[Federal Register Volume 64, Number 217 (Wednesday, November 10, 1999)]
[Notices]
[Pages 61336-61343]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-29184]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-896; FRL-6388-3]
Notice of Filing Pesticide Petitions to Establish a Tolerance 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-896, must be
received on or before December 10, 1999.
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'' section. To
ensure proper receipt by EPA, it is imperative that you identify docket
control number PF-896 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/telephone
Product Manager number/e-mail address Address Petition number(s)
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Cynthia Giles-Parker (PM 22)....... Rm. 247, CM #2, 703-305- 1921 Jefferson Davis PP 8F4998
7740, e-mail: giles- Hwy, Arlington, VA
parker.cynthia@epa.gov.
Shaja Brothers..................... Rm. 237, CM #2, 703-308- Do. PP 9E3810, 9E3813,
3194, e-mail: OE3912, 9E5075, and
[email protected] 9E6061
.gov.
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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 potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
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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 in the ``FOR FURTHER INFORMATION
CONTACT'' section.
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'' 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-896. 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-896 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, Environmental Protection Agency,
401 M St., SW., 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
[[Page 61337]]
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-896. 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 in the ``FOR FURTHER INFORMATION
CONTACT'' section.
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 pesticide petitions as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemicals 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 these petitions contain 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 supports 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: November 1, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
The petitioner summaries of the pesticide petitions are printed
below as required by section 408(d)(3) of the FFDCA. The summaries of
the petitions were prepared by the petitioners and represent the views
of the petitioners. EPA is publishing the petition summaries verbatim
without editing them 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.
1. GMJA Specialties
8F4998
EPA has received a pesticide petition (8F4998) from GMJA
Specialties, 10001 13th Avenue, East Bradenton, FL 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 PT807-HCl N,N-Diethyl-N-2-(4-methybenzyloxy)ethylamine
hydrochloride in or on the raw agricultural commodity (RAC) oranges at
0.01 parts per million (ppm). EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
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 PT807-HCl in plants and
animals is understood. In plants (oranges), unchanged parent is the
only residue identified in fruit. Valencia orange trees were treated
with 14C PT807-HCl at a nominal rate of 1,000 ppm
(approximately 60x the maximum recommended application rate). Fruit
from the previous season's crop present on the tree at the time of
application was harvested 50 days after treatment (DAT) and mature
fruit (not present on the tree at application) was harvested 370 DAT.
Total radioactive residue (TRR) levels were 0.538 ppm in 50 DAT orange
samples and were 0.051 ppm in 370 DAT orange samples. Most of the
radioactivity was present on the peel (88.63% TRR or 0.475 ppm in the
50 DAT fruit, and 64.19% TRR or 0.033 ppm in the 370 DAT fruit).
Unchanged parent PT807-HCl was detected in 50 DAT mature fruit (0.386
ppm), but not in the 370 DAT mature fruit (less than 0.001 ppm).
The metabolism of PT807-HCl in oranges has been determined. The
only significant metabolite is unchanged parent. No detectable residues
of PT807-HCl are anticipated in oranges treated at the recommended
application rate.
14C PT807-HCl was extensively metabolized and readily
eliminated in the urine and feces following oral administration to a
lactating goat. The efficient elimination process resulted in neglible
to modest retention of radioactive residues in milk and tissues (less
than 0.2% of the administered dose). No residues of unchanged parent
were identified in tissues or milk. The rapid elimination of PT807-HCl
and its metabolites coupled with the highly exaggerated dose
(approximately 3,600x the dietary burden) clearly indicate that no
detectable residues of PT807-HCl will accumulate in milk and tissues.
2. Analytical method. An analyticial method capable of extracting
PT807-HCl from whole oranges, juice, and dried pulp using organic
solvents has been validated. Extracted PT807-HCl residues are analyzed
using high performance liquid chromatography (HPLC) with a ultraviolet
(UV) detector. The limit of
[[Page 61338]]
quantitation (LOQ) of the method is 0.01 ppm.
3. Magnitude of residues. Seventeen field trials were conducted
using various varieties of oranges in California (4 trials), Florida
(12 trials), and Texas (1 trial). Two of the trials (1 in California
and 1 in Florida) were declined studies with sampling intervals of 0,
7, 14, 30, and 60 days after application. For all other trials, oranges
were harvested at the earliest possible time for normal commercial
harvest after a single application with PT807-HCl at the maximum
recommended application rate, 6 gram active ingredient per acre (g/ai/
A). At some of the test sites (depending on the variety of oranges),
the previous season's crop was present on the tree at application for
these trials, oranges were collected 0 to 68 DAT. In all other trials,
fruit were not present on the trees at applications and mature oranges
were collected at normal harvest (197 to 359 DAT). Samples were
analyzed for residues of PT807-HCl by HPLC with UV detection. Residues
of PT807-HCl were nondetectable (less than 0.01ppm) in all treated and
control samples.
A processing study was conducted using oranges treated at 5x the
maximum application rate in California. The harvested oranges were from
the previous season's crop and were on the tree at the time of
application. Therefore, the application represents the maximum possible
residues. No detectable residues were measured in whole oranges, juice,
or oil. Residues of PT807-HCl were detected in dried pulp at 0.015 and
0.017 ppm (average 0.016 ppm). Correcting the measured residues for the
exaggerated application rate, no detectable residues are likely in any
processed product of oranges.
Residues of PT807-HCl were determined to be stable in whole orange,
fruit, oil, juice, and dried pulp stored frozen up to 113 days.
B. Toxicological Profile
1. Acute toxicity. PT807-HCl exhibits low acute oral and dermal
toxicity (Toxicity Category III, LD50 of 531 milligrams/
kilograms (mg/kg) and greater than 2,525 mg/kg, respectively) and
inhalation toxicity (Toxicity Category IV, LC50 of greater
than 2.08 milligrams per liter (mg/L). PT807-HCl is minimally
irritating to the eyes, only slightly irritating to the skin (Toxicity
Categories III and IV, respectively), and is not a dermal sensitizer.
An acute neurotoxicity study in rats showed no specific evidence of
neurotoxicity; transient non-specific signs of toxicity were observed
in this study.
2. Genotoxicity. The genotoxic potential of PT807-HCl has been
assessed in an Ames Salmonella assay, a Chinese hampster ovary (CHO)
hypoxanthine guanine phophoribosyl transferase (HGPRT) gene mutation
assay, mouse micronucleus assay, an in vitro CHO assay for chromosomal
aberrations, and an in vivo unscheduled DNA synthesis (UDS) assay. The
in vitro chromosomal aberration assay was positive with and without
metabolic activation; however, all of the remaining assays were
negative, indicating very low genotoxic potential of PT807-HCl. The
contribution of the positive in vitro chromosomal aberration assay is
weakened by the negative finding in an in vivo study (mouse
micronucleus) measuring a similar endpoint.
3. Reproductive and developmental toxicity. Based on currently
available data, PT807-HCl does not present a unique hazard to infants
or children and there is no evidence that children are likely to be
more sensitive to the toxic effects of PT807-HCl. A 2-generation
reproductive toxicity study with PT807-HCl in rats showed developmental
delays in pups associated with decreased weight gain at 2,000 and 4,000
ppm, doses which were also toxic to the adult animals. PT807-HCl showed
evidence of developmental effects in rats only at a severely maternally
toxic dose level. No evidence of developmental toxicity was seen in
rabbits.
4. Subchronic toxicity. Studies have been conducted with PT807-HCl
in mice, rats, and dogs. In dietary studies in rats and dogs, the most
notable findings include decreased food consumptions and a consequent
decrease in body weight gain (resulting primarily from poor
palatability of the test material). Dogs also showed a trend toward
anemia, and males showed arrested or delayed sexual maturation at the
high dose (equivalent to approximately 222 mg/kg/day). Marked weight
loss and decreased weight gain was observed at this dose, and this dose
level is considered to have exceeded, a maximum tolerance dose (MTD).
Rats dosed by gavage showed signs of neurotoxic effects (tremors in
coordination changes in activity) at doses greater than or equal to 300
mg/kg/day. These clinical signs disappeared 2-4 hours post-dosing. Rats
receiving dietary administration of up to 5,000 ppm PT807-HCl for 13
weeks did not exhibit any neurotoxic effects. In mice, treatment-
related decreased food consumption and body weight gain were seen in
males at 7,000 ppm highest dose tested (HDT). No treatment-related
toxicity was evident at dietary doses up to 3,500 ppm (479 and 635 mg/
kg/day for males and females respectively).
5. Chronic toxicity. Ecolyst is not oncogenic when administered to
rats at dietary concentration of up to 10,000 ppm for 24 months, and
when administered to mice at doses up to 7,000 ppm (equivalent to 1,050
mg/kg/day/(male) 1,250 mg/kg/day(female) for 18 months. In the rat,
survival was increased in the treated animals. Systemic toxicity was
evident from decreased body weight gains and increased incidences of
hepatocellular hypertrophy and foci cellular alteration of hepatocytes
in both rats and mice receiving dietary levels of 5,000 and 10,000 ppm
of PT807-HCl. In the mouse, decreased body weights were noted in males
at 7,000 ppm (1,050 mg/kg/day) HDT. No other treatment-related effects
were noted. There were no treatment-related effects of dietary
administration of PT807-HCl to dogs at doses up to 5,000 ppm
(equivalent to 152 male/136 female mg/kg/day) except for a transient
decrease in body weight and food consumption in the first few weeks of
the study, and food consumption in the first few weeks of the study,
primarily at the 5,000 ppm level, due to poor palatability of the test
diet.
6. Plant and animal metabolism. Valencia orange trees treated with
approximately 470 mg 14C PT807-HCl in 400 ml spray solution/
tree. Samples were extracted and radioactivity was partitioned into
organic, aqueous, and non-extractable fractions. Extractable,
radioactivity was analyzed by HPLC to separate parent and metabolites.
Unchanged parent PT807-HCl was detected in leaves (14.191 ppm),
immature fruit (0.093), and mature fruit (0.386 ppm) from the previous
season's crop that was harvested approximately 50 DAT, but not in
mature fruit (less than 0.001 ppm) harvested 370 DAT. 14C
PT807-HCl is extensively metabolized and readily eliminated by animals
as indicated in a lactating goat study. A lactating goat was dosed with
14C PT807-HCl once a day for 5 consecutive days at a target
rate of 10 ppm in the diet. Approximately 100% of the total dose was
recovered. Most of the radioactivity (approximately 100% of the total
dose was recovered. Most of the radioactivity (approximately 93.8% of
the administered dose) was excreted in the urine and approximately 5.6%
of the dose was excreted in the feces. Tissues and milk contained less
than 0.2% of the administered dose. Unchanged parent compound was not
detected in any of the tissue. The rapid elimination of PT807-HCl and
its metabolites coupled with the highly
[[Page 61339]]
exaggerated dose (approximately 3,600x the dietary burden) clearly
indicates that no detectable residues of PT807-HCl will accumulate in
milk and tissues.
7. Metabolite toxicology. PT807-HCl was rapidly excreted from the
rat following oral administration. Approximately 70-80% of the
administered dose as excreted from the urine and 10-20% was excreted
from the feces. Minimal radioactive residue remained in the tissue. A
small quantity of the unchanged parent 14C PT807-HCl (M-14)
was detected in urine and feces of the treated rats. The metabolism of
PT807-HCl occurs through a variety of pathways, including oxidation,
reduction, hydroxylation, deamination, N-dealkylation, and conjugation.
8. Endocrine disruption. No evidence of endocrine disruption,
including estrogenic or anti-estrogenic activity was present in the
animal studies. The developmental toxicity studies showed no effects
suggesting endocrine disruption (e.g., change in fetal sex ratios, or
malformed or altered reproductive organ development). Maturational
delays were seen in both sexes of pups in the reproductive toxicity
study at high dose levels; these findings correlated with the decreased
body weight gain at these doses. There were no effects on anogenital
distance, estrous cyclicity of adult females or on reproduction and
fertility. FO females at 2,000 and 4,000 ppm showed
histopathological evidence of decreased cyclicity at weaning of their
litters; no such findings were apparent in the F1 females
which were necropsied 1-2 weeks after weaning. The findings in the
FO females attributed to the combined stress of weaning and
weight loss. As described below, high dose dogs given a dose exceeding
an MTD and showing marked weight loss, showed evidence of maturational
arrest of the germinal epithelium and absence of sperm in the
epidydimides. All four high dose female dogs were in anestrus (as
compared to two of the four control females). These findings are
considered related to the marked weight loss and weight gain decrease
in this study at the high dose level. No similar findings were seen in
a chronic dog study at dose levels up to 5,000 ppm.
C. Aggregate Exposure
1. Dietary exposure--i. Food. There are no anticipated dietary
exposures to PT807-HCl outside of those requested in this tolerance
petition. The chronic dietary exposure from the consumption of oranges
and its processed products, treated with PT807-HCl is very low. The
exposure is only 0.5% of the reference dose (RfD) (0.000063 mg/kg/day)
for the most high exposed population, children 1 to 6 years old. The
dietary exposure is only 0.17% of the reference dose (RfD) (0.000021
mg/kg/day) for the U.S. population.
ii. Drinking water. There are no registered uses of PT807-HCl at
this time; thus, the only potential source of residues in drinking
water is this requested use on oranges. Available data suggest that
PT807-HCl will not be a ground water contaminant because it does not
exhibit the mobility or persistence characteristics of pesticides that
are normally found in ground water. As a worst-case screen, GMJA
specialties used EPA's GENEEC model to estimate drinking water risk,
although GENEEC is an inappropriate model for the purpose because it
was designed to estimate surface water runoff for ecological risk
assessment purposes and greatly overestimates likely residues in
surface water. Nevertheless, it is the model EPA currently is using to
estimate drinking water exposure in order to assess aggregate risk.
Based on the results of the generic expected environmental
concentration (GENEEC) model, the 56-day chronic EEC (calculated from
the lowest Koc value measured for PT807-HCl) is 0.315
g/L. Using the standard drinking water consumption scenarios
of 2 liters per day for a 70 kg adult and 1 liter per day for a 10 kg
child, the calculated consumption of PT807-HCl in drinking water is
0.009 g/kg/day for an adult and 0.032 g/kg/day for a
child. These consumption values correspond to 0.07% of the RfD for
adults and 0.26% of the RfD for children ages 1 to 6 years old. As
discussed above, drinking water concentrations calculated by the GENEEC
procedure represent very conservative screening level assessments of
drinking water exposure.
2. Non-dietary exposure. There are currently no registered uses for
PT807-HCl, and therefore, there is no anticipated non-occupational
exposure to the chemical.
D. Cumulative Effects
GMJA Specialities/Tropicana Products, Inc. is not aware of any
currently registered products that are structurally similar to PT-807-
HCl or that would be likely to share a common mechanism of action.
Therefore, no cummulative exposures are considered in the PT807-HCl
dietary risk assessment.
E. Safety Determination
1. U.S. population. The RfD was 0.0125 mg/kg/day based on a no
observed adverse effect level (NOAEL) of 12.5 mg/kg/day and an
uncertainty factor of 1,000. Although we do not believe there were any
findings of concern in the toxicology studies that warrant a 1,000-fold
safety factor, we used it as a very consecutive, worst-case screening
value. NOAEL was obtained from the results of the rat reproduction
study that showed developmental delay and decreased weight gain in pups
at levels that were also toxic to adult rats.
2. Infants and children. The chronic dietary exposure from the
consumption of oranges and its processed products treated with PT807-
HCl is very low. The exposure is only 0.5% of the RfD (0.000063 mg/kg/
day) for the most highly exposed sub-population, children 1 to 6 years
old. The dietary exposure is only 0.17% of the RfD (0.000021 mg/kg/day)
for the U.S. population.
F. International Tolerance
There are not Codex Maximum Residue Levels (MRLs) established for
PT807-HCl.
2. Interregional Project Number 4
PP 9E3810, 9E3813, 0E3912, 9E5075, and 9E6061
EPA has received pesticide petitions (9E3810, 9E3813, 0E3912,
9E5075, and 9E6061) from the Interregional Project Number 4, Center for
Minor Crop, Pest Management, Technology Centre of New Jersey, Rutgers
University, 681 U.S. Highway No. 1 South, North Brunswick, NJ 08902-
3390 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180
by establishing tolerances for residues of esfenvalerate,(S)-cyano-(3-
phenoxyphenyl)methyl(S)-4-chloro-alpha-(1-methylethyl) benzeneacetate
in or on the raw agricultural commodities (RAC) as follows:
1. PP 9E3810 proposes the establishment of a tolerance for bok choy
at 1.0 ppm. Registration will be limited to areas east of the
Mississippi River based on the geographical representation of the
residue data submitted to EPA.
2. PP 9E3813 proposes the establishment of a tolerance for sweet
potatoes at 0.05 ppm.
3. PP 0E3912 proposes the establishment of a tolerance for cardoon
at 1.0 ppm. Registration will be limited to California based on the
geographical representation of the residue data submitted to EPA.
4. PP 9E5075 proposes the establishment of a tolerance for canola
seed at 0.3 ppm.
5. PP 9E6061 proposes the establishment of a tolerance for brussels
[[Page 61340]]
sprout at 0.2 ppm for regional registration only.
Fenvalerate is a racemic mixture of four isomers (S,S; R,S; S,R;
and R,R). Technical Asana (esfenvalerate) is enriched in the
insecticidally active S,S-isomer (84%). Tolerance expressions are
proposed for esfenvalerate based on the sum of all isomers.
EPA has determined that the petitions contain 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
petitions. Additional data may be needed before EPA rules on the
petitions. This notice includes a summary of the petitions prepared by
E.I. du Pont Nemours and Company, Agricultural Products, Wilmington,
Delaware 19898.
A. Residue Chemistry
1. Plant metabolism. The metabolism and chemical nature of residues
of esfenvalerate in plants is adequately understood. The fate of
fenvalerate has been extensively studied using radioactive tracers in
plant metabolism/nature of the residue studies previously submitted to
the Agency. These studies have demonstrated that the parent compound is
the only residue of toxicological significance. The registrant has
concluded that the qualitative nature of the residue is the same for
both fenvalerate and esfenvalerate.
2. Analytical method. There is a practical analytical method
utilizing gas chromatography with electron capture detection available
for enforcement with a limit of detection (LOD) that allows monitoring
food with residues at or above tolerance levels. The LOD for the
updated method is the same as that of the current Pesticide Analytical
Manual, Volume II (PAM II), which is 0.01 ppm.
3. Magnitude of residues. The following tolerances have been
proposed: cardoon at 1.0 ppm, bok choy at 1.0 ppm, sweet potatoes at
0.05 ppm, canola at 0.3 ppm, and brussels sprout at 0.2 ppm. Magnitude
of residue studies support the proposed tolerances.
B. Toxicological Profile
1. Acute toxicity. A battery of acute toxicity studies places
technical esfenvalerate in Toxicity Category II (Warning) for acute
oral toxicity rat lethal dose (LD50 87.2 mg/kg), Category
III (Caution) for acute dermal (rabbit LD50 > 2,000 mg/kg)
and primary eye irritation (mild irritation in rabbits), and Category
IV (Caution) for primary skin irritation (minimal skin irritation in
rabbits that reversed within 72 hours after treatment). Acute
inhalation on technical grade active ingredient (a.i.) was waived due
to negligible vapor pressure. A dermal sensitization test on
esfenvalerate in guinea pigs showed no sensitization.
2. Genotoxicity. Esfenvalerate was not mutagenic in reverse
mutation assays in S. typhimurium and E. Coli and did not induce
mutations Chinese hamster V79 cells or chromosome aberrations in
Chinese hamster ovary (CHO) cells. Esfenvalerate did not induce
micronuclei in bone marrow of mice given up to 150 mg/kg
intraperitoneally. Esfenvalerate did not induce unscheduled DNA
synthesis (UDS) in HeLa cells. Other genetic toxicology studies
submitted on racemic fenvalerate indicate that the mixture containing
equal parts of the four stereoisomers is not mutagenic in bacteria. The
racemic mixture was also negative in a mouse host mediated assay and in
a mouse dominant lethal assay.
3. Reproductive and developmental toxicity. Esfenvalerate was
administered to pregnant female rats by gavage in a pilot developmental
study at doses of 0, 1, 2, 3, 4, 5, or 20 mg/kg/day and a main study at
0, 2.5, 5, 10, or 20 mg/kg/day. Maternal clinical signs (abnormal gait
and mobility) were observed at 2.5 mg/kg/day and above. A no observed
adverse effect level (NOAEL) of 2 mg/kg/day was established for the
pilot study. The developmental NOAEL was > 20 mg/kg/day.
Esfenvalerate was administered by gavage to pregnant female rabbits
in a pilot developmental study at doses of 0, 2, 3, 4, 4.5, 5, or 20
mg/kg/day and a main study at doses of 0, 3, 10, or 20 mg/kg/day.
Maternal clinical signs (excessive grooming) were observed at 3 mg/kg/
day and above. A maternal NOAEL of 2 mg/kg/day was established on the
pilot study. The developmental NOAEL was > 20 mg/kg/day.
A 2-generation feeding study with esfenvalerate was conducted in
the rat at dietary levels of 0, 75, 100, or 300 ppm. Skin lesions and
minimal (non-biologically significant) parental body weight effects
occurred at 75 ppm. The NOAEL for reproductive toxicity was 75 ppm
(4.2-7.5 mg/kg/day) based on decreased pup weights at 100 ppm.
4. Subchronic toxicity. Two 90-day feeding studies with
esfenvalerate were conducted in rats, one at 50, 150, 300, or 500 ppm
esfenvalerate, and a second at 0, 75, 100, 125, or 300 ppm to provide
additional dose levels. The NOAEL was 125 ppm (6.3 mg/kg/day) based on
clinical signs (jerky leg movements) observed at 150 ppm (7.5 mg/kg/
day) and above.
A 90-day feeding study in mice was conducted at 0, 50, 150, or 500
ppm esfenvalerate with a NOAEL of 150 ppm (30.5 mg/kg) based on
clinical signs of toxicity at 500 ppm (106 mg/kg).
A 21-day dermal study in rabbits with fenvalerate conducted at 100,
300, or 1,000 mg/kg/day with a NOAEL of 1,000 mg/kg/day.
5. Chronic toxicity. In a 1-year study, dogs were fed 0, 25, 50, or
200 ppm esfenvalerate with no treatment related effects at any dietary
level. The NOAEL was 200 ppm (5 mg/kg/day). An effect level for dietary
administration of esfenvalerate for dogs of 300 ppm had been
established earlier in a 3-week pilot study used to select dose levels
for the chronic dog study.
One chronic study with esfenvalerate and three chronic studies with
fenvalerate have been conducted in mice.
In an 18-month study, mice were fed 0, 35, 150, or 350 ppm
esfenvalerate. Mice fed 350 ppm were sacrificed within the first 2
months of the study after excessive self-trauma related to skin
stimulation and data collected were not used in the evaluation of the
carcinogenic potential of esfenvalerate. The NOAEL was 35 ppm (4.29 and
5.75 mg/kg/day for males and females, respectively) based on lower body
weight and body weight gain at 150 ppm. Esfenvalerate did not produce
carcinogenicity.
In a 2-year feeding study, mice were administered 0, 10, 50, 250,
or 1,250 ppm fenvalerate in the diet. The NOAEL was 10 ppm (1.5 mg/kg/
day) based on granulomatous changes (related to fenvalerate only, not
esfenvalerate) at 50 ppm (7.5 mg/kg/day). Fenvalerate did not produce
carcinogenicity.
In an 18-month feeding study, mice were fed 0, 100, 300, 1,000, or
3,000 ppm fenvalerate in the diet. The NOAEL is 100 ppm (15.0 mg/kg/
day) based on fenvalerate-related microgranulomatous changes at 300 ppm
(45 mg/kg/day). No compound related carcinogenicity occurred.
Mice were fed 0, 10, 30, 100, or 300 ppm fenvalerate for 20 months.
The NOAEL was 30 ppm (3.5 mg/kg/day) based on red blood cell effects
and granulomatous changes at 100 ppm (15 mg/kg/day). Fenvalerate was
not carcinogenic at any concentration tested.
In a 2-year study, rats were fed 1, 5, 25, or 250 ppm fenvalerate.
A 1,000 ppm group was added in a supplemental study to establish an
effect level. The NOAEL was 250 ppm (12.5 mg/kg/day). At 1,000 ppm (50
mg/kg/day), hind limb weakness, lower body weight, and higher organ-to-
body
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weight ratios were observed. Fenvalerate was not carcinogenic at any
concentration.
EPA has classified esfenvalerate in Group E - evidence of
noncarcinogenicity for humans.
6. Animal metabolism. After oral dosing with fenvalerate, the
majority of the administered radioactivity was eliminated in the
initial 24 hours. The metabolic pathway involved cleavage of the ester
linkage followed by hydroxylation, oxidation, and conjugation of the
acid and alcohol moieties.
7. Metabolite toxicology. The parent molecule is the only moiety of
toxicological significance appropriate for regulation in plant and
animal commodities.
8. Endocrine disruption. Estrogenic effects have not been observed
in any studies conducted on fenvalerate or esfenvalerate. In subchronic
or chronic studies there were no lesions in reproductive systems of
males or females. In the recent reproduction study with esfenvalerate,
full histopathological examination of the pituitary and the
reproductive systems of males and females was conducted. There were no
compound-related gross or histopathological effects. There were also no
compound-related changes in any measures of reproductive performance
including mating, fertility, or gestation indices or gestation length
in either generation. There have been no effects on offspring in
developmental toxicity studies.
C. Aggregate Exposure
1. Dietary exposure. Tolerances have been established for the
residues of fenvalerate/esfenvalerate, in or on a variety of
agricultural commodities. For purposes of assessing dietary exposure,
chronic and acute dietary assessments have been conducted using all
existing and pending tolerances for esfenvalerate. EPA recently
reviewed the existing toxicology data base for esfenvalerate and
selected the following toxicological endpoints. For acute toxicity, EPA
established a NOAEL of 2.0 mg/kg/day from rat and rabbit developmental
studies based on maternal clinical signs at higher concentrations. A
margin of exposure (MOE) of 100 was required for chronic toxicity. EPA
established the chronic population adjusted dose (cPAD) for
esfenvalerate at 0.02 mg/kg/day. This cPAD was also based on the NOAEL
of 2.0 mg/kg/day in the rat developmental study with an uncertainty
factor of 100. Esfenvalerate is classified as a Group E carcinogen - no
evidence of carcinogenicity in either rats or mice. Therefore, a
carcinogenicity risk analysis for humans is not required.
i. Food. A chronic dietary exposure assessment was conducted using
Novigen's Dietary Exposure Estimate Model (DEEM). Anticipated residues
and adjustment for percent crop treated were used in the chronic
dietary risk assessment. The percentages of the cPAD utilized by the
most sensitive sub-population, children 1-6 years old, was 4.6% based
on a daily dietary exposure of 0.000911 mg/kg/day. Chronic exposure for
the overall U.S. population was 1.9% of the cPAD based on a dietary
exposure of 0.000376 mg/kg/day. Results of the chronic dietary risk
assessment adding cardoon, bok choy, sweet potatoes, canola, and
brussels sprout had no significant effect on chronic dietary exposure
when compared to the previous chronic dietary risk assessment. EPA has
no concern for exposures below 100% of the cPAD because the cPAD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health.
Potential acute exposures from food commodities were estimated
using a Tier 3 (Monte Carlo) Analysis and appropriate processing
factors for processed food and distribution analysis. This analysis
used field trial data to estimate exposure, and federal and market
survey information to derive the percent of crop treated. Regional
consumption information was taken into account. The MOEs for the most
sensitive sub-population (children 1-6 years old) were 202 and 103 at
the 99th, and 99.9th percentile of exposure,
respectively, based on daily exposures of 0.009914 and 0.019390 mg/kg/
day. The MOEs for the general population are 355 and 171 at the
99th and 99.9th percentile of exposure,
respectively, based on daily exposure estimates of 0.005638 and
0.011710 mg/kg/day. The registrant has stated there is no cause for
concern if total acute exposure calculated for the 99.9th
percentile yields an MOE of 100 or larger. This acute dietary exposure
estimate is considered conservative and EPA considered the MOEs
adequate in a recent Final Rule (62 FR 63019) (FRL 5754-6) November 26,
1997.
ii. Drinking water. Esfenvalerate is immobile in soil and will not
leach into ground water. Due to the insolubility and lipophilic nature
of esfenvalerate, any residues in surface water will rapidly and
tightly bind to soil particles and remain with sediment, therefore, not
contributing to potential dietary exposure from drinking water.
A screening evaluation of leaching potential of a typical
pyrethroid was conducted using EPA's Pesticide Root Zone Model (PRZM).
Based on this screening assessment, the potential concentrations of a
pyrethroid in ground water at depths of 1 and 2 meters are essentially
zero (much less than 0.001 parts per billion) (ppb).
Surface water concentrations for pyrethroids were estimated using
PRZM3 and Exposure Analysis Modeling System (EXAMS) using Standard EPA
cotton runoff and Mississippi pond scenarios. The maximum concentration
predicted in the simulated pond was 0.052 ppb. Concentrations in actual
drinking water would be much lower than the levels predicted in the
hypothetical, small, stagnant farm pond model since drinking water
derived from surface water would be treated before consumption.
Chronic drinking water exposure was estimated to be 0.000001 mg/kg/
day for both the United States general population and for non-nursing
infants. Less than 0.1% of the cPAD was occupied by both population
groups.
Using these values, the contribution of water to the acute dietary
risk estimate was estimated for the U.S. population to be 0.000019 mg/
kg/day at the 99th percentile and 0.000039 mg/kg/day at the
99.9th percentile resulting in MOEs of 105,874 and 51,757,
respectively. For the most sensitive subpopulation, non-nursing infants
less than 1-year old, the exposure is 0.000050 mg/kg/day and 0.000074
mg/kg/day at the 99th and 99.9th percentile,
respectively, resulting in MOEs of 39,652 and 27,042, respectively.
Therefore, the registrant concludes that there is reasonable
certainty of no harm from drinking water.
2. Non-dietary exposure. Esfenvalerate is registered for non-crop
uses including spray treatments in and around commercial and
residential areas, treatments for control of ectoparasites on pets,
home care products including foggers, pressurized sprays, crack and
crevice treatments, lawn and garden sprays, and pet and pet bedding
sprays. For the non-agricultural products, the very low amounts of a.i.
they contain, combined with the low vapor pressure (1.5 x
10-9 mm Mercury at 25 deg.C.) and low dermal penetration,
would result in minimal inhalation and dermal exposure.
To assess risk from (nonfood) short- and intermediate-term
exposure, the registrant selected a toxicological endpoint of 2.0 mg/
kg/day, the NOAEL from the rat and rabbit developmental studies. For
dermal penetration/
[[Page 61342]]
absorption, the registrant selected 25% dermal absorption based on the
weight-of-evidence available for structurally related pyrethroids. For
inhalation exposure, the registrant used the oral NOAEL of 2.0 mg/kg/
day and assumed 100% absorption by inhalation.
Individual non-dietary risk exposure analyses were conducted using
a flea infestation scenario that included pet spray, carpet and room
treatment, and lawn care, respectively. The total potential short- and
intermediate-term aggregate non-dietary exposure including lawn,
carpet, and pet uses are: 0.000023 mg/kg/day for adults, 0.00129 mg/kg/
day for children 1-6 years old and 0.00138 mg/kg/day for infants less
than 1-year old.
EPA concluded November 26, 1997 (62 FR 63019)(FRL 5754-6) that the
potential non-dietary exposure for esfenvalerate are associated with
substantial margins of safety.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency considers
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' In a recent Final Rule on esfenvalerate
(62 FR 63019), EPA concluded, ``Available information'' in this context
might include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanism of toxicity and conducting cumulative risk assessments. For
most pesticides, although the Agency has some information in its files
that may turn out to be helpful in eventually determining whether a
pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning common mechanisms of toxicity
in a meaningful way. EPA has begun a pilot process to study this issue
further through the examination of particular classes of pesticides.
The Agency hopes that the results of this pilot process will increase
the Agency's scientific understanding of this question such that EPA
will be able to develop and apply scientific principles for better
determining which chemicals have a common mechanism of toxicity and
evaluating the cumulative effects of such chemicals. The Agency
anticipates, however, that even as its understanding of the science of
common mechanisms increases, decisions on specific classes of chemicals
will be heavily dependent on chemical-specific data, much of which may
not be presently available.
Although at present the Agency does not know how to apply the
information in its less concerning common mechanism issues to most risk
assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include those that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances), and
pesticides that produce a common toxic metabolite (in which case a
common mechanism of activity will be assumed). Although esfenvalerate
is similar to other members of the synthetic pyrethroid class of
insecticides, EPA does not have, at this time, available data to
determine whether esfenvalerate has a common method of toxicity with
other substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
esfenvalerate does not appear to produce a toxic metabolite produced by
other substances for the purposes of this tolerance action. Therefore
for the purpose of this tolerance action, the registrant has not
assumed that esfenvalerate has a common mechanism of toxicity with
other substances.
E. Safety Determination
Both the chronic and acute toxicological endpoints are derived from
maternal NOAELs of 2.0 mg/kg/day in developmental studies in rats and
rabbits. There were no fetal effects. In addition, no other studies
conducted with fenvalerate or esfenvalerate indicate that immature
animals are more sensitive than adults. Therefore, the registrant
concludes that the safety factor used for protection of adults is fully
appropriate for the protection of infants and children. No additional
safety factor is necessary as described below.
1. U.S. population. A chronic dietary exposure assessment using
anticipated residues, monitoring information, and percent crop treated
indicated the percentage of the cPAD utilized by the general population
to be 1.9%. There is generally no concern for exposures below 100% of
the cPAD because the cPAD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health.
For acute exposure, a MOE greater than 100 is considered adequate.
A Tier 3 acute dietary exposure assessment found the general population
to have MOEs of 355 and 171 at the 99th and
99.9th percentile of exposure, respectively. These values
were generated using actual field trial residues and market share data
for percentage of crop treated. These results depict an accurate
exposure pattern at an exaggerated daily dietary exposure rate.
Short- and intermediate-term aggregate exposure risk from chronic
dietary food and water plus indoor and outdoor residential exposure for
the U.S. population is an exposure of 0.0082 mg/kg/day with an MOE of
244. Therefore, the registrant concludes that there is a reasonable
certainty that no harm will result from chronic dietary, acute dietary,
non-dietary, or aggregate exposure to esfenvalerate residues.
2. Infants and children. FFDCA section 408 provides that EPA shall
apply an additional tenfold margin of safety for infants and children
unless EPA determines that a different margin of safety will be safe
for infants and children. EPA has stated that reliable data supports
the use of the standard MOE and uncertainty factor (100 for combined
interspecies and intraspecies variability), and not the additional
tenfold MOE/uncertainty factor when EPA has a complete data base under
existing guidelines and when the severity of the effect in infants or
children or the potency or unusual toxic properties of a compound do
not raise concerns regarding the adequacy of the standard MOE/safety
factor. In a recent final rule (62 FR 63019), EPA concluded that
reliable data support use of the standard 100-fold uncertainty factor
for esfenvalerate, and that an additional uncertainty factor is not
needed to protect the safety of infants and children. This decision was
based on no evidence of developmental toxicity at doses up to 20 mg/kg/
day (10 times the maternal NOAEL) in prenatal developmental toxicity
studies in both rats and rabbits; offspring toxicity only at dietary
levels which were also found to be toxic to parental animals in the 2-
generation reproduction study; and no evidence of additional
sensitivity to young rats or rabbits following prenatal or postnatal
exposure to esfenvalerate.
A chronic dietary exposure assessment found the percentages of the
cPAD utilized by the most sensitive sub-population to be 4.6% for
children 1-6 years old based on a dietary exposure of 0.000911 mg/kg/
day. The percent cPAD for nursing and non-nursing infants was 1.1% and
2.7%, respectively. The registrant has no cause for concern if cPADs
are below 100%.
[[Page 61343]]
The most sensitive sub-population, children 1-6 years old, had
acute dietary MOEs of 202 and 103 at the 99th and
99.9th percentile of exposure, respectively. Nursing infants
had MOEs of 198 and 146 at the 99th and 99.9th
percentile of exposure, respectively. Non-nursing infants had MOEs of
300 and 156 at the 99th and 99.9th percentile of
exposure, respectively. The registrant has no cause for concern if
total acute exposure calculated for the 99.9th percentile
yields a MOE of 100 or larger.
The potential short- or intermediate-term aggregate exposure of
esfenvalerate from chronic dietary food and water plus indoor and
outdoor residential exposure to children (1-6 years old) is 0.0113 mg/
kg/day with an MOE of 177. For infants (less than 1-year old) the
exposure is 0.0098 mg/kg/day with an MOE of 204. Thus, the registrant
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to esfenvalerate
residues (62 FR 63019).
F. International Tolerances
There are no Codex MRL values established for fenvalerate on
cardoon, bok choy, sweet potatoes, canola, brussels sprout, and
rapeseed; therefore, no harmonization is required.
[FR Doc. 99-29184 Filed 11-9-99; 8:45 am]
BILLING CODE 6560-50-F
