Document ID: EPA-HQ-OPP-2007-0104-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  

(7/1/2006)

EPA Registration Division contact: [insert name and telephone number
with area code]

 

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
petition documents.  In cases where the outline element does not apply
please insert “NA-Remove” and maintain the outline.  The comment
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the information specific to your action.]

TEMPLATE:

Bayer CropScience

[Insert petition number]

	EPA has received a pesticide petition [insert petition number] from
[Bayer CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, Research
Triangle Park, NC  27709] 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    SEQ
CHAPTER \h \r 1 cyfluthrin; cyano
(4-fluoro-3-phenoxyphenyl)methyl-3-(2,2-dichloroethenyl)-2,2-dimethyl-cy
clopropanecarboxylate in or on the raw agricultural commodity [beet,
sugar, roots] at [0.09] parts per million (ppm) and in [beet, sugar,
dried pulp] at [11] ppm.  EPA has determined that the petition contains
data or information regarding the elements set forth in section 408
(d)(2) of the FDDCA; 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.    SEQ CHAPTER \h \r 1   The metabolism of
cyfluthrin in plants is adequately understood.  Studies have been
conducted to delineate the metabolism of radiolabeled cyfluthrin in
various crops all showing similar results.  The residue of concern is
cyfluthrin.

	2. Analytical method.    SEQ CHAPTER \h \r 1 Adequate analytical
methodology using GC/EC detection is available for enforcement purposes.

	3. Magnitude of residues.  A total of 12 field trials were conducted to
measure the magnitude of cyfluthrin residues in sugar beet following the
planting of sugar beet seeds treated with CLOTHIANIDIN + CYFLUTHRIN 600
SE at a target rate of 60 g clothianidin/100,000 seeds and 16 g
cyfluthrin/100,000 seeds.  CLOTHIANIDIN + CYFLUTHRIN 600 SE is an
emulsifiable concentrate containing clothianidin and cyfluthrin. 
Following treatment, the seeds were planted at seeding rates ranging
from 52,870 to 71,320 seeds/A.  The resulting soil application rates for
cyfluthrin were 0.019 to 0.025 lb ai/A (0.021 to 0.028 kg ai/ha).  In
all trials, duplicate composite samples of sugar beet roots and tops
were collected at crop maturity.  Cyfluthrin residue was quantitated in
sugar beet roots and tops by gas chromatography/mass spectrometry.  The
LOQ for cyfluthrin was 0.01 ppm in sugar beet roots and tops.  The
highest average field trial (HAFT) cyfluthrin residue was 0.049 ppm
(maximum residue = 0.088 ppm) in sugar beet roots and <0.01 ppm (maximum
residue = <0.01 ppm) in sugar beet tops at commercial harvest.  A
processing study showed concentration of cyfluthrin residues in dried
pulp, but no concentration of residues in molasses or refined sugar.

B. Toxicological Profile

	1. Acute toxicity.    SEQ CHAPTER \h \r 1 There is a full battery of
acute toxicity studies for cyfluthrin supporting an overall toxicity
Category II for the active ingredient.

	2. Genotoxicty.    SEQ CHAPTER \h \r 1 Based on the results of a
complete genotoxicity database, there is no evidence of mutagenicity
activity in a battery of studies, including several gene mutation assays
(reverse mutation and recombination assays in bacteria and a Chinese
hamster ovary(CHO)/HGPRT assay), a structural chromosome aberration
assay (CHO/sister chromatid exchange assay), and an unscheduled DNA
synthesis assay in rat hepatocytes.  All tests were negative for
genotoxicity.  

	3. Reproductive and developmental toxicity.    SEQ CHAPTER \h \r 1 A
developmental toxicity study in rats indicated a maternal NOAEL of 3
mg/kg bw/day based on reduced body weight gain and food consumption at
10 mg/kg bw/day.  The developmental NOAEL was 10 mg/kg bw/day, based on
reduced fetal body weights and increased skeletal variations at the
maternally toxic dose of 40 mg/kg bw/day.   An oral developmental
toxicity study in rabbits with a maternal NOAEL of 20 mg/kg bw/day and
a maternal LOAEL of 60 mg/kg bw/day, based on decreased body weight gain
and decreased food consumption during the dosing period.  A fetal NOAEL
of greater than 180 mg/kg bw/day was also observed in this study.  A
two-generation  reproduction study in rats indicated parental and
offspring NOAELs of 3.0 mg/kg bw/day, based on reductions in body weight
and food consumption in the parents and course tremors and decreased
mean litter weights in the offspring at 9.0 mg/kg bw/day.  The NOAELs
were confirmed in a supplemental two-generation study. 

	4. Subchronic toxicity.    SEQ CHAPTER \h \r 1 In a 28-day oral gavage
study in rats, cyfluthrin demonstrated a NOAEL of 20 mg/kg bw/day, based
on clinical signs of neurotoxicity, decreased body weight gain and
changes in liver and adrenal weights at 80 and 40 mg/kg bw/day,
respectively.  In a 90-day feeding study in rats the resulting NOAEL was
9.5 mg/kg bw/day, based on decreased body weight gain, gait
abnormalities, skin lesions and mortality seen at 37.5 mg/kg bw/day.   A
six-month toxicity feeding study in dogs established a NOAEL of 5 mg/kg
bw/day.  The LOAEL was 15 mg/kg bw/day based on clinical signs of
neurotoxicity and gastrointestinal disturbances.

Two subchronic inhalation studies were conducted with cyfluthrin.  In
the first study cyfluthrin was administered via inhalation for five days
per week for 3 weeks.  The resulting NOAEL was 1.4 mg/m3, based on
treatment-related behavioral effects, body weight decreases and organ
weight changes at 10.5 mg/m3.  In the second study cyfluthrin was
administered via inhalation for 13 weeks.  The resulting NOAEL was 0.09
mg/m3, based treatment-related behavioral effects in females and
increased urinary protein in males at 0.71 mg/m3. 

	5. Neurotoxicity.    SEQ CHAPTER \h \r 1 An acute neurotoxicity study
in rats was conducted using beta-cyfluthrin.  The NOAEL for this study
is 2 mg/kg, based on clinical signs, changes in FOB parameters and
decreases in motor activity noted at 10 mg/kg.  In a subchronic
neurotoxicity study with beta-cyfluthrin the resulting NOAEL was
8 mg/kg, based on clinical signs, changes in FOB parameters, and
slightly decreased body weight gain and food consumption.  In a
Developmental neurotoxicity study with beta-cyfluthrin the resulting
maternal and offspring NOAEL was 11.0 mg/kg body weight/day based on
decreased body weight and a change in startle response in PND 22 male
pups.  The database for cyfluthrin is complete and there is no
indication of pre- or post-natal susceptibility.  There is no indication
of delayed neurotoxicity as a result of exposure to cyfluthrin.  

	6. Chronic toxicity.    SEQ CHAPTER \h \r 1 A 12-month chronic feeding
study in dogs established a no-observed adverse effect level (NOAEL) of
2.4 mg/kg bw/day (males) and 3.6 mg/kg bw/day (females).  The lowest
effect level (LOAEL) for this study is established at 11 mg/kg bw/day,
clinical signs, gait abnormalities and abnormal postural reactions in
males and females.  A 24-month chronic feeding/ carcinogenicity study in
rats demonstrated a NOAEL of 2.6 mg/kg bw/day and LOAEL of 11.6 mg/kg
bw/day, based on decreased body weights.  A 24-month carcinogenicity
study in mice was conducted.  The NOAEL was 31.9 (males) and 140.6
(females) mg/kg/bw/day.  The LOAEL was 114.8 mg/kg bw/day (males) based
on ear skin lesions and reduced body weight gains, and 309.7 mg/kg
bw/day (females) based on clinical signs, macroscopic and microscopic
pathology findings and reduced body weights, body weight gains, and food
consumption.  Under the conditions of these studies, there was no
evidence of carcinogenic potential.  

	7. Animal metabolism.    SEQ CHAPTER \h \r 1 A metabolism study in rats
showed that cyfluthrin is rapidly absorbed and excreted, mostly as
conjugated metabolites in the urine, within 48 hours.  An enterohepatic
circulation was observed.  

	8. Metabolite toxicology.    SEQ CHAPTER \h \r 1 The residue of concern
is cyfluthrin.  No toxicology data have been required for cyfluthrin
metabolites.  Available data indicate that the metabolites are much less
toxic than the parent and are not of concern. 

	9. Endocrine disruption.    SEQ CHAPTER \h \r 1 There is no evidence of
endocrine effects in any of the studies conducted with cyfluthrin, thus,
there is no indication at this time that cyfluthrin causes endocrine
effects. 

C. Aggregate Exposure

	1. Dietary exposure.     SEQ CHAPTER \h \r 1 The insecticide cyfluthrin
has uses on food crops in agriculture and also non-dietary uses for
homeowners.  Aggregate exposure for cyfluthrin should consider dietary
exposure, both food and drinking water and non-dietary exposure both
applicator and post application exposure.  For the dietary exposure an
acute Population Adjusted Dose (aPAD) of 0.02 mg/kg bw/day was selected
using an uncertainty factor of 100 based on the acute neurotoxicity
study.  A chronic Population Adjusted Dose (cPAD) of 0.024 mg/kg bw/day
was based on the chronic toxicity test in dogs with an uncertainty
factor of 100.

™ software system (Exponent, Inc.) and the 1994-96 and 1998 USDA
consumption data.  For the chronic analysis, mean residue values were
calculated from the appropriate field trial studies conducted for
cyfluthrin and submitted as part of the cyfluthrin petitions.  For the
acute analysis, the entire distribution of field trial residue values
was used for non-blended and partially blended commodities and the mean
value used for blended commodities.  Processing factors were obtained
from GLP processing studies for the appropriate commodities.  Percent
crop treated values were obtained from Doane Market Research Data for
registered crops, using the mean value for the chronic analysis and the
maximum value of the last three years for the acute analysis.  Percent
crop treated values for the proposed use were based on Bayer CropScience
market projections at market maturity.  Using these data and assumptions
for the acute analysis the most highly exposed sub-population was All
Infants at 85 % (0.00467 mg/kg bw/day) of the acute PAD with the US
Population at 42 % (0.008475 mg/kg bw/day) of the acute PAD.  For the
chronic analysis, the most highly exposed sub-population was
Children 1-2 utilizing 5.8 % (0.001386 mg/kg bw/day) of the chronic
PAD.  The US Population utilized 1.5 % (0.00105 mg/kg bw/day) of the
chronic PAD.  Actual exposures are likely to be much less because of the
many conservative assumptions incorporated in this analysis.  

	ii. Drinking Water.  The estimated drinking water concentration was
taken form   SEQ CHAPTER \h \r 1 US EPA’s calculation of the drinking
water estimated environmental concentrations (EEC) for cyfluthrin
published in the Federal Register (FR Vol. 70, no. 176, 13-Sep-05). 
These EECs were directly incorporated into the calculation of the
dietary exposure. 

	2. Non-dietary exposure.    SEQ CHAPTER \h \r 1 Non-occupational
exposure to cyfluthrin may occur as a result of inhalation or contact
from indoor residential, indoor commercial and outdoor residential uses.
 Pursuant to the requirements of FIFRA as amended by the Food Quality
Protection Act of 1996 non-dietary and aggregate risk analyses for
cyfluthrin were conducted.  The analyses include evaluation of potential
non-dietary acute application and post-application exposures. 
Non-occupational, non-dietary exposure was assessed based on the
assumption that a flea infestation control scenario represents a
“worst case” scenario.  For the flea control infestation scenario
indoor fogger, and professional residential turf same day treatments
were included for cyfluthrin.  Deterministic (point values) were used to
present a worse case upper-bound estimate of non-dietary exposure.  The
non-dietary exposure estimates were expressed as systemic absorbed doses
for a summation of inhalation, dermal and incidental ingestion
exposures.  These worst-case non-dietary exposures were aggregated with
chronic dietary exposures to evaluate potential health risks that might
be associated with cyfluthrin products.  The chronic dietary exposures
were expressed as an oral absorbed dose to combine with the non-dietary
systemic absorbed doses for comparison to a systemic absorbed dose
no-observed-effect-level (NOEL).  Results for each potential exposed
subpopulation (of adults, children 1-6 years, and infants <1 year) were
compared to the systemic absorbed dose NOEL for cyfluthrin to provide
estimates of margins of exposure (MOE).  The large MOEs for cyfluthrin
clearly demonstrate a substantial degree of safety.  The total
non-dietary MOEs are 3800, 2700, and 2500 for adults, children (1-6
years), and infants (<1 year), respectively.  The aggregate MOE for
adults is approximately 2400 and the MOEs for infants and children
exceed 1000.  The non-dietary methods used in the analyses can be
characterized as highly conservative due to the conservatism inherent in
the calculation procedures and input assumptions.  An example of this is
the conservatism inherent in the jazzercise methodology’s
over-representation of residential post-application exposures. 
Therefore, it can be concluded that large MOEs associated with potential
non-dietary and aggregate exposures to cyfluthrin will result in little
or no health risks to exposed persons.  The aggregate risk analysis
demonstrates compliance with the health-based requirements of the Food
Quality Protection Act of 1996 for the current label uses.  The
additional proposed new use will have no impact on the analysis for
non-dietary exposure.  

D. Cumulative Effects

	  SEQ CHAPTER \h \r 1 Cyfluthrin is a member of the pyrethroid class of
pesticides. EPA is not currently following a cumulative risk approach
based on a common mechanism of toxicity for the pyrethroids while
research on this subject is still ongoing (FR Vol. 70, No. 176,
13-Sep-05).  

E. Safety Determination

	1. U.S. population.    SEQ CHAPTER \h \r 1 Using the assumptions and
data described above, based on the completeness and reliability of the
toxicity data, it is concluded that chronic dietary exposure to the
registered and proposed uses of cyfluthrin will utilize at most 1.5 % of
the chronic PAD for the US Population.  The acute dietary exposure to
cyfluthrin will utilize at most 42 % of the acute PAD.  The actual
exposure both acute and chronic is likely to be much less as more
realistic data and models are developed.  EPA generally has no concern
for exposures below 100% of the PAD because the PAD represents the level
at or below which daily aggregate exposure over a lifetime will not pose
appreciable risk to human health.   Potential exposure from drinking
water was included in the calculations.  Large margins of safety exist
for the non-dietary and aggregate exposure.  Therefore, there is a
reasonable certainty that no harm will occur to the US Population from
aggregate exposure (food, drinking water and non-dietary) to residues of
cyfluthrin.  

	2. Infants and children.    SEQ CHAPTER \h \r 1 The relevant toxicity
studies as discussed in the toxicology section above show no extra
sensitivity of infants and children to cyfluthrin, therefore the FQPA
safety factor can be removed. Using the assumptions and data described
in the exposure section above, the percent of the chronic PAD that will
be used for exposure to residues of cyfluthrin in food for Children 1-2
(the most highly exposed sub-population) is 5.8 %.  Infants utilize 2.5
% of the chronic PAD.  For the acute assessment children 1-2 utilize 76
% of the acute PAD and Infants utilize 85 % of the acute PAD.  As in
the adult situation, drinking water exposure was included in the
calculation of the PAD.  As with adults, large margins of safety exist
for the non-dietary and aggregate exposure for infants and children. 
Therefore, there is a reasonable certainty that no harm will occur to
infants and children from aggregate exposure to residues of cyfluthrin. 

F. International Tolerances

	Cyfluthrin is a broad spectrum insecticide used throughout the world to
control pests in crop and non-crop use areas.  CODEX MRL exist for
cyfluthrin for apples at 0.5 ppm, cattle milk at 0.01 ppm, cotton seed
at 0.05 ppm, maize at 0.05 ppm, peppers, sweet at 0.2 ppm, rape seed at
0.05 ppm and tomatoes at 0.5 ppm.  There is no existing international
tolerance for the proposed new use.  

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