Document ID: EPA-HQ-OPP-2007-0300-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-24T04:00Z

EPA Registration Division Contact: Sidney Jackson.  (703) 305-7610.

Docket ID: EPA-HQ-OPP-2007-0300

Interregional Research Project No. 4 (IR-4), 

PP#: 7E7255

EPA has received pesticide petition (PP 7E7255) from the IR-4 Project
Headquarters, 500 College Road East, Suite 201W, Princeton, New Jersey,
08540, proposing pursuant to section 408 (d) of the Federal Food, Drug
and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 C. F. R. § 180.418 by
establishing tolerances for residues of the insecticide
zeta-cypermethrin  (S-Cyano(3-phenoxyphenyl)methyl (+() cis-trans
3-(2,2-dichloroethenyl)-2,2 dimethylcyclopropanecarboxylate and its
inactive isomers) in or on the raw agricultural commodities: borage,
seed at 0.2 parts per million (ppm); castor oil plant, seed at 0.2 ppm;
Chinese tallowtree, seed at 0.2 ppm; crambe, seed at 0.2 ppm; cuphea,
seed at 0.2 ppm; echium, seed at 0.2 ppm; euphorbia, seed at 0.2 ppm;
evening primrose, seed at 0.2 ppm; flax, seed at 0.2 ppm; gold of
pleasure, seed at 0.2 ppm; hare’s ear mustard, seed at 0.2 ppm;
jojoba, seed at 0.2 ppm; lesquerella, seed at 0.2 ppm; lunara, seed at
0.2 ppm; meadowfoam, seed at 0.2 ppm; milkweed, seed at 0.2 ppm;
mustard, seed at 0.2 ppm; niger seed, seed at 0.2 ppm; oil radish, seed
at 0.2 ppm; poppy, seed at 0.2 ppm; rose hip, seed at 0.2 ppm; sesame,
seed at 0.2 ppm; stokes aster, seed at 0.2 ppm; sweet rocket, seed at
0.2 ppm; tallowwood, seed at 0.2 ppm; tea oil plant, seed at 0.2 ppm;
and vernonia, seed at 0.2 ppm.  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
support granting of the petition.  Additional data may be needed before
EPA rules on the petition.

A.  Residue Chemistry

1.  Plant metabolism.  The metabolism of cypermethrin in plants is
adequately understood.  Studies have been conducted to delineate the
metabolism of radiolabelled cypermethrin in various crops all showing
similar results.  The residue of concern is the parent compound only.

2.  Analytical method. There is a practical analytical method for
detecting and measuring

levels of cypermethrin in or on food with a limit of detection that
allows monitoring of food with residues at or above the levels set in
these tolerances (Gas Chromatography with Electron Capture Detection
(GC/ECD).

3.  Magnitude of residues.  

Crop field trial residue data from studies conducted at the maximum
label rates for representative commodities for canola (rapeseed),
sunflower, and safflower show that the proposed zeta-cypermethrin
tolerances on borage, seed, 0.2 ppm; castor oil plant, seed, 0.2 ppm;
Chinese tallowtree, seed, 0.2 ppm; crambe, seed, 0.2 ppm; cuphea, seed,
0.2 ppm; echium, seed, 0.2 ppm; euphorbia, seed, 0.2 ppm; evening
primrose, seed, 0.2 ppm; flax, seed, 0.2 ppm; gold of pleasure, seed,
0.2 ppm; hare’s ear mustard, seed, 0.2 ppm; jojoba, seed, 0.2 ppm;
lesquerella, seed, 0.2 ppm; lunara, seed, 0.2 ppm; meadowfoam, seed, 0.2
ppm; milkweed, seed, 0.2 ppm; mustard, seed, 0.2 ppm; niger seed, seed,
0.2 ppm; oil radish, seed, 0.2 ppm; poppy, seed, 0.2 ppm; rose hip,
seed, 0.2 ppm; sesame, seed, 0.2 ppm; stokes aster, seed, 0.2 ppm; sweet
rocket, seed, 0.2 ppm; tallowwood, seed, 0.2 ppm; tea oil plant, seed,
0.2 ppm; and vernonia, seed, 0.2 ppm, will not be exceeded when the
zeta-cypermethrin products labeled for these uses are used as directed.

B.  Toxicological Profile

1.  Acute toxicity.  For the purposes of assessing acute dietary risk,
FMC has used the NOEL of 10.0 mg/kg/day from the zeta-cypermethrin acute
neurotoxicity study in rats.  The LOAEL of  50.0 mg/kg/day was based on
clinical signs. This acute dietary endpoint is used to determine acute
dietary risks to all population subgroups.

2.  Genotoxicity.  The following genotoxicity tests were all negative:
in vivo chromosomal aberration in rat bone marrow cells; in vitro
cytogenic chromosome aberration; unscheduled DNA synthesis; CHO/HGPTT
mutagen assay; weakly mutagenic:  gene mutation (Ames).

3.  Reproductive and developmental toxicity.  No evidence of additional
sensitivity to young rats was observed following pre- or postnatal
exposure to zeta-cypermethrin.

a.  A two-generation reproductive toxicity study with zeta-cypermethrin
in rats demonstrated a NOEL of  7.0 mg/kg/day and a LOEL of  27.0
mg/kg/day for parental/systemic toxicity based on body weight, organ
weight, and clinical signs.  There were no adverse effects in
reproductive performance.  The NOEL for reproductive toxicity was
considered to be  > 45.0 mg/kg/day (the highest dose tested). 

b.  A developmental study with zeta-cypermethrin in rats demonstrated a
maternal NOEL of 12.5 mg/kg/day and a LOEL of 25 mg/kg/day based on
decreased maternal body weight gain, food consumption and clinical
signs.  There were no signs of developmental toxicity at 35.0 mg/kg/day,
the highest dose level tested.

c. A developmental study with cypermethrin in rabbits demonstrated a
maternal NOEL of 100 mg/kg/day and a LOEL of 450 mg/kg/day based on
decreased body weight gain.  There were no signs of developmental
toxicity at 700 mg/kg/day, the highest dose level tested.

4.  Subchronic toxicity.  Short- and intermediate-term toxicity
(incidental oral exposure).  The NOEL of 10.0 mg/kg/day based on
clinical signs at the LEL of 50.0 mg/kg/day in the zeta-cypermethrin
acute neurotoxicity study in rats would also be used for short-term
%aPAD and MOE calculations (as well as acute, discussed in (1) above),
and the NOEL of 5.0 mg/kg/day based on decreased motor activity in the
zeta-cypermethrin subchronic neurotoxicity study in rats, would be used
for intermediate-term MOE calculations.

5.  Chronic toxicity.  a. The chronic reference dose (RfD) of 0.06
mg/kg/day for zeta-cypermethrin is based on a NOEL of 6.0 mg/kg/day from
a cypermethrin chronic feeding study in dogs and an uncertainty factor
of 100.  The endpoint effect of concern was based on clinical signs.

b.  Cypermethrin is classified as a Group C chemical (possible human
carcinogen with limited evidence of carcinogenicity in animals) based
upon limited evidence for carcinogenicity in female mice; assignment of
a Q* has not been recommended.

6.  Animal metabolism.  The metabolism of cypermethrin in animals is
adequately understood.  Cypermethrin has been shown to be rapidly
absorbed, distributed, and excreted in rats when administered orally. 
Cypermethrin is metabolized by hydrolysis and oxidation.

7.  Metabolite toxicology.  The Agency has previously determined that
the metabolites of cypermethrin are not of toxicological concern and
need not be included in the tolerance expression nor in the risk
exposure assessments.

8.  Endocrine Disruption.  No special studies investigating potential
estrogenic or other endocrine effects of cypermethrin have been
conducted.  However, no evidence of such effects were reported in the
standard battery of required toxicology studies which have been
completed and found acceptable.  Based on these studies, there is no
evidence to suggest that cypermethrin has an adverse effect on the
endocrine system.

C.  Aggregate Exposure

1.  Dietary exposure.  a.  Food.  Permanent tolerances, in support of
registrations, currently exist for residues of zeta-cypermethrin on: 
alfalfa hay, alfalfa forage, alfalfa seed, aspirated grain fractions,
sugar beets (roots and tops), head, stem and leafy Brassica vegetables,
cabbage, field corn grain, pop corn grain, field corn forage, field corn
stover, pop corn stover, sweet corn (K+CWHR), sweet corn forage, sweet
corn stover, cottonseed, dried shelled peas and beans, edible podded
legume vegetables, fruiting vegetables (except Cucurbits), leafy
vegetables, head lettuce, bulb and green onions, pecans, rice grain,
rice hulls, rice straw, sorghum forage, sorghum grain, sorghum stover,
soybean seed, succulent shelled peas and beans, sugarcane, wheat forage,
wheat grain, wheat hay, wheat straw, almond hulls, nongrass animal feed
forage and hay, berries, cilantro leaves, pome fruit, stone fruit,
grape, grass forage and hay, tree nuts, peanut, rapeseed (canola),
sunflower, sunflower refined oil, turnip greens, cucurbit vegetables,
root and tuber vegetables, meat, fat and meat byproducts of cattle,
goats, hogs, horses and poultry, eggs, milk and milk fat.  For the
purposes of assessing the potential dietary exposure for these existing
and the subject proposed tolerances, FMC has utilized available
information on anticipated residues, monitoring data and percent crop
treated as follows:

i.  Acute exposure and risk.  Acute dietary exposure risk assessments
are performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure.  For the purposes of assessing acute
dietary risk for zeta-cypermethrin, FMC has used the NOEL of 10.0
mg/kg/day from the zeta-cypermethrin acute neurotoxicity study in rats
with an uncertainty factor (UF) of 100 (acute RfD = 0.10 mg/kg/day). 
The LEL of 50.0 mg/kg/day was based on clinical signs.  This acute
dietary endpoint is used to determine acute dietary risks to all
population subgroups.  Available information on anticipated residues,
monitoring data and percent crop treated was incorporated into a Tier 3
analysis, using Monte Carlo modeling for commodities that may be
consumed in a single serving.  These assessments show that the percent
acute Population Adjusted Dose (%aPAD) all fall below the EPA’s level
of concern ((100%).   The 95th percentile of exposure for the overall U.
S. population was estimated to be 0.002448 mg/kg/day (%aRfD of 2.45);
99th percentile 0.007176 mg/kg/day (%aRfD of 7.18); and 99.9th
percentile 0.024759 mg/kg/day (%aRfD of 24.76).  The 95th percentile of
exposure for all infants (< 1 year) was estimated to be 0.005153
mg/kg/day (%aRfD of 5.15); 99th percentile 0.012833 mg/kg/day (%aRfD of
12.83); and 99.9th percentile 0.035742 mg/kg/day (%aRfD of 35.74). The
95th percentile of exposure for children 1 to 2 years old and children 3
to 5 years old was estimated to be, respectively,  0.006932 mg/kg/day
(%aRfD of 6.93) and 0.004758 mg/kg/day (%aRfD of 4.76); 99th percentile
0.016035 mg/kg/day (%aRfD of 16.03) and 0.011416 (%aRfD of 11.42); and
99.9th percentile 0.053308 mg/kg/day (%aRfD of 53.31) and 0.047651
(%aRfD of 47.65). The 95th percentile of exposure for females (13-49
years) was estimated to be 0.001983 mg/kg/day (%aRfD of 1.98); 99th
percentile 0.005391 mg/kg/day (%aRfD of 5.39); and 99.9th percentile
0.020292 mg/kg/day (%aRfD of 20.29).  Therefore, FMC concludes that the
acute dietary risk of zeta-cypermethrin, as estimated by the dietary
risk assessment, does not appear to be of concern.

Chronic exposure and risk.  The chronic reference dose (cRfD) of 0.06
mg/kg/day for zeta-cypermethrin is based on a NOEL of 6.0 mg/kg/day from
a cypermethrin chronic feeding study in dogs and an uncertainty factor
of 100.  The endpoint effect of concern was based on clinical signs.  A
chronic dietary exposure/risk assessment has been performed for
zeta-cypermethrin using the above cRfD.  Available information on
anticipated residues, monitoring data and percent crop treated was
incorporated into the analysis to estimate the anticipated residue
contribution (ARC).  The ARC is generally considered a more realistic
estimate than an estimate based on tolerance level residues.  The ARC
are estimated to be 0.000958 mg/kg body weight (bwt)/day and utilize 1.6
percent of the cRfD for the overall U. S. population.  The ARC for all
infants (<1 year) are estimated to be 0.001486 mg/kg bwt/day and
utilizes 2.5 percent of the cRfD.  The ARC for children 1 to 2 years old
and children 3 to 5 years old are estimated to be 0.003881 mg/kg bwt/day
and 0.002680 mg/kg bwt/day and utilizes 6.5 percent and 4.5 percent of
the cRfD, respectively. The ARC for females (13-49 years) is estimated
to be 0.000631 mg/kg bwt/day and utilizes 1.1 percent of the RfD. 
Generally speaking, the EPA has no cause for concern if the total
dietary exposure from residues for uses for which there are published
and proposed tolerances is less than 100 percent of the cRfD. 
Therefore, FMC concludes that the chronic dietary risk of
zeta-cypermethrin, as estimated by the dietary risk assessment, does not
appear to be of concern.

Drinking water.  Laboratory and field data have demonstrated that
cypermethrin is immobile in soil and will not leach into groundwater. 
Other data show that cypermethrin is virtually insoluble in water and
extremely lipophilic.  As a result, FMC concludes that residues reaching
surface waters from field runoff will quickly adsorb to sediment
particles and be partitioned from the water column.  Drinking water
estimated concentrations (DWEC) and the corresponding drinking water
level of comparison (DWLOC) values were calculated for chronic and acute
exposures. The results show that all DWLOC values exceed the DWEC
values. Thus, exposure to zetacypermethrin and cypermethrin residues in
drinking water is not of concern.

US EPA’s draft SOP for Incorporating Estimates of Drinking Water
Exposure Into Aggregate Risk Assessments was used to perform a drinking
water analysis.  This SOP utilizes a variety of tools to conduct
drinking water assessment. These tools include water models such as FQPA
Index Reservoir Screening Tool (FIRST), PRZM/EXAMS, SCIGROW and
monitoring data. If monitoring data are not available then the models
are used to predict potential residues in drinking water. The technique
recommended in the drinking water SOP compares a calculated Drinking
Water Level of Comparison (DWLOC) value to the Drinking Water Estimated
Concentration (DWEC) value. The DWEC value results from either the
monitoring data residues or modeled water residues. If the DWLOC value
exceeds the DWEC value then there is reasonable certainty that no harm
will result from the acute or chronic aggregate exposure.

In the case of cypermethrin and zetacypermethrin, monitoring data do not
exist.  Therefore, the FIRST model was used to estimate a surface water
residue.  The risk assessment for drinking water compares two values:
the DWLOC and the DWEC. The DWLOC is the drinking water level of
comparison. This is the maximum allowable drinking water concentration
(in ppb). The DWEC is the drinking water

environmental concentration, which is derived either from monitoring
studies or from modeling.

If the DWLOC is greater than the DWEC, then the overall exposure from
water, food, and

residential is considered to be acceptable. The calculated DWLOC values
for acute and chronic exposures for all adults, adult females and
children exceed the modeled DWEC surface water residues. Therefore,
there is reasonable certainty that no harm will result from cumulative
and aggregate (food and water) exposure to cypermethrin and
zetacypermethrin residues.

2.  Non-dietary exposure.   Zeta-cypermethrin is registered for
agricultural crop applications only, therefore non-dietary exposure
assessments are not warranted.

D.  Cumulative Effects.  In consideration of potential cumulative
effects of cypermethrin and other substances that may have a common
mechanism of toxicity, to our knowledge there are currently no available
data or other reliable information indicating that any toxic effects
produced by cypermethrin would be cumulative with those of other
chemical compounds; thus only the potential risks of cypermethrin have
been considered in this assessment of its aggregate exposure.  FMC
intends to submit information for the EPA to consider concerning
potential cumulative effects of cypermethrin consistent with the
schedule established by EPA at 62 Federal Register 42020 (August 4,
1997) and other EPA publications pursuant to the Food Quality Protection
Act.

E.  Safety Determination

1.  U. S. population.  The chronic reference dose (cRfD) of 0.06
mg/kg/day for zeta-cypermethrin is based on a NOEL of 6.0 mg/kg/day from
a cypermethrin chronic feeding study in dogs and an uncertainty factor
of 100.  The endpoint effect of concern was based on clinical signs.  A
chronic dietary exposure/risk assessment has been performed for
zeta-cypermethrin using the above cRfD.  Available information on
anticipated residues, monitoring data and percent crop treated was
incorporated into the analysis to estimate the anticipated residue
contribution (ARC).  The ARC is generally considered a more realistic
estimate than an estimate based on tolerance level residues. The ARC are
estimated to be 0.000958 mg/kg body weight (bwt)/day and utilize 1.6
percent of the cRfD for the overall U. S. population.  The ARC for all
infants (<1 year) are estimated to be 0.001486 mg/kg bwt/day and
utilizes 2.5 percent of the cRfD.  The ARC for children 1 to 2 years old
and children 3 to 5 years old are estimated to be 0.003881 mg/kg bwt/day
and 0.002680 mg/kg bwt/day and utilizes 6.5 percent and 4.5 percent of
the cRfD, respectively. The ARC for females (13-49 years) is estimated
to be 0.000631 mg/kg bwt/day and utilizes 1.1 percent of the RfD. 
Generally speaking, the EPA has no cause for concern if the total
dietary exposure from residues for uses for which there are published
and proposed tolerances is less than 100 percent of the cRfD. 
Therefore, FMC concludes that the chronic dietary risk of
zeta-cypermethrin, as estimated by the dietary risk assessment, does not
appear to be of concern.

Acute dietary exposure risk assessments are performed for a food-use
pesticide if a toxicological study has indicated the possibility of an
effect of concern occurring as a result of a one day or single exposure.
 For the purposes of assessing acute dietary risk for zeta-cypermethrin,
FMC has used the NOEL of 10.0 mg/kg/day from the zeta-cypermethrin acute
neurotoxicity study in rats with an uncertainty factor (UF) of 100
(acute RfD = 0.10 mg/kg/day).  The LEL of 50.0 mg/kg/day was based on
clinical signs.  This acute dietary endpoint is used to determine acute
dietary risks to all population subgroups.  Available information on
anticipated residues, monitoring data and percent crop treated was
incorporated into a Tier 3 analysis, using Monte Carlo modeling for
commodities that may be consumed in a single serving.  These assessments
show that the percent acute Population Adjusted Dose (%aPAD) all fall
below the EPA’s level of concern ((100%).   The 95th percentile of
exposure for the overall U. S. population was estimated to be 0.002448
mg/kg/day (%aRfD of 2.45); 99th percentile 0.007176 mg/kg/day (%aRfD of
7.18); and 99.9th percentile 0.024759 mg/kg/day (%aRfD of 24.76).  The
95th percentile of exposure for all infants (< 1 year) was estimated to
be 0.005153 mg/kg/day (%aRfD of 5.15); 99th percentile 0.012833
mg/kg/day (%aRfD of 12.83); and 99.9th percentile 0.035742 mg/kg/day
(%aRfD of 35.74). The 95th percentile of exposure for children 1 to 2
years old and children 3 to 5 years old was estimated to be,
respectively,  0.006932 mg/kg/day (%aRfD of 6.93) and 0.004758 mg/kg/day
(%aRfD of 4.76); 99th percentile 0.016035 mg/kg/day (%aRfD of 16.03) and
0.011416 (%aRfD of 11.42); and 99.9th percentile 0.053308 mg/kg/day
(%aRfD of 53.31) and 0.047651 (%aRfD of 47.65). The 95th percentile of
exposure for females (13-49 years) was estimated to be 0.001983
mg/kg/day (%aRfD of 1.98); 99th percentile 0.005391 mg/kg/day (%aRfD of
5.39); and 99.9th percentile 0.020292 mg/kg/day (%aRfD of 20.29). 
Therefore, FMC concludes that the acute dietary risk of
zeta-cypermethrin, as estimated by the dietary risk assessment, does not
appear to be of concern.

2.  Infants and children.  a.  General.  In assessing the potential for
additional sensitivity of infants and children to residues of
zeta-cypermethrin, FMC considered data from developmental toxicity
studies in the rat and rabbit, and a two-generation reproductive study
in the rat.  The data demonstrated no indication of increased
sensitivity of rats to zeta-cypermethrin or rabbits to cypermethrin in
utero and/or postnatal exposure to zeta-cypermethrin or cypermethrin. 
The developmental toxicity studies are designed to evaluate adverse
effects on the developing organism resulting from pesticide exposure
during prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals and data on systemic
toxicity.  FFDCA section 408 provides that EPA may apply an additional
margin of safety for infants and children in the case of threshold
effects to account for pre- and post-natal toxicity and the completeness
of the database.  

b. Developmental toxicity studies.  In the prenatal developmental
toxicity studies in rats and rabbits, there was no evidence of
developmental toxicity at the highest doses tested (35.0 mg/kg/day in
rats and 700 mg/kg/day in rabbits).  Decreased body weight gain was
observed at the maternal LOEL in each study; the maternal NOEL was
established at 12.5 mg/kg/day in rats and 100 mg/kg/day in rabbits.

c.  Reproductive toxicity study. In the two-generation reproduction
study in rats, offspring toxicity (body weight) and parental toxicity
(body weight, organ weight, and clinical signs) was observed at 27.0
mg/kg/day and greater.  The parental systemic NOEL was 7.0 mg/kg/day and
the parental systemic LOEL was 27.0 mg/kg/day.  There were no
developmental (pup) or reproductive effects up to 45.0 mg/kg/day,
highest dose tested.

d.  Pre- and post-natal sensitivity.  i.   Pre-natal. There was no
evidence of developmental toxicity in the studies at the highest doses
tested in the rat (70.0 mg/kg/day) or in the rabbit (700 mg/kg/day). 
Therefore, there is no evidence of a special dietary risk (either acute
or chronic) for infants and children which would require an additional
safety factor.

ii.  Post-natal. Post-natal. Based on the absence of pup toxicity up to
dose levels which produced toxicity in the parental animals, there is no
evidence of special post-natal sensitivity to infants and children in
the rat reproduction study.

e.  Conclusion.  Based on the above, FMC concludes that reliable data
support use of the standard 100-fold uncertainty factor, and that an
additional uncertainty factor is not needed to protect the safety of
infants and children.  As stated above, aggregate exposure assessments
utilized significantly less than 1 percent of the RfD for either the
entire U. S. population or any of the 26 population subgroups including
infants and children.  Therefore, it may be concluded that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to cypermethrin residues.

F.  International Tolerances. 

There are no Canadian, or Mexican residue limits for residues of
cypermethrin or zeta-cypermethrin in or on representative commodities
for oilseed crops.

The Codex MRLs for cypermethrin are oilseed, except peanut at 0.2 ppm.

ZETA.IR4.AUG2007

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