 72.7x lower
than the maternal developmental NOAELs established in the rat and
rabbit teratology studies, respectively. The developmental effects
observed in either the rat or rabbit occurred only at maternally toxic
doses. Therefore, no additional safety factor is needed for children.
Using the assumption stated for the general population, BASF
concluded that the most sensitive child population group is that of
children <1-year. Using the same RfD and the same conservative exposure
assumptions employed in the dietary risk analysis for the general
population, it was calculated that the exposure to this group is to be
approximately 2% of the RfD for the use proposed in this document.
Therefore, based on the completeness and reliability of the toxicity
data, and the exposure assessment discussed above, BASF concludes that
there is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to residues of epoxiconazole,
including all anticipated dietary exposure and all other non-
occupational exposures.
F. International Tolerances
A maximum residue level has not been established by the Codex
Alimentarius Commission for epoxiconazole in bananas.
II. Tomen Agro, Inc.
9E06020
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
petition.
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-
phenethylamine moieties.
iii. Hydroxylation/glycosylation of parent at the phenyl-ring 3
position.
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
an
[[Page 57343]]
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
activation.
iii. CHO cell assay, with and without metabolic activation in
vitro.
iv. In vitro rat primary hepatocyte unscheduled DNA synthesis UDS
assay.
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
2,500 ppm.
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
rats:
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
initiating potential.
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
in rats.
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
[[Page 57344]]
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
quantified.
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
imported commodities.
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
milk.
[FR Doc. 00-24436 Filed 9-21-00; 8:45 a.m.]
BILLING CODE 6560-50-S