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Pymetrozine - Pesticide Petition Filing 7/01

ENVIRONMENTAL PROTECTION AGENCY

[PF-1033; FRL-6793-9]

Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.

DATES: Comments, identified by docket control number PF-1033, must be
received on or before August 20, 2001.

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-1033 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT: By mail: Dan Peacock, Insecticide-
Rodenticide Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (703) 305-5407; e-mail address:
peacock.dan@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

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                                                        Examples of
             Categories              NAICS codes   potentially affected
                                                         entities
------------------------------------------------------------------------
Industry                                     111  Crop production
                                             112  Animal production
                                             311  Food manufacturing
                                           32532  Pesticide
                                                   manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select "Laws and
Regulations." "Regulation and Proposed Rules," and then look up the
entry for this document under the "Federal Register--Environmental
Documents." You can also go directly to the Federal Register listings
at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for
this action under docket control number PF-1033. 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-1033 in the subject line on the
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-1033. Electronic comments may
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under FOR FURTHER INFORMATION
CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used
that support your views.
    4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.

II. What Action is the Agency Taking?

    EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Comestic 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:July 2, 2001
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summaries of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioners. EPA is publishing the petition summary verbatim without
editing it in any way. 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.

Syngenta Crop Protection, Inc.

PP 8F4984, 8F5031, 0F6141

    EPA has received pesticide petitions (8F4984, 8F5031, 0F6141) from
Syngenta Crop Protection, Inc., PO Box 18300 Greensboro, NC 27419-8300
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 a tolerance for residues of pymetrozine in or on the raw
agricultural commodities cotton gin byproducts at 3.0 parts per million
(ppm), cottonseed at 0.4 ppm, cucurbit vegetables at 0.1 ppm, hops at
5.0 ppm, fruiting vegetables at 0.2 ppm, leafy vegetables (except
Brassica) at 6.0 ppm, head and stem Brassica vegetables at 2.0 ppm,
leafy Brassica greens at 5.0 ppm and pecans at 0.02 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 supports granting of the petition. Additional data
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of pymetrozine in plants is
understood for the purposes of the proposed tolerances. Studies in
rice, tomatoes, cotton and potatoes gave similar results. The metabolic
pathways have demonstrated that pymetrozine, per se, is the residue of
concern for tolerance setting purposes.
    2. Analytical method. Syngenta has submitted an analytical method
(AG-643) for the determination of pymetrozine in crop substrates. The
limit of detection (LOD) for the analytical method is 1.0 ng and the
limit of quantification (LOQ) is 0.02 ppm. Samples are extracted,
purified with solid-phase and liquid-liquid partitions and analyzed by
high performance liquid chromotography (HPLC). Analytical method has
undergone independent laboratory validation. The
pymetrozine Analytical Method AG-643 is proposed as the tolerance
enforcement method. Syngenta has also submitted an analytical method
(AG-647) for the determination of the major crop metabolite of
pymetrozine, GS-23199. GS-23199 is considered a marker for metabolite
residues. This metabolite is not proposed as part of the tolerance
expression. Samples are extracted, purified with solid-phase and/or
liquid-liquid partitions and analyzed by HPLC.
    3. Magnitude of residues. Residue data were generated for
pymetrozine for tolerance setting and dietary exposure estimates. Data
were also generated for a major metabolite, GS-23199. Adequate residue
trials were performed for pymetrozine on the uses proposed in this
notice of filing.

B. Toxicological Profile

    1. Acute toxicity. Pymetrozine has low acute toxicity. The oral
LD50 in rats is > 5,820 milligrams/kilogram(mg/kg) for males
and females, combined. The rat dermal LD50 is > 2,000 mg/kg
and the rat inhalation LD50 is > 1.8 milligrams/liter(mg/L)
air. Pymetrozine is not a skin sensitizer in guinea pigs and does not
produce dermal irritation in rabbits. It produces minimal eye
irritation in rabbits. End-use water-dispersible granule formulations
of pymetrozine have similar low acute toxicity profiles.
    2. Genotoxicity. Pymetrozine did not induce point mutations in
bacteria (Ames assay in Salmonella typhimurium and Escherichia coli) or
in cultured mammalian cells (Chinese hamster V79) and was not genotoxic
in an in vitro unscheduled DNA synthesis assay in rat hepatocytes.
Chromosome aberrations were not observed in an in vitro test using
Chinese hamster ovary cells and there were no clastogenic or aneugenic
effects on mouse bone marrow cells in an in vivo mouse micronucleus
test. These studies show that pymetrozine is not mutagenic or
genotoxic.
    3. Reproductive and developmental toxicity. In a teratology study
in rats, pymetrozine caused decreased body weights and food consumption
in females given 100 and 300 mg/kg/day during gestation. This maternal
toxicity was accompanied by fetal skeletal anomalies and variations
consistent with delayed ossification. The no-observed-adverse-effect
level (NOAEL) for maternal and fetal effects in rats was 30 mg/kg/day.
In a rabbit teratology study, maternal death, reduced body weight gain
and food consumption were observed at 125 mg/kg/day (highest dose
tested). Embryo- and feto-toxicity (abortion in one female and total
resorptions in two females) accompanied maternal toxicity. Body weight
and food consumption decreases, early resorptions and postimplantation
losses were also observed in maternal rabbits given 75 mg/kg/day. There
was an increased incidence of fetal skeletal anomalies and variations
at these maternally toxic doses. The NOAEL for maternal and fetal
effects in rabbits was 10 mg/kg/day. Pymetrozine is not teratogenic in
rats or rabbits. In a two generation reproduction study in rats,
parental body weights and food consumption were decreased, liver and
spleen weights were reduced and histopathological changes in liver,
spleen and pituitary were observed at approximately 110-440 mg/kg/day
(highest dose tested). Liver hypertrophy was observed in a few parental
males at approximately 10-40 mg/kg/day. Reproductive parameters were
not affected by treatment with pymetrozine. The NOAEL for reproductive
toxicity is approximately 110-440 mg/kg/day. The NOAEL for toxicity to
adults and pups is approximately 1-4 mg/kg/day.
    4. Subchronic toxicity. Pymetrozine was evaluated in 13-week
subchronic toxicity studies in rats, dogs and mice. Liver, kidneys,
thymus and spleen were identified as target organs. The NOAEL was 33
mg/kg/day in rats and 3 mg/kg/day in dogs. In mice, increased liver
weights and microscopical changes in the liver were observed at all
doses tested. The NOAEL in mice was <198 mg/kg/day. No dermal
irritation or systemic toxicity occurred in a 28-day repeated dose
dermal toxicity study with pymetrozine in rats given 1,000 mg/kg/day.
Minimum direct dermal absorption (1.1%) of pymetrozine was detected in
rats over a 21 hour period of dermal exposure. Maximum radioactivity
left on or in the skin at the application site and considered for
potential absorption was 11.9%.
    5. Chronic toxicity. Based on chronic toxicity studies in the dog
and rat, a reference dose (RfD) of 0.0057 mg/kg/day is proposed for
pymetrozine. This RfD is based on a NOAEL of 0.57 mg/kg/day established
in the chronic dog study and an uncertainty factor of 100 to account
for interspecies extrapolation and interspecies variability. Minor
changes in blood chemistry parameters, including higher plasma
cholesterol and phospholipid levels, were observed in the dog at the
lowest-observed-adverse-effect level (LOAEL) of 5.3 mg/kg/day. The
NOAEL established in the rat chronic toxicity study was 3.7 mg/kg/day
and was based on reduced body weight gain and food consumption,
hematology and blood chemistry changes, liver pathology and biliary
cysts.
    The carcinogenic potential of pymetrozine has been evaluated in
rats and mice. A liver tumor response was observed in male and female
mice and female rats at high doses exceeding the maximum tolerated
dose. These liver tumors correlated with reversible biochemical
(induction of liver metabolizing enzymes) and morphological (hepatocyte
and smooth endoplasmic reticulum proliferation) changes and a
reversible saturation of metabolic processes. EPA has assigned a cancer
classification of "likely" to pymetrozine and calculated a Q1* value.
However, Syngenta believes that the mechanism of action leading to
liver tumors at maximum tolerated doses is a non-genotoxic threshold
event and should be regulated as such.
    6. Animal metabolism. The metabolism of pymetrozine in the rat is
well understood. Metabolism involves oxidation of substituent groups of
the triazine ring yielding ketones and carboxylic acids. Hydrolysis of
the enamino bridge between rings results in products that are further
metabolized. The metabolic pathways in animals and plants are similar.
    7. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent compound. Metabolites of pymetrozine are
considered to be of equal or lesser toxicity than the parent.
    8. Endocrine disruption. Pymetrozine does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. There is no evidence that pymetrozine has any effect on
endocrine function in developmental and reproduction studies.
Furthermore, histological investigation of endocrine organs in chronic
dog, rat and mouse studies did not indicate that the endocrine system
is targeted by pymetrozine.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. A tier 3 chronic analysis was
conducted for pymetrozine using average (mean) field trial residues for
the following crops and crop groups: cotton, pecans, hops, cucurbits,
fruiting vegetables, tuberous and corm, Brassica leafy vegetables and
leafy vegetables. The average field trial values were adjusted for the
percent of crop-treated and residue values for processed commodities
were calculated by applying processing factors (either default or
empirically-derived) to average field trial values of the raw
agricultural commodity. Secondary residues in animal commodities were
not included in the exposure assessment since a three-level dairy feeding
study in lactating livestock showed no residues at any of the feeding levels
and the highest feeding level (10 ppm) was at least 10-fold higher than
what would be expected in treated feed. Exposure was evaluated using
the Dietary Exposure Evaluation Model (DEEM) and food
consumption information from USDA's 1994-96 Continuing Survey of Food
Intake by Individuals (CSFII). Dietary exposure for the general
population was 0.5% of the chronic reference dose (cRfD) of 0.0038 mg/
kg/day based on a no-observed-adverse-effect level (NOAEL) of 0.38 mg/
kg/day from a chronic feeding study in rats and a 100X uncertainty
factor. Exposure to the U.S. population for each season, each region
and for all ethnic groups in the DEEM were also compared to
the cRfD of 0.0038 mg/kg/day and ranged from 0.4-0.9%. Exposure to all
male subpopulations and seniors (55+ years old) ranged between 0.4-0.5%
of the cRfD (0.0038 mg/kg/day). Chronic dietary exposure to females,
infants and children was compared to a chronic population adjusted dose
(cPAD) of 0.0013 mg/kg/day based on the NOAEL of 0.38 mg/kg/day
(described above) and a 300X uncertainty factor. The chronic dietary
exposure results for the most sensitive female population subgroup,
females (13+ years and nursing), was 2.2% of the cPAD. The most
sensitive population containing children exclusively was children (1-6
years old) with an exposure of 2.5% of the cPAD. Lifetime cancer risk
to pymetrozine was evaluated by comparing exposure to a Q* value of
0.0119. The assessment was conducted as for the chronic assessment
described above. Lifetime risk for the U.S. population was 2.24 x
10-7. The most sensitive adult population was females (13+,
nursing) with a lifetime risk of 3.46 x 10-7. These exposure
estimates are conservative since field trial residues were utilized and
do not reflect residue reductions expected in normal food commerce,
storage or food preparation. Therefore, these results show that there
is more than a reasonable certainty of no harm resulting from chronic
exposure through the consumption of pymetrozine-treated commodities.
    A tier 3 probabilistic acute dietary analysis was conducted with a
full distribution of residues for each commodity described above. Each
residue distribution was adjusted for percent of crop treated by adding
zeroes to the distribution to account for the percent of crop not
treated. This acute assessment was conducted using the DEEM
software and food consumption information from USDA's 1994-96 CSFII.
Processing factors were used to adjust average field trial values for
processed (blended) commodities and were obtained either empirically or
from default values. EPA has required that exposure to females (13+
years old) be compared to a NOAEL of 10 mg/kg/day based on a rabbit
developmental study and a 300X uncertainty factor. Acute exposure to
the most sensitive female subpopulation, females (13-50 years old), was
1.61% of the acute population adjusted-dose (aPAD) of 0.033 mg/kg/day
(300X uncertainty factor). For the U.S. population and infants and
children, exposures were compared to a lowest-observed-adverse-effect
level (LOAEL) of 125 mg/kg/day from an acute neurotoxicity study in
rats. Uncertainty factors of 300X and 900X were applied to the LOAEL
for the general population and infants and children subgroups,
respectively. Acute exposure for the U.S. population was 0.13% of the
aPAD of 0.42 mg/kg body weight/day (300X uncertainty factor). For the
infants and children populations, the most sensitive population
subgroup was non-nursing infants with an exposure of 1.77% of the aPAD
of 0.14 mg/kg/day (900X-uncertainty factor). These results show a very
large margin of safety associated with the consumption of pymetrozine-
treated commodities and even under conservative assumptions all
populations receive less than 2% of the acute population adjusted dose.
    ii. Drinking water. The acute drinking water exposure to
pymetrozine was evaluated based on the crops above using EPA's surface
water Tier 1 model (GENEEC). Hops with 3 applications at 0.1875 lb ai/
acre was the highest contributor at 4.27 ppb. Using the current aPAD of
0.033 mg/kg for females 13+, the margin of exposure percent (MOE%) of
risk cup anticipated is 0.43%. For children the aPAD of 0.14 mg/kg
yields an MOE% of risk cup of 0.30%.
    Hops was also the highest contributor to surface water exposure at
0.31 ppb. Using the current cPAD of 0.0013 mg/kg/day (for females and
children) the surface water exposure results in an MOE% of risk cup of
2.38% for children. Using a Q* of 0.0119 the risk to a typical 70 kg
adult drinking 2 liters of water per day would be estimated at 1.05 x
10**-7.
    2. Non-dietary exposure. Pymetrozine is registered on ornamentals
and exposure could occur through post-application re-entry to treated
plants. Syngenta believes that risks due to short-term, intermediate-
term or chronic exposure are either not applicable or insignificant.

D. Cumulative Effects

    The potential for cumulative effects of pymetrozine and other
substances that have a common mechanism of toxicity has also been
considered. Pymetrozine belongs to a new chemical class known as
pyridine azomethines and exhibits a unique mode of action. There is no
reliable information to indicate that toxic effects produced by
pymetrozine would be cumulative with those of any other chemical
including another pesticide. Therefore, Syngenta believes it is
appropriate to consider only the potential risks of pymetrozine in an
aggregate risk assessment.

E. Safety Determination

    1. U.S. population. Using the exposure assumptions and the proposed
RfD described above, the aggregate exposure to pymetrozine will utilize
0.5% of the RfD for the U.S. population. The RfD represents the level
at or below which daily aggregate exposure over a lifetime will not
pose appreciable risks to human health. EPA generally has no concern
for exposures below 100 percent of the RfD. In addition, Lifetime
cancer risk for the U.S. population was 2.24 x 10-7, which
is below the level of EPA concern. Therefore, Syngenta concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to pymetrozine residues.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of pymetrozine, data
from developmental toxicity studies in the rat and rabbit and a two-
generation reproduction study in the rat have been considered.
    In a teratology study in rats, developmental toxicity anomalies and
variations associated were observed only at maternally toxic doses.
Similarly, in a rabbit teratology study, effects were observed only at
maternally toxic doses. The NOAELs in the rat and rabbit teratology
studies were 30 and 10 mg/kg/day, respectively. In the two-generation
rat reproduction study, there were no effects on reproductive
parameters. Offspring body weights were slightly reduced and eye
opening was slightly delayed at dose levels producing parental
toxicity. The NOAEL for parental and offspring toxicity was
approximately 1-4 mg/kg/day.
    FFDCA section 408 provides that EPA shall apply an additional 10-
fold margin of safety for infants and children in the case of threshold
effects to account for prenatal and postnatal toxicity and the
completeness of the database unless EPA determines that a
different margin of safety will be safe for infants and children. EPA
has added an additional 3-fold factor to the acute dietary risk
assessment for infants and children due to the lack of a NOAEL in the
critical study. An additional 3-fold factor is also needed due to the
uncertainty resulting from the data gap for the developmental
neurotoxicity study in rats. This latter safety factor is applicable to
the following subgroup populations: Females 13-50; infants, children
(1-6 years old), and children (7-12 years old) for all risk assessment
scenarios for acute and chronic dietary and residential scenarios. No
greater additional factor is needed because, using the exposure
assumptions described above, the percent of the pymetrozine chronic PAD
that will be utilized by the most exposed sub-population (children, 1-6
years old) is 2.5%. Therefore, based on the completeness and
reliability of the toxicity database, Syngenta concludes that there is
reasonable certainty that no harm will result to infants and children
from exposure to pymetrozine residues.

F. International Tolerances

    There are no established European (CODEX), Canadian, or Mexican
Maximum Residue Limits (MRLs) for pymetrozine. There are provisional
MRLs in Germany for hops (10 ppm) and potatoes (0.02 ppm). The European
Union is currently evaluating a proposed tolerance of 5 ppm on hops. At
this time, international harmonization of residue levels is not an
issue.

[FR Doc. 01-18098 Filed 7-18-01; 8:45 a.m.]