[Federal Register Volume 62, Number 186 (Thursday, September 25, 1997)]
[Notices]
[Pages 50337-50367]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25499]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-767; FRL-5748-2]
Notice of Filing of Pesticide Petitions
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 the docket control number PF-767, must
be received on or before October 27, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT:By mail: George LaRocca, Registration
Division [PM-13], Office of Pesticide Programs, 401 M St., SW.,
Washington, DC 20460. Office location, telephone number and e-mail
address: Rm. 204, Crystal Mall #2, 1921 Jefferson Davis Hwy.,
Arlington, VA, (703) 305-6100, e-mail: larocca.george@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: 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.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-767] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket controlnumber [PF-767] and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: September 19, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
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. AgrEvo USA Company
PP 2F4055, 6F3436, 4F2993, 6F3309
EPA has received a request from AgrEvo USA Company (acting as
registered US agent for Hoechst Schering AgrEvo, S. A., Little Falls
Centre, 2711 Centerville Road,
[[Page 50338]]
Wilmington, DE 19808, proposing pursuant to section 408(d) of the
Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR
part 180 by removing the time limitation for tolerances established for
residues of the insecticides and pyrethroid Deltamethrin and
Tralomethrin in or on the following raw agricultural commodities:
Deltamethrin - cottonseed at 0.04 parts per million (ppm) and
cottonseed oil at 0.2 ppm; and Tralomethrin - broccoli at 0.50 ppm,
cottonseed at 0.02 ppm, lettuce, head at 1.00 ppm, lettuce, leaf at
3.00 ppm, soybeans at 0.05 ppm, sunflower seed at 0.05 ppm and
cottonseed oil at 0.20 ppm. The IUPAC name for deltamethrin is [(1R,
3R)-3(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (S)-
alpha-cyano-3-phenoxybenzyl ester] and for tralomethrin is [(1R,
3S)3[(1' RS)(1',2',2',2',-tetrabromo-ethyl)]-2,2-dimethylcyclopropane-
carboxylic acid (S)-alpha-cyano-3-phenoxybenzyl ester]. The tolerances
were originally requested in Pesticide Petition Numbers 2F4055, 6F3436,
4F2993, 6F3309. Based on the fact that tralomethrin is rapidly
metabolized in plants and animals to deltamethrin, and the
toxicological profile of the two compounds is similar, it is
appropriate to consider combined exposure assessments for tralomethrin
and deltamethrin. EPA has determined that the request 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 permanent tolerance. Additional data may be needed before EPA rules
on the petition.
A. Residue Chemistry
1. Plant metabolism. Deltamethrin metabolism studies in tomatoes,
corn, apples, and cotton demonstrate the same metabolic pathway.
Furthermore, plant metabolism studies have been conducted following
application of tralomethrin in cotton, corn, cabbage, and tomatoes.
These studies have demonstrated that the metabolism of tralomethrin
involves debromination to deltamethrin and its isomers. Thus, a similar
metabolic pathway has been shown to occur in a variety of crops
following either direct application of deltamethrin (cotton, corn,
apples, and tomatoes) or in-plant formation of deltamethrin via
debromination of applied tralomethrin (tomatoes, cotton, corn, and
cabbage). As a result of this substantial information base, it is
concluded that the residues of toxicological concern in/on growing
crops following application of tralomethrin or deltamethrin are
tralomethrin, cis-deltamethrin, and its isomers, trans-deltamethrin and
alpha-R-deltamethrin.
2. Analytical method. Analytical methods for determining residues
of tralomethrin and deltamethrin in the commodities for which
registrations have been approved, have been previously submitted to,
and reviewed by, the Agency. These methods, based on gas
nyhromatography (GLC) equipped with an electron capture detector (ECD)
and a DB-1 (or equivalent) capillary column, are used for the
determination of tralomethrin, cis-deltamethrin, trans-deltamethrin,
and alpha-R-deltamethrin in various raw agricultural, animal derived,
and processed commodities. These methods were independently validated
and are appropriate for the determination of residues of tralomethrin
and deltamethrin in various food and feed commodities after application
of these ingredients to target growing crops, and after use in food/
feed handling establishments.
3. Magnitude of residues. Residues of tralomethrin, deltamethrin,
and its metabolites are not expected to exceed the established
tolerance levels as a result of the use of these active ingredients on
target crops.
B. Toxicological Profile
1. Acute toxicity. The acute oral LD50 values for
deltamethrin in the rat are 66.7 mg/kg for males, 86 mg/kg for females
and for tralomethrin 99 mg/kg for males, 157 mg/kg for females when
administered in sesame oil. The oral LD50 for deltamethrin
when administered in aqueous methyl cellulose was greater than 5,000
mg/kg for both sexes. The dermal LD50 in rabbits was greater
than 2,000 mg/kg for both materials. Inhalation 4-hour LC50
values in the rat are 2.2 mg/L for deltamethrin and greater than 0.286
mg/L for tralomethrin.
2. Genotoxicity. No indication of genotoxicity was noted in a
battery of in vivo and in vitro studies conducted with either
deltamethrin or tralomethrin.
3. Reproductive and developmental toxicity-- a. Deltamethrin A rat
developmental toxicity study conducted with deltamethrin indicated a
maternal no-observed-effect levels (NOEL) of 3.3 mg/kg/day based on
clinical observations, decreased weight gain and mortality. The
developmental NOEL was 11 mg/kg/day [highest dose tested] (HDT). In a
rabbit developmental toxicity study with deltamethrin, the maternal
NOEL was considered to be 10 mg/kg/day based on decreased defecation at
25 and 100 mg/kg/day, and mortality at 100 mg/kg/day. The developmental
NOEL was considered to be 25 mg/kg/day based on retarded ossification
of the pubic and tail bones at 100 mg/kg (HDT). A three-generation rat
reproduction study and a more recent, two-generation rat reproduction
study with deltamethrin indicated the NOEL for both parents and
offspring was 80 ppm (4-12 mg/kg/day for adults and 18-44 mg/kg/day for
offspring) based on clinical signs of toxicity, reduced weight gain and
mortality at 320 ppm (HDT).
b. Tralomethrin. In a rat developmental toxicity study with
tralomethrin the NOEL for maternal and developmental toxicity was
judged to be greater than or equal to 18 mg/kg/day (HDT). No evidence
of developmental toxicity was observed in either of two rabbit
developmental toxicity studies conducted with tralomethrin. In one
study, the maternal NOEL was 12.5 mg/kg/day based on mortality while
the developmental NOEL was judged to be greater than or equal to 25 mg/
kg/day (HDT). In the second study, the maternal NOEL was 8 mg/kg/day
based on body weight effects while the developmental NOEL was 32 mg/kg/
day (HDT). In a two-generation reproduction study with tralomethrin in
rats, the parental NOEL was 0.75 mg/kg/day based on body weight
deficits while the NOEL for offspring was 3.0 mg/kg/day, also based on
body weight deficits.
4. Subchronic toxicity-- a. Deltamethrin. A 90-day rat oral
toxicity study was conducted with deltamethrin which was administered
by gavage. The NOEL was judged to be 1.0 mg/kg/day based on reduced
body weight gain and slight hypersensitivity. In a more recent 90-day
rat dietary study with deltamethrin, the NOEL was judged to be 300 ppm
(23.9 mg/kg/day for males, 30.5 mg/kg/day for females)
based on uncoordinated movement, unsteady gait, tremors, increased
sensitivity to sound, shakes and spasmodic convulsions. The difference
in the NOEL between the two studies is attributed to the different
routes of exposure (gavage in oil vs. administered in diet). A 12-week
study was conducted with deltamethrin in mice. The NOEL was 300 ppm
(61.5 mg/kg/day in males and 77.0 mg/kg/day in females)
based on chronic contractions, convulsions, poor condition, decreased
weight gain and mortality. Two 13-week dog studies were conducted with
deltamethrin. In the first study, beagle dogs were administered
deltamethrin by capsule using PEG 200 as a vehicle. The NOEL for this
study was 1 mg/kg/day based on tremors, unsteadiness, jerking
movements, salivation, vomiting, liquid
[[Page 50339]]
feces and/or dilatation of the pupils. In the second study,
deltamethrin was administered by capsule without a vehicle to beagle
dogs. The NOEL for this study was 10 mg/kg/day based on unsteady gait,
tremors, head shaking, vomiting and salivation. The difference in
toxicity between the two studies is attributed to the enhanced
absorption resulting from the use of PEG 200 as a vehicle in the first
study. A 21-day dermal toxicity study was conducted with deltamethrin
in rats. The NOEL for systemic toxicity was determined to be 1,000 mg/
kg/day. In a subchronic inhalation study, rats were exposed to
aerosolized deltamethrin for 6 hours per day, 5 days per week, for a
total of 14 days over 3 weeks. Based on slightly decreased body weights
and neurological effects at higher dose levels, it was concluded that 3
g/l was the NOEL for systemic effects in this study.
b. Tralomethrin. Tralomethrin was administrated by gavage in corn
oil to rats for 13 weeks. Based on mortality, decreased activity and
motor control, soft stools, labored breathing and significantly lower
absolute and relative mean liver weights, the NOEL was considered to be
1 mg/kg/day. Tralomethrin was administered by capsule to beagle dogs
for 13 weeks. The NOEL for this study was 1.0 mg/kg/day based on
refusal of milk supplement, tremors, exaggerated patellar response,
unsteadiness and uncoordinated movement. A 21-day dermal toxicity study
was conducted with tralomethrin on rats. No systemic effects were
observed, therefore, the systemic NOEL for this study was 1,000 mg/kg/
day.
5. Chronic toxicity-- a. Deltamethrin. Deltamethrin was
administered in the diet to beagle dogs for 2 years. No treatment-
related effects were observed and the NOEL was judged to be 40 ppm
(1.1 mg/kg/day). In a more recent study, deltamethrin was
administered by capsule (without a vehicle) to beagle dogs for 1-year.
The NOEL in this study was considered to be 1 mg/kg/day based on
clinical signs, decreased food consumption and changes in several
hematology and blood chemistry parameters. Two rat chronic toxicity/
oncogenicity studies were conducted with deltamethrin. In the first
study, the test substance was administered via the diet to rats for 2
years. The NOEL for this study was 20 ppm (1 mg/kg/day)
based on slightly decreased weight gain. In a more recent study,
deltamethrin was administered to rats in the diet for 2 years. The NOEL
for this study was considered to be 25 ppm (1.1 and 1.5 mg/
kg/day for males and females, respectively), based on neurological
signs, weight gain effects and increased incidence and severity of
eosinophilic hepatocytes and/or balloon cells. No evidence of
carcinogenicity was noted in either study. Two mouse oncogenicity
studies were conducted with deltamethrin. In the first study,
deltamethrin was administered in the diet for 2 years. No adverse
effects were observed and the NOEL was judged to be 100 ppm
(12 and 15 mg/kg/day, respectively, for males and females).
In a more recent study, deltamethrin was administered in the diet to
mice for 97 weeks. The NOEL was considered to be 1,000 ppm
(15.7 and 19.6 mg/kg/day) based on a higher incidence of
poor physical condition and a slight transient weight reduction. There
was no evidence of oncogenicity in either study.
b. Tralomethrin. Tralomethrin was administered to beagle dogs by
capsule for 1-year at initial dosages of 0, 0.75, 3.0 and 10.0 mg/kg/
day. Due to trembling, ataxia, prostration and convulsions, the high
dosage was lowered to 8 mg/kg/day at study week 4 and lowered again to
6 mg/kg/day on study week 14. On the fourteenth week of study, the 0.75
mg/kg/day dosage was raised to 1.0 mg/kg/day. Based on body weight
changes, convulsions, tremors, ataxia and salivation, the NOEL for this
study was considered to be 1 mg/kg/day. Tralomethrin was administered
by gavage to rats for 24 months. The NOEL for this study was 0.75 mg/
kg/day based on salivation, uncoordinated movement, inability to
support weight on limbs and decreased body weight parameters. No
evidence of carcino-genicity was observed. A 2-year mouse oncogenicity
study was conducted with tralomethrin administered by gavage. The NOEL
was judged to be 0.75 mg/kg/day based on higher incidences of
dermatitis and mortality, salivation, uncoordinated involuntary
movements and aggressiveness. No evidence of oncogenicity was observed.
6. Animal metabolism-- a. Deltamethrin. The absorption of
deltamethrin appears to be highly dependent upon the route and vehicle
of administration. Once absorbed, deltamethrin is rapidly and
extensively metabolized and excreted, primarily within the first 48
hours.
b. Tralomethrin. Tralomethrin is rapidly metabolized to
deltamethrin after debromination. The metabolic pattern of the
debrominated tralomethrin is exactly the same as that of the metabolic
pattern of deltamethrin.
7. Neurotoxicity. Acute delayed neurotoxicity studies in hens were
conducted for both deltamethrin and tralomethrin. In both cases, the
study results were negative indicating that neither material causes
delayed neurotoxicity.
8. Endocrine effects. No special studies have been conducted to
investigate the potential of deltamethrin or tralomethrin to induce
estrogenic or other endocrine effects. However, the standard battery of
required toxicity studies has been completed. These studies include an
evaluation of the potential effects on reproduction and development,
and an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure. These studies are generally considered
to be sufficient to detect any endocrine effects, yet no such effects
were detected. Thus, the potential for deltamethrin or tralomethrin to
produce any significant endocrine effects is considered to be minimal.
C. Aggregate Exposure
Based on the fact that tralomethrin is rapidly metabolized in
plants and animals to deltamethrin, and the toxicological profile of
the two compounds is similar, it is appropriate to consider combined
exposure assessments for tralomethrin and deltamethrin. Deltamethrin
and tralomethrin are broad spectrum insecticides used to control pests
of crops, ornamental plants and turf, and domestic indoor and outdoor
(including dog collars), commercial, and industrial food use areas.
Thus, aggregate non-occupational exposure would include exposures
resulting from non-food uses in addition to consumption of potential
residues in food and water. Exposure via drinking water is expected to
be negligible since deltamethrin binds tightly to soil and rapidly
degrades in water.
1. Dietary exposure-- a. Food. Food tolerances have been
established (with expiration dates of November 15, 1997), for residues
of tralomethrin and/or deltamethrin and its metabolites in or on a
variety of raw agricultural commodities. These tolerances, in support
of registrations, currently exist for residues of tralomethrin on
broccoli, cottonseed, head lettuce, leaf lettuce, soybeans, sunflower
seed, and cottonseed oil. Also, such tolerances, in support of
registrations, currently exist for deltamethrin on cottonseed and
cottonseed oil. Additionally, tolerances which are not time-limited
have been established for tralomethrin to support its use in food/feed
handling establishments, and for deltamethrin on tomatoes and
concentrated tomato products to support the importation of tomato
commodities treated with deltamethrin. Further, a food/feed
[[Page 50340]]
handling establishment use, and associated tolerances, is pending for
deltamethrin. Potential acute exposures from food commodities were
estimated using a Tier 3 acute dietary risk assessment (Monte Carlo
Analysis) following EPA guidance. Potential chronic exposures from food
commodities under the established food and feed additive tolerances for
deltamethrin and tralomethrin, plus the pending tolerances for
deltamethrin associated with use in food/feed handling areas, were
estimated using NOVIGEN's DEEM (Dietary Exposure Evaluation Model).
This chronic risk assessment was conducted using anticipated residues
based on field trial or monitoring data, percent crop treated, and
percent food handling establishments treated.
b. Drinking water. Tralomethrin and deltamethrin are immobile in
soil and, therefore, will not leach into groundwater. Additionally, due
to the insolubility and lipophilic nature of deltamethrin and
tralomethrin, 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 (PRZM3). 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 normally be treated before consumption. Based on
these analyses, the contribution of water to the dietary risk estimate
is negligible.
2. Non-dietary exposure. As noted above, deltamethrin and
tralomethrin are broad spectrum insecticides registered for use on a
variety of food and non-food agricultural commodities. Additionally,
registrations are held for non-agricultural applications including turf
and lawn care treatments, broadcast carpet treatments (professional use
only), indoor fogger, spot, crack and crevice treatments, insect baits,
lawn and garden sprays and indoor and outdoor residential, industrial
and institutional sites including those for Food/Feed Handling
Establishments.
To evaluate non-dietary exposure, the ``flea infestation control''
senario was chosen to represent a plausible but worst case non-dietary
(indoor and outdoor) non-occupational exposure. This scenario provides
a situation where deltamethrin and/or tralomethrin is commonly used and
they can be used concurrently for a multitude of uses, e.g., spot and/
or broadcast treatment of infested indoor surfaces such as carpets and
rugs, treatment of pets and treatment of the lawn. This hypothetical
situation provides a very conservative, upper bound estimate of
potential non-dietary exposures. Consequently, if health risks are
acceptable under these conditions, the potential risks associated with
other more likely scenarios would also be acceptable.
Because tralomethrin is rapidly metabolized to deltamethrin, and
the toxicology profiles of deltamethrin and tralomethrin are virtually
identical, a non-dietary and aggregate (non-dietary + chronic dietary)
exposure/risk assessment has been conducted for the combination of both
active ingredients. The total exposure to both materials was expressed
as ``deltamethrin equivalents'' and these were compared to the
toxicology endpoints identified for deltamethrin.
C. Cumulative Effects
When considering a tolerance, the Agency must consider ``available
information'' concerning the cumulative effects of a particular
pesticides residues and ``other substances that have a common mechanism
of toxicity''. AgrEvo USA Company, acting as registered US agent for
Hoechst Schering AgrEvo SA, believes that ``available information'' in
this context includes not only toxicity, chemistry, and exposure data,
but also scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments.
Further, AgrEvo does not have, at this time, available data to
determine whether tralomethrin and/or deltamethrin have a common
mechanism of toxicity with other substances. For the purposes of this
tolerance action, therefore, no assumption has been made that
tralomethrin and/or deltamethrin have a common mechanism of toxicity
with other substances.
AgrEvo USA Company, acting as registered US agent for Hoechst
Schering AgrEvo SA, will submit information for EPA to consider
concerning potential cumulative effects of deltamethrin and/or
tralomethrin consistent with the schedule established by EPA at 62 FR
42020 (August 4, 1997,) and other EPA publications pursuant to the Food
Quality Protection Act (FQPA).
D. Safety Determination
1. U.S. population. The toxicity and residue data base for
deltamethrin and tralomethrin are considered to be valid, reliable and
essentially complete according to existing regulatory requirements. No
evidence of oncogenicity has been observed for either compound. For
acute exposures, the toxicology endpoint from the deltamethrin rat
development toxicity study, 3.3 mg/kg/day, is used. For chronic
exposures to deltamethrin and tralomethrin, the Reference Dose (RfD) of
0.01 mg/kg bodyweight/day established for deltamethrin based on the
NOEL from the 2-year rat feeding study and a 100-fold safety factor to
account for interspecies extrapolation and intraspecies variation is
used.
For the overall U.S. population, acute dietary exposure at the
99.9th percentile results in a Margin of Exposure (MOE) of 5,382; the
MOE for the 99th percentile is 16,661; and at the 95th percentile the
MOE is 57,470. For the overall US population, chronic dietary exposure
results in a utilization of 0.2 percent of the reference dose. Using an
upper bound estimate of potential non-dietary exposures for a worst
case scenario (flea treatment) results in an MOE of 160,000 for adults.
Utilizing the scenario of chronic dietary exposure plus an upper bound
estimate of potential non-dietary exposure from a worst case scenario
(flea treatment), it is shown that for aggregate exposure to
deltamethrin and tralomethrin there is an MOE of 83,000 for adults.
There is generally no concern for MOE greater than 100. For chronic
exposure, there is generally no concern for exposure below 100 percent
of the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health.
In conclusion, there is reasonable certainty that no harm will
result to the U.S. population, in general, from dietary or aggregate
exposure to either deltamethrin and/or tralomethrin.
2. Infants and children. Data from developmental toxicity studies
in rats and rabbits, and multigeneration reproduction studies in rats
are generally used to assess the potential for increased sensitivity of
infants and children. The developmental toxicity studies are designed
to evaluate adverse effects on the developing organism
[[Page 50341]]
resulting from pesticide exposure during prenatal development.
Reproduction studies provide information relating to reproductive and
other effects on adults and offspring from pre-natal and post-natal
exposure to the pesticide. None of these studies conducted with
deltamethrin or tralomethrin indicated developmental or reproductive
effects as a result of exposure to these materials.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre-and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects in children is
complete. Although no indication of increased susceptibility to younger
animals was noted in any of the above studies, or in the majority of
studies with other pyrethroids, several recent publications have
reported that deltamethrin is more toxic to neonate and weanling
animals than to adults. However, a joint industry group currently
investigating this issue was unable to reproduce these findings.
Furthermore, the RfD (0.01 mg/kg/day) that has been established for
deltamethrin is already more than 1,000-fold lower than the lowest NOEL
from the developmental and reproduction studies. Therefore, the RfD of
0.01 mg/kg/day is appropriate for assessing chronic aggregate risk to
infants and children and an additional uncertainty factor is not
warranted. Also, the NOEL of 3.3 mg/kg/day from the rat developmental
toxicity study is appropriate to use in acute dietary, short term non-
dietary, and aggregate exposure assessments.
For the population subgroup described as non-nursing infants, less
than 1 year old, the MOE for acute dietary exposure at the 99.9th
percentile is 13,853; at the 99th percentile the MOE is 74,022; and at
the 95th percentile the MOE is 663,629. For the population subgroup
described as children 1-6 years old, the MOE for acute dietary exposure
is 2,300 for the 99.9th percentile; at the 99th percentile the MOE is
10,409; and at the 95th percentile the MOE is 42,070. For non-nursing
infants, chronic dietary exposure results in a utilization of 0.3
percent of the reference dose, and for children 1-6 years old 0.4
percent of the reference dose is utilized. Using an upper bound
estimate of potential non-dietary exposures for a worst case scenario
(flea treatment) results in an MOE of 6,100 for infants less than 1
year old, and an MOE of 6,600 for children 1-6 years old. Utilizing the
scenario of chronic dietary exposure plus an upper bound estimate of
potential non-dietary exposure from a worst case scenario (flea
treatment) it is shown that for aggregate exposure to deltamethrin and
tralomethrin, there is an MOE of 5,800 for infants less than 1-year
old, and an MOE of 6,100 for children 1-6 years old. There is generally
no concern for MOE s greater than 100. For chronic exposure, there is
generally no concern for exposure below 100 percent of the RfD because
the RfD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health.
In summary, there is reasonable certainty that no harm will result
to infants and children from aggregate exposure to either deltamethrin
or tralomethrin.
E. International Tolerances
The proposed/established CODEX maximum residue levels (MRL) and for
deltamethrin are as follows: cotton at 0.05 ppm and food/feed handling
uses at 0.05 ppm. As far as can be determined at this time, no CODEX
MRL's are established or proposed for tralomethrin.
F. Conclusions
The existing tolerances for deltamethrin and tralomethrin do not
pose a significant risk to human health, including that of children,
and are in compliance with the requirements of the FQPA of 1996.
Therefore, the time limitations associated with these tolerances can be
removed. (John Hebert)
2. Bayer Corporation
PP 4F3046, 9F3731, 3F4204, 4F4309, 4F4313, 2F4137, 4H5427, 9H5574,
3H5670, 4H5686, 4H5687
EPA has received a request regarding pesticide petitions (PP
4F3046, 9F3731, 3F4204, 4F4309, 4F4313, 2F4137, 4H5427, 9H5574, 3H5670,
4H5686, 4H5687) from Bayer Corporation, 8400 Hawthorn Road, P.O. Box
4913, Kansas City, MO 64210 to remove the time limitations on the
established tolerances at 40 CFR Sec. 180.436, Sec. 185.1250 and
Sec. 186.1250 for the insecticide cyfluthrin, [cyano[4-fluoro-3-
phenoxyphenyl]-methyl-3-[2,2-dicloroethenyl]-2,2-dimethyl-
cyclopropanecarboxylate] in or on the raw agricultural commodities
alfalfa, forage, at 5.0 ppm; alfalfa, hay, at 10.0 ppm; aspirated grain
fractions at 300 ppm; carrots at 0.2 ppm; cattle, fat, at 1.0 ppm;
cattle, meat, at 0.4 ppm; cattle, meat by-products (mbyp) at 0.4 ppm;
corn, forage (sweet), at 15.0 ppm; corn, fodder (sweet), at 30 ppm;
corn (sweet, K+CWHR), at 0.05 ppm; cottonseed at 1.0 ppm; cottonseed,
oil, at 2.0 ppm; cottonseed, hulls, at 2.0 ppm; citrus, whole fruit, at
0.2 ppm; citrus oil, at 0.3 ppm; citrus dried pulp, at 0.3 ppm; eggs at
0.01 ppm; goats, fat, at 1.0 ppm; goats, meat, at 0.4 ppm; goats, meat
by-products (mbyp) at 0.4 ppm; hogs, fat, at 1.0 ppm; hogs, meat, at
0.4 ppm; hogs, meat by-products (mbyp) at 0.4 ppm; horses, fat, at 1.0
ppm; horses, meat, at 0.4 ppm; horses, meat by-products (mbyp) at 0.4
ppm; milkfat, at 15.0 ppm (representing 0.5 ppm in whole milk);
peppers, at 0.5 ppm; poultry, fat, at 0.01 ppm; poultry, meat, at 0.01
ppm; poultry, meat by-products (mbyp) at 0.01 ppm; radishes at 1.0 ppm;
sheep, fat, at 1.0 ppm; sheep, meat, at 0.4 ppm; sheep, meat by-
products (mbyp) at 0.4 ppm; sorghum, fodder, at 5.0 ppm; sorghum,
forage, at 2.0 ppm; sorghum, grain at 4.0 ppm, sunflower, forage, at
1.0 ppm; sunflower, seed, at 0.02 ppm; sugarcane, at 0.05 ppm;
sugarcane, molasses, at 0.2 ppm; tomatoes, at 0.2 ppm; tomato,
concentrated products, at 0.5 ppm; and tomato, pomace (wet and dry) at
5.0 ppm. All data requested by EPA have been submitted. Therefore, a
request for unconditional registration and removal of the time
limitations on established tolerances is being made.
Consistent with section 408(d) of FFDCA, as recently amended by the
Food Quality Protection Act, Bayer submitted a summary and
authorization for the summary to be published in the Federal Register
in a notice of receipt of the request. The summary represents the views
of Bayer; EPA is in the process of evaluating the request. Consistent
with section 408(d)(3), EPA is including the summary as a part of this
notice of filing. EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data support granting the
request.
A. Residue Chemistry
1. Plant metabolism. The metabolism of cyfluthrin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radio labeled cyfluthrin in various crops all showing
similar results. The residue of concern is cyfluthrin.
2. Analytical method. Adequate analytical methodology (gas/liquid
chromatography with an electron capture detector) is available for
enforcement purposes.
3. Magnitude of residues. Cyfluthrin is the active ingredient in
the registered end-use product Baythroid 2 Emulsifiable Pyrethroid
Insecticide, EPA Reg. No. 3125-351. Baythroid 2 is registered for use
on alfalfa, carrots,
[[Page 50342]]
citrus, cotton, peppers, radishes, sorghum, sugarcane, sweet corn,
sunflowers and tomatoes.
Tolerances to support these uses were proposed in pesticide
petitions 4F3046, 9F3731, 3F4204, 4F4309, 4F4313, 2F4137, and 4F4313
and food/feed additive petitions 4H5427, 9H5574, 3H5670, 4H5686, and
4H5687. Residue data covering all the uses associated with these
petitions have been previously submitted to EPA for review and have
been found by EPA to support the establishment of the tolerances.
Consequently, regulations establishing these tolerances were
promulgated in response to these petitions. See [53 FR 30676]
(cottonseed), [60 FR 28353] (carrots, radishes, peppers and tomatoes),
[60 FR 28353] (sugarcane), [61 FR 10678] (alfalfa, sunflowers, and
sweet corn), [61 FR 39883] (sorghum), and [62 FR 25518] (citrus).
B. Toxicological Profile
The database for cyfluthrin is current and complete. Toxicology
data cited in support of these tolerances include:
1. Acute toxicity. There is a battery of acute toxicity studies for
cyfluthrin supporting an overall toxicity Category II.
2. Genotoxicty. Mutagenicity tests were conducted, 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. An oral developmental
toxicity study in rats with a maternal and fetal NOEL of 10 milligrams/
kilogram of body weight/day (mg/kg bw/day) (highest dose tested).
An oral developmental toxicity study in rabbits with a maternal
NOEL of 20 mg/kg bw/day and a maternal Lowest Effect Level (LEL) of 60
mg/kg bw/day, based on decreased body weight gain and decreased food
consumption during the dosing period. A fetal NOEL of 20 mg/kg bw/day
and a fetal LEL of 60 mg/kg bw/day were also observed in this study.
The LEL was based on increased resorptions and increased
postimplantation loss.
A three-generation reproduction study in rats with systemic
toxicity NOELs of 7.5 and 2.5 mg/kg bw/day for parental animals and
their offspring, respectively. At higher dose levels, the body weights
of parental animals and their offspring were reduced.
4. Subchronic toxicity. A subchronic toxicity feeding study using
rats demonstrated a NOEL of 22.5 mg/kg bw/day, the highest dose tested.
A 6-month toxicity feeding study in dogs established a NOEL of 5
mg/kg bw/day. The LEL was 15 mg/kg bw/day based on clinical signs and
reduced thymus weights.
5. Chronic toxicity. A 12-month chronic feeding study in dogs
established a NOEL of 4 mg/kg bw/day. The lowest effect level (LEL) for
this study is established at 16 mg/kg bw/day, based on slight ataxia,
increased vomiting, diarrhea and decreased body weight.
A 24-month chronic feeding/ carcinogenicity study in rats
demonstrated a NOEL of 2.5 mg/kg bw/day and LEL of 6.2 mg/kg bw/day,
based on decreased body weights in males, decreased food consumption in
males, and inflammatory foci in the kidneys in females.
A 24-month carcinogenicity study in mice was conducted. Under the
conditions of the study there were no carcinogenic effects observed. A
24-month chronic feeding/carcinogenicity study in rats was conducted.
There were no carcinogenic effects observed under the conditions of the
study.
6. Animal metabolism. 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.
7. Metabolite toxicology. No toxicology data have been required for
cyfluthrin metabolites. The residue of concern is cyfluthrin.
8. Endocrine effects. 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-- Food. Dietary exposure was estimated using
Novigen's Dietary Exposure Evaluation Model (DEEMa) software; results
from field trial and processing studies; consumption data from the USDA
Continuing Surveys of Food Intake by Individuals (CSFIIs), conducted
from 1989 through 1992; and information on the percentages of the crop
treated with Cyfluthrin.
Cyfluthrin is registered for use in alfalfa, citrus, sweet corn,
cotton, sorghum, sunflower, sugarcane, carrots, peppers, radishes and
tomatoes. In addition, it has an import tolerance for hops. Various
formulations are registered for use in food handling establishments and
in combination with another active ingredient, for use in field corn,
pop corn and sweet corn.
Chronic dietary exposure estimates for the overall U.S. population
were 0.5% of the Reference dose (RfD) (0.008 mg/kg bw/day). For the
most highly exposed population subgroup, children 1 to 6 years of age,
the exposure was estimated to be 0.000062 mg/kg bw/day, or 0.8% of the
RfD. Acute dietary exposures were estimated for the overall US
population, females 13 years and older, children, ages 1-6 and 7-12
years, infants, non-nursing and nursing. The exposure was compared to
the NOEL of 20 mg/kg bw/day to estimate the Margins of Exposures
(MOEs).
For the overall U.S. population the 95th, 99th and 99.9th
percentile of exposure the MOEs were calculated as 29,981; 9,519; and
3,658 respectively.
For women aged 13 years and older the 95th, 99th and 99.9th
percentile of exposure the MOEs were calculcated as 45,996; 20,103 and
10,011 respectively.
Lastly, for the potentially highest exposed population subgroup,
non-nursing infants, the 95th, 99th and 99.9th percentile of exposure
to the MOEs were calculated at 16,107; 3,072; and 1,343, respectively.
2. Drinking water. Cyfluthrin is immobile in soil, therefore, will
not leach into groundwater. Additionally, due the insolubility and
lipophilic nature of cyfluthrin, 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 (PRZM3).
Based on this screening assessment, the potential concentrations of a
pyrethroid in ground water at 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 52 parts per trillion. Concentration in actual drinking water would
be much lower. Based on these analyses, the contribution of water to
the dietary risk estimate is negligible.
3. Non-dietary exposure. 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
[[Page 50343]]
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
(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="" moe.="" the="" large="" moes="" for="" cyfluthrin="" clearly="" demonstrate="" a="" substantial="" degree="" of="" safety.="" the="" total="" non-dietary="" moes="" are="" 3,800,="" 2,700,="" and="" 2,500="" for="" adults,="" children="" (1-6="" years),="" and="" infants=""><1 year),="" respectively.="" the="" aggregate="" moe="" for="" adults="" is="" approximately="" 3,800="" and="" the="" moes="" for="" infants="" and="" children="" exceed="" 2,500.="" the="" non-dietary="" methods="" used="" in="" the="" analyses="" can="" be="" characterized="" as="" highly="" conservative.="" this="" is="" due="" to="" the="" conservatism="" inherent="" in="" the="" calculation="" procedures="" and="" input="" assumptions.="" an="" example="" of="" this="" is="" the="" conservatism="" inherent="" in="" the="" jazzercise="" over="" representation="" of="" residential="" post-application="" exposures.="" it="" is="" important="" to="" acknowledge="" that="" these="" moes="" are="" likely="" to="" significantly="" underestimate="" actual="" moes="" due="" to="" a="" variety="" of="" conservative="" assumptions="" and="" biases="" inherent="" in="" the="" derivatization="" of="" exposure="" by="" this="" method.="" 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="" and="" supports="" the="" continued="" registration="" and="" use="" of="" residential,="" commercial,="" and="" agricultural="" products="" containing="" cyfluthrin.="" d.="" cumulative="" effects="" further,="" bayer="" does="" not="" have,="" at="" this="" time,="" available="" data="" to="" determine="" whether="" cyfluthrin="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" for="" the="" purposes="" of="" this="" tolerance="" action,="" therefore,="" no="" assumption="" has="" been="" made="" that="" cyfluthrin="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" bayer="" will="" submit="" information="" for="" epa="" to="" consider="" concerning="" potential="" cumulative="" effects="" of="" cyfluthrin="" consistent="" with="" the="" schedule="" established="" by="" epa="" in="" the="" federal="" register="" of="" august="" 4,="" 1997,="" (62="" fr="" 42020)="" and="" other="" epa="" publications="" pursuant="" to="" the="" food="" quality="" protection="" act.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" based="" on="" the="" exposure="" assessments="" described="" above="" and="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" it="" can="" be="" concluded="" that="" total="" aggregate="" exposure="" to="" cyfluthrin="" from="" all="" uses="" will="" utilize="" less="" than="" 1%="" percent="" of="" the="" rfd="" for="" chronic="" dietary="" exposures="" and="" that="" moes="" in="" excess="" of="" 1,000="" exist="" for="" aggregate="" exposure="" to="" cyfluthrin="" for="" non-occupational="" exposure.="" epa="" generally="" has="" no="" concerns="" for="" exposures="" below="" 100="" percent="" of="" the="" rfd,="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" margins="" of="" exposure="" of="" 100="" or="" more="" (300="" for="" infants="" and="" children)="" also="" indicate="" an="" adequate="" degree="" of="" safety.="" thus,="" it="" can="" be="" concluded="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" cyfluthrin="" residues.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" cyfluthrin,="" the="" data="" from="" developmental="" studies="" in="" both="" rat="" and="" rabbit="" and="" a="" two-generation="" reproduction="" study="" in="" the="" rat="" can="" be="" considered.="" the="" developmental="" toxicity="" studies="" evaluate="" any="" potential="" adverse="" effects="" on="" the="" developing="" animal="" resulting="" from="" pesticide="" exposure="" of="" the="" mother="" during="" prenatal="" development.="" the="" reproduction="" study="" evaluates="" any="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" through="" two="" generations,="" as="" well="" as="" any="" observed="" systemic="" toxicity.="" the="" toxicology="" data="" which="" support="" these="" tolerances="" include:="" an="" oral="" developmental="" toxicity="" study="" in="" rats="" with="" a="" maternal="" and="" fetal="" noel="" of="" 10="" mg/kg="" bw/day="" (hdt).="" an="" oral="" developmental="" toxicity="" study="" in="" rabbits="" with="" a="" maternal="" noel="" of="" 20="" mg/kg="" bw/day="" and="" a="" maternal="" lel="" of="" 60="" mg/kg="" bw/day,="" based="" on="" decreased="" body="" weight="" gain="" and="" decreased="" food="" consumption="" during="" the="" dosing="" period.="" a="" fetal="" noel="" of="" 20="" mg/kg="" bw/day="" and="" a="" fetal="" lel="" of="" 60="" mg/kg="" bw/day="" were="" also="" observed="" in="" this="" study.="" the="" lel="" was="" based="" on="" increased="" resorptions="" and="" increased="" postimplantation="" loss.="" an="" oral="" developmental="" toxicity="" study="" performed="" with="" beta-="" cyfluthrin,="" the="" resolved="" isomer="" mixture="" of="" cyfluthrin,="" has="" been="" submitted="" to="" the="" agency="" and="" is="" currently="" under="" review.="" a="" developmental="" toxicity="" study="" in="" rats="" exposed="" via="" inhalation="" to="" liquid="" aerosols="" of="" cyfluthrin="" revealed="" developmental="" toxicity,="" but="" only="" in="" the="" presence="" of="" maternal="" toxicity.="" the="" developmental="" noel="" was="" 0.46="">3 on the basis of reduced placental and fetal weights,
and delayed ossification. The NOEL for overt maternal toxicity was < 0.46="">3, the lowest dose tested (LDT).
A three-generation reproduction study in rats with systemic
toxicity NOELs of 7.5 and 2.5 mg/kg bw/day for parental animals and
their offspring, respectively. At higher dose levels, the body weights
of parental animals and their offspring were reduced. Another multiple-
generation reproduction study in rats has been submitted to the Agency
and is currently under review.
The Agency used the rabbit developmental toxicity study with a
maternal NOEL of 20 mg/kg bw/day to assess acute dietary exposure and
determine a MOE for the overall U.S. population and certain subgroups.
Since this toxicological endpoint pertains to developmental toxicity
the population group of concern for this analysis was women aged 13 and
above, the subgroup which most closely approximates women of child-
bearing age. The MOE is calculated as the ratio of the NOEL to the
exposure. The Agency calculated the MOE to be over 600. Generally,
MOE's greater than 100 for data derived from animal studies are
regarded as showing no appreciable risk.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal effects and the completeness of the
toxicity database.
The results of the three-generation study in rats provided evidence
suggesting that, with respect to effects of cyfluthrin on body weight,
pups were more sensitive than adult rats. Thus, the Agency determined
that an additional 3-fold uncertainty factor (UF) should be used in
risk assessments to ensure adequate protection of infants and children.
[[Page 50344]]
Generally, EPA considers MOEs of at least 100 to indicate an
adequate degree of safety. With an additional 3 x uncertainty factor,
this would be 300 for infants and children. Using the exposure
assessments described above and based on the described toxicity data
aggregate exposure to infants and children indicate a MOE in excess of
2,500. Thus, it can be concluded that there is a reasonable certainty
that no harm will result to infants and children from aggregate
exposure to cyfluthrin residues.
3. Conclusions. The available data indicate that there is
reasonable certainty of no harm from the aggregate exposure from all
currently registered uses of cyfluthrin. Thus, consistent with the
provisions of the FFDCA as amended August 3, 1996, the time limitations
on established cyfluthrin tolerance should be removed.
F. International Tolerances
Codex maximum residue levels (MRLs) are established for residues of
cyfluthrin on milk (0.01 mg/kg); cottonseed (0.05 mg/kg); peppers,
sweet (0.2 mg/kg); and tomatoes (0.5 mg/kg). (Stephanie Willett)
3. DuPont Agricultural Products
PP-7F2013
EPA has received a request from DuPont Agricultural Products, P. O.
Box 80038, Wilmington, DE 19880-0038 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 removing the time limitation for a
tolerance established for residues of the insecticide and pyrethroid
fenvalerate, including the s,s-enriched isomer esfenvalerate
(Asana XL Insecticide), ((S)-cyano-(3-phenoxyphenyl)methyl
(S)-4-chloro-alpha-(1-methylethyl)benzeneacetate in or on the raw
agricultural commodity cottonseed at 0.2 parts per million (ppm). The
tolerance was originally requested in PP-7F2013. EPA has determined
that the request 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 and chemical nature of residues
of fenvalerate in plants is adequately understood. The fate of
fenvalerate has been extensively studied using radioactive tracers in
plant and animal 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.
2. Analytical method. There is a practical analytical method
utilizing electron-capture gas chromatography with nitrogen phosphorous
detection available for enforcement with a limit of detection that
allows monitoring food with residues at or above tolerance levels.
3. Magnitude of residues. Tolerances are based on the sum of all
isomers of fenvalerate. Fenvalerate is a racemic mixture of four
isomers (about 25% each). This product was registered as
Pydrin . However since 1992, an S,S-isomer enriched
formulation, Asana (esfenvalerate), has been the only
fenvalerate formulation sold in the U.S. for agricultural use. Since
the S,S-isomer is the insecticidally active isomer, the use rate for
Asana is four times lower than that for Pydrin . A
petition is pending (PP-4F4329), to convert tolerances (still to be
expressed as the sum of all isomers) based on the use rates for
Asana. Bridging residue studies have shown Asana
residues to be 3-4 times lower than Pydrin residues.
EPA has established a tolerance of 0.2 ppm for fenvalerate on
cottonseed. Magnitude of residue and processing studies support this
tolerance. This request is for the removal of the time limitation
currently imposed on the tolerance of 0.2 ppm for fenvalerate on
cottonseed.
B. Toxicological Profile
The following studies have been submitted to EPA:
1. Acute toxicity. A rat acute oral study on esfenvalerate
technical has an LD50 of 87.2 milligram (mg)/kilogram (kg).
A rabbit acute dermal study on esfenvalerate has an LD50 of
>2,000 mg/kg. Acute inhalation on technical grade active ingredient
(a.i.) waived due to negligible vapor pressure. A primary eye
irritation test using esfenvalerate in the rabbit showed mild
irritation (conjunctivitis) that cleared by day 7. A primary dermal
irritation test using esfenvalerate in the rabbit which showed minimal
irritation that reversed within 72 hours after treatment. A dermal
sensitization test on esfenvalerate in guinea pigs which showed no
sensitization.
2. Genotoxicty. Esfenvalerate was not mutagenic in reverse mutation
assays in Salmonella and E. Coli in vitro assay in Chinese hamster lung
cells. Esfenvalerate did not induce chromosome aberrations in an in
vitro assay in Chinese hamster ovary 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 in HeLa cells.
3. Reproductive and developmental toxicity. In a pilot
developmental study in the rat with doses of 0, 1, 2, 3, 4, 5, and 20
mg/kg/day esfenvalerate maternal clinical signs of abnormal gait or
mobility occurred at 4 mg/kg/day and above. In a developmental study in
the rat with doses of 0, 2.5, 5, 10, and 20 mg/kg/day esfenvalerate by
gavage maternal signs observed at 2.5 mg/kg/day were erratic jerking
and extension of forelimbs, rapid side-to-side head movement, and
excessive grooming. There was no maternal No-Observed-Effect-Level
(NOEL) in the main study but a NOEL of 2 mg/kg/day was established on
the pilot study. There were no fetal or developmental effects in either
study at 20 mg/kg/day, the highest dose tested. Therefore, the fetal/
developmental NOEL was 20 mg/kg/day.
In a pilot developmental study in the rabbit with doses of 0, 2, 3,
4, 4.5, 5, and 20 mg/kg/day esfenvalerate by gavage. The maternal NOEL
was 2 mg/kg/day based on excessive grooming at 3 mg/kg/day and above.
In a developmental study in the rabbit with doses of 0, 3, 10, and 20
mg/kg/day esfenvalerate by gavage there was no maternal NOEL in the
main study, but a maternal NOEL of 2 mg/kg/day was established in the
pilot study. There were no fetal or developmental effects in either
study at the highest dose tested. Therefore, the fetal/developmental
NOEL was 20 mg/kg/day.
A two-generation feeding study with esfenvalerate in the rat at
dietary levels of 0, 75, 100, or 300 ppm. The high dietary
concentration was lowered to 150 ppm for the second generation. Very
mild body weight effects and sores at 75 ppm in both generations were
considered secondary effects caused by scratching related to skin
stimulation from dermal exposure. Therefore 75 ppm (4.2 mg/kg/day for
first generation parental males, 5.6 mg/kg/day for first generation
parental females, 6.0 mg/kg/day for second generation parental males,
and 7.3 mg/kg/day for second generation parental females) was
considered an No-Observed-Adverse-Effect-Level (NOAEL) for both adult
rats and their offspring. Effects were observed in adults and pups of
both generations at 100 ppm and above. Pups
[[Page 50345]]
were no more sensitive than adult animals.
4. Subchronic toxicity. A 90-day feeding study in rats was
conducted at 0, 75, 100, 125, and 300 ppm esfenvalerate with a NOEL of
125 ppm (6.3 mg/kg/day). This study provided intermediate dose levels
to supplement a 90-day feeding study in rats conducted at 0, 50, 150,
300 and 500 ppm esfenvalerate with a NOEL of 50 ppm (2.5 mg/kg/day)
based on jerky leg movements at 150 ppm (7.5 mg/kg/day) and above.
A 90-day feeding study in mice was conducted at 0, 50, 150, and 500
ppm esfenvalerate and 2,000 ppm fenvalerate with a NOEL of 50 ppm
esfenvalerate (10.5 mg/kg/day) based on lower glucose and triglycerides
at 150 ppm. Neurologic symptoms were observed with 500 ppm
esfenvalerate and 2,000 ppm fenvalerate.
A 3-month subchronic study in dogs is satisfied by a 1-year oral
study in dogs, in which the NOEL was 200 ppm (5 mg/kg/day).
A 21-day dermal study in rabbits with fenvalerate was conducted at
100, 300, and 1,000 mg/kg/day with an NOAEL of 1,000 mg/kg/day.
5. Chronic toxicity. In a 1-year study in which dogs were fed 0,
25, 50, or 200 ppm esfenvalerate with no treatment related effects at
any dietary level the NOEL 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 the 2-week pilot study used to select dose
levels for the chronic-dog study.
In a 20-month study with fenvalerate in mice fed 0, 10, 30, 100,
and 300 ppm the NOEL was 30 ppm ( 6 mg/kg/day) based on red
blood cell effects and granulomatous changes at 100 ppm. Fenvalerate
was not carcinogenic at any concentration.
In a 18-month study in mice fed 0, 35, 150, and 350 ppm
esfenvalerate. Mice fed the 350 ppm dose were sacrificed within the
first two months of the study, after excessive morbidity and mortality
due to self-trauma induced by pharmacological effects related to skin
stimulation. Therefore, data collected from the 350 ppm group were not
used in the evaluation of the oncogenic potential of esfenvalerate. The
NOEL 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 study with fenvalerate in rats fed 1, 5, 25, and 250
ppm a 1,000 ppm group was added to establish an effect level. The NOEL
was 250 ppm (12.5 mg/kg/day). At 1,000 ppm, hind limb weakness, lower
body weight, and higher organ-to-body 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 effects. 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. For purposes of assessing dietary exposure,
chronic and acute dietary assessments have been conducted using all
existing and pending tolerances for esfenvalerate. The toxicological
endpoints used in both dietary assessments are derived from maternal
NOEL's of 2.0 mg/kg/day from rat and rabbit teratology studies. There
were no fetal effects in these studies.
2. Food. A chronic dietary exposure assessment using anticipated
residues and monitoring data and adjusting for percent crop treated,
found the percentages of the Reference Dose (RfD) utilized by the most
sensitive sub-population (children 1-6 years) to be 5.2%. Chronic
exposure for the overall U.S. population was 2.1% of the RfD. This
assessment included pending tolerances and all food tolerances for
incidental residues from use in food handling establishments.
A Tier 3 acute dietary assessment indicated the most sensitive sub-
population was children 1-6 years with Margin of Exposures (MOEs) of
352, 200, and 103 at the 95th, 99th, and
99.9th percentile of exposure, respectively. The MOEs for
nursing infants are 410, 199, and 151 at the 95th,
99th, and 99.9th percentile of exposure,
respectively. The MOEs for non-nursing infants are 661, 270, and 134 at
the 95th, 99th, and 99.9th percentile
of exposure, respectively. The MOEs for the general population are 742,
352, and 170 at the 95th, 99th, and
99.9th percentile of exposure, respectively. This analysis
used field trial data to estimate exposure and market share information
for the percent of crop treated. It used Monte Carlo modeling and
appropriate processing factors for processed food and distribution
analysis. Food handling establishment commodities are not relevant to
this type of analysis and EPA methodology does not include them in Tier
3 exposure modeling.
3. Drinking water. Esfenvalerate is immobile in soil and,
therefore, will not leach into groundwater. Additionally, 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 (PRZM3).
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 pound model since drinking water derived from
surface water would be treated before consumption. Based on these
analyses, the contribution of water to the dietary risk estimate is
negligible.
4. 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
[[Page 50346]]
products, the very low amounts of active ingredient they contain,
combined with the low vapor pressure (1.5 x 10-9 millimeters
(mm) Mercury at 25 deg.C) and low dermal penetration, would result in
minimal inhalation and dermal exposure.
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 pet spray product
assessment indicated MOEs of 740,000, 2,600, and 2,500 for adults,
children 1-6 years, and children < 1="" year,="" respectively.="" the="" carpet="" and="" room="" treatment="" assessment="" indicated="" moes="" of="" 110,000,="" 4,500,="" and="" 4,200="" for="" adults,="" children="" 1-6="" years,="" and="" children="">< 1="" year,="" respectively.="" the="" lawn="" care="" assessment="" indicated="" moes="" of="" 700,000,="" 26,000,="" and="" 24,000="" for="" adults,="" children="" 1-6="" years,="" and="" children="">< 1="" year,="" respectively.="" 5.="" aggregate="" exposure--="" dietary="" and="" non-dietary.="" based="" on="" the="" toxicity="" endpoints="" selected="" for="" esfenvalerate,="" absorbed="" doses="" were="" combined="" and="" compared="" to="" the="" relevant="" systemic="" noel="" for="" estimating="" moes.="" the="" non-dietary="" risk="" analysis="" moes="" combined="" with="" the="" chronic="" dietary="" risk="" analysis="" moes="" indicated="" aggregate="" moes="" of="" 4,400,="" 860,="" and="" 1,000="" for="" adults,="" children="" 1-6="" years,="" and="" children="">< 1="" year,="" respectively.="" it="" is="" important="" to="" acknowledge="" that="" these="" moes="" are="" likely="" to="" significantly="" underestimate="" the="" actual="" moes="" due="" to="" a="" variety="" of="" conservative="" assumptions="" and="" biases="" inherent="" in="" the="" exposure="" assessment="" methods="" used="" for="" their="" derivation.="" therefore,="" it="" can="" be="" concluded="" that="" the="" potential="" non-dietary="" and="" dietary="" aggregate="" exposures="" for="" esfenvalerate="" are="" associated="" with="" a="" substantial="" degree="" of="" safety.="" the="" aggregate="" risk="" analyses="" demonstrate="" compliance="" with="" the="" health-based="" requirements="" of="" the="" food="" quality="" protection="" act="" of="" 1996="" (fqpa)="" (7="" u.s.c.="" 136="" note)="" and="" supports="" the="" continued="" registration="" and="" use="" of="" residential,="" agricultural,="" and="" commercial="" products="" containing="" this="" a.i.="" d.="" cumulative="" effects="" section="" 408(b)(2)(d)(v)="" of="" the="" ffdca="" requires="" that,="" when="" considering="" whether="" to="" establish,="" modify,="" or="" revoke="" a="" tolerance,="" the="" agency="" consider="" ``available="" information''="" concerning="" the="" cumulative="" effects="" of="" a="" particular="" pesticide's="" residues="" and="" ``other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity''.="" at="" this="" time,="" available="" methodologies="" do="" not="" exist="" to="" resolve="" the="" complex="" scientific="" issues="" concerning="" common="" mechanism="" of="" toxicity="" of="" pyrethroids="" in="" a="" meaningful="" way.="" dupont="" intends="" to="" submit="" information="" for="" epa="" to="" consider="" concerning="" potential="" cumulative="" effects="" of="" esfenvalerate="" consistent="" with="" the="" schedule="" established="" by="" epa="" at="" 62="" fr="" 42020="" (august="" 4,="" 1997)(frl-5734-6)="" and="" other="" epa="" publications="" pursuant="" to="" the="" fqpa.="" in="" consideration="" of="" potential="" cumulative="" effects="" of="" esfenvalerate="" 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="" esfenvalerate="" would="" be="" cumulative="" with="" those="" of="" other="" chemical="" compounds.="" in="" addition,="" since="" esfenvalerate="" does="" not="" appear="" to="" produce="" a="" toxic="" metabolite="" produced="" by="" other="" substances;="" only="" the="" potential="" risks="" of="" esfenvalerate="" have="" been="" considered="" in="" this="" assessment="" of="" its="" aggregate="" exposure.="" e.="" safety="" determination="" both="" the="" chronic="" and="" acute="" toxicological="" endpoints="" are="" derived="" from="" maternal="" noel's="" 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="" safety="" factor="" used="" for="" protection="" of="" adults="" is="" fully="" appropriate="" for="" the="" protection="" of="" infants="" and="" children;="" no="" additional="" safety="" factor="" is="" necessary.="" 1.="" u.s.="" population.="" a="" chronic="" dietary="" exposure="" assessment="" using="" anticipated="" residues,="" monitoring="" information,="" and="" percent="" crop="" treated="" indicated="" the="" percentage="" of="" the="" rfd="" utilized="" by="" the="" general="" population="" to="" be="" 2.1%.="" there="" is="" generally="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" 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="" of="" greater="" than="" 100="" is="" considered="" an="" adequate="" moe.="" a="" tier="" 3="" acute="" dietary="" exposure="" assessment="" found="" the="" general="" population="" to="" have="" moe's="" of="" 742,="" 352,="" 170="" at="" the="">th, 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.
The aggregate exposure to use of esfenvalerate as pet spray, carpet
treatment, lawn care, and in the diet indicated an MOE of 4,400 for
adults.
Therefore, 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. A chronic dietary exposure assessment
found the percentages of the RfD utilized by the most sensitive sub-
population to be 5.2% for children 1-6 years. The acute dietary
exposure assessment found the most sensitive sub-population to be
children 1-6 years with MOEs of 352, 200, and 103 at the
95th, 99th, and 99.9th percentile of
exposure, respectively. Nursing infants had MOEs of 410, 199, and 151
at the 95th, 99th, and 99.9th
percentile of exposure, respectively. Non-nursing infants had MOEs of
661, 270, and 134 at the 95th, 99th, and
99.9th percentile of exposure, respectively. The aggregate
exposure to use of esfenvalerate as pet spray, carpet treatment, lawn
care, and in the diet indicated an MOE of 860 for children 1-6 years
and an MOE of 1,000 for children < 1="" year.="" thus,="" there="" is="" reasonable="" certainty="" that="" no="" harm="" to="" infants="" and="" children="" will="" result="" from="" chronic="" dietary,="" acute="" dietary,="" non-dietary,="" or="" aggregate="" exposure="" to="" esfenvalerate="" residues.="" f.="" international="" tolerances="" codex="" maximum="" residue="" levels="" (mrl's)="" have="" been="" established="" for="" residues="" of="" fenvalerate="" on="" a="" number="" of="" crops="" that="" also="" have="" u.s.="" tolerances.="" several="" of="" these="" mrl's="" are="" different="" than="" the="" proposed="" u.s.="" tolerances="" for="" esfenvalerate.="" therefore,="" some="" harmonization="" of="" these="" maximum="" residue="" levels="" is="" desirable.="" (john="" hebert)="" 4.="" fmc="" corporation="" pp="" 2f2623,="" 4f2986,="" 3f2824,="" 7f3498,="" and="" 4f3011="" epa="" has="" received="" a="" request="" regarding="" pesticide="" petitions="" (pp="" 2f2623,="" 4f2986,="" 3f2824,="" 7f3498,="" and="" 4f3011)="" from="" fmc="" corporation,="" 1735="" market="" street,="" philadelphia,="" pa="" 19103.="" the="" request="" proposes="" to="" remove="" any="" time="" limitations="" on="" established="" tolerances="" for="" residues="" of="" the="" insecticide="" zeta-cypermethrin="" (s-cyano(3-phenoxyphenyl)methyl="">) cis, trans 3-(2,2-dichloroethenyl)-2,2-
dimethylcyclopropanecarboxylate) in or on the raw agricultural
commodities cottonseed at 0.5 ppm, pecans 0.05 ppm, lettuce, head at
10.0 ppm, onions, bulb at 0.10 ppm and cabbage at 2.0 ppm (established
at 40 CFR 180.418). These tolerances were established under (PP)
2F2623, 4F2986, 3F2824, 7F3498, and 4F3011. EPA has determined that the
request contains data or information regarding the elements set forth
in
[[Page 50347]]
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 requests. Additional data may be needed before
EPA rules on the requests.
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 cotton, pecans, head
lettuce, bulb onions, and cabbage show that the established
cypermethrin tolerances on cottonseed of 0.5 ppm, pecans 0.05 ppm,
lettuce, head at 10.0 ppm, onions, bulb at 0.10 ppm and cabbage at 2.0
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 0.5 mg/kg/day based on the NOEL of 1.0
mg/kg/day from the cypermethrin chronic toxicity study in dogs and a
correction factor of two to account for the differences in the
percentage of the biologically active isomer. The LOEL of this study of
5.0 mg/kg/day was based on gastrointestinal disturbances observed in
the first week of the study. 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 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. The
systemic NOEL of 2.5 mg/kg/day based on the systemic NOEL of 5.0 mg/kg/
day from the cypermethrin chronic toxicity study in dogs and a
correction factor of two to account for the biologically active isomer
would also be used for short- and intermediate-term MOE calculations
(as well as acute, discussed in (1) above). This NOEL was based on
neurotoxic clinical signs observed in the first week of treatment of
the study.
5. Chronic toxicity--a. The RfD has been established at 0.0050 mg/
kg/day. This RfD is based on a cypermethrin chronic toxicity study in
dogs with a NOEL of 1.0 mg/kg/day, based on gastrointestinal
disturbances observed at the LOEL of 5.0 mg/kg/day during the first
week of the study; an uncertainty factor of 200 is used to account for
the differences in the percentage of the biologically active isomer.
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.
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. Tolerances have been established for
the residues of the insecticide zeta-cypermethrin, in or on a variety
of raw agricultural commodities. Tolerances, in support of
registrations, currently exist for residues of zeta-cypermethrin on
cottonseed; pecans; lettuce, head; onions, bulb; and cabbage and
livestock commodities of cattle, goats, hogs, horses, and sheep. For
the purposes of assessing the potential dietary exposure for these
existing tolerances, FMC has utilized available information on
anticipated residues, monitoring data and percent crop treated as
follows:
b. 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 0.5 mg/kg/
day based on the NOEL of 1.0 mg/kg/day from the cypermethrin chronic
toxicity study in dogs and a correction factor of two to account for
the differences in the percentage of the biologically active isomer.
The LOEL of this study of 5.0 mg/kg/day was based on gastrointestinal
disturbances observed in the first week of the study.
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
margins of exposure (MOE) are significantly greater than the EPA
standard of 100 for all subpopulations.
The 95th percentile of exposure for the overall U.S. population was
estimated to be 0.000528 mg/kg/day (MOE of 947); 99th
percentile 0.001746 mg/kg/day (MOE of 286); and 99.9th
percentile 0.004069 mg/kg/day (MOE of 123).
[[Page 50348]]
The 95th percentile of exposure for all infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000560="" mg/kg/day="" (moe="" of="" 892);="">th
percentile 0.000885 mg/kg/day (MOE of 565); and 99.9th
percentile 0.001260 mg/kg/day (MOE of 397).
The 95th percentile of exposure for nursing infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000207="" mg/kg/day="" (moe="" of="" 2,417);="">th
percentile 0.000569 mg/kg/day (MOE of 879); and 99.9th
percentile 0.001442 mg/kg/day (MOE of 347).
The 95th percentile of exposure for non-nursing infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000607="" mg/kg/day="" (moe="" of="" 824);="">th percentile 0.000925 mg/kg/day (MOE of 540); and
99.9th percentile 0.001190 mg/kg/day (MOE of 420).
The 95th percentile of exposure for children 1 to 6 years old and 7
to 12 years old (the most highly exposed population subgroup) was
estimated to be, respectively, 0.000740 mg/kg/day (MOE of 676) and
0.000596 mg/kg/day (MOE of 839); 99th percentile 0.001856
mg/kg/day (MOE of 269) and 0.002047 mg/kg/day (MOE 244); and
99.9th percentile 0.005021 mg/kg/day (MOE of 100) and
0.004843 (MOE of 103). 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.
c. Chronic exposure and risk. The acceptable reference dose (RfD)
of 0.0050 mg/kg/day for zeta-cypermethrin is based on a NOEL of 1.0 mg/
kg/day from the cypermethrin chronic dog study and an uncertainty
factor of 200 (used to account for the differences in the percentage of
the biologically active isomer). The endpoint effect of concern were
based on gastrointestinal disturbances observed in the first week of
the study at the LOEL of 5.0 mg/kg/day. A chronic dietary exposure/risk
assessment has been performed for zeta-cypermethrin using the above
RfD. 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
0.000017 mg/kg body weight (bwt)/day and utilize 0.3 percent of the RfD
for the overall U. S. population. The ARC for non-nursing infants (<1 year)="" and="" nursing="" infants=""><1 year)="" are="" estimated="" to="" be="" 0.000011="" mg/kg/="" day="" and="" 0.000002="" mg/kg/day="" and="" utilizes="" 0.2="" percent="" and="" 0="" percent="" of="" the="" rfd,="" respectively.="" the="" arc="" for="" children="" 1-6="" years="" old="" and="" children="" 7-12="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000027="" mg/kg="" bwt/day="" and="" 0.000022="" mg/kg="" bwt/day="" and="" utilizes="" 0.5="" percent="" and="" 0.4="" percent="" of="" the="" rfd,="" respectively.="" 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="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" cypermethrin,="" as="" estimated="" by="" the="" dietary="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" 2.="" 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.="" further,="" a="" screening="" evaluation="" of="" leaching="" potential="" of="" a="" typical="" pyrethroid="" was="" conducted="" using="" epa's="" pesticide="" root="" zone="" model="" (przm3).="" based="" on="" this="" screening="" assessment,="" the="" potential="" concentrations="" of="" a="" pyrethroid="" in="" groundwater="" at="" depths="" of="" 1="" and="" 2="" meters="" are="" essentially="" zero=""><0.001 parts="" per="" billion).="" 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="" parts="" per="" billion.="" 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="" normally="" be="" treated="" before="" consumption.="" based="" on="" these="" analyses,="" the="" contribution="" of="" water="" to="" the="" dietary="" risk="" estimate="" is="" negligible.="" therefore,="" fmc="" concludes="" that="" together="" these="" data="" indicate="" that="" residues="" are="" not="" expected="" to="" occur="" in="" drinking="" water.="" 3.="" 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="" fr="" 42020="" (august="" 4,="" 1997)="" and="" other="" epa="" publications="" pursuant="" to="" the="" food="" quality="" protection="" act.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" based="" on="" a="" complete="" and="" reliable="" toxicology="" database,="" the="" acceptable="" reference="" dose="" (rfd)="" for="" zeta-cypermethrin="" is="" 0.0005="" mg/kg/day,="" based="" on="" a="" noel="" of="" 1.0="" mg/kg/day="" and="" a="" loel="" of="" 5.0="" mg/kg/day="" from="" the="" cypermethrin="" chronic="" dog="" study="" and="" an="" uncertainty="" factor="" of="" 200.="" available="" information="" on="" anticipated="" residues,="" monitoring="" data="" and="" percent="" crop="" treated="" was="" incorporated="" into="" an="" analysis="" to="" estimate="" the="" anticipated="" residue="" contribution="" (arc)="" for="" 26="" population="" subgroups.="" the="" arc="" is="" generally="" considered="" a="" more="" realistic="" estimate="" than="" an="" estimate="" based="" on="" tolerance="" level="" residues.="" the="" arc="" are="" estimated="" to="" be="" 0.000017="" mg/kg="" body="" weight="" (bwt)/day="" and="" utilize="" 0.3="" percent="" of="" the="" rfd="" for="" the="" overall="" u.="" s.="" population.="" the="" arc="" for="" non-nursing="" infants=""><1 year)="" and="" nursing="" infants=""><1 year)="" are="" estimated="" to="" be="" 0.000011="" mg/kg/="" day="" and="" 0.000002="" mg/kg/day="" and="" utilizes="" 0.2="" percent="" and="" 0="" percent="" of="" the="" rfd,="" respectively.="" the="" arc="" for="" children="" 1-6="" years="" old="" and="" children="" 7-12="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000027="" mg/kg="" bwt/day="" and="" 0.000022="" mg/kg="" bwt/day="" and="" utilizes="" 0.5="" percent="" and="" 0.4="" percent="" of="" the="" rfd,="" respectively.="" 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="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" zeta-cypermethrin,="" as="" estimated="" by="" the="" aggregate="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" for="" the="" overall="" u.s.="" population,="" the="" calculated="" margins="" of="" exposure="" (moe)="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 947;="" 286="" at="" the="">th percentile; and 123 at the 99.9th
percentile.
For all infants < 1="" year="" old,="" the="" calculated="" margins="" of="" exposure="" (moe)="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 892;="" 565="" at="" the="">th percentile; and 397 at the 99.9th
percentile.
For nursing infants < 1="" year="" old,="" the="" calculated="" margins="" of="" exposure="" (moe)="" at="" [[page="" 50349]]="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 2,417;="" 879="" at="" the="">th percentile; and 347 at the 99.9th
percentile.
For non-nursing infants < 1="" year="" old,="" the="" calculated="" margins="" of="" exposure="" (moe)="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 824;="" 540="" at="" the="">th percentile; and 420 at the 99.9th
percentile. For the most highly exposed population subgroups, children
1-6 years old and children 7-12 years old, the calculated MOEs at the
95th percentile were estimated to be, respectively, 676 and 839; 269
and 244 at the 99th percentile; and 100 and 103 at the
99.9th percentile. Therefore, FMC concludes that there is
reasonable certainty that no harm will result from acute exposure to
zeta-cypermethrin.
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 (35.0 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. 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.
F. 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.
Subchronic toxicity-- Short- and intermediate-term toxicity. The
systemic NOEL of 2.5 mg/kg/day based on the systemic NOEL of 5.0 mg/kg/
day from the cypermethrin chronic toxicity study in dogs and a
correction factor of two to account for the biologically active isomer
would also be used for short- and intermediate-term MOE calculations
(as well as acute, discussed in (1) above). This NOEL was based on
neurotoxic clinical signs observed in the first week of treatment of
the study.
G. International Tolerances
There are no Codex, Canadian, or Mexican residue limits for
residues of zeta-cypermethrin in or on cotton, pecans, lettuce, head,
onions, bulb, or cabbage. (Stephanie Willett)
5. FMC Corporation
PP 2F2623, 4F2986, 3F2824, 7F3498, 4F3011, 4F4291
EPA has received a request regarding (PP 2F2623, 4F2986, 3F2824,
7F3498, 4F3011, 4F4291) from FMC Corporation, 1735 Market Street,
Philadelphia, PA 19103. The request proposes to remove any time
limitations on established tolerances for residues of the insecticide
cypermethrin (-alpha -Cyano(3-phenoxyphenyl)methyl
() cis, trans 3-(2,2-dichloroethenyl)-2,2-
dimethylcyclopropanecarboxylate) in or on the raw agricultural
commodities cottonseed at 0.5 ppm, pecans 0.05 ppm, lettuce, head at
10.0 ppm, onions, bulb at 0.10 ppm, cabbage at 2.0 ppm, Brassica, head
and stem at 2.0 ppm and Brassica, leafy at 14.0 ppm (established at 40
CFR 180.418). These tolerances were established under [PP] 2F2623,
4F2986, 3F2824, 7F3498, 4F3011, and 4F4291. EPA has determined that the
request 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 requests. Additional data may be needed before
EPA rules on the requests.
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 cotton, pecans, head
lettuce, bulb onions, cabbage, Brassica, head and stem, and Brassica,
leafy show that the established cypermethrin tolerances on cottonseed
of 0.5 ppm, pecans 0.05 ppm, lettuce, head at 10.0 ppm, onions, bulb at
0.10 ppm, cabbage at 2.0 ppm, Brassica, head and stem at 2.0 ppm and
Brassica, leafy at 14.0 ppm will not be exceeded when the 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 1.0 mg/kg/day from the chronic toxicity
study in dogs. The LOEL of this study of 5.0 mg/kg/day was based on
gastrointestinal disturbances observed in the first week of the study.
This acute dietary endpoint is used to determine acute dietary risks to
all population subgroups.
2. Genotoxicty. The following genotoxicity tests were all negative:
[[Page 50350]]
gene mutation (Ames); chromosome aberration in Chinese hamster bone
marrow cells; host mediated assay in mice; dominant lethal assay in
mice.
3. Reproductive and developmental toxicity. No evidence of
additional sensitivity to young rats or rabbits was observed following
pre- or postnatal exposure to cypermethrin.
a. A three-reproductive toxicity study in rats demonstrated a NOEL
of 2.5 mg/kg/day and a LOEL of 7.5 mg/kg/day for parental/systemic
toxicity based on decreased body weight gain in both sexes. There were
no adverse effects in reproductive performance. The NOEL for
reproductive toxicity was considered to be 37.5 mg/kg/day, the highest
dose level tested.
b. A developmental study in rats demonstrated a maternal NOEL of
17.5 mg/kg/day and a LOEL of 35 mg/kg/day based on decreased body
weight gain. There were no signs of developmental toxicity at 70 mg/kg/
day, the highest dose level tested.
c. A developmental study 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. The
systemic NOEL of 5.0 mg/kg/day from the chronic toxicity study in dogs
is also used for short- and intermediate-term MOE calculations (as well
as acute, discussed in (1) above). This NOEL was based on neurotoxic
clinical signs observed in the first week of treatment of the study.
5. Chronic toxicity-- a. The RfD has been established at 0.010 mg/
kg/day. This RfD is based on a chronic toxicity study in dogs with a
NOEL of 1.0 mg/kg/day, based on gastrointestinal disturbances observed
at the LOEL of 5.0 mg/kg/day during the first week of the study; an
uncertainty factor of 100 is used.
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.
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-- Food . Tolerances have been established for
the residues of cypermethrin, in or on a variety of raw agricultural
commodities. Tolerances, in support of registrations, currently exist
for residues of cypermethrin on cottonseed; pecans; lettuce, head;
onions, bulb; cabbage; Brassica, head and stem; Brassica, leafy and
livestock commodities of cattle, goats, hogs, horses, and sheep. A
pending tolerance for onions, green also exists. For the purposes of
assessing the potential dietary exposure for these existing and pending
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 cypermethrin, the maternal NOEL of 1.0
mg/kg/day from the chronic toxicity study in dogs was used. The LOEL of
this study of 5.0 mg/kg/day was based on gastrointestinal disturbances
observed in the first week of the study. This acute dietary endpoint
was 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 MOEs are significantly greater
than the EPA standard of 100 for all subpopulations. The
95th percentile of exposure for the overall U. S. population
was estimated to be 0.00067 mg/kg/day (MOE of 1,493); 99th
percentile 0.002109 mg/kg/day (MOE of 474); and 99.9th
percentile 0.004543 mg/kg/day (MOE of 220). The 95th
percentile of exposure for all infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000562="" mg/kg/day="" (moe="" of="" 1,780);="">th percentile 0.000896
mg/kg/day (MOE of 1,116); and 99.9th percentile 0.001362 mg/
kg/day (MOE of 734). The 95th percentile of exposure for
nursing infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000213="" mg/kg/day="" (moe="" of="" 4,706="" );="">th percentile 0.000587 mg/kg/day (MOE of
1,704); and 99.9th percentile 0.001660 mg/kg/day (MOE of
602). The 95th percentile of exposure for non-nursing
infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000613="" mg/kg/day="" (moe="" of="" 1,631);="" 99th="" percentile="" 0.000939="" mg/kg/day="" (moe="" of="" 1,065);="" and="">th percentile 0.001224 mg/kg/day (MOE of 817). The
95th percentile of exposure for children 1 to 6 years old
(the most highly exposed population subgroup) was estimated to be
0.000819 mg/kg/day (MOE of 1,221); 99th percentile 0.002400
mg/kg/day (MOE of 417); and 99.9th percentile 0.005694 mg/
kg/day (MOE of 176). Therefore, FMC concludes that the acute dietary
risk of cypermethrin, as estimated by the dietary risk assessment, does
not appear to be of concern.
ii. Chronic exposure and risk. The acceptable RfD is based on a
NOEL of 1.0 mg/kg/day from the chronic dog study and an uncertainty
factor of 100 is 0.010 mg/kg/day. The endpoint effect of concern were
based on gastrointestinal disturbances observed in the first week of
the study at the LOEL of 5.0 mg/kg/day. A chronic dietary exposure/risk
assessment has been performed for cypermethrin using the above RfD.
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 0.000024 mg/kg bwt/day and
utilize 0.2% of the RfD for the overall U. S. population. The ARC for
non-nursing infants (< 1="" year)="" and="" children="" 1-6="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000018="" mg/kg="" bwt/day="" and="" 0.000042="" mg/kg="" bwt/day="" and="" utilizes="" 0.2%="" and="" 0.4%="" of="" the="" rfd,="" respectively.="" 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%="" of="" the="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" cypermethrin,="" as="" estimated="" by="" the="" dietary="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" 2.="" drinking="" water.="" laboratory="" and="" field="" data="" have="" demonstrated="" that="" cypermethrin="" is="" immobile="" in="" soil="" and="" [[page="" 50351]]="" 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.="" further,="" a="" screening="" evaluation="" of="" leaching="" potential="" of="" a="" typical="" pyrethroid="" was="" conducted="" using="" epa's="" pesticide="" root="" zone="" model="" (przm3).="" based="" on="" this="" screening="" assessment,="" the="" potential="" concentrations="" of="" a="" pyrethroid="" in="" groundwater="" 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="" normally="" be="" treated="" before="" consumption.="" based="" on="" these="" analyses,="" the="" contribution="" of="" water="" to="" the="" dietary="" risk="" estimate="" is="" negligible.="" therefore,="" fmc="" concludes="" that="" together="" these="" data="" indicate="" that="" residues="" are="" not="" expected="" to="" occur="" in="" drinking="" water.="" 3.="" non-dietary="" exposure.="" analyses="" were="" conducted="" which="" included="" an="" evaluation="" of="" potential="" non-dietary="" (residential)="" applicator,="" post-="" application="" and="" chronic="" dietary="" aggregate="" exposures="" associated="" with="" cypermethrin="" products="" used="" for="" residential="" flea="" infestation="" control="" and="" agricultural/commercial="" applications.="" the="" aggregate="" analysis="" conservatively="" assumes="" that="" a="" person="" is="" concurrently="" exposed="" to="" the="" same="" active="" ingredient="" via="" the="" use="" of="" consumer="" or="" professional="" flea="" infestation="" control="" products="" and="" to="" chronic="" level="" residues="" in="" the="" diet.="" in="" the="" case="" of="" potential="" non-dietary="" health="" risks,="" conservative="" point="" estimates="" of="" non-dietary="" exposures,="" expressed="" as="" total="" systemic="" absorbed="" dose="" for="" each="" product="" use="" category="" (indoor="" total="" release="" fogger="" and="" lawn="" care)="" and="" exposed="" population="" group="" (adults,="" children="" 1-="" 6="" years,="" and="" infants="">< 1="" year)="" are="" compared="" to="" the="" systemic="" absorbed="" dose="" no-observed-effects-level="" (noel)="" for="" cypermethrin="" to="" provide="" estimates="" of="" the="" moes.="" based="" on="" the="" toxicity="" endpoints="" selected="" by="" epa="" for="" cypermethrin,="" inhalation="" and="" incidental="" oral="" ingestion="" absorbed="" doses="" were="" combined="" and="" compared="" to="" the="" relevant="" systemic="" noel="" for="" estimating="" moes.="" in="" the="" case="" of="" potential="" aggregate="" health="" risks,="" the="" above="" mentioned="" conservative="" point="" estimates="" of="" non-dietary="" exposure="" (expressed="" as="" systemic="" absorbed="" dose)="" are="" combined="" with="" estimates="" (arithmetic="" mean="" values)="" of="" chronic="" average="" dietary="" (oral)="" absorbed="" doses.="" these="" aggregate="" absorbed="" dose="" estimates="" are="" also="" provided="" for="" adults,="" children="" 1-6="" years="" and="" infants="">< 1="" year.="" the="" combined="" or="" aggregated="" absorbed="" dose="" estimates="" (summed="" across="" non-dietary="" and="" chronic="" dietary)="" are="" then="" compared="" with="" the="" systemic="" absorbed="" dose="" noel="" to="" provide="" estimates="" of="" aggregate="" moes.="" the="" total="" non-dietary="" moes="" (combined="" across="" all="" product="" use="" categories)="" for="" the="" inhalation="" +="" incidental="" oral="" routes="" are="" 97,000="" for="" adults,="" 2,100="" for="" children="" 1-6="" years="" old,="" and="" 1,900="" for="" infants="">< 1="" year).="" the="" aggregate="" moe="" (inhalation="" +="" incidental="" oral="" +="" chronic="" dietary,="" summed="" across="" all="" product="" use="" categories)="" was="" estimated="" to="" be="" 66,000="" for="" adults,="" 2,000="" for="" children="" 1-6="" years="" old="" and="" 1,900="" for="" infants=""><1 year).="" it="" can="" be="" concluded="" that="" the="" potential="" non-dietary="" and="" aggregate="" (non-dietary="" +="" chronic="" dietary)="" exposures="" for="" cypermethrin="" are="" associated="" with="" substantial="" margins="" of="" safety.="" 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="" fr="" 42020="" (august="" 4,="" 1997)="" and="" other="" epa="" publications="" pursuant="" to="" the="" food="" quality="" protection="" act.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" based="" on="" a="" complete="" and="" reliable="" toxicology="" database,="" the="" acceptable="" rfd="" is="" 0.010="" mg/kg/day,="" based="" on="" a="" loel="" of="" 5.0="" mg/kg/day="" from="" the="" chronic="" dog="" study="" and="" an="" uncertainty="" factor="" of="" 100.="" available="" information="" on="" anticipated="" residues,="" monitoring="" data="" and="" percent="" crop="" treated="" was="" incorporated="" into="" an="" analysis="" to="" estimate="" the="" anticipated="" residue="" contribution="" (arc)="" for="" 26="" population="" subgroups.="" the="" arc="" is="" generally="" considered="" a="" more="" realistic="" estimate="" than="" an="" estimate="" based="" on="" tolerance="" level="" residues.="" the="" arc="" are="" estimated="" to="" be="" 0.000024="" mg/kg="" body="" weight="" (bwt)/day="" and="" utilize="" 0.2%="" of="" the="" rfd="" for="" the="" overall="" u.="" s.="" population.="" the="" arc="" for="" non-nursing="" infants=""><1 year)="" and="" children="" 1-6="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000018="" mg/kg="" bwt/day="" and="" 0.000042="" mg/kg="" bwt/day="" and="" utilizes="" 0.2%="" and="" 0.4%="" of="" the="" rfd,="" respectively.="" 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%="" of="" the="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" cypermethrin,="" as="" estimated="" by="" the="" aggregate="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" for="" the="" overall="" u.s.="" population,="" the="" calculated="" moe="" at="" the="">th percentile was estimated to be 1,493; 474 at the
99th percentile; and 220 at the 99.9th
percentile. For all infants < 1="" year="" old,="" the="" calculated="" moe="" at="" the="">th percentile was estimated to be 1,780; 1,116 at the
99th percentile; and 734 at the 99.9th
percentile. For nursing infants < 1="" year="" old,="" the="" calculated="" moe="" at="" the="">th percentile was estimated to be 4,706; 1,704 at the
99th percentile; and 602 at the 99.9th
percentile. For non-nursing infants < 1="" year="" old,="" the="" calculated="" moe="" at="" the="">th percentile was estimated to be 1,631; 1,065 at the
99th percentile; and 817 at the 99.9th
percentile. For the most highly exposed population subgroup, children 1
- 6 years old, the calculated MOE at the 95th percentile was
estimated to be 1,221 ; 417 at the 99th percentile; and 176
at the 99.9th percentile. Therefore, FMC concludes that
there is reasonable certainty that no harm will result from acute
exposure to cypermethrin.
2. Infants and children-- a. General. In assessing the potential
for additional sensitivity of infants and children to residues of
cypermethrin, FMC considered data from developmental toxicity studies
in the rat and rabbit, and a three-reproductive study in the rat. The
data demonstrated no indication of increased sensitivity of rats or
rabbits to in utero and/or postnatal exposure to 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.
[[Page 50352]]
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 (70 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 17.5 mg/kg/day in rats and 100 mg/kg/day in rabbits.
c. Reproductive toxicity study. In the three-reproduction study in
rats, offspring toxicity (reduced mean litter weight gain) was observed
only at the highest dietary level tested (37.5 mg/kg/day), while
toxicity in the parental animals was observed at the lower treatment
levels. The parental systemic NOEL was 2.5 mg/kg/day and the parental
systemic LOEL was 7.5 mg/kg/day. There were no developmental (pup) or
reproductive effects up to 37.5 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 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. 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% 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 Codex, Canadian, or Mexican residue limits for
residues of cypermethrin in or on cotton; pecans; lettuce, head;
onions, bulb; cabbage; Brassica, head and stem, or Brassica, leafy.
(Stephanie Willett)
6. FMC Corporation, Agricultural Products Group
PP 6F3453, 7F3546, 5F4484, and 0E3921
EPA has received a request to remove the time limitations on
established tolerances from FMC Corporation, Agricultural Products
Group, 1735 Market Street, Philadelphia, Pennsylvania 19103 and from
the Interregional Research Project No. 4 (IR-4), New Jersey
Agricultural Experiment Station, P.O. Box 231, Rutgers University, New
Brunswick, NJ 08903. The request proposes to remove the time
limitations on established tolerances for residues of the insecticide
bifenthrin ((2-methyl [1,1'-biphenyl]-3-yl) methyl-3-(2-chloro-3,3,3,-
trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate), in or on
the raw agricultural commodities cottonseed at 0.5 parts per million
(ppm); corn, grain (field, seed, and pop) at 0.05 ppm; hops, dried at
10.0 ppm; and strawberries at 3.0 ppm (established at 40 CFR 180.442).
These tolerances were established under [PP] 6F3453, 7F3546, 5F4484,
and 0E3921. EPA has determined that the request 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 requests. Additional data may be needed before EPA rules on the
requests.
A. Residue Chemistry
1. Plant metabolism. The metabolism of bifenthrin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radiolabeled bifenthrin 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 bifenthrin 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) analytical method P-2132M.
3. Magnitude of residues. Crop field trial residue data from
studies conducted at the maximum label rates for cotton; corn (field,
seed, pop); strawberries, and hops show that the established bifenthrin
tolerances on cottonseed of 0.5 ppm; corn, grain (field, seed, and pop)
of 0.05 ppm; corn, fodder of 5.0 ppm; corn, forage of 2.0 ppm;
strawberries of 3.0 ppm, and hops, dried of 10.0 ppm will not be
exceeded when the bifenthrin 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 maternal NOEL of 1.0 mg/kg/day from the oral
developmental toxicity study in rats. The maternal LEL of this study of
2.0 mg/kg/day was based on tremors from day 7-17 of dosing. This acute
dietary endpoint is used to determine acute dietary risks to all
population subgroups.
2. Genotoxicty. The following genotoxicity tests were all negative:
gene mutation in Salmonella (Ames); chromosomal aberrations in Chinese
hamster ovary and rat bone marrow cells; HGPRT locus mutation in mouse
lymphoma cells; and unscheduled DNA synthesis in rat hepatocytes.
3. Reproductive and developmental toxicity-- a. Parental toxicity.
In the rat reproduction study, parental toxicity occurred as decreased
body weight at 5.0 mg/kg/day with a NOEL of 3.0 mg/kg/day. There were
no developmental (pup) or reproductive effects up to 5.0 mg/kg/day
(highest dose tested).
b. Post-natal sensitivity. 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.
4. Subchronic toxicity. Short- and intermediate-term toxicity. The
maternal NOEL of 1.0 mg/ kg/day from the oral developmental toxicity
study in rats is also used for short- and intermediate-term margins of
exposure (MOE) calculations (as well as acute, discussed in (1) above).
The maternal lowest effect level (LEL) of this study of 2.0 mg/kg/day
was based on tremors from day 7-17 of dosing.
5. Chronic toxicity--a. The reference dose (RfD) has been
established at 0.015 mg/kg/day. This RfD is based on a 1 year oral
feeding study in dogs with a NOEL of 1.5 mg/kg/day, based on
intermittent tremors observed at the Lowest Observed Effect Level
(LOEL) of 3.0 mg/kg/day; an uncertainty factor of 100 is used.
b. Bifenthrin is classified as a Group C chemical (possible human
carcinogen) based upon urinary bladder tumors in mice; assignment of a
Q* has not been recommended.
6. Animal metabolism. The metabolism of bifenthrin in animals is
adequately understood. Metabolism studies in rats with single doses
demonstrated that about 90% of the
[[Page 50353]]
parent compound and its hydroxylated metabolites are excreted.
7. Metabolite toxicology. The Agency has previously determined that
the metabolites of bifenthrin are not of toxicological concern and need
not be included in the tolerance expression.
8. Endocrine disruption. No special studies investigating potential
estrogenic or other endocrine effects of bifenthrin 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 bifenthrin has an adverse effect on the
endocrine system.
C. Aggregate Exposure
1. Dietary exposure-- Food. Tolerances have been established for
the residues of bifenthrin, in or on a variety of raw agricultural
commodities. Tolerances, in support of registrations, currently exist
for residues of bifenthrin on hops; strawberries; corn grain, forage,
and fodder; cottonseed; and livestock commodities of cattle, goats,
hogs, horses, sheep, and poultry. Additionally, time-limited tolerances
associated with emergency exemptions were recently established for
broccoli, cauliflower, raspberries, cucurbits, and canola. A pending
tolerance for artichokes also exists. For the purposes of assessing the
potential dietary exposure for these existing and pending tolerances as
well as the existing time-limited tolerances under FIFRA section 18
emergency exemptions, 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 1 day or single exposure. For the purposes of assessing acute
dietary risk for bifenthrin, the maternal NOEL of 1.0 mg/kg/day from
the oral developmental toxicity study in rats was used. The maternal
LEL of this study of 2.0 mg/kg/day was based on tremors from day 7-17
of dosing. This acute dietary endpoint was 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 MOE are significantly greater than the EPA standard of
100 for all subpopulations. The 95th percentile of exposure for the
overall U.S. population was estimated to be 0.000362 mg/kg/day (MOE of
2,762); 99th percentile 0.000732 mg/kg/day (MOE of 1,367); and 99.9th
percentile 0.002282 mg/kg/day (MOE of 438). The 95th percentile of
exposure for all infants < 1="" year="" old="" was="" estimated="" to="" be="" 0.000652="" mg/="" kg/day="" (moe="" of="" 1,534);="" 99th="" percentile="" 0.001138="" mg/kg/day="" (moe="" of="" 879);="" and="" 99.9th="" percentile="" 0.001852="" mg/kg/day="" (moe="" of="" 540).="" the="" 95th="" percentile="" of="" exposure="" for="" nursing="" infants="">< 1="" year="" old="" was="" estimated="" to="" be="" 0.000193="" mg/kg/day="" (moe="" of="" 5,180);="" 99th="" percentile="" 0.000456="" mg/="" kg/day="" (moe="" of="" 2,192);="" and="" 99.9th="" percentile="" 0.000475="" mg/kg/day="" (moe="" of="" 2,107).="" the="" 95th="" percentile="" of="" exposure="" for="" non-nursing="" infants="">< 1="" year="" old="" was="" estimated="" to="" be="" 0.000766="" mg/kg/day="" (moe="" of="" 1,306="" );="" 99th="" percentile="" 0.001203="" mg/kg/day="" (moe="" of="" 832);="" and="" 99.9th="" percentile="" 0.001977="" mg/kg/day="" (moe="" of="" 506).="" the="" 95th="" percentile="" of="" exposure="" for="" children="" 1="" to="" 6="" years="" old="" (the="" most="" highly="" exposed="" population="" subgroup)="" was="" estimated="" to="" be="" 0.000632="" mg/kg/day="" (moe="" of="" 1,583);="" 99th="" percentile="" 0.001196="" mg/kg/day="" (moe="" of="" 836);="" and="" 99.9th="" percentile="" 0.005277="" mg/kg/="" day="" (moe="" of="" 190).="" therefore,="" fmc="" concludes="" that="" the="" acute="" dietary="" risk="" of="" bifenthrin,="" as="" estimated="" by="" the="" dietary="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" ii.="" chronic="" exposure="" and="" risk.="" the="" acceptable="" rfd="" is="" based="" on="" a="" noel="" of="" 1.5="" mg/kg/day="" from="" the="" chronic="" dog="" study="" and="" an="" uncertainty="" factor="" of="" 100="" is="" 0.015="" mg/kg/day.="" the="" endpoint="" effect="" of="" concern="" were="" tremors="" in="" both="" sexes="" of="" dogs="" at="" the="" lel="" of="" 3.0="" mg/kg/day.="" a="" chronic="" dietary="" exposure/risk="" assessment="" has="" been="" performed="" for="" bifenthrin="" using="" the="" above="" rfd.="" 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="" 0.00002="" mg/kg="" body="" weight="" (bwt)/day="" and="" utilize="" 0.1%="" of="" the="" rfd="" for="" the="" overall="" u.s.="" population.="" the="" arc="" for="" non-nursing="" infants="">< 1="" year)="" and="" children="" 1-6="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000042="" mg/kg="" bwt/day="" and="" 0.000032="" mg/kg="" bwt/day="" and="" utilizes="" 0.3%="" and="" 0.2%="" of="" the="" rfd,="" respectively.="" 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%="" of="" the="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" bifenthrin,="" as="" estimated="" by="" the="" dietary="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" 2.="" drinking="" water.="" laboratory="" and="" field="" data="" have="" demonstrated="" that="" bifenthrin="" is="" immobile="" in="" soil="" and="" will="" not="" leach="" into="" groundwater.="" other="" data="" show="" that="" bifenthrin="" 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.="" further,="" a="" screening="" evaluation="" of="" leaching="" potential="" of="" a="" typical="" pyrethroid="" was="" conducted="" using="" epa's="" pesticide="" root="" zone="" model="" (przm3).="" based="" on="" this="" screening="" assessment,="" the="" potential="" concentrations="" of="" a="" pyrethroid="" in="" groundwater="" 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="" normally="" be="" treated="" before="" consumption.="" based="" on="" these="" analyses,="" the="" contribution="" of="" water="" to="" the="" dietary="" risk="" estimate="" is="" negligible.="" therefore,="" fmc="" concludes="" that="" together="" these="" data="" indicate="" that="" residues="" are="" not="" expected="" to="" occur="" in="" drinking="" water.="" 3.="" non-dietary="" exposure.="" analyses="" were="" conducted="" which="" included="" an="" evaluation="" of="" potential="" non-dietary="" (residential)="" applicator,="" post-="" application="" and="" chronic="" dietary="" aggregate="" exposures="" associated="" with="" bifenthrin="" products="" used="" for="" residential="" flea="" infestation="" control="" and="" agricultural/commercial="" applications.="" the="" aggregate="" analysis="" conservatively="" assumes="" that="" a="" person="" is="" concurrently="" exposed="" to="" the="" same="" active="" ingredient="" via="" the="" use="" of="" consumer="" or="" professional="" flea="" infestation="" control="" products="" and="" to="" chronic="" level="" residues="" in="" the="" diet.="" in="" the="" case="" of="" potential="" non-dietary="" health="" risks,="" conservative="" point="" estimates="" of="" non-dietary="" exposures,="" expressed="" as="" total="" systemic="" absorbed="" dose="" (summed="" across="" inhalation="" and="" incidental="" ingestion="" routes)="" for="" each="" relevant="" product="" use="" category="" (i.e.,="" lawn="" care)="" and="" receptor="" subpopulation="" (i.e.,="" adults,="" children="" 1-6="" years="" and="" infants="">< 1="" year)="" are="" compared="" to="" the="" systemic="" [[page="" 50354]]="" absorbed="" dose="" noel="" for="" bifenthrin="" to="" provide="" estimates="" of="" the="" moes.="" based="" on="" the="" toxicity="" endpoints="" selected="" by="" epa="" for="" bifenthrin,="" inhalation="" and="" incidental="" oral="" ingestion="" absorbed="" doses="" were="" combined="" and="" compared="" to="" the="" relevant="" systemic="" noel="" for="" estimating="" moes.="" in="" the="" case="" of="" potential="" aggregate="" health="" risks,="" the="" above-mentioned="" conservative="" point="" estimates="" of="" inhalation="" and="" incidental="" ingestion="" non-dietary="" exposure="" (expressed="" as="" systemic="" absorbed="" dose)="" are="" combined="" with="" estimates="" (arithmetic="" mean="" values)="" of="" chronic="" average="" dietary="" (oral)="" absorbed="" doses.="" these="" aggregate="" absorbed="" dose="" estimates="" are="" also="" provided="" for="" adults,="" children="" 1-6="" years="" and="" infants="">< 1="" year.="" the="" combined="" or="" aggregated="" absorbed="" dose="" estimates="" (summed="" across="" non-="" dietary="" and="" chronic="" dietary)="" are="" then="" compared="" with="" the="" systemic="" absorbed="" dose="" noel="" to="" provide="" estimates="" of="" aggregate="" moes.="" the="" non-="" dietary="" and="" aggregate="" (non-dietary="" +="" chronic="" dietary)="" moes="" for="" bifenthrin="" indicate="" a="" substantial="" degree="" of="" safety.="" the="" total="" non-="" dietary="" (inhalation="" +="" incidental="" ingestion)="" moes="" for="" post-application="" exposure="" for="" the="" lawn="" care="" product="" evaluated="" was="" estimated="" to="" be="">
51,000 for adults, 1,900 for children 1-6 years old and 1,800 for
infants < 1="" year.="" the="" aggregate="" moe="" (inhalation="" +="" incidental="" oral="" +="" chronic="" dietary,="" summed="" across="" all="" product="" use="" categories)="" was="" estimated="" to="" be="" 25,000="" for="" adults,="" 1,800="" for="" children="" 1-6="" years="" old="" and="" 1,600="" for="" infants="">< 1="" year).="" it="" can="" be="" concluded="" that="" the="" potential="" non-dietary="" and="" aggregate="" (non-dietary="" +="" chronic="" dietary)="" exposures="" for="" bifenthrin="" are="" associated="" with="" substantial="" margins="" of="" safety.="" d.="" cumulative="" effects="" in="" consideration="" of="" potential="" cumulative="" effects="" of="" bifenthrin="" 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="" bifenthrin="" would="" be="" cumulative="" with="" those="" of="" other="" chemical="" compounds;="" thus="" only="" the="" potential="" risks="" of="" bifenthrin="" 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="" bifenthrin="" consistent="" with="" the="" schedule="" established="" by="" epa="" in="" the="" federal="" register="" of="" august="" 4,="" 1997="" (62="" fr="" 42020)="" (frl-5734-6),="" and="" other="" epa="" publications="" pursuant="" to="" the="" fqpa.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" based="" on="" a="" complete="" and="" reliable="" toxicology="" data="" base,="" the="" acceptable="" reference="" dose="" (rfd)="" is="" 0.015="" mg/kg/day,="" based="" on="" a="" noel="" of="" 1.5="" mg/kg/day="" from="" the="" chronic="" dog="" study="" and="" an="" uncertainty="" factor="" of="" 100.="" available="" information="" on="" anticipated="" residues,="" monitoring="" data="" and="" percent="" crop="" treated="" was="" incorporated="" into="" an="" analysis="" to="" estimate="" the="" anticipated="" residue="" contribution="" (arc)="" for="" 26="" population="" subgroups.="" the="" arc="" is="" generally="" considered="" a="" more="" realistic="" estimate="" than="" an="" estimate="" based="" on="" tolerance="" level="" residues.="" the="" arc="" are="" estimated="" to="" be="" 0.00002="" mg/kg="" body="" weight="" (bwt)/day="" and="" utilize="" 0.1%="" of="" the="" rfd="" for="" the="" overall="" u.s.="" population.="" the="" arc="" for="" non-nursing="" infants="">< 1="" year)="" and="" children="" 1-6="" years="" old="" (subgroups="" most="" highly="" exposed)="" are="" estimated="" to="" be="" 0.000042="" mg/kg="" bwt/day="" and="" 0.000032="" mg/kg="" bwt/day="" and="" utilizes="" 0.3%="" and="" 0.2%="" of="" the="" rfd,="" respectively.="" 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%="" of="" the="" rfd.="" therefore,="" fmc="" concludes="" that="" the="" chronic="" dietary="" risk="" of="" bifenthrin,="" as="" estimated="" by="" the="" aggregate="" risk="" assessment,="" does="" not="" appear="" to="" be="" of="" concern.="" for="" the="" overall="" u.s.="" population,="" the="" calculated="" moe="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 2,762;="" 1,367="" at="" the="" 99th="" percentile;="" and="" 438="" at="" the="" 99.9th="" percentile.="" for="" all="" infants="">< 1="" year="" old,="" the="" calculated="" moe="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 1,534;="" 879="" at="" the="" 99th="" percentile;="" and="" 540="" at="" the="" 99.9th="" percentile.="" for="" nursing="" infants="">< 1="" year="" old,="" the="" calculated="" moe="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 5,180;="" 2,192="" at="" the="" 99th="" percentile;="" and="" 2,107="" at="" the="" 99.9th="" percentile.="" for="" non-nursing="" infants="">< 1="" year="" old,="" the="" calculated="" moe="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 1,306;="" 832="" at="" the="" 99th="" percentile;="" and="" 506="" at="" the="" 99.9th="" percentile.="" for="" the="" most="" highly="" exposed="" population="" subgroup,="" children="" 1-6="" years="" old,="" the="" calculated="" moe="" at="" the="" 95th="" percentile="" was="" estimated="" to="" be="" 1,583;="" 836="" at="" the="" 99th="" percentile;="" and="" 190="" at="" the="" 99.9th="" percentile.="" therefore,="" fmc="" concludes="" that="" there="" is="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" acute="" exposure="" to="" bifenthrin.="" 2.="" infants="" and="" children--="" a.="" general.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" bifenthrin,="" fmc="" considered="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit,="" and="" a="" two-generation="" reproductive="" study="" in="" the="" rat.="" 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="" data="" base.="" b.="" developmental="" toxicity="" studies.="" in="" the="" rabbit="" developmental="" study,="" there="" were="" no="" developmental="" effects="" observed="" in="" the="" fetuses="" exposed="" to="" bifenthrin.="" the="" maternal="" noel="" was="" 2.67="" mg/kg/day="" based="" on="" head="" and="" forelimb="" twitching="" at="" the="" loel="" of="" 4="" mg/kg/day.="" in="" the="" rat="" developmental="" study,="" the="" maternal="" noel="" was="" 1="" mg/kg/day,="" based="" on="" tremors="" at="" the="" loel="" of="" 2="" mg/kg/day.="" the="" developmental="" (pup)="" noel="" was="" also="" 1="" mg/kg/day,="" based="" upon="" increased="" incidence="" of="" hydroureter="" at="" the="" loel="" 2="" mg/kg/day.="" there="" were="" 5/23="" (22%)="" litters="" affected="" (5/141="" fetuses="" since="" each="" litter="" only="" had="" one="" affected="" fetus)="" in="" the="" 2="" mg/kg/day="" group,="" compared="" with="" zero="" in="" the="" control,="" 1,="" and="" 0.5="" mg/kg/day="" groups.="" according="" to="" recent="" historical="" data="" (1992-1994)="" for="" this="" strain="" of="" rat,="" incidence="" of="" distended="" ureter="" averaged="" 11%="" with="" a="" maximum="" incidence="" of="" 90%.="" c.="" reproductive="" toxicity="" study.="" in="" the="" rat="" reproduction="" study,="" parental="" toxicity="" occurred="" as="" decreased="" body="" weight="" at="" 5.0="" mg/kg/day="" with="" a="" noel="" of="" 3.0="" mg/kg/day.="" there="" were="" no="" developmental="" (pup)="" or="" reproductive="" effects="" up="" to="" 5.0="" mg/kg/day="" (highest="" dose="" tested).="" d.="" pre-="" and="" post-natal="" sensitivity--="" i.="" pre-natal.="" since="" there="" was="" not="" a="" dose-related="" finding="" of="" hydroureter="" in="" the="" rat="" developmental="" study="" and="" in="" the="" presence="" of="" similar="" incidences="" in="" the="" recent="" historical="" control="" data,="" the="" marginal="" finding="" of="" hydroureter="" in="" rat="" fetuses="" at="" 2="" mg/kg/day="" (in="" the="" presence="" of="" maternal="" toxicity)="" is="" not="" considered="" a="" significant="" developmental="" finding.="" nor="" does="" it="" provide="" sufficient="" evidence="" of="" a="" special="" dietary="" risk="" (either="" acute="" or="" chronic)="" for="" infants="" and="" children="" which="" would="" require="" an="" additional="" safety="" factor.="" ii.="" 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="" [[page="" 50355]]="" and="" children.="" as="" stated="" above,="" aggregate="" exposure="" assessments="" utilized="" significantly="" less="" than="" 1%="" 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="" bifenthrin="" residues.="" f.="" international="" tolerances="" there="" are="" no="" codex,="" canadian,="" or="" mexican="" residue="" limits="" for="" residues="" of="" bifenthrin="" in="" or="" on="" cotton;="" corn,="" field,="" seed,="" pop;="" strawberries;="" or="" hops.="" (adam="" heyward)="" 7.="" mclaughlin="" gormley="" king="" company="" pp="" 7f4915="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 7f4915)="" from="" mclaughlin="" gormley="" king="" company,="" 8810="" tenth="" avenue="" north,="" minneapolis,="" mn="" 55427,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act,="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" residues="" of="" (rs)-2-methyl-4-oxo-3-(2-="" propynyl)="" cyclopent-2-enyl="" (1rs)-cis,="" trans-chrysanthemate="" (common="" name,="" prallethrin;="" trade="" name="">), a Type I synthetic
pyrethroid in or on food commodities at 1 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. Analytical method. An adequate analytical method is available to
detect residues of ETOC in or on food commodities.
Prallethrin can be extracted from samples and analyzed by gas
chromatography, with final electron capture detection. The method has
been confirmed through an independent laboratory validation.
2. Magnitude of residues. Studies were conducted to determine
residues resulting from the application of ETOC by ULV spray
and contact spray in a simulated feed or food processing situation, and
in a simulated warehouse situation. No residues were detected following
contact sprays in either situation, with the exception of a trace
amount in a peanut sample after the tenth treatment at 4X the normal
application rate. No residues were detected in covered commodities
after ULV spraying of ETOC, but residues were detected in
uncovered commodities and samples with permeable wrapping.
B. Toxicological Profile
1. Acute toxicity. An oral dosage rat study reported Category II
toxicity with the LD50 being 640 mg/kg for males and 460 mg/
kg for females. An acute dermal study with rats reported Category IV
toxicity. An acute inhalation study with rats reported Category II
toxicity with an LC50 of 0.288 mg/liter for males and 0.333
mg/liter for females. Rabbits were tested for eye and skin irritation.
Eye irritation was minimal (Category III) and there was no skin
irritation (Category IV). ETOC is not a skin sensitizer,
based on a Guinea Pig dermal sensitization study. Rats were dosed at
30, 100, and 300 mg/kg by oral gavage to test acute neurotoxicity.
While there was some temporary motor activity reduction, there were no
permanent treatment-related anomalies.
2. Genotoxicity. A bacterial reverse mutation test using Salmonella
typhimurium and Escherichia coli indicated that ETOC was not
mutagenic. A gene mutation assay with Chinese hamster lung cells in
both the presence and absence of S9 metabolic activation reported no
mutagenicity. An in vitro chromosomal aberration test reported
clastogenic potential against Chinese hamster ovary cells (CHO-K1) in
the presence of S9 mix. An in vivo mouse bone marrow micronucleus test
did not induce micronuclei formation in bone marrow cells of mice. An
in vivo/in vitro unscheduled DNA synthesis test reported no induction
of DNA damage in rat hepatocytes in vivo.
3. Reproductive and developmental toxicity. A range-finding study
was conducted by administering 30, 60, 100, 300, 600, and 800/1,000 mg/
kd/day by oral gavage to rabbits on days 7 through 19 of presumed
gestation. Significantly decreased body weights occurred in those
rabbits receiving 300 mg/kg/day and above, food consumption decreased
at 100 mg/kg/day and above, and deaths occurred at 300 mg/kg/day and
above. Doses as high as 100 mg/kg/day did not produce adverse effects
in the offspring. ETOC was then administered by oral gavage
at doses of 10, 30, 100, and 200 mg/kg/day to rabbits on days 7 through
19 of presumed gestation. The maternal NOAEL was 100 mg/kg/day. The 200
mg/kg/day dosage caused reduced maternal body weight gains and reduced
absolute and relative feed consumption values. The developmental NOAEL
was reported as 200 mg/kg/day. ETOC is not considered a
developmental toxin. A teratology study was conducted by administering
10, 30, 100, and 300 mg/kg/day by oral gavage to rats on days 6-15 of
presumed gestation. The developmental NOEL was >300 mg/kg/day and the
developmental LOEL was not determined. Compound related maternal
mortality was reported at 300 mg/kg/day. The maternal LOEL was 30 mg/
kg/day, as determined by increased mortality at 300 mg/kg/day levels,
clinical signs at the 30, 100, and 300 mg/kg/day dosages, and decreased
body weight gain and food consumption. Rats were dosed with 12.5, 25.0,
and 50 mg/kg/day by subcutaneous injection on days 7 through 17 of
presumed gestation. No NOEL or LOEL was established, but the occurrence
of lumbar rib variants was significantly higher in the offspring of the
50 mg/kg/day group than in the controls. Rabbits were dosed at 1, 3,
and 10 mg/kg/day by subcutaneous injection on days 6 through 18 of
presumed gestation. No effects were reported on either the dams or the
offspring. ETOC was incorporated into the feed at
concentrations of 120, 600, 3,000, and 6,000 ppm to evaluate the
reproductive effects on two generations of rats. The systemic toxicity
and reproductive toxicity NOEL's were both established at 600 ppm, and
the LOEL's were both 3,000 ppm, respectively. There were dosage-
dependent effects on weight gains, body weights, feed consumption
values, liver weights, and reduction of pup body weight at the 3,000
and 6,000 ppm dose levels. There were no adverse effects on viability
or fertility in either generation up to the 6,000 ppm level.
4. Subchronic toxicity. A 21-day dermal toxicity rat study was
conducted at 30, 150 and 750 mg/kg/day. The test article was considered
a mild irritant. The dermal NOEL was 150 mg/kg/day and the systemic
NOEL was 30 mg/kg/day. A 13-week oral mouse study was conducted at
inclusion levels of 300, 3,000, 6,000, or 12,000 ppm. The NOEL was
3,000 ppm, and the LOEL was 6,000 ppm. A 3-month feeding study
incorporating 100, 300, 1,000, and 3,000 ppm into the diet of rats
reported a NOEL of 300 ppm, and a LOEL of 1,000 ppm. EPA later
recommended raising the NOEL to 1,000 ppm and the LOEL to 3,000 ppm. A
3-month oral study on beagle dogs dosed at 3, 10, and 30 mg/kg/day,
administered by capsule, reported a NOEL of 3 mg/kg/day and a LOEL of
10 mg/kg/day. A 4-week inhalation study exposed rats to 1.01, 4.39, and
19.6 mg/m3 of 92.0% ETOC, with median aerodynamic particle
diameter of 3.77 to 4.89 m. The NOEL was 1.01 mg/m3 and the
LOEL was 4.39 mg/m3.
[[Page 50356]]
5. Chronic toxicity. A 52-week oral toxicity study was conducted on
beagle dogs administered dosage levels of 2. 5, 5.0, 10.0 or 20.0 mg/
kg/day. The NOEL was reported at 2.5 mg/kg/day; EPA's RfD/Peer Review
Committee later recommended 5 mg/kg/day in a DER dated June 6, 1995.
The LOEL was 5.0 mg/kg/day based upon reduced weight gain, clinical
signs, elevated cholesterol levels and deposition of lipofuscin in
renal and bladder epithelium. A 106-week combined oral toxicity and
oncogenicity study was performed on rats using dietary concentrations
of 80, 400, and 2,000 ppm. It was determined that there was no
carcinogenic potential in rats. The NOEL was 80 ppm, and the LOEL was
400 ppm. There were no ophthalmologic, biochemical changes, or gross
pathological treatment-related effects except for increased liver and
thyroid weights in the 400 ppm and above level. An 80 week dietary
oncogenicity study on rats with dose levels of 120, 600, 3,000 and
6,000 ppm showed that the principal effect of ETOC was
increased liver weights in those rats given the 3,000 to 6,000 ppm
diet. There was no indication of any treatment related effect on the
incidence of neoplastic findings.
6. Animal metabolism. Solutions of (4S), (1R)-trans- and (4S),
(1R)- cis-S-4068SF (ETOC) labeled with 14C were
given to rats by single oral dose or subcutaneous administration at 2
mg/kg. Both isomers were rapidly absorbed, widely distributed to
various tissues, and then readily metabolized and excreted. Neither
isomer was retained or accumulated in any tissues. There was no marked
difference in metabolic fate between sexes and administration routes.
The absorption and disposition of 14C-S-4068SF cis and trans
isomers in rats was determined after oral administration of the
compounds at 2 and 100 mg/kg and at 2mg/kg after 14 daily doses of the
non-labeled compounds at the same dose level. The results indicated
that the dose was rapidly eliminated at all dose levels. A greater
proportion was excreted in the urine of rats receiving the trans-
compound compared to the cis-compound, indicating a greater ester
cleavage of the trans-isomer. Concentrations of compound in tissues
were not significantly affected by repeat doses of unlabelled compound
and concentrations at the higher dose level were in proportion to the
increase in dose. The greatest concentrations were detected in the
organs responsible for excretion and metabolism (liver and kidneys).
Concentrations in these tissues were greater in females.
7. Endocrine effects. The standard battery of required toxicity
studies is generally considered to be sufficient to detect any
endocrine effects, and is complete for ETOC. No developmental
or reproductive effects were noted. The potential for ETOC to
produce any significant endocrine effects is considered minimal
8. Metabolite toxicology. There is no evidence that prallethrin
contains metabolites of toxicological concern.
C. Aggregate Exposure
1. Dietary exposure. A chronic dietary exposure analysis was
conducted for exposure to potential prallethrin residues in all food
commodities that can be exposed to prallethrin by indoor ULV fogging
treatment, crack and crevice, and hard surface applications in food-
handling establishments. Residue amounts from MGK field trials in a
simulated warehouse situation were used in the analysis. Chronic
dietary exposure to prallethrin has been conservatively estimated to be
less than 1% of the RfD for all population groups.
2. Drinking water. ETOC is presently registered only for
indoor, non-food uses. No agricultural uses are planned for
ETOC, so residues in drinking water are not likely to be
present.
3. Non-dietary exposure. Acute and short-term non-dietary exposure
assessments were conducted to determine the non-dietary exposure risk
of prallethrin from both registered and pending, occupational and
residential uses. These assessments considered oral, dermal, and
inhalation exposure to prallethrin during application and post-
application of total release aerosols, crack and crevice sprays,
broadcast carpet/hard surface sprays, pet dipping, and indoor ULV
fogging concentrate/contact spray. Incidental ingestion of
ETOC residues by children's hand-to-mouth behavior was
included in the assessment. All of the MOE's for the occupational
setting were greater than 5,200, the residential MOE's were greater
than 4,900, and the aggregate residential assessment was greater than
1,400. These MOE values allow a reasonable certainty that no harm will
occur from exposure to residues of prallethrin.
D. Cumulative Effects
The EPA guidelines for product safety testing address noticeable
toxic effects rather than the underlying mode of toxicity. There is
very little information or data available to determine whether or not
the toxic mode of action of prallethrin is sufficiently similar to
other Type I pyrethroids to be cumulative.
E. Safety Determination
1. U.S. population. Based on the conservative aggregate exposure
estimates noted above and the complete and reliable toxicology database
for prallethrin, it is safe to conclude that the aggregate exposure of
the whole U.S. population to prallethrin will be 0.2% or less of the
RfD of 0.05 mg/kg bw/day. Children from 1 to 6 years old may be exposed
to a slightly higher amount of prallethrin; 0.3% of the RfD.
Generally speaking, EPA has no concerns about exposures which are
less than 100% of the RfD because the RfD represents the level at or
below which daily aggregate dietary exposure over a lifetime will not
pose appreciable risks to human health. It is therefore concluded that
there is a reasonable certainty that no harm will result from aggregate
exposure to prallethrin residues.
2. Infants and children. Developmental toxicity studies of
prallethrin orally administered to rats and rabbits did not demonstrate
any pre-natal sensitivies for developing fetuses. The maternal NOEL for
rats was 10 mg/kg/day, and the maternal NOEL for rabbits was 100 mg/kg/
day.
A two-generation reproduction study of rats administered
prallethrin in their feed did not reveal any treatment-related
reproductive or developmental effects in either generation. The NOEL
for adult rats was found to be 120 ppm while the LEL was 600 ppm. The
NOEL for fetotoxicity was found to be 600 ppm and the LEL was 3,000
ppm.
Since no special sensitivities to offspring were noted in these
studies, there is no need for an additional fold safety factor to be
applied to risk assessments.
F. International Tolerances
There are no international maximum residue limits established for
prallethrin; therefore, incompatibility is not an issue. (Adam Heyward)
8. Valent U. S. A. Corporation
PP 2F4144, 3F4186, 4F4327
EPA has received a request from Valent U. S. A. Corporation, 1333
North California Blvd., Walnut Creek, CA 94596-8025 pursuant to section
408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d),
to amend 40 CFR 180.466 to remove the time limitations on tolerances
for residues of the pyrethroid insecticide chemical fenpropathrin,
alpha-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclo-
propanecarboxylate, in or on the raw agricultural commodities
cottonseed at 1.0 parts per million
[[Page 50357]]
(ppm), peanut nutmeat at 0.01 ppm, peanut vine hay at 20 ppm,
strawberry at 2.0 ppm, tomato at 0.6 ppm, meat and meat by-products of
cattle, goats, hogs, horses and sheep at 0.1 ppm, fat of cattle, goats,
hogs, horses and sheep at 1.0 ppm, milk fat (reflecting 0.08 ppm in
whole milk) at 2.0 ppm, and poultry meat, fat, meat by-products and
eggs at 0.05 ppm, and in the processed products cottonseed oil at 3.0
ppm and cottonseed soapstock at 2.0 ppm. The tolerances were first
established in response to pesticide petitions PP 2F4144, 3F4186, and
4F4327 and were only made time limited because of concerns associated
with toxicity to aquatic arthropods. EPA has determined that the
request contains data or information consistent with 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 request. Additional data may be
needed before EPA rules on the request.
A. Residue Chemistry
Summary. An extensive plant and animal metabolism data base
demonstrates that the appropriate definition of aged fenpropathrin
residue is parent. Ruminant and poultry feeding studies have shown that
feed to residue ratios are very low in most commodities, with higher
(but still relatively low) ratios in fat and milk fat. This section
will describe residue data supporting the establishment of tolerances
for residues of fenpropathrin in or on the raw agricultural commodities
cottonseed at 1.0 parts per million (ppm), peanut nutmeat at 0.01 ppm,
peanut vine hay at 20 ppm, strawberry at 2.0 ppm, tomato at 0.6 ppm,
meat and meat by-products of cattle, goats, hogs, horses and sheep at
0.1 ppm, fat of cattle, goats, hogs, horses and sheep at 1.0 ppm, milk
fat (reflecting 0.08 ppm in whole milk) at 2.0 ppm, and poultry meat,
fat, meat by-products and eggs at 0.05 ppm, and in the processed
products cottonseed oil at 3.0 ppm and cottonseed soapstock at 2.0 ppm.
The approved analytical method is capillary gas-liquid chromatography
with flame ionization detection.
1. Plant metabolism. The plant metabolism of fenpropathrin has been
studied in five different crop plant species: cotton, apple, tomato,
cabbage, and bean. Radiocarbon labeling has been in the cyclopropyl
ring of the acid, in the aryl rings of the alcohol, and in the nitrile
of fenpropathrin, a cyanohydrin ester. The permutations of radiocarbon
label position and plant species yield a total of 17 separate, reviewed
studies. Each of the studies involved foliar treatment of the plants
under either greenhouse or field conditions and, while the actual
treatment conditions and times to harvest varied from study to study,
the results of the many studies are remarkably consistent. The total
toxic residue is best defined as parent, fenpropathrin.
Fenpropathrin remains associated with the site of application and
only traces are found in seeds (e.g., bean or cotton) or in other parts
of the plant not directly exposed to the application. Much of the
parent residue can be removed from the plant material with a mild
hexane/acetone or hexane rinse, demonstrating that the residue is
located on or near the outside surface of the plant material. The
primary metabolic pathway for fenpropathrin in plants is similar to
that in mammals. There are no qualitatively unique plant metabolites;
the primary aglycones are identical in both plants and animals.
2. Analytical method. Adequate analytical methodology is available
to detect and quantify fenpropathrin (and its metabolites) at residue
levels in numerous matrices. The methods use solvent extraction and
partition and/or column chromatography clean-up steps, followed by
separation and quantitation using capillary column gas-liquid
chromatography with flame ionization detection. The extraction
efficiency has been validated using radiocarbon samples from the plant
and animal metabolism studies. The enforcement methods have been
validated at independent laboratories, and by EPA. The limit of
quantitation for fenpropathrin in raw agricultural commodity samples is
0.01 ppm.
3. Magnitude of residues-- Cotton. The time limited section 408
tolerance for fenpropathrin in/on cottonseed is 1.0 ppm. The use
pattern allows a maximum single application rate of 0.3 lb ai/acre, a
total maximum seasonal use of 0.8 lb ai/acre, and a 21-day phi. The
field residue experiments were performed in six years at thirty-three
sites in nine states. There were 38 separate treatments yielding 101
separate, treated samples for analysis. The existing time limited
tolerance of 1.0 ppm is based on all of the field residue data,
including treatments at exaggerated rates. For the subset of the field
residue samples that most closely match the present, labeled use
pattern, 0.3 lb ai/acre, 5 applications, and a 21-day phi, the average
residue was 0.069 ppm (n = 14, n-1 = 0.091). The
highest average residue (HAR) found in these crop field trials for
fenpropathrin in/on cottonseed was 0.28 ppm.
There are existing time limited section 408 tolerances for
fenpropathrin in the processed products cottonseed oil (3.0 ppm) and
cottonseed soapstock (2.0 ppm). Three processing studies yielding
hulls, extracted meal, crude cottonseed oil, refined cottonseed oil,
and cottonseed soapstock were performed. These studies demonstrated
that fenpropathrin residues were reduced in extracted meal but did
concentrate in refined cottonseed oil (average concentration factor =
2.77) and soapstock. Tolerances for the processed products cottonseed
oil and cottonseed soapstock were needed because the concentration
factors were greater than unity. Soapstocks are no longer considered
significant feed commodities. The HAR times the average concentration
factor for cottonseed oil (0.28 ppm x 2.77 = 0.78 ppm) is less than the
tolerance of 1.0 ppm. Under present residue chemistry guidelines,
tolerances for cottonseed oil and soapstock would no longer be
required.
The calculated mean residue value for cottonseed of 0.07 ppm was
used in both the chronic and acute dietary exposure and risk
assessments since cottonseed is a blended commodity. Processing factors
used in the assessments were refined cottonseed oil (2.77), cottonseed
meal (0.48), and cottonseed hulls (0.90).
Peanut. The time limited section 408 tolerances for fenpropathrin
in/on peanut nutmeat is 0.01 ppm and in/on peanut vine hay is 20.0 ppm.
The use pattern allows a maximum single application rate of 0.3 lb ai/
acre, a total maximum seasonal use of 0.8 lb ai/acre, and a 14-day
interval before digging the peanuts or feeding the vines or hay. The
field residue experiments were performed in two years at seven sites in
five states. There were 9 separate treatments yielding 22 separate,
treated samples for analysis for nutmeats, green vines, and dried vine
hay. Data from the subset of the field residue samples that most
closely match the present, labeled use pattern, 0.3 lb ai/acre, 2 or
more applications, and a 14-day phi were used to support the
tolerances.
Peanut nutmeats. No finite residues were detected (< 0.01="" ppm)="" in="" 17="" of="" 18="" samples.="" in="" a="" single="" sample="" a="" finite="" residue="" of="" .01="" ppm="" was="" detected.="" peanut="" vine="" hay.="" field="" dried="" vines,="" peanuts="" removed,="" were="" sampled="" at="" 14-days="" plus="" 2-="" to="" 9-days="" field="" drying="" time="" following="" the="" last="" application.="" the="" average="" residue="" found="" in/on="" peanut="" vine="" hay="" was="" 8.31="" ppm="" (n="16,">n-1 = 4.64 ppm). The HAR for peanut
vine hay was 16 ppm. A peanut processing study using a very highly
exaggerated field
[[Page 50358]]
application rate showed positive concentration in peanut oil and other
processed products. However, Agency guidance has indicated that no
additional tolerances are needed.
Except for a single sample of peanut nutmeat (0.01 ppm) all
appropriate field trial data were non-detects. Therefore, 0.005, or
half the limit of detection (LOD), was used for the chronic dietary
risk assessment, and 0.01 ppm (full LOD) was used for the acute
assessment. Calculated mean residue values were used for peanut
commodities in both the chronic and acute assessments because peanuts
is a blended commodity. The processing factor for deodorized bleached
refined oil (1.33) was used in the risk assessments since this is the
grade of peanut oil available for human consumption. For feed, the
processing value for expeller presscake (1.33) was used for peanut
meal.
Strawberry. The time limited section 408 tolerance for
fenpropathrin in/on strawberries is 2.0 ppm. The use pattern allows a
maximum single application rate of 0.4 lb ai/acre, a minimum 30-day
interval between treatments, a total maximum seasonal use of 0.8 lb ai/
acre, and a 2-day phi. The field residue experiments were performed in
three years at twelve sites in six states. There were 47 separate
treatments yielding 128 separate, treated samples for analysis. For the
subset of the field residue samples that most closely match the
present, labeled use pattern, 0.4 lb ai/acre, 1 or 2 applications with
a (approximately) 30-day interval between treatments, and a 2-day phi,
the average residue was 0.65 ppm (n = 34, n-1 =
0.44). The HAR found in these crop field trials in/on strawberries was
1.45 ppm.
For chronic dietary exposure and risk assessment, the mean residue
value (0.65 ppm) was used. For acute assessment, the complete
distribution of the appropriate field trial data was used.
Tomato. The time limited section 408 tolerance for fenpropathrin
in/on tomato is 0.6 ppm. The use pattern allows a maximum single
application rate of 0.2 lb ai/acre, a total maximum seasonal use of 0.8
lb ai/acre, and a 3-day phi. The field residue experiments were
performed in four years ateighteen sites in eight states. There were 27
separate treatments yielding 118 separate, treated samples for
analysis. For the subset of the field residue samples that most closely
match the present, labeled use pattern, 0.2 lb ai/acre, 4 (or more)
applications, and a 3-day phi, the average residue was 0.166 ppm (n =
54, n-1 = 0.132). The highest average residue (HAR)
found in these crop field trials for fenpropathrin in/on tomatoes was
0.55 ppm.
A tomato processing study using an exaggerated field application
rate showed positive concentration in wet and dried tomato pomace.
However, Agency guidance has indicated that no additional tolerances
are needed.
The mean residue value of 0.17 ppm was used for all tomatoes in the
chronic dietary assessment, and for the blended commodities in the
acute assessment (paste, puree, juice, and catsup). In the acute
assessments, a complete distribution of the appropriate field trial
data was used for whole and dried tomatoes. Appropriate concentration
factors were used for processed commodities: tomato juice (0.05),
canned tomatoes (0.08), tomato paste (0.3).
Secondary residues. Residues in animal feed may transfer to animal
products, meat, milk, and eggs, used in human food. The existing time
limited tolerances are meat and meat by-products of cattle, goats,
hogs, horses and sheep at 0.1 ppm, fat of cattle, goats, hogs, horses
and sheep at 1.0 ppm, milk fat (reflecting 0.08 ppm in whole milk) at
2.0 ppm, and poultry meat, fat, meat by-products and eggs at 0.05 ppm.
The feed items that are associated with the existing registered uses
for beef and dairy cattle are peanut hay, cottonseed, cotton gin by-
products (feeding restriction), cottonseed hulls, cottonseed meal and
peanut meal in descending order of the magnitude of the anticipated
residues. For poultry and swine only cottonseed and peanut meals are
significant feed items. Tissue to feed residue ratios vary from a high
of 0.0139 in fat to 0.001625 in milk, to a low of 0.00004 in liver in
cattle. In poultry, tissue to feed ratios vary from a high of 0.0069 in
fat to a low of 0.0002 in muscle. Both chronic and acute dietary
assessments show very low residue contribution from secondary residues
in animal products to all population sub-groups.
B. Toxicological profile
Summary. The existing registrations and tolerances of fenpropathrin
are supported at EPA by a complete toxicology data base. Toxicity
endpoints of concern have been identified by the Agency's Health
Effects Division, Hazard Identification Assessment Review Committee.
The identified endpoints are an Acute Dietary of 6.0 mg/kg/day
(systemic) and a Chronic Dietary of 2.5 mg/kg/day (RfD = 0.025 mg/kg/
day, UF = 100). No endpoints of concern were identified by the
Committee for occupational or residential, dermal or inhalation
exposures of any duration.
1. Acute toxicity. The following acute toxicity studies using
fenpropathrin technical as the test material have been reviewed and
accepted by EPA to support registration.
Acute oral, rat. The rat oral LD50 values were
determined to be 54.0 and 48.5 milligrams per kilogram body weight (mg/
kg) for male and female rats, respectively. Toxicity Category I.
Acute dermal, rat. The rat dermal LD50 values were
determined to be 1600 and 870 mg/kg for male and female rats,
respectively. Toxicity Category II.
Acute inhalation, rat. A high dosage inhalation study is
technically not possible because of the low vapor pressure and thick,
viscous nature of fenpropathrin technical. The study has been waived by
the Agency. Toxicity Category IV.
Primary eye irritation, rabbit. No corneal involvement; mild iris
and conjunctival irritation. Toxicity Category III.
Primary dermal irritation, rabbit. No irritation. Toxicity Category
IV.
Dermal sensitization, guinea pig. Not a sensitizer.
Acute oral and acute dermal toxicity studies have also been
submitted on the mouse and rabbit. In the acute oral and dermal
studies, clinical signs of toxicity included tremors,
hyperexcitability, muscular fibrillation, ataxia of the hind limbs,
urinary incontinence, diarrhea, and salivation. The intoxicated animals
from the oral studies showed no major changes in tissues or organs at
necropsy. Where there were sexual differences in toxicity, females were
consistently slightly more sensitive than males. Surviving animals
recovered in two days in the case of rats and mice and within 4 days in
the case of rabbits. In surviving animals, all clinical signs were
completely reversible.
2. Genotoxicty. Fenpropathrin does not present a genetic hazard.
The Agency has reviewed, accepted, and classed as negative the
following genotoxicity tests: A gene mutation assay (Ames), a
chromosomal aberration study in rodents, an in vitro cytogenics assay,
a sister chromatide exchange on CHO-K1 cells, and DNA damage/repair in
Bacillus subtilis.
3. Reproductive and developmental toxicity. There is no evidence
from reproduction or developmental toxicity studies that the developing
fetus, young growing and developing animals, or adult reproducing
animals are any more sensitive to fenpropathrin effects than mature
adult animals. In addition, reproductive parameters were
[[Page 50359]]
unaffected at dosages higher than those that caused overt adult
toxicity.
Three-generation reproduction study, rats. Dietary concentrations
of 0, 40, 120, and 360 ppm were fed continuously to rats for three
generations to assess the effect of fenpropathrin on reproductive
function. (Parent) Systemic no effect level (NOEL) of 40 ppm (M/F 3.0/
3.4 mg/kg/day). Systemic lowest effect level (LEL) of 120 (M/F 8.9/10.1
mg/kg/day)--body tremors with spasmodic muscle twitches, increased
sensitivity, and maternal lethality. Reproductive NOEL 120 ppm (M/F
8.9/10.1 mg/kg/day). Reproductive LEL 360 ppm (M/F 26.9/32.0 mg/kg/
day)--Decreased mean F2 loss. (Pups) Developmental NOEL 40
ppm (M/F 3.0/3.4 mg/kg/day). Developmental LEL 120 ppm (M/F 8.9/10.1
mg/kg/day)--body tremors, increased mortality.
Developmental toxicity, rabbits. Female rabbits were treated by
gavage on days 7 through 19 of pregnancy with 0, 4, 12, and 36 mg/kg/
day in corn oil to assess the maternal and developmental toxicity of
fenpropathrin. Maternal NOEL 4 mg/kg/day, maternal LEL 12 mg/kg/day
(grooming, anorexia, flicking of the forepaws). Developmental NOEL > 36
mg/kg/day, there were no compound-related effects on development.
Clinical signs included grooming, anorexia, flicking of the forepaws
and hindfeet, shaky movements, trembling, stamping of the hindfeet, and
lethargy.
Developmental toxicity, rats. Female rats were treated by gavage on
days 6 through 15 of pregnancy with 0, 0.4, 1.5, 2.0, 3.0, 6.0 and 10
mg/kg/day in corn oil to assess the maternal and developmental toxicity
of fenpropathrin. Maternal NOEL 6 mg/kg/day, maternal LEL of 10 mg/kg/
day (death, moribundity, ataxia, sensitivity to external stimuli,
spastic jumping, tremors, prostration, convulsion, hunched posture,
squinted eyes, chromodacryorrhea, and lacrimation). Developmental NOEL
> 10 mg/day. No developmental effects were observed at a dose that was
lethally neurotoxic to 7 of 30 dams.
4. Subchronic toxicity- Subchronic feeding, rat 3-month.
Fenpropathrin was fed to rats at dietary concentrations of 0. 3, 30,
100, 300 and 600 ppm. The NOEL was determined to be 300 ppm (15 mg/kg/
day). The LEL was 600 ppm (30 mg/kg/day)--body weight reduction (F),
body tremors, reduced kaolin-cephalin clotting time (F), increased
alkaline phosphatase and potassium (M), increased brain (F) and kidney
(M) weights.
Subchronic feeding, dog 3-month. Groups of six male and six female
beagle dogs were fed diets containing 250, 500. and 750 ppm
fenpropathrin for 13 weeks. The NOEL was not determined and is less
than 250 ppm (7.25 mg/kg/day). At this dosage there were signs of GI
tract disturbance (note dog chronic, below). At higher feeding levels
the following effects were observed: 500 ppm (15 mg/kg/day) produced
tremors and body weight loss in females, 750 ppm (22.25 mg/kg/day)
produced tremors, ataxia and blood changes (reduced RBC, HCT, HGB).
Dermal, rabbit 21-day. Ten rabbits of each sex at each dose, half
with intact skin and half with abraded skin, were treated dermally with
500, 1200 and 3000 mg/kg/day. The experimental animals were treated 5
days per week for three weeks. There was localized dermal irritation
but there were no systemic effects. The systemic NOEL was determined to
be greater than 3000 mg/kg/day.
5. Chronic toxicity. A complete chronic data base supported by
appropriate subchronic studies for fenpropathrin is available to the
Agency. A chronic RfD has been identified, and a safety factor of 100
is appropriate. Fenpropathrin shows no evidence of oncogenicity at
maximum tolerated dosages. Clinical signs of chronic toxicity were
observed as body tremors, at high dosages with little other effects
noted.
Oral toxicity study, dogs 12-month. Groups of male and female
beagle dogs were fed diets containing 0, 100, 250. and 750 ppm
fenpropathrin for 52 weeks. Systemic NOEL of 100 ppm (2.5 milligram
(mg)/kilogram (kg)/day) and a systemic LEL of 250 ppm (6.25 mg/kg/day).
Chronic/carcinogenicity feeding, rat 24-month. Groups of male and
female Charles River CD rats were fed diets containing 0, 50, 150, 450,
and 600 ppm fenpropathrin for 104 weeks. Systemic NOEL's of 450 ppm in
males, 150 ppm in females (17.06 mg/kg/day and 7.23 mg/kg/day,
respectively). Systemic LEL of 600 ppm [(HDT): 22.80 mg/kg/day] in
males (increased mortality, body tremors, increased pituitary, kidney,
and adrenal weights), and systemic LEL of 450 ppm (19.45 mg/kg/day) in
females (increased mortality and body tremors). There were no oncogenic
effects observed at any dose level.
Chronic/carcinogenicity feeding study, mouse 24-month. Groups of
male and female Charles River (UK) CD-1 mice were fed diets containing
0, 40, 150, and 600 ppm fenpropathrin for 104 weeks. Systemic NOEL
greater than 600 ppm HDT (males and females; 56.0 and 65.2 mg/kg/day,
respectively). There were no indications of toxicity or carcinogenicity
other than marginally increased hyperactivity in females dosed at 600
ppm.
Carcinogenicity. Fenpropathrin has been classified in EPA Weight-
of-the Evidence Category ``Group E--Evidence of Non-Carcinogenicity for
Humans'' for carcinogenicity by the EPA/RFD/PR committee reviewed 1/29/
93 and EPA verified 3/18/93. Studies in two species with adequate
dosing show no evidence of oncogenicity.
6. Animal metabolism. Acceptable rat metabolism studies have been
performed using single high (25 mg/kg), and single and multiple low
(2.5 mg/kg) doses using both sexes. Elimination was similar in both
sexes. The urine: feces ratio of elimination was 1:2 following the high
or low single dose, and 1:1 following the 15 daily doses. The half life
was 11-16 hours in the urine, and 7-9 hours in the feces. After 7 days,
greater than 99% of the administered dose was excreted. A small
percentage of radiolabel was found in the tissues (primarily in the
fat). The major biotransformations included cleavage of the ester,
oxidation at the methyl group of the acid moiety, and hydroxylation at
the 4'-position of the alcohol moiety. Ester cleavage products,
2,2,3,3-tetramethylcyclopropanecarboxylic acid and (after oxidation) 3-
phenoxybenzoic acid, were excreted either directly or conjugated as
sulfates or glucuronides. Parent was detected in the feces, but not in
the urine. Eight urinary metabolites and 4 fecal metabolites were
identified.
There are no qualitatively unique plant metabolites . The primary
aglycones are identical in both plants and animals; the only difference
is in the nature of the conjugating moieties employed.
7. Metabolite toxicology. The metabolism and potential toxicity of
the small amounts of terminal plant metabolites have been tested on
mammals. Glucoside conjugates of 3-phenoxy-benzyl alcohol and 3-
phenoxybenzoic acid, administered orally to rats, were absorbed as the
corresponding aglycones following cleavage of the glycoside linkage in
the gut. The free or reconjugated aglycones were rapidly and completely
eliminated by normal metabolic pathways. The glucose conjugates of 3-
phenoxybenzyl alcohol and 3-phenoxy-benzoic acid are less toxic to mice
than the corresponding aglycones.
8. Endocrine disruption. No special studies to investigate the
potential for estrogenic or other endocrine effects of fenpropathrin
have been performed. However, as summarized above, a large
[[Page 50360]]
and detailed toxicology data base exists for the compound including
studies acceptable to the Agency in all required categories. These
studies include evaluations of reproduction and reproductive toxicity
and detailed pathology and histology of endocrine organs following
repeated or long term exposure. These studies are considered capable of
revealing endocrine effects and no such effects were observed.
C. Aggregate Exposure
1. Dietary exposure. Toxicity endpoints of concern have been
identified by the Agency's Health Effects Division, Hazard
Identification Assessment Review Committee (July 17 and 24, 1997). The
identified endpoints are a Chronic Dietary of 2.5 mg/kg/day (RfD =
0.025 mg/kg/day, UF = 100) and an Acute Dietary of 6.0 mg/kg/day
(systemic). Thus, both chronic and acute exposure and risk analyses are
necessary.
2. Food. Chronic and acute dietary exposure analyses were performed
for fenpropathrin using anticipated residues and accounting for
proportion of the crop treated. The crops included in the analyses are
cottonseed, currants, peanuts, strawberries, tomatoes, and the
secondary residues in meat, milk, and eggs. These exposure/risk
analyses have been submitted to the Agency along with a detailed
description of the methodology and assumptions used.
Chronic dietary exposure was calculated for the U.S. population and
26 population subgroups. The results from several representative
subgroups are listed below. In all cases, chronic dietary exposure was
at or below 0.2 % of the reference dose and strawberries was the
commodity contributing the most exposure.
----------------------------------------------------------------------------------------------------------------
Population subgroup Exposure (mg/kg bw/day) Percent of RfD
----------------------------------------------------------------------------------------------------------------
Total U.S. Population 0.000020 008
Females (13+/Nursing) 0.000036 0.14
Non-Hispanic other than B/W 0.000053 0.21
Children (1-6 Years) 0.000035 0.14
All Infants (<1 year="" old)="" 0.000002="" 0.008="" non-nursing="" infants=""><1 year="" old)="" 0.000003="" 0.012="" ----------------------------------------------------------------------------------------------------------------="" acute="" dietary="" exposure="" was="" calculated="" for="" the="" u.s.="" population="" and="" five="" children="" subgroups.="" the="" calculated="" exposures="" and="" margins="" of="" exposure="" (moe)="" for="" the="" higher="" exposed="" proportions="" of="" the="" subgroups="" are="" listed="" below.="" it="" should="" be="" noted="" that="" the="" population="" sizes="" are="" small="" at="" the="" lower="" probability="" exposures="" (e.g.="">th and
99.9th percentiles) oftentimes leading to unrealistically
high calculated exposures. In all cases, margins of exposure exceed
one-hundred.
Calculated Acute Dietary Exposures to Fenpropathrin Residues in Food
----------------------------------------------------------------------------------------------------------------
99th Percentile 99.9th Percentile
---------------------------------------------------------------------------
Population Subgroup Exposure (mg/kg Exposure (mg/kg
bw/day) MOE bw/day) MOE
----------------------------------------------------------------------------------------------------------------
U.S. Population .000682 8,804 .002800 2,143
Children 1-6 .000916 6,547 .007465 804
Children 7-12 .000619 9,687 .003012 1,992
All Infants .001084 5,533 .001510 3,974
Nursing Infants (<1) .000297="" 20,230="" .000416="" 14,412="" non-nursing="" infants=""><1) .001237="" 4,851="" .001572="" 3,816="" ----------------------------------------------------------------------------------------------------------------="" 3.="" drinking="" water.="" since="" fenpropathrin="" is="" applied="" outdoors="" to="" growing="" agricultural="" crops,="" the="" potential="" exists="" for="" fenpropathrin="" or="" its="" metabolites="" to="" reach="" ground="" or="" surface="" water="" that="" may="" be="" used="" for="" drinking="" water.="" fenpropathrin="" is="" extremely="" insoluble="" in="" water="" (14="" ppb),="" with="" a="" high="" octanol/water="" partitioning="" coefficient="">ow 1.19
x 105) and a relatively short soil half-life for parent and
environmental metabolites. The Agency has determined that it is
unlikely that fenpropathrin or its metabolites can leach to potable
groundwater. The residence time of fenpropathrin in surface water is
short because of its very low water solubility and high affinity to
bind to soil. In pond studies, fenpropathrin half-lives in the water
column were less than 1.5 days.
To quantify the potential small exposure from drinking water,
screening evaluations of leaching potential of a typical pyrethroid,
cypermethrin, were conducted using EPA's Pesticide Root Zone Model
(PRIZM3). Based on this assessment, the potential concentrations of the
pyrethroid in groundwater at depths of 1 to 2 meters are essentially
zero (< 0.001="" parts="" per="" billion).="" potential="" surface="" water="" concentrations="" for="" the="" pyrethroid="" were="" estimated="" using="" prizm3="" coupled="" with="" epa's="" exposure="" analysis="" modeling="" system="" (exams)="" using="" standard="" epa="" cotton="" runoff="" and="" mississippi="" farm="" pond="" scenarios.="" the="" maximum="" concentration="" predicted="" in="" the="" simulated="" pond="" water="" was="" 0.052="" ppb.="" using="" standard="" assumptions="" about="" body="" weight="" and="" water="" consumption,="" the="" chronic="" exposure="" from="" this="" drinking="" water="" would="" be="" 1.5="" x="">-6 and 5.2 x 10-6 mg/kg bw/day for adults and
children, respectively; less than 0.02 percent of the RfD for children.
Concentrations in actual drinking water would be much lower than the
levels predicted in the hypothetical small stagnant farm pond modeled,
since drinking water from surface sources receives treatment prior to
consumption. Based on these analyses, the contribution of water to any
the dietary risk analyses is negligible.
4. Non-dietary exposure. Fenpropathrin, as the product TAME
[[Page 50361]]
2.4 EC Spray, is registered for professional non-food use both indoors
and outdoors on ornamentals and non-bearing nursery fruit trees.
Fenpropathrin has no animal health, homeowner, turf, termite, or
industrial uses. Quantitative information concerning human exposure
from this ornamental use is not available, but exposure to the general
public from this use of fenpropathrin is expected to be minimal. It is
important to note that no endpoints of concern were identified by the
Health Effects Division, Hazard Identification Assessment Review
Committee for occupational or residential, dermal or inhalation
exposures of any duration. Thus, no risk assessment is needed.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' ``Available information'' in this
context include not only toxicity, chemistry, and exposure data, but
also scientific policies and methodologies for understanding common
mechanisms 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 mechanism of toxicity
in a meaningful way.
There are numerous other pesticidal compounds, pyrethroids and
natural pyrethrins, that are structurally related to fenpropathrin and
may have similar effects on animals. In consideration of potential
cumulative effects of fenpropathrin and other substances that may have
a common mechanism of toxicity, there are currently no available data
or other reliable information indicating that any toxic effects
produced by fenpropathrin would be cumulative with those of other
chemical compounds. Thus, only the potential risks of fenpropathrin
have been considered in this assessment of aggregate exposure and
effects.
Valent will submit information for EPA to consider concerning
potential cumulative effects of fenpropathrin consistent with the
schedule established by EPA at 62 FR 42020 (August 4, 1997) and other
EPA publications pursuant to the Food Quality Protection Act.
E. Safety Determination
The Food Quality Protection Act introduces a new standard of
safety, a reasonable certainty of no harm. To make this determination,
at this time the Agency should consider only the incremental risk of
fenpropathrin in its exposure assessment. Since the potential chronic
and acute exposures to fenpropathrin are small (< 100%="" of="" rfd,="" moe="">>
100) the provisions of the FQPA of 1996 will not be violated.
1. U.S. population-- Chronic. Using the dietary exposure assessment
procedures described above for fenpropathrin, chronic dietary exposure
is minimal with all population subgroups at or below 0.2 percent of the
RfD. Addition of the small potential chronic exposure from drinking
water (calculated above) increases the occupancy of the RfD by only
0.006 percent. Generally, the Agency has no cause for concern if total
residue contribution is less than 100 percent of the RfD.
Acute. The potential acute exposure from food to the U.S.
population (shown above) provides an MOE greatly exceeding 100. In a
conservative policy, the Agency has no cause for concern if total acute
exposure calculated for the 99.9th percentile yields a MOE
of 100 or larger.
2. Infants and children-- Safety factor for infants and children.
In assessing the potential for additional sensitivity of infants and
children to residues of fenpropathrin, FFDCA section 408 provides that
EPA shall apply an additional margin of safety, up to ten-fold, for
added protection for infants and children in the case of threshold
effects unless EPA determines that a different margin of safety will be
safe for infants and children.
The toxicological data base for evaluating pre- and post-natal
toxicity for fenpropathrin is complete with respect to current data
requirements. There are no special pre- or post-natal toxicity concerns
for infants and children, based on the results of the rat and rabbit
developmental toxicity studies or the three-generation reproductive
toxicity study in rats. EPA HED Hazard ID Committee has concluded that
reliable data support use of the standard 100-fold uncertainty factor
and that an additional uncertainty factor is not needed to be further
protective of infants and children.
Chronic risk. Using the conservative exposure assumptions described
above, the percentage of the RfD that will be utilized by dietary (food
only) exposure to residues of fenpropathrin ranges from 0.14 % for
children (1-6 years old) and 0.012% for non-nursing infants (< 1="" year="" old).="" addition="" of="" the="" small="" potential="" chronic="" exposure="" from="" drinking="" water="" (calculated="" above)="" increases="" the="" occupancy="" of="" the="" rfd="" by="" only="" 0.02="" percent.="" generally,="" the="" agency="" has="" no="" cause="" for="" concern="" if="" total="" residue="" contribution="" is="" less="" than="" 100="" percent="" of="" the="" rfd.="" acute.="" the="" potential="" acute="" exposure="" from="" food="" to="" populations="" of="" infants="" and="" children="" (shown="" above)="" provide="" moe="" values="" greatly="" exceeding="" 100="" in="" a="" conservative="" policy,="" the="" agency="" has="" no="" cause="" for="" concern="" if="" total="" acute="" exposure="" calculated="" for="" the="">th percentile
yields a MOE of 100 or larger.
Aggregate acute or chronic dietary exposure to various sub-
populations of children and adults demonstrate acceptable risk. Chronic
exposures to fenpropathrin occupy considerably less than 100% of the
RfD, and all acute MOE values exceed 100. Chronic and acute dietary
risk to children from fenpropathrin should not be of concern. Further,
fenpropathrin has no other uses, such as indoor pest control, homeowner
or turf, that could lead to unique, enhanced exposures to vulnerable
sub-groups of the population. It can be concluded that there is a
reasonable certainty that no harm will result to any sub-group of the
U.S. population, including infants and children, from aggregate chronic
or acute exposure to fenpropathrin residues.
F. International Tolerances
Codex Maximum Residue Limits
----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------
186 Fenpropathrin
Main uses 8 Insecticide/acaracide
JMPR 83
ADI 0.03 mg/kg body weight (1993)
[[Page 50362]]
Residue Fenpropathrin (fat soluble)
----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------
Commodity
------------------------------------------------------- MRL (mg/kg) Step JMPR CCPR
Code Name
----------------------------------------------------------------------------------------------------------------
MM 0812 Cattle meat 0.5 (fat) 6 93
ML 0812 Cattle milk 0.1 F 6st 93
MO 0812 Cattle, Edible offal of 0.05 CXL (1995)
SO 0691 Cotton seed 1 CXL (1995)
OC 0691 Cotton seed oil, Crude 3 CXL (1995)
VO 0440 Egg plant 0.2 6 93
PE 0112 Eggs 0.01 (*) CXL (1995)
VC 0425 Gherkin 0.2 CXL (1995)
FB 0269 Grapes 5 6 93
VO 0445 Peppers, Sweet 1 CXL (1995)
FP 0009 Pome fruits 5 CXL (1995)
PM 0110 Poultry meat 0.02 (fat) CXL (1995)
PO 0111 Poultry, Edible offal
of 0.01 (*) CXL (1995)
VO 0448 Tomato 1 CXL (1995)
----------------------------------------------------------------------------------------------------------------
There are small differences between the section 408 tolerances and
the Codex MRL values for secondary residues in animal products. These
minor differences are mainly caused by differences in the methods used
to calculate animal feed dietary exposure. The only substantial
difference between the US tolerance and the Codex MRL value is for
tomatoes. The JMPR reviewer required that the MRL exceed the highest
field residue, and rounded to unity. The EPA reviewer agreed with
Valent that one set of field residue samples was possibly compromised
by the presence of a high rate processing treatment nearby. High
outliers were ignored, and the tolerance was set at 0.6 ppm. (Adam
Heyward)
9. Zeneca Ag Products
PP 7G3518, 7F3521, 4F4406
EPA has received a request from Zeneca Ag Products, P. O. Box
15458, Wilmington, DE, 19850-5458 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 removing the time limitation for tolerances
established for residues of the insecticide and pyrethriod Tefluthrin
in or on the raw agricultural commodities corn, grain, field and pop;
corn, forage and fodder, field, pop and sweet; and corn, fresh
(including sweet K and corn with huskremoved (CWHR)) at 0.06 ppm. The
International Union of Pure and Applied Chemist (IUPAC) name for
tefluthrin is (2,3,5,6-tetrafluro-4-methylphenyl)methyl-(1 alpha, 3
alpha)-(Z)-(+/-)-3(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-
dimethylcyclopropanecarboxylate) and its metabolite (Z)-3-(2-chloro-
3,3,3-trifluroro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid.
The tolerances were originally requested in Pesticide Petition Numbers
7G3518, 7F3521, and 4F4406. 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 nature of tefluthrin residues in plants
and animals for corn use is adequately understood. The residue of
concern is tefluthrin and its metabolite. There is no reasonable
expectation of secondary residues in animal tissues and milk from the
use as delineated in 40 CFR 180.6(a)(3).
2. Analytical method. An adequate analytical method, gas liquid
chromatography with an electron capture detector, is available for
enforcement purposes. The enforcement methodology has been submitted to
the Food and Drug Administration, and is published in the Pesticide
Analytical Manual Vol. II (PAM II).
3. Magnitude of residues. Tefluthrin (also know as FORCE
Insecticide) is an effective granular soil insecticide registered for
use against a number of soil corn pest; the most economically
significant being soil dwelling pest, such as corn rootworm, wireworm,
cutworm, and white grubs. Residue data covering all the uses associated
with the permanent tolerances requested by this petition have been
previously submitted to EPA for review and have been found by EPA to
support the requested tolerances. See February 1, 1989 (54 FR 5080);
and May 3, 1996 (61 FR 19852) (FRL-5358-5).
B. Toxicological Profile
1. Acute toxicity. Acute toxicity studies with the technical grade
of the active ingredient tefluthrin: Oral LD50 in the rat is
22 mg/kg) for (males) and 35 mg/kg for (females); dermal
LD50 in the rat is 316 mg/kg in (males) and 177 mg/kg in
(females); acute inhalation LC50 in the rat is 0.04
milligram/liter (mg/l) and 0.05 mg/l in female and male rats,
respectively; primary eye irritation in the rabbit study showed slight
irritation; primary dermal irritation in the rabbit study showed none
to slight irritation, and the dermal sensitization in the guinea pig
study showed no skin sensitization.
2. Genotoxicty. The following genotoxicity test were all negative:
A gene mutation assay (Ames), dominant lethal (mouse in vivo), mouse
micronucleus (in vivo), acute cytogenetic study in the rat, unscheduled
DNA synthesis and a mouse lymphoma cells test.
3. Reproductive and developmental toxicity. In a rat developmental
study,
[[Page 50363]]
delayed ossification was noted in the highest dose group (5 mg/kg/day),
along with significant maternal toxicity (decreased body weight (bwt)).
The developmental no observed effect level (NOEL) for this study was
established at 3 mg/kg/day. However, the effects observed were most
likely a secondary effect resulting from maternal stress.
In a developmental toxicity study in rabbits given gavage doses of
0, 3, 6, and 12 mg/kg/day, the maternal NOEL is 3 mg/kg/day and the
developmental NOEL is > 12 mg/kg/day. No developmental effects were
observed under the conditions of the study.
In a rat multi-generation reproduction study, conducted at 0, 15,
50, and 250 ppm with tefluthrin in the diet, a reproductive NOEL was
established at 50 ppm (3.4 mg/kg/day) based on reduced pup weight and
litter size observed at 250 ppm (12.5 mg/kg/day). Parental toxicity (in
the form of abnormal, sprayed, or high-stepping gait) was also observed
at 250 ppm. Thus, the effects observed in offspring at 250 ppm is
considered to be secondary to maternal toxicity.
4. Subchronic toxicity. A 90-day feeding study in which rats were
fed doses of 0, 50, 150, and 350 ppm with a NOEL of 50 ppm and a lowest
observed effect level (LOEL) of 150 ppm based on mild dose changes in
hemoglobin, cholesterol, and liver weight.
A 90-day feeding study in which dogs were fed doses of 0, 0.1, 0.5,
and 1.5 mg/kg with a NOEL of 0.5 mg/kg and a LOEL of 1.5 mg/kg based on
increased triglycerides and AST.
A 21-day dermal study in which rats were exposed dermally to doses
of 1, 5, and 50 mg/kg/day, 6 hours/day with a toxicological NOEL of
1mg/kg.
5. Chronic toxicity. A 12-month feeding study in dogs was conducted
with a NOEL of 0.5 mg/kg/day. The LOEL for this study is established at
2 mg/kg/day based upon ataxia.
A 24-month rat and mouse chronic feeding/oncogenicity studies were
conducted with systemic NOEL's of 1.1mg/kg/day and 3.4 mg/kg/day with
no oncogenic effects observed at dose levels up to and including 18.2
mg/kg/day and 54.4 mg/kg/day, the highest dose levels tested for rats
and mice, respectively.
6. Animal metabolism. A metabolism study in the rat demonstrated
that distribution patterns and excretion rates in multiple oral dosing
periods are similar to single-dose studies. The metabolism of
tefluthrin in livestock has been studied in the goat and chicken. The
nature of tefluthrin residue in animals for corn use is adequately
understood. The residue of concern is tefluthrin and its metabolite.
There is no reasonable expectation of secondary residues in animal
tissues and milk from the use as delineated in 40 CFR 180.6(a)(3).
7. Metabolite toxicology. The nature of tefluthrin residue in
plants and animals for corn use is adequately understood. The residue
of concern is tefluthrin and its metabolite. There is no reasonable
expectation of secondary residues in animal tissues and milk from the
use as delineated in 40 CFR 180.6(a)(3). An adequate analytical method,
gas liquid chromatography with an electron capture detector, is
available for enforcement purposes. The enforcement methodology has
been submitted to the Food and Drug Administration, and is published in
the Pesticide Analytical Manual Vol. II (PAM II).
8. Endocrine disruption. EPA is required to develop a screening
program to determine whether certain substances (including all
pesticides and inerts) ``may have an effect produced by a naturally
occurring estrogen, or such other endocrine effect... .'' The Agency is
currently working with interested stakeholders, including other
government agencies, public interest groups, industry and research
scientists, in developing a screening and testing program and a
priority setting scheme to implement this program. Congress has allowed
3 years from passage of the Food Quality Protection Act (FQPA) (August
3, 1999) to implement this program. At that time, EPA may require
further testing of this active ingredient and end use products for
endocrine disrupter effects.
C. Aggregate Exposure
The primary source of human exposure to tefluthrin will be from
ingestion of raw and processed food commodities which have been treated
with tefluthrin. These commodities include corn, grain, field and pop;
corn, forage and fodder, field, pop and sweet; and corn, fresh
(including sweet K and CWHR) as listed in 40 CFR 180.440. There is no
reasonable expectation of secondary residues in animal tissues, milk,
or eggs from use as delineated in 40 CFR 180.6(a)(3).
1. Dietary exposure. For purposes of assessing the potential
dietary exposure under these tolerances, aggregate exposure is
estimated based on the Theoretical Maximum Residue Contribution (TMRC)
from the existing tolerances for tefluthrin in food crops. The TMRC is
obtained by multiplying the tolerance level residues by the consumption
data which estimates the amount of those food products eaten by various
population subgroups. The following assumptions were used in conducting
this exposure assessment: 100 percent of the crops were treated, and
the raw agricultural commodities (RAC) residues would be at the level
of the tolerance. This results in an overestimate of human exposure and
a conservative assessment of risk.
2. Food. The acute dietary risk assessment used tolerance level
residues and assumed that 100 percent of all crops were treated. Thus,
this acute dietary exposure estimate is considered ``worst-case'' and
severely overestimates potential exposure. The acute dietary Margin of
Exposure (MOE) for the most highly exposed population subgroup was
children ages one to six. The MOE's were 2,436 at the 95th percentile,
1,342 at the 99th percentile, and 738 at the 99.9th percentile. EPA
concludes that there is a reasonable certainty of no harm for MOE of
100 or greater. Therefore, the acute dietary risk assessment for
tefluthrin clearly indicates a reasonable certainty of no harm.
For the chronic dietary assessment Zeneca used the standard EPA
conservative exposure assumptions (i.e. tolerance level residues and
100 percent market share), and based on the completeness and
reliability of the toxicity data Zeneca has concluded that the
aggregate exposure to this chemical will utilize less than one percent
(0.40 percent) of the reference dose (RfD) for the U. S. population.
The most highly exposed population subgroup was children ages one to
six with a total dietary exposure of 0.000049 mg/kg bwt/day (1.0
percent of the RfD). Since EPA generally has no concern for exposures
below 100 percent of the RfD, there is a reasonable certainty that no
harm will result from aggregate exposure to residues.
3. Drinking water. Tefluthrin is immobile in soil and, therefore,
will not leach into ground water. Additionally, due to the insolubility
and lipophilic nature of tefluthrin, 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 synthetic
pyrethroid was conducted using EPA's Pesticide Root Zone Model (PRZM3).
Based on this screening assessment, potential concentrations of a
pyrethroid in ground water at depths of 1 to 2 meters are essentially
zero (<0.001 ppb).="" surface="" water="" concentrations="" for="" pyrethroids="" were="" estimated="" using="" przm3="" and="" exposure="" analysis="" [[page="" 50364]]="" modeling="" systems="" (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="" normally="" be="" treated="" before="" consumption.="" based="" on="" these="" analyses,="" the="" contribution="" of="" water="" to="" the="" dietary="" risk="" estimate="" is="" negligible.="" 4.="" non-dietary="" exposure.="" the="" potential="" for="" non-occupational="" exposure="" to="" the="" general="" population="" is="" expected="" to="" be="" essentially="" zero.="" tefluthrin="" is="" not="" registered="" for="" aquatic="" and/or="" domestic="" outdoor="" or="" indoor="" uses.="" the="" major="" use="" (corn)="" is="" applied="" only="" once="" per="" year="" at="" planting="" as="" a="" granular="" formulation.="" the="" other="" use="" is="" limited="" to="" commercial="" seed="" treatment="" of="" field="" corn,="" popcorn,="" seedcorn,="" and="" sweet="" corn="" seed.="" there="" is="" a="" commercial="" use="" in="" liquid="" slurry="" seed="" treaters="" and="" seed="" coating="" equipment,="" which="" is="" not="" for="" use="" on="" agricultural="" establishments="" in="" hopper-box,="" planter-box,="" slurry-box,="" or="" other="" seed="" treatment="" applications.="" the="" other="" minor="" use="" is="" for="" the="" treatment="" of="" fire="" ants="" for="" containerized="" and="" balled="" nursery="" stock="" under="" the="" usda/="" aphis="" imported="" fire="" ant="" quarantine="" program="" (department="" of="" agriculture-="" animal="" and="" plant="" health="" inspection="" service-7="" cfr="" part="" 301).="" d.="" cumulative="" effects="" zeneca="" will="" submit="" information="" for="" epa="" to="" consider="" concerning="" potential="" cumulative="" effects="" of="" tefluthrin="" consistent="" with="" the="" schedule="" established="" by="" epa="" on="" august="" 4,="" 1997="" (62="" fr="" 42020)="" (frl-5734-6)="" and="" other="" epa="" publications="" pursuant="" to="" the="" fqpa.="" at="" this="" time,="" zeneca="" cannot="" make="" a="" determination,="" based="" on="" available="" and="" reliable="" information,="" that="" tefluthrin="" and="" other="" substances="" that="" may="" have="" a="" common="" mechanism="" of="" toxicity="" would="" have="" cumulative="" effects.="" therefore,="" for="" purposes="" of="" this="" request="" it="" is="" appropriate="" only="" to="" consider="" the="" potential="" risks="" of="" tefluthrin="" in="" an="" aggregate="" exposure="" assessment.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" epa="" recently="" reviewed="" all="" of="" the="" toxicity="" end="" points="" for="" the="" synthetic="" pyrethroids.="" based="" on="" this="" review="" epa="" concluded="" that="" the="" chronic="" rfd="" is="" 0.005="" mg/kg/day.="" this="" rfd="" is="" based="" on="" a="" 1-year="" dog="" feeding="" study="" with="" a="" noel="" of="" 0.5="" mg/kg/day="" for="" ataxia,="" and="" a="" 100-fold="" uncertainty="" factor.="" in="" addition,="" epa="" derived="" an="" acute="" noel="" of="" 0.5="" mg/kg/day="" for="" use="" in="" acute="" dietary="" risk="" assessment.="" this="" noel="" is="" based="" on="" the="" 1-year="" dog="" feeding="" study="" in="" which="" increased="" incidence="" of="" tremors="" in="" both="" sexes="" of="" dogs="" was="" observed="" on="" the="" first="" day="" of="" dosing.="" using="" these="" rfd's="" and="" epa's="" standard="" default="" assumptions="" (i.e.="" tolerance="" level="" residues="" and="" 100="" percent="" market="" share),="" zeneca="" assessed="" the="" potential="" acute="" and="" chronic="" dietary="" risk="" to="" the="" general="" u.s.="" population="" and="" 22="" subpopulations.="" these="" analyses="" are="" considered="" ``worst-case'',="" and="" the="" results="" concluded="" that="" for="" the="" u.s.="" population,="" uses="" were="" 0.000021="" mg/kg/day="" (0.4="" of="" the="" rfd).="" the="" acute="" moe's="" at="" the="" 95th,="" 99th,="" and="" 99.9th="" percentile="" were="" 5.195,="" 2,449,="" and="" 1,091="" respectively.="" the="" most="" highly="" exposed="" population="" subgroup="" (children="" ages="" one="" to="" six),="" utilizes="" 1.0="" percent="" of="" the="" chronic="" rfd,="" and="" the="" acute="" dietary="" moe's="" at="" the="" 95th,="" 99th,="" and="" 99.9th="" percentiles="" were="" 2,436,="" 1,342,="" and="" 738,="" respectively.="" these="" assessments="" indicate="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" residues.="" 2.="" infants="" and="" children.="" section="" 408="" of="" the="" ffdca="" 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="" pre-="" and="" post-="" natal="" toxicity="" and="" the="" completeness="" of="" the="" database="" unless="" epa="" determines="" that="" a="" different="" margin="" of="" safety="" will="" be="" safe="" for="" infants="" and="" children.="" epa="" generally="" defines="" the="" level="" of="" appreciable="" risk="" as="" exposure="" that="" is="" greater="" than="" \1/100\="" of="" the="" noel="" in="" the="" animal="" study="" appropriate="" to="" the="" particular="" risk="" assessment.="" this="" 100-fold="" uncertainty="" (safety)="" factor/margin="" of="" exposure="" is="" designed="" to="" account="" for="" combined="" inter-="" and="" intra-species="" variability.="" epa="" believes="" that="" reliable="" data="" support="" using="" the="" standard="" 100-fold="" margin/factor,="" not="" the="" additional="" 10-fold="" margin/factor,="" when="" epa="" has="" a="" complete="" database="" under="" existing="" guidelines="" and="" when="" the="" severity="" of="" the="" effect="" in="" infants="" and="" children="" or="" the="" potency="" or="" unusual="" toxic="" properties="" of="" a="" compound="" do="" not="" raise="" concerns="" regarding="" the="" adequacy="" of="" the="" standard="" margin/factor.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" tefluthrin,="" epa="" considered="" the="" data="" from="" oral="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit,="" as="" well="" as="" data="" from="" a="" multi-generation="" reproduction="" study="" in="" the="" rat.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" in="" the="" developing="" organism="" resulting="" from="" pesticide="" exposure="" during="" prenatal="" development="" in="" the="" mothers.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" data="" on="" systemic="" toxicity.="" 3.="" pre-natal="" effects.="" in="" a="" rat="" developmental="" study="" delayed="" ossification="" was="" noted="" in="" the="" highest="" dose="" group="" (5="" mg/kg/day),="" along="" with="" significant="" maternal="" toxicity="" (decreased="" bwt).="" the="" developmental="" noel="" for="" this="" study="" was="" established="" at="" 3="" mg/kg/day.="" however,="" the="" effects="" observed="" were="" most="" likely="" a="" secondary="" effect="" resulting="" from="" maternal="" stress.="" in="" a="" developmental="" toxicity="" study="" in="" rabbits="" given="" gavage="" doses="" of="" 0,="" 3,="" 6,="" and="" 12="" mg/kg/day="" the="" maternal="" noel="" is="" 3="" mg/kg/day,="" and="" the="" developmental="" noel="" is=""> 12 mg/kg/day. No developmental effects were
observed under the conditions of the study.
4. Post-natal effects. In a rat multi-generation reproduction study
conducted at 0, 15, 50, and 250 ppm with tefluthrin in the diet, a
reproductive NOEL was established at 50 ppm (3.4 mg/kg/day), based on
reduced pup weight and litter size observed at 250 ppm (12.5 mg/kg/
day). Parental toxicity (in the form of abnormal, sprayed, or high-
stepping gait) was also observed at 250 ppm. Thus, the effects observed
in offspring at 250 ppm is considered to be secondary to maternal
toxicity.
In EPA's review of the toxicity endpoints for tefluthrin they
concluded that the data on developmental and reproductive toxicity
tests do not indicate any increased pre- or post-natal sensitivity.
Therefore, EPA concluded that reliable data support use of a 100-fold
safety factor, and additional 10-fold safety factor is not needed. This
aggregate assessment of tefluthrin clearly demonstrates that there is
no harm for all population groups.
F. International Tolerances
There are no Codex Maximum Residue Levels (MRL's) established for
tefluthrin. (John Hebert)
10. Zeneca Ag Products
PPs 7F3560, 7H5543, 7F3488, 1F3952, 1H5607, 1F3992, 2F4109, 2F4100,
2F4114, 1F3985, and 6F4769
EPA has received a request from Zeneca Ag Products, 1800 Concord
Pike, P.O. Box 15458, Wilmington, Delaware 19850-5458, 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 180.438 by removing the
time limitation for tolerances established for residues of lambda-
cyhalothrin and its epimer in or on the following crops and
commodities: broccoli at 0.4 ppm;
[[Page 50365]]
cabbage at 0.4 ppm; cattle, fat at 3.0 ppm; cattle, meat at 0.2 ppm;
cattle, meat and meat by-products (mbyp) at 0.2 ppm; corn, grain (field
and pop) at 0.05 ppm; corn, fodder at 1.0 ppm; corn, forage at 6.0 ppm;
corn, sweet (k+kwhr) at 0.05 ppm; cottonseed at 0.05 ppm; dry bulb
onion at 0.1 ppm; eggs at 0.01 ppm; garlic at 0.1 ppm; goats, fat at
3.0 ppm; goats, meat at 0.2 ppm; goats, mbyp at 0.2 ppm, hogs, fat at
3.0 ppm; hogs, meat at 0.2 ppm; hogs, mbyp at 0.2 ppm; horses, fat at
3.0 ppm; horses, meat at 0.2 ppm; horses, mbyp at 0.2 ppm; lettuce,
head at 2.0 ppm; milk, fat (reflecting 0.2 ppm in whole milk) at 5.0
ppm; peanuts at 0.05 ppm; peanuts, hulls at 0.05 ppm; poultry, fat at
0.01 ppm; poultry, meat at 0.01 ppm; poultry, mbyp at 0.01 ppm; rice,
grain at 1.0 ppm; rice, hulls at 5.0 ppm; rice, straw at 1.8 ppm;
sheep, fat at 3.0 ppm; sheep, meat at 0.2 ppm; sheep, mbyp at 0.2 ppm;
soybeans at 0.01 ppm; sorghum, grain at 0.02 ppm; sorghum, grain dust
at 1.5 ppm; sunflower, seeds at 0.2 ppm; sunflower, forage at 0.2 ppm;
tomatoes at 0.1 ppm; wheat, grain at 0.05 ppm; wheat, forage at 2.0
ppm; wheat, hay at 2.0 ppm; wheat, straw at 2.0 ppm; wheat, grain dust
at 2.0 ppm; corn, grain flour at 0.15 ppm; sunflower, oil at 0.30 ppm;
sunflower, hulls at 0.50 ppm; tomato pomace (dry or wet) at 6.0 ppm;
and wheat, bran at 0.2 ppm. The IUPAC name for lambda-cyhalothrin is a
1:1 mixture of (S)-alpha-cyano-3-phenoxybenzyl-(Z)-(1R,3R)-3-(2-chloro-
3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate and
(R)-alpha-cyano-3-phenoxybenzyl-(Z)-(1S,3S)-3-(2-chloro-3,3,3-
trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate and the
epimer of lambda-cyhalothrin is a 1:1 mixture of (S)-alpha-cyano-3-
phenoxybenzyl-(Z)-(1S,3S)-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-
dimethylcyclopropanecarboxylate and (R)-alpha-cyano-3-phenoxybenzyl-
(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-
dimethylcyclopropanecarboxylate. These tolerances were originally
requested in Pesticide Petition Numbers 7F3560, 7H5543, 7F3488, 1F3952,
1H5607, 1F3992, 2F4109, 2F4100, 2F4114, 1F3985, and 6F4769. EPA has
determined that the petitions 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 the request. Additional data
may be needed before EPA rules on the request.
A. Residue Chemistry
1. Plant metabolism.The metabolism of lambda-cyhalothrin has been
studied in cotton, soybean, cabbage and wheat plants. The studies show
that the metabolism generally follows that of other pyrethroid
insecticides. The ester linkage is cleaved to form
cyclopropanecarboxylic acids and the corresponding phenoxybenzyl
alcohol. Overall the studies show that unchanged lambda-cyhalothrin is
the principal constituent of the residue on edible portions of these
crops.
2. Analytical method. An adequate analytical method (gas liquid
chromatography with an electron capture detector) is available for
enforcement purposes.
3. Magnitude of residues. Field residue trials, meeting EPA study
requirements, have been conducted for each crop in this petition. These
data have previously been reviewed and classified by the Agency as
supportive of these tolerances.
B. Toxicological Profile
The following toxicity studies have been conducted to support this
request.
1. Acute toxicity. Acute toxicity studies with the technical grade
of the active ingredient lambda-cyahothrin: oral LD50 in the
rat of 79 millgrams/kilogram (mg/kg) (males) and 56 mg/kg (females),
dermal LD50 in the rat of 632 mg/kg (males) and 696 mg/kg
females, primary eye irritation study showed mild irritation and
primary dermal irritation study showed no irritation.
2. Genotoxicty. The following genotoxicity tests were all negative:
a gene mutation assay (Ames), a mouse micronucleus assay, an in-vitro
cytogenetics assay, and a gene mutation study in mouse lymphoma cells.
3. Reproductive and developmental toxicity. A three-generation
reproduction study in rats fed diets containing 0, 10, 30, and 100 ppm
with no developmental toxicity observed at 100 ppm, the highest dose
tested. The maternal NOEL and LOEL for the study are established at 30
(1.5 mg/kg/day) and 100 ppm (5 mg/kg/day), respectively, based upon
decreased parental body weight gain. The reproductive NOEL and LOEL are
established at 30 (1.5 mg/kg/day) and 100 ppm (5 mg/kg/day),
respectively, based on decreased pup weight gain during weaning.
A developmental toxicity study was conducted in rats given gavage
doses of 0, 5, 10, and 15 mg/kg/day with no developmental toxicity
observed under the conditions of the study. The developmental NOEL is
greater than 15 mg/kg/day, the highest dose tested. The maternal NOEL
and LOEL are established at 10 and 15 mg/kg/day, respectively, based on
reduced body weight gain.
A developmental toxicity study was conducted in rabbits given
gavage doses of 0, 3, 10, and 30 mg/kg/day with no developmental
toxicity observed under the conditions of the study. The maternal NOEL
and LOEL are established at 10 and 30 mg/kg/day, respectively based on
decreased body weight gain. The developmental NOEL is greater than 30
mg/kg/day, the highest dose tested.
4. Subchronic toxicity. A 90-day feeding study in rats fed doses of
0, 10, 50 and 250 ppm with a NOEL of 50 ppm and a LOEL of 250 ppm based
on body weight gain reduction.
A study where lambda-cyhalothrin in olive oil was applied to the
skin of rats for 21 successive days at dose rates of 1, 10, or 100
(reduced to 50 after 2-3 applications) mg/kg/day. A NOEL of 10 mg/kg/
day is based on clinical signs of slight general toxicity at 50 mg/kg/
day.
5. Chronic toxicity. A 12-month feeding study was conducted in dogs
fed dose (by capsule) levels of 0, 0.1, 0.5, 3.5 mg/kg/day with a NOEL
of 0.1 mg/kg/day. The LOEL for this study is established at 0.5 mg/kg/
day based upon clinical signs of neurotoxicity.
A 24-month chronic feeding/carcinogenicity study was conducted with
rats fed diets containing 0, 10, 50, and 250 ppm. The NOEL was
established at 50 ppm and LOEL at 250 ppm based on reduced body weight
gain. There were no carcinogenic effects observed under the conditions
of the study.
A carcinogenicity study was conducted in mice fed dose levels of 0,
20, 100, or 500 ppm (0, 3, 15, or 75 mg/kg/day) in the diet for 2
years. A systemic NOEL was established at 100 ppm and systemic LOEL at
500 ppm based on decreased body weight gain in males throughout the
study at 500 ppm. The Agency has classified lambda-cyhalothrin as a
Group D carcinogen (not classifiable due to an equivocal finding in
this study). It is Zeneca's position that no treatment-related
carcinogenic effects were observed under the conditions of the study.
6. Animal metabolism. Metabolism studies in rats demonstrated that
distribution patterns and excretion rates in multiple oral dose studies
are similar to single-dose studies. Accumulation of unchanged compound
in fat upon chronic administration shows slow elimination. Otherwise,
lambda-cyhalothrin was rapidly metabolized and excreted. The metabolism
of
[[Page 50366]]
lambda-cyhalothrin in livestock has been studied in the goat, chicken,
and cow. Unchanged lambda-cyhalothrin is the major residue component of
toxicological concern in meat and milk.
Human metabolism of lambda-cyhalothrin was assessed by
administering 5 mg lambda-cyhalothrin orally to six male volunteers
(average dose was 0.06 mg/kg) and dermally at 20 mg/800 cm2
to five volunteers. No adverse effects were noted in the individuals
given an oral dose, and only mild signs of parasthesia were noted in
individuals receiving a dermal dose. Absorption by these two routes of
exposure were determined by analysis of urinary metabolites. An average
amount of 59% of the oral dose was absorbed. Dermal absorption was
extremely low, and estimated to be 0.12% (range 0.04-0.19%).
7. Metabolite toxicology. The Agency has previously determined that
the metabolites of lambda-cyhalothrin are not of toxicological concern
and need not be included in the tolerance expression. Given this
determination, it is concluded that there is no need to discuss
metabolite toxicity.
8. Endocrine disruption. EPA is required to develop a screening
program to determine whether certain substances (including all
pesticides and inerts) ``may have an effect in humans that is similar
to an effect produced by a naturally occurring estrogen, or such other
endocrine effect***.'' The Agency is currently working with interested
stakeholders, including other government agencies, public interest
groups, industry and research scientists in developing a screening and
testing program and a priority setting scheme to implement this
program. Congress has allowed 3 years from the passage of FQPA (August
3, 1999) to implement this program. At that time, EPA may require
further testing of this active ingredient and end use products for
endocrine disrupter effects.
C. Aggregate Exposure
Zeneca has conducted an aggregate exposure assessment for lambda-
cyhalothrin. This assessment included exposures resulting from
agricultural crop use and non-dietary residential use.
1. Dietary exposure. For the purposes of assessing the potential
chronic dietary exposure for all existing and pending tolerances for
lambda-cyhalothrin, Zeneca has utilized available information on
anticipated residues (FDA monitoring data, average field trial residues
and processing data) and percent crop treated. For the acute dietary
assessment, a Monte Carlo modeling was used to estimate exposure.
2. Food. The Agency has stated that the acute dietary risk
assessment for lambda-cyhalothrin should be based on a toxicological
NOEL from a 1-year dog study. Zeneca disagrees with EPA's selection of
a multiple-dose toxicological endpoint (0.5 mg/kg) for the acute
dietary risk assessment, and have requested the Agency to base the
acute dietary NOEL on single-dose effects. Acute risk, by EPA
definition, results from 1-day consumption of food and water, and
reflects toxicity which could be expressed following a single oral
exposure to pesticide residues. Therefore, an appropriate NOEL must be
based on effects noted after a single dose, even if the endpoint is
selected from a repeat dose study, such as a 1-year dog. Nonetheless,
sufficient margins of exposure are achieved at percentiles of exposure
up to and including the 99.9th percentile based on the Agency's NOEL of
0.5 mg/kg.
Based on the Agency's selected acute toxicity endpoint of 0.5 mg/kg
bw day, the acute dietary MOE for the most highly exposed population
subgroup was children 1-6 years old. The MOEs were 658 at the 95th
percentile, 248 at the 99th percentile, and 132 at the 99.9th
percentile. EPA concludes that there is a reasonable certainty of no
harm for a MOE of 100 or greater. Therefore, the acute dietary risk
assessment for lambda-cyhalothrin clearly indicates a reasonable
certainty of no harm. The assessment of chronic dietary exposure was
estimated to be 5.0% of the chronic reference dose (RfD) for the
overall U.S. population. The RfD for lambda-cyhalothrin, 0.001 mg/kg bw
/day, is based on the NOEL of 0.1 mg/kg from the 1-year dog study and
an Uncertainty Factor of 100. For the most exposed subgroup, children
1-6 years old, the exposure was estimated to be 0.000159 mg/kg bw/day,
or 15.9% of the RfD. Since EPA generally has no concern for exposures
below 100 percent of the RfD, there is a reasonable certainty that no
harm will result from chronic dietary exposure to lambda-cyhalothrin
residues.
3. Drinking water. Laboratory and field data have demonstrated that
lambda-cyhalothrin and its degradates are immobile in soil and will not
leach into ground water. Other data show that lambda-cyhalothrin is
virtually insoluble in water and extremely lipophilic. As a result,
residues reaching surface waters from field runoff will quickly adsorb
to sediment particles and be partitioned from the water column.
Together these data indicate that residues are not expected in drinking
water.
A screening evaluation of leaching potential of a typical
pyrethroid was conducted using EPA's Pesticide Root Zone Model (PRZM3).
Based on this screening assessment, the potential concentrations of a
pyrethorid in ground water at depths of 1 and 2 meters are essentially
zero (< 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="" normally="" be="" treated="" before="" consumption.="" based="" on="" these="" analyses,="" the="" contribution="" of="" water="" to="" the="" dietary="" risk="" estimate="" is="" negligible.="" 4.="" non-dietary="" exposure.="" other="" potential="" sources="" of="" exposure="" are="" from="" non-occupational="" sources="" such="" as="" structural="" pest="" control="" and="" ornamental="" plant="" and="" lawn="" use="" of="" lambda-cyhalothrin.="" in="" its="" review="" of="" toxicity="" endpoints="" for="" assessing="" risks="" for="" lambda-cyhalothrin,="" the="" agency="" concluded="" that="" the="" most="" appropriate="" endpoint="" for="" non-dietary="" risk="" assessment="" is="" 10="" mg/kg="" bw/day="" based="" on="" the="" noel="" from="" the="" 21-day="" dermal="" toxicity="" study.="" exposure="" was="" estimated="" using="" available="" market="" use="" information="" and="" surrogate="" indoor="" exposure="" data.="" the="" resulting="" moes="" were="" 15,000="" for="" the="" u.s.="" population,="" 7,000="" for="" non-nursing="" infants="" and="" 7,200="" for="" children="" 1-6="" years="" old.="" the="" aggregate="" risk="" assessment="" of="" combined="" exposures="" from="" chronic="" dietary,="" drinking="" water="" and="" non-dietary="" residential="" sources="" has="" been="" conducted.="" the="" resulting="" moes="" are="" 14,000="" for="" the="" u.s.="" population,="" 6,500="" for="" non-nursing="" infants="" and="" 6,500="" for="" children="" 1-6="" years="" old.="" epa="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" of="" no="" harm="" for="" moe="" of="" 100="" or="" greater.="" therefore,="" the="" non-="" dietary="" and="" overall="" aggregate="" risk="" assessments="" for="" lambda-cyhalothrin="" clearly="" indicates="" a="" reasonable="" certainty="" of="" no="" harm.="" d.="" cumulative="" effects="" zeneca="" ag="" products="" will="" submit="" information="" for="" epa="" to="" consider="" concerning="" potential="" cumulative="" effects="" of="" lambda-cyhalothrin="" consistent="" with="" the="" schedule="" established="" by="" epa="" at="" 62="" fr="" 42020="" (august="" 4,="" 1997)(frl-5734-6)="" and="" other="" epa="" publications="" pursuant="" to="" the="" fqpa.="" at="" this="" time,="" zeneca="" cannot="" make="" a="" determination="" based="" on="" [[page="" 50367]]="" available="" and="" reliable="" information="" that="" lambda-cyhalothrin="" and="" other="" substances="" that="" may="" have="" a="" common="" mechanism="" of="" toxicity="" would="" have="" cumulative="" effects.="" therefore="" for="" purposes="" of="" this="" request="" it="" is="" appropriate="" only="" to="" consider="" the="" potential="" risks="" of="" lambda-cyhalothrin="" in="" an="" aggregate="" exposure="" assessment.="" e.="" safety="" determination="" the="" acceptable="" rfd="" based="" on="" a="" noel="" of="" 0.1="" mg/kg="" bw/day="" from="" the="" chronic="" dog="" study="" and="" a="" safety="" factor="" of="" 100="" is="" 0.001="" mg/kg="" bw/day.="" a="" chronic="" dietary="" exposure/risk="" assessment="" has="" been="" performed="" for="" lambda-="" cyhalothrin="" using="" the="" above="" rfd.="" 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.="" 1.="" u.s.="" population.="" the="" arc="" from="" established="" tolerances="" and="" the="" current="" and="" pending="" actions="" are="" estimated="" to="" be="" 0.00005="" mg/kg="" bw/day="" and="" utilize="" 5.0="" per="" cent="" of="" the="" rfd="" for="" the="" u.s.="" population.="" for="" the="" acute="" dietary="" assessment="" the="" moes="" at="" the="" 95th,="" 99th,="" and="" 99.9th="" percentiles="" are="" 2074,="" 742,="" and="" 237,="" respectively.="" 2.="" infants="" and="" children.="" ffdca="" section="" 408="" provides="" that="" epa="" shall="" apply="" an="" additional="" tenfold="" 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="" unless="" epa="" determines="" that="" a="" different="" margin="" of="" safety="" will="" be="" safe="" for="" infants="" and="" children.="" epa="" generally="" defines="" the="" level="" of="" appreciable="" risk="" as="" exposure="" that="" is="" greater="" than="" 1/100="" of="" the="" noel="" in="" the="" animal="" study="" appropriate="" to="" the="" particular="" risk="" assessment.="" this="" hundredfold="" uncertainty="" (safety)="" factor/margin="" of="" exposure="" is="" designed="" to="" account="" for="" combined="" inter="" and="" intraspecies="" variability.="" epa="" believes="" that="" reliable="" data="" support="" using="" the="" standard="" hundredfold="" margin/factor="" and="" not="" the="" additional="" tenfold="" margin/factor="" when="" epa="" has="" a="" complete="" database="" under="" existing="" guidelines="" and="" when="" the="" severity="" of="" the="" effect="" in="" infants="" and="" children="" or="" the="" potency="" or="" unusual="" toxic="" properties="" of="" a="" compound="" do="" not="" raise="" concerns="" regarding="" the="" adequacy="" of="" the="" standard="" margin/factor.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" lambda-cyhalothrin,="" epa="" considered="" the="" data="" from="" oral="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit,="" as="" well="" as="" data="" from="" a="" multi-generation="" reproduction="" study="" in="" the="" rat.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" in="" the="" developing="" organism="" resulting="" from="" pesticide="" exposure="" during="" prenatal="" development="" in="" the="" mothers.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" data="" on="" systemic="" toxicity.="" i.="" pre-natal="" effects.="" a="" developmental="" toxicity="" study="" in="" rats="" given="" gavage="" doses="" of="" 0,="" 5,="" 10,="" and="" 15="" mg/kg/day="" with="" no="" developmental="" toxicity="" observed="" under="" the="" conditions="" of="" the="" study.="" the="" developmental="" noel="" is="" greater="" than="" 15="" mg/kg/day,="" the="" highest="" dose="" tested.="" the="" maternal="" noel="" and="" loel="" are="" established="" at="" 10="" and="" 15="" mg/kg/day,="" respectively,="" based="" on="" reduced="" body="" weight="" gain.="" a="" developmental="" toxicity="" study="" in="" rabbits="" given="" gavage="" doses="" of="" 0,="" 3,="" 10,="" and="" 30="" mg/kg/day="" with="" no="" developmental="" toxicity="" observed="" under="" the="" conditions="" of="" the="" study.="" the="" maternal="" noel="" and="" loel="" are="" established="" at="" 10="" and="" 30="" mg/kg/day,="" respectively="" based="" on="" decreased="" body="" weight="" gain.="" the="" developmental="" noel="" is="" greater="" than="" 30="" mg/kg/day,="" the="" highest="" dose="" tested.="" ii.="" post-natal="" effects.="" a="" three-generation="" reproduction="" study="" in="" rats="" fed="" diets="" containing="" 0,="" 10,="" 30,="" and="" 100="" ppm="" with="" no="" developmental="" toxicity="" observed="" at="" 100="" ppm,="" the="" highest="" dose="" tested.="" the="" maternal="" noel="" and="" loel="" for="" the="" study="" are="" established="" at="" 30="" (1.5="" mg/kg/day)="" and="" 100="" ppm="" (5="" mg/kg/day),="" respectively,="" based="" upon="" decreased="" parental="" body="" weight="" gain.="" the="" reproductive="" noel="" and="" loel="" are="" established="" at="" 30="" (1.5="" mg/kg/day)="" and="" 100="" ppm="" (5="" mg/kg/day),="" respectively,="" based="" on="" decreased="" pup="" weight="" gain="" during="" weaning.="" in="" epa's="" review="" of="" the="" toxicity="" endpoints="" for="" lambda-cyhalothrin="" they="" concluded="" that="" the="" data="" on="" developmental="" and="" reproductive="" toxicity="" tests="" do="" not="" indicate="" any="" increased="" pre-="" or="" post-natal="" sensitivity.="" therefore,="" epa="" concluded="" that="" reliable="" data="" support="" use="" of="" a="" hundredfold="" safety="" factor="" and="" that="" an="" additional="" tenfold="" safety="" factor="" is="" not="" needed.="" based="" on="" this="" information="" the="" arc="" for="" children="" 1-6="" years="" old,="" and="" non-nursing="" infants="" (subgroups="" most="" highly="" exposed)="" utilizes="" 0.000159="" mg/kg="" bw/day="" (15.9%="" of="" the="" rfd)="" and="" 0.000101="" mg/kg="" bw/day="" (10.1%="" of="" the="" rfd),="" respectively.="" generally="" speaking,="" the="" agency="" has="" no="" cause="" for="" concern="" if="" anticipated="" residues="" contribution="" for="" all="" published="" and="" proposed="" tolerances="" is="" less="" than="" the="" rfd.="" for="" the="" acute="" dietary="" assessment="" the="" moes="" at="" the="" 95th,="" 99th,="" and="" 99.9th="" percentiles="" are="" 658,="" 248,="" and="" 132,="" respectively="" for="" children="" 1-6="" years="" old.="" for="" non-nursing="" infants="" the="" moes="" at="" the="" 95th,="" 99th="" and="" 99.9th="" percentiles="" are="" 710,="" 316,="" and="" 152,="" respectively.="" f.="" international="" tolerances="" there="" are="" codex="" maximum="" residue="" levels="" established="" for="" residues="" of="" cyhalothrin,="" as="" the="" sum="" of="" all="" isomers,="" in="" or="" on="" the="" following="" crops="" and="" commodities:="" pome="" fruits="" at="" 0.2="" ppm;="" cabbage,="" head="" at="" 0.2="" ppm;="" potatoes="" at="" 0.02="" ppm;="" cotton="" seed="" at="" 0.02="" ppm;="" cotton="" seed="" oil,="" crude="" at="" 0.02="" ppm;="" and="" cotton="" seed="" oil,="" edible="" at="" 0.02="" ppm.="" (adam="" heyward)="" [fr="" doc.="" 97-25499="" filed="" 9-22-97;="" 3:06="" pm]="" billing="" code="" 6560-50-f="">