[Federal Register Volume 63, Number 72 (Wednesday, April 15, 1998)]
[Notices]
[Pages 18411-18420]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-9395]
[[Page 18411]]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-801; FRL-5781-9]
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-801, must
be received on or before May 15, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119FF, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Sidney Jackson (PM 5)......... Rm. 268, CM #2, 703- 1921 Jefferson
305-7610, e- Davis Hwy,
mail:[email protected] Arlington, VA
pamail.epa.gov.
Bipin Gandhi (PM 5)........... Rm. 4W53, CS #2, 703- Do.
308-8380, e-mail:
gandhi.bipin@epamail..
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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 support 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-801] (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 number FRL-5781-9 and appropriate petition
number. Electronic comments on 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: April 1, 1998
James Jones,
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. Interregional Research Project
PP 2E4101
EPA has received a pesticide petition (PP 2E4101) from the
Interregional Research Project Number 4 (IR-4), 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 the insecticide cyfluthrin, [cyano[4-fluoro-3-
phenoxyphenyl]-methyl-3-[2,2- dicloroethenyl]-2,2-
dimethylcyclopropanecarboxylate] in or on the raw agricultural
commodity dried hops at 20.0 parts per million (ppm) and to remove the
established tolerance for fresh hops at 4.0 ppm. EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408(d)(2) of the Federal Food Drug and Cosmetic
Act (FFDCA); however, EPA has not fully evaluated the sufficiency of
the submitted data at this time or whether the data supports granting
of the proposed tolerance. Additional data may be needed before EPA
rules on the petition. This notice includes a summary of the petition
prepared by Bayer Corporations (Bayer), the registrant.
A. Residue Chemistry
1. Plant metabolism. The metabolism of cyfluthrin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radiolabeled cyfluthrin in various crops all showing
similar results. The residue of concern is cyfluthrin.
[[Page 18412]]
2. Analytical method. Adequate analytical methodology (gas liquid
chromatography with an electron capture detector) is available for
enforcement purposes. The methodology was successfully validated by
EPA's Beltsville laboratory in support of tolerances on cottonseed. The
enforcement methodology has been submitted to the Food and Drug
Administration for publication in the Pesticide Analytical Manual Vol.
II (PAM II). Because of the long lead time for publication of the
method in PAM II, the analytical methodology is being made available in
the interim to anyone interested in pesticide enforcement when
requested from Calvin Furlow, Public Response and Program Resource
Branch, Field Operations Division (7502C), Office of Pesticide
Programs, U.S. Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. Office location and telephone number: Rm. 119FF,
CM #2, 1921 Jefferson-Davis Hwy., Arlington, VA 22202, (703) 305-5232.
The established tolerances for residues of cyfluthrin in/on eggs,
milks, fat, meat and meat by-products of cattle, goats, hogs, horses,
sheep and poultry are adequate to cover secondary residues resulting
from the proposed use as delineated in 40 CFR 180.6(a)(2).
3. Magnitude of residues. Import tolerances for cyfluthrin are
presently established on fresh hops at 4.0 ppm and on dried hops at
20.0 ppm. IR-4 has conducted field trials in Washington, Oregon and
Idaho in order to support expansion of the tolerances to include the
domestic production of hops in the United States.
The residue data submitted to the EPA by IR-4 consist of three
trials, one each in Washington, Oregon and Idaho. In each trial, hops
were planted in three plots, two treated and one untreated. Cyfluthrin
(Baythroid 2) was applied by foliar (ground) application at a rate of
0.05 pounds(lb) active ingredient(ai)/acre(A) to one plot and 0.1 lb
ai/A to another. Five separate applications were made with an interval
of 7-days between the last application and harvest.
Residues of cyfluthrin were detected in all treated samples from
each trial and no interferences were detected in samples from control
plots. The residue data are consistent for each trial. Cyfluthrin
applied at 0.05 lb ai/A was detected from 0.44 to 0.78 ppm on fresh
hops and from 1.83 to 2.36 ppm on dried hops. At 0.10 lb ai/A, residues
were detected at 1.10 to 2.70 ppm on fresh hops and 3.76 to 7.57 ppm on
dried hops.
B. Toxicological Profile
The data base for cyfluthrin is essentially complete. Data lacking
but desirable are an acute neurotoxicity study in rats and a 90-day
neurotoxicity study in rats. Although these data are lacking, Bayer
believes the available toxicity data are sufficient to support the
proposed tolerance and these missing data will not significantly change
its risk assessment. Bayer has committed to submit the acute
neurotoxicity study and the 90-day neurotoxicity study.
1. Acute toxicity. Results of acute toxicity tests show an acute
oral lethal dose (LD50) grater than or equal to 16.2
milligram (mg)/ kilogram (kg), a dermal (LD50) >5,000 mg/kg,
inhalation lethal concentration (LC50 greater than or equal
to 0.468 mg/liter(L), primary eye irritation and primary dermal
irritation show toxicity categories III and IV, respectively. Dermal
sensitization tests conducted show that cyfluthrin is not a dermal
sensitizer.
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 no-observed effect
level (NOEL) of 10 mg/kg/day (highest dose tested). An oral
developmental toxicity study in rabbits with a maternal NOEL of 20 mg/
kg/day and a maternal lowest effect level (LEL) of 60 mg/kg/day, based
on decreased body weight gain and decreased food consumption during the
dosing period. A fetal NOEL of 20 mg/kg/day and a fetal LEL of 60 mg/
kg/day were also observed in this study. The LEL was based on increased
resorptions and increased postimplantation loss.
A developmental toxicity study in rats by the inhalation route of
administration with a maternal NOEL of 0.0011 mg/l and a LEL of 0.0047
mg/l, based on reduced mobility, dyspnea, piloerection, ungroomed coats
and eye irritation. The fetal NOEL is 0.00059 mg/l and the fetal LEL is
0.0011 mg/l, based on sternal anomalies and increased incidence of
runts. A second developmental toxicity study in rats by the inhalation
route of administration has been submitted to the Agency. A 3-
generation reproduction study in rats with a systemic NOEL of 2.5 mg/
kg/day and a systemic LEL of 7.5 mg/kg/day due to decreased parent and
pup body weights. The reproductive NOEL and LEL are 7.5 mg/kg/day and
22.5 mg/kg/day respectively.
4. Subchronic toxicity. In a 28-day oral toxicity study in rats,
cyfluthrin demonstrated a NOEL of 20 mg/kg/day. The lowest-observed-
effect level (LOEL) was 80 (40) mg/kg/day in both sexes based on
clinical signs of nerve toxicity, decreases in body weight gain, and
changes in liver and adrenal weights. The high dose was 80 mg/kg/day
during the first and third weeks and 40 mg/kg/day during the second and
fourth weeks.
In a six month dog feeding study established a NOEL at 5 mg/kg/day
for male and females. The LOEL for this study was 15 mg/kg/day for both
sexes, based on neurological effects (hindlimb abnormalities) and
gastrointestinal disturbances.
A 21-day repeated dose dermal toxicity study, male and female rats
were treated with cyfluthrin by dermal occlusion at target doses of 0,
100, 340, or 1,000 mg/kg/day for 6 hours/day (average actual dose
levels were 0, 113, 376 or 1,077 mg/kg/day). No mortality was observed,
and there were no treatment-related effects on body weight,
ophthalmology, organ weights, clinical biochemistry, or hematology. The
LOEL for dermal effects was 376 mg/kg/day for male and female Sprague-
Dawley rats based on gross and histological skin lesions. The NOEL for
dermal effects was 113 mg/kg/day. The LOEL for systemic effects was
1,077 mg/kg/day based on decreased food consumption, red nasal
discharge and urine staining. The NOEL for systemic effects was 376 mg/
kg/day.
5. Chronic toxicity. A 12-month chronic feeding study in dogs with
a NOEL of 4 mg/kg/day. The LEL for this study is established at 16 mg/
kg/day, based on slight ataxia, increased vomiting, diarrhea and
decreased body weight.
A 24-month chronic feeding/carcinogenicity study in rats showed a
NOEL of 2.5 mg/kg/day and LEL of 6.2 mg/kg/day, based on decreased body
weights in males, decreased food consumption in males, and inflammatory
foci in the kidneys in females.
6. Carcinogenicity. A 24-month carcinogenicity study in mice was
conducted. There were no carcinogenic effects observed under the
conditions of the study.
A 24-month chronic feeding/carcinogenicity study in rats was
conducted. There were no carcinogenic effects observed under the
conditions of the study.
[[Page 18413]]
Cyfluthrin has been classified as a Group E chemical (evidence of
non-carcinogenicity for humans) by the Agency. The classification was
based on a lack of convincing evidence of carcinogenicity in adequate
studies with two animal species, rat and mouse.
7. 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.
8. Ednocrine effects. No special studies investigating potential
estrogenic or endocrine effects of cyfluthrin have been conducted.
However, the standard battery of required 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. According to
Bayer no endocrine effects were noted in any of the studies.
C. Aggregate Exposure
1. Dietary exposure. In examining aggregate exposure, FFDCA section
408 requires that EPA take into account available and reliable
information concerning exposure from the pesticide residue in the food
in question, residues in other foods for which there are tolerances,
residues in ground water or surface water that is consumed as drinking
water, and other non-occupational exposures through pesticide use in
gardens, lawns, or buildings (residential and other indoor uses).
Dietary exposure to residues of a pesticide in a food commodity are
estimated by multiplying the average daily consumption of the food
forms of that commodity by the tolerance level or the anticipated
pesticide residue level. The Theoretical Maximum Residue Contribution
(TMRC) is an estimate of the level of residues consumed daily if each
food item contained pesticide residues equal to the tolerance. In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children. The TMRC is a ``worst case'' estimate since it is
based on the assumptions that food contains pesticide residues at the
tolerance level and that 100% of the crop is treated by pesticides that
have established tolerances. If the TMRC exceeds the Reference Dose
(RfD) or poses a lifetime cancer risk that is greater than
approximately one in a million, EPA attempts to derive a more accurate
exposure estimate for the pesticide by evaluating additional types of
information (anticipated residue data and/or percent of crop treated
data) which show, generally, that pesticide residues in most foods when
they are eaten are well below established tolerances.
2. Food. Under a petition to establish tolerances for cyfluthrin in
or on citrus (PP 4F4313 and FAP 4H5687, the EPA has recently performed
a chronic dietary exposure/risk assessment for cyfluthrin using a RfD
of 0.025 mg/kg body weight(bwt)/day, based on a NOEL of 50 ppm (2.5 mg/
kg bwt/day) and an uncertainty factor of 100. The NOEL was determined
in a 2-year rat feeding study. The endpoint effects of concern were
decreased body weights in males and inflammation of the kidneys in
females at the LEL of 6.2 mg/kg/day. This dietary exposure/risk
assessment estimated the current dietary exposure for the U.S.
population resulting from established tolerances, including the current
4 ppm tolerance on fresh hops, is 0.002907 mg/kg/bwt day. This
represents 11.6% of the RfD. The exposure to children (1-6 years old),
the subgroup population exposed to the highest risk was 0.00662 mg/kg/
bwt/day or 26.4% of the RfD. The current action will increase the
exposure to 0.003266 mg/kg/bwt day or 13% of the RfD for the U.S.
population and 0.006622 mg/kg/bwt day or 26.4% or the RfD for children
(1-6 years old). Generally speaking, 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 the RfD. Therefore,
Bayer concludes that the chronic dietary risk of cyfluthrin, as
estimated by the dietary risk assessment, does not appear to be of
concern.
3. Drinking water. Cyfluthrin is immobile in soil, therefore, will
not leach into ground water. Additionally, due to 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, Bayer does not anticipate dietary exposures to cyfluthrin
from drinking water.
4. 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. Reliable data to
determine aggregate exposures from these sources are currently not
available. However, determinations of worst case exposure from
inhalation in indoor settings (continuous exposure at saturation vapor
concentration) indicated that adequate margins of safety existed even
under these conditions. Since this evaluation greatly overestimated
exposure, the contribution to aggregate exposure from inhalation in
normal uses would be expected to be negligible. Estimations of outdoor
residential exposure have been required for cyfluthrin in a data call-
in issued in 1995. These data are being generated by the Outdoor
Residential Exposure Task Force (ORETF). However, available data show
that the acute dermal toxicity of cyfluthrin is very low, with the
LD50 being greater than 5,000 mg/kg, the highest dose
tested. Sub-acute (21-day) dermal toxicity data showed only localized
(skin) effects at higher level exposures (1,000 mg/kg/day and 340 mg/
kg/day). Other than skin effects at these high exposure levels, no
effects were observed at any exposure levels, the highest level tested
being 1,000 mg/kg/day. The use rate for cyfluthrin on residential turf
is 1 g (1,000 mg) active ingredient per 1,000 square feet which would
indicate that potential exposures would be well below levels tested. In
addition, the localized skin effects seen at the prolonged higher
exposures in animal tests have not been reported for non-occupational
exposures to cyfluthrin in currently accepted uses, indicating that
exposures are below the threshold of any observable effects. Indoor
uses are limited to areas with little or no contact, so exposures would
be expected to be even less. Thus, the dermal route of exposure does
not appear to be significant and the contribution to aggregate exposure
from dermal contact would be expected to be negligible.
D. Cumulative Effects
In consideration of potential cumulative effects of cyfluthrin and
other substances that have a common mechanism of toxicity, Bayer
concludes that there are currently no available data or other reliable
information indicating that any toxic effects produced by cyfluthrin
would be cumulative with those of other chemical compounds; thus only
the potential risks of cyfluthrin have been considered in this
assessment of its aggregate exposure.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data it can be concluded that total aggregate exposure to
cyfluthrin from all current uses as well as the proposed tolerance will
utilize little more than 13% of the RfD for the U.S. population. EPA
generally has no concerns for exposures below 100% of
[[Page 18414]]
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. 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 2-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 2-generations, as well as any observed
systemic toxicity.
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. Based on current toxicological data requirements,
the toxicology database for cyfluthrin relative to pre- and post-natal
effects is complete. The NOELs observed in the developmental and
reproduction study are equivalent or higher than the NOEL from the 2-
year rat feeding study, used with a 100 fold uncertainty factor to
establish the reference dose. Therefore, Bayer believes that an
additional uncertainty factor is not warranted and that the RfD at
0.025 mg/kg/day is appropriate for assessing aggregate risk to infants
and children.
Using the conservative exposure assumptions described above,
cyfluthrin residues resulting from established tolerances, including a
tolerance of 20 ppm on dry hops, would utilize 26.4% of the RfD for
children (1-6 years old), the subgroup population exposed to the
highest risk. Generally, EPA has no cause for concern if the exposure
is less than 100% of the RfD. Therefore, based on the completeness and
the reliability of the toxicity data and the conservative exposure
assessment, Bayer concludes that there is a reasonable certainty that
no harm will result to infants and children from aggregate exposure to
the residues of cyfluthrin, including all anticipated dietary exposure
and all other non-occupational exposures.
F. International Tolerances
A Codex maximum residue levels (MRLs) or 20 ppm has been
established for residues of cyfluthrin on dried hops.
2. Interregional Research Project
PP Nos. 6E3404, 6E4685, 1E3966, 9E3697, and 5E4580
EPA has received pesticide petitions (PP Nos. 6E3404,
6E4685,1E3966, 9E3697, and 5E4580) from the Interregional Research
Project Number 4 (IR-4), 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 tolerances for residues of esfenvalerate, (S)-
cyano-(3-phenoxyphenyl)methyl (S)-4-chloro-alpha-(1-methylethyl)
benzeneacetate in or on the raw agricultural commodities mustard greens
at 5 ppm (PP 6E3404), kiwifruit at 0.5 ppm (PP 6E4685), globe artichoke
at 1.0 ppm (PP 1E3966), cranberry at 0.2 ppm (PP 9E3697), and kohlrabi
at 2.0 ppm (PP 5E4580). EPA has determined that these petitions contain
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of submitted data at this time or whether these data
support granting the proposed tolerances. Additional data may be needed
before EPA rules on the petitions. This notice contains a summary of
the petitions submitted by DuPont Agricultural Products, the
registrant.
A. Residue Chemistry
1. Plant metabolism. The metabolism and chemical nature of residues
of fenvalerate in plants and animals are adequately understood. The
fate of fenvalerate has been extensively studied using radioactive
tracers in plant and animal metabolism/nature of the residue studies.
These studies have demonstrated that the parent compound is the only
residue of toxicological significance. EPA has concluded that the
qualitative nature of the residue is the same for both fenvalerate and
esfenvalerate.
2. Analytical method. There is a practical analytical method
utilizing 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. The
limit of detection for updated method is the same as that of the
current PAM II, which is 0.01 ppm.
3. Magnitude of residues. Fenvalerate is a racemic mixture of four
isomers (about 25% each). Technical Asana (the S,S-isomer enriched
formulation, 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 4
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.
B. Toxicological Profile
1. Acute toxicity. A battery of acute toxicity studies places
technical esfenvalerate in Toxicity Category II for acute oral toxicity
(rat lethal dose LD50 87.2 mg/kg, Category III for acute
dermal (rabbit LD50 >2,000 mg/kg) and primary eye irritation
(mild irritation in rabbits), and Category IV for primary skin
irritation (minimal skin irritation in rabbits that reversed within 72
hours after treatment). Acute inhalation on technical grade active
ingredient (a.i.) was waived due to negligible vapor pressure. A dermal
sensitization test on esfenvalerate in guinea pigs showed no
sensitization.
2. Genotoxicity. Esfenvalerate was not mutagenic in reverse
mutation assays in S. typhimurium and E. coli and did not induce
mutations Chinese hamster V79 cells or chromosome aberrations in
Chinese hamster ovary cells. Esfenvalerate did not induce micronuclei
in bone marrow of mice given up to 150 mg/kg intra peritoneally.
Esfenvalerate did not induce unscheduled deoxyribonucleic acid (DNA)
synthesis in HeLa cells. Other genetic toxicology studies submitted on
racemic fenvalerate indicate that the mixture containing equal parts of
the four stereoisomers is not mutagenic in bacteria. The racemic
mixture was also negative in a mouse host mediated assay and in a mouse
dominant lethal assay.
3. Reproductive and developmental toxicity. Esfenvalerate was
administered to pregnant female rats by gavage in a pilot developmental
study at doses of 0, 1, 2, 3, 4, 5, and 20 mg/kg/day and a main study
at 0, 2.5, 5, 10, and 20 mg/kg/day. Maternal clinical signs (abnormal
gait and mobility) were observed at 2.5 mg/kg/day and above. A maternal
NOEL of 2 mg/kg/day was established for the pilot study. The
developmental NOEL was >20 mg/kg/day.
Esfenvalerate was administered by gavage to pregnant female rabbits
in a pilot developmental study at doses of 0, 2, 3, 4, 4.5, 5, and 20
mg/kg/day and a main study at doses of 0, 3, 10, and 20 mg/kg/day.
Maternal clinical signs (excessive grooming) were observed at 3 mg/kg/
day and above. A maternal NOEL of 2 mg/kg/day was established on the
[[Page 18415]]
pilot study. The developmental NOEL was > 20 mg/kg/day.
A 2-generation feeding study with esfenvalerate was conducted in
the rat at dietary levels of 0,75, 100, and 300 ppm. Skin lesions and
minimal (non biologically significant) parental body weight effects
occurred at 75 ppm. The NOEL for reproductive toxicity was 75 ppm (4.2-
7.5 mg/kg/day) based on decreased pup weights at 100 ppm.
4. Subchronic toxicity. Two 90-day feeding studies with
esfenvalerate were conducted in rats - one at 50, 150, 300, and 500 ppm
esfenvalerate, and a second at 0, 75, 100, 125, and 300 ppm to provide
additional dose levels. The NOEL was 125 ppm (6.3 mg/kg/day) based on
clinical signs (jerky leg movements) observed at 150 ppm (7.5 mg/kg/
day) and above.
A 90-day feeding study in mice was conducted at 0, 50, 150, and 500
ppm esfenvalerate with a NOEL of 150 ppm (30.5 mg/kg) based on clinical
signs of toxicity at 500 ppm (106 mg/kg).
A 3-month subchronic study in dogs was 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 conducted at 100,
300, and 1,000 mg/kg/day with a no-observed-adverse effect level
(NOAEL) of 1,000 mg/kg/day.
5. Chronic toxicity. In a 1-year study, dogs were fed 0, 25, 50, or
200 ppm esfenvalerate with no treatment related effects at any dietary
level. The NOEL was established at 200 ppm (5 mg/kg/day). An effect
level for dietary administration of esfenvalerate for dogs of 300 ppm
had been established earlier in a three week pilot study used to select
dose levels for the chronic dog study.
One chronic study with esfenvalerate and three chronic studies with
fenvalerate have been conducted in mice.
In an 18-month study, mice were fed 0, 35, 150, or 350 ppm
esfenvalerate. Mice fed 350 ppm were sacrificed within the first 2
months of the study after excessive self-trauma related to skin
stimulation and data collected were not used in the evaluation of the
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 feeding study, mice were administered 0, 10, 50, 250 or
1,250 ppm fenvalerate in the diet. The NOEL was 10 ppm (1.5 mg/kg/day)
based on granulomatous changes (related to fenvalerate only, not
esfenvalerate) at 50 ppm (7.5 mg/kg/day). Fenvalerate did not produce
carcinogenicity.
In an 18-month feeding study, mice were fed 0, 100, 300, 1,000, or
3,000 ppm fenvalerate in the diet. The NOEL is 100 ppm (15.0 mg/kg/day)
based on fenvalerate-related microgranulomatous changes at 300 ppm (45
mg/kg/day). No compound related carcinogenicity occurred.
Mice were fed 0, 10, 30, 100, or 300 ppm fenvalerate for 20-months.
The NOEL was 30 ppm (3.5 mg/kg/day) based on red blood cell effects and
granulomatous changes at 100 ppm (15 mg/kg/day). Fenvalerate was not
carcinogenic at any concentration.
In a 2-year study, rats were fed 1, 5, 25, or 250 ppm fenvalerate.
A 1,000 ppm group was added in a supplemental study to establish an
effect level. The NOEL was 250 ppm (12.5 mg/kg/day). At 1,000 ppm (50
mg/kg/day), hind limb weakness, lower body weight, and higher organ-to-
body weight ratios were observed. Fenvalerate was not carcinogenic at
any concentration. (A conclusion that fenvalerate is associated with
the production of spindle cell sarcomas at 1,000 ppm was retracted by
EPA).
EPA has classified esfenvalerate in Group E - evidence of non-
carcinogenicity for humans.
6. Animal metabolism. In animal studies, after oral dosing with
radioactive 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.
C. Aggregate Exposure
1. Dietary exposure. Tolerances have been established for the
residues of fenvalerate/esfenvalerate, in or on a variety of
agricultural commodities. In addition, pending tolerance petitions
exist for use of esfenvalerate on sugar beets, sorghum, head lettuce,
celery, pistachios, and a number of other minor use commodities. For
purposes of assessing dietary exposure, chronic and acute dietary
assessments have been conducted using all existing and pending
tolerances for esfenvalerate. EPA recently (August 2, 1997) reviewed
the existing toxicology data base for esfenvalerate and selected the
following toxicological endpoints. For acute toxicity, EPA established
a NOEL of 2.0 mg/kg/day from rat and rabbit developmental studies based
on maternal clinical signs at higher concentrations. An MOE of 100 was
required. For chronic toxicity. EPA established the Reference Dose
(RfD) for esfenvalerate at 0.02 mg/kg/day. This RfD was also based on a
NOEL of 2.0 mg/kg/day in the rat developmental study with an
uncertainty factor of 100. Esfenvalerate is classified as a Group E
carcinogen - no evidence of carcinogenicity in either rats or mice.
Therefore, a carcinogenicity risk analysis for humans is not required.
2. Food. A chronic dietary exposure assessment was conducted using
Novigen's DEEM (Dietary Exposure Estimate Model). Anticipated residues
and adjustment for percent crop treated were used in the chronic
dietary risk assessment. The percentages of the RfD utilized by the
most sensitive sub-population, children 1-6 years, was 4.6% based on a
daily dietary exposure of 0.000911 mg/kg/day. Chronic exposure for the
overall US population was 1.9% of the RfD based on a dietary exposure
of 0.000376 mg/kg/day. This assessment has been approved by EPA and
included pending tolerances (including mustard greens, kiwifruit, globe
artichoke, cranberry, and kohlrabi) and all food tolerances for
incidental residues from use in food handling establishments. EPA has
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.
Potential acute exposures from food commodities were estimated
using a Tier 3 (Monte Carlo) Analysis and appropriate processing
factors for processed food and distribution analysis. This analysis
used field trial data to estimate exposure and federal and market
survey information to derive the percent of crop treated. These data
are considered reliable and used the upper end estimate of percent crop
treated in order to not underestimate any significant subpopulation.
Regional consumption information was taken into account. The MOEs for
the most sensitive sub-population (children 1-6 years) were 202 and 103
at the 99th, and 99.9th percentile of exposure,
respectively, based on daily exposures of 0.009908 and 0.019445 mg/kg/
day. The MOEs for the general population are 355 and 171 at the
99th and 99.9th percentile of exposure,
respectively, based on daily exposure estimates of 0.005635 and
0.011717 mg/kg/day. The EPA has stated there is no cause for concern if
total acute exposure
[[Page 18416]]
calculated for the 99.9th percentile yields an MOE of 100 or larger.
This acute dietary exposure estimate is considered conservative and EPA
considered the MOEs adequate in a recent final rule published in the
Federal Register at 62 FR 63019 (November 26, 1997) (FRL-5781-1).
3. Drinking water. Esfenvalerate is immobile in soil and will not
leach into groundwater. Due to the insolubility and lipophilic nature
of esfenvalerate, any residues in surface water will rapidly and
tightly bind to soil particles and remain with sediment, therefore not
contributing to potential dietary exposure from drinking water.
A screening evaluation of leaching potential of a typical
pyrethroid was conducted using EPA's Pesticide Root Zone Model (PRZM).
Based on this screening assessment, the potential concentrations of a
pyrethroid in ground water at depths of 1 and 2 meters are essentially
zero (much less than 0.001 parts per billion (ppb).
Surface water concentrations for pyrethroids were estimated using
PRZM3 and Exposure Analysis Modeling System (EXAMS) using Standard EPA
cotton runoff and Mississippi pond scenarios. The maximum concentration
predicted in the simulated pond was 0.052 ppb. Concentrations in actual
drinking water would be much lower than the levels predicted in the
hypothetical, small, stagnant farm pond model since drinking water
derived from surface water would be treated before consumption.
Chronic drinking water exposure was estimated to be 0.000001 mg/kg/
day for both the U.S. general population and for non-nursing infants.
Less than 0.1% of the RfD was occupied by both population groups.
Using these values, the contribution of water to the acute dietary
risk estimate was estimated for the U.S. population to be 0.000019 mg/
kg/day at the 99th percentile and 0.000039 mg/kg/day at the
99.9th percentile resulting in MOEs of 105,874 and 51,757,
respectively. For the most sensitive subpopulation, non-nursing infants
less than 1-year old, the exposure is 0.000050 mg/kg/day and 0.000074
mg/kg/day at the 99th and 99.9th percentile,
respectively, resulting in MOEs of 39,652, and 27,042, respectively.
Therefore, DuPont believes that there is reasonable certainty of no
harm from drinking water.
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 products, the very low amounts of
active ingredient they contain, combined with the low vapor pressure
(1.5 x 10-9 mm Mercury at 25 deg. C.) and low dermal
penetration, would result in minimal inhalation and dermal exposure.
To assess risk from (nonfood) short and intermediate term exposure,
EPA has recently selected a toxicological endpoint of 2.0 mg/kg/day,
the NOEL from the rat and rabbit developmental studies. For dermal
penetration/absorption, EPA selected 25% dermal absorption based on the
weight-of-evidence available for structurally related pyrethroids. For
inhalation exposure, EPA used the oral NOEL of 2.0 mg/kg/day and
assumed 100% absorption by inhalation.
Individual non-dietary risk exposure analyses were conducted using
a flea infestation scenario that included pet spray, carpet and room
treatment, and lawn care, respectively. The total potential short- and
intermediate-tern aggregate non-dietary exposure including lawn,
carpet, and pet uses are: 0.000023 mg/kg/day for adults, 0.00129 mg/kg/
day for children 1-6 years and 0.00138 mg/kg/day for infants less than
1-year old.
EPA concluded in the final rule published in the Federal Register
at 62 FR 63019 (November 26, 1997) that the potential non-dietary
exposure for esfenvalerate are associated with substantial margins of
safety.
5. Aggregate exposure dietary and non dietary. EPA has concluded
that aggregate chronic exposure to esfenvalerate from food and drinking
water will utilize 1.9% of the RfD for the U.S. population based on a
dietary exposure of 0.000377 mg/kg/day. The major identifiable subgroup
with the highest aggregate exposure are children 1-6 years old. EPA
generally has 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.
The acute aggregate risk assessment takes into account exposure
from food and drinking water. The potential acute exposure from food
and drinking water to the overall U.S. population provides an acute
dietary exposure of 0.011756 mg/kg/day with an MOE of 170. This acute
dietary exposure estimate is considered conservative, using anticipated
residue values and percent crop-treated data in conjunction with Monte
Carlo analysis.
Short- and intermediate-term aggregate exposure takes into account
chronic dietary food and water (considered to be a background exposure
level) plus indoor and outdoor residential exposure. The potential
short- and intermediate-term aggregate risk for the U.S. population is
an exposure of 0.0082 mg/kg/day with an MOE of 244.
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. EPA
has previously determined in the final rule published in the Federal
Register at 62 FR 63019 (November 26, 1997) that there was reasonable
certainty that no harm will result from aggregate exposure to
esfenvalerate residues. Head lettuce was included in that risk
assessment.
D. Cumulative Effects
Section 408 (b) (2) (D) (v) 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''. In a recent final rule on esfenvalerate
published in the Federal Register at 62 FR 63019 (November 26, 1997)
EPA concluded, available information in this context might include not
only toxicity, chemistry, and exposure data, but also scientific
policies and methodologies for understanding common 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. EPA has begun a pilot process to study this issue
further through the examination of particular classes of pesticides.
The Agency hopes that the results of this pilot process will increase
the Agency's scientific understanding of this question such that EPA
will be able to develop and apply scientific principles for better
[[Page 18417]]
determining which chemicals have a common mechanism of toxicity and
evaluating the cumulative effects of such chemicals. The Agency
anticipates, however, that even as its understanding of the science of
common mechanisms increases, decisions on specific classes of chemicals
will be heavily dependent on chemical specific data, much of which may
not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed). Although esfenvalerate is
similar to other members of the synthetic pyrethroid class of
insecticides, EPA does not have, at this time, available data to
determine whether esfenvalerate has a common method of toxicity with
other substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
esfenvalerate does not appear to produce a toxic metabolite produced by
other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that esfenvalerate has a common mechanism of
toxicity with other substances.
E. Safety Determination
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 1.9%. 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 355 and 171 at the 99th
and 99.9th percentile of exposure, respectively. These
values were generated using actual field trial residues and market
share data for percentage of crop treated. These results depict an
accurate exposure pattern at an exaggerated daily dietary exposure
rate.
Short- and intermediate-term aggregate exposure risk from chronic
dietary food and water plus indoor and outdoor residential exposure for
the U.S. population is an exposure of 0.0082 mg/kg/day with an MOE of
244.
Therefore, there is a reasonable certainty that no harm will result
from chronic dietary, acute dietary, non-dietary, or aggregate exposure
to esfenvalerate residues.
2. Infants and children. FFDCA section 408 provides that EPA shall
apply an additional tenfold margin of safety for infants and children
unless EPA determines that a different margin of safety will be safe
for infants and children. EPA has stated that reliable data support
using the standard MOE and uncertainty factor (100 for combined inter-
and intra-species variability) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor. In a
recent final rule published in the Federal Register at 62 FR 63019
(November 26 1997), EPA concluded that reliable data support use of the
standard 100-fold uncertainty factor for esfenvalerate, and that an
additional uncertainty factor is not needed to protect the safety of
infants and children. This decision was based on, no evidence of
developmental toxicity at a doses up to 20 mg/kg/day (ten times the
maternal NOEL) in prenatal developmental toxicity studies in both rats
and rabbits; offspring toxicity only at dietary levels which were also
found to be toxic to parental animals in the 2-generation reproduction
study; and no evidence of additional sensitivity to young rats or
rabbits following pre- or postnatal exposure to esfenvalerate.
A chronic dietary exposure assessment found the percentages of the
RfD utilized by the most sensitive sub-population to be 4.6% for
children 1-6 years based on a dietary exposure of 0.000912 mg/kg/day.
The % RfD for nursing and non-nursing infants was 1.1% and 2.7%,
respectively. The Agency has no cause for concern if RfD are below
100%.
The most sensitive sub-population, children 1-6 years, had acute
dietary MOEs of 202 and 103 at the 99th and
99.9th percentile of exposure, respectively. Nursing infants
had MOEs of 195 and 146 at the 99th and 99.9th
percentile of exposure, respectively. Non-nursing infants had MOEs of
304 and 158 at the 99th and 99.9th percentile of
exposure, respectively. The Agency has no cause for concern if total
acute exposure calculated for the 99.9th percentile yields a MOE of 100
or larger.
EPA has recently concluded that the potential short- or
intermediate-term aggregate exposure of esfenvalerate from chronic
dietary food and water plus indoor and outdoor residential exposure to
children (1-6 years old) is 0.0113 mg/kg/day with an MOE of 177. For
infants (less than 1-year old) the exposure is 0.0098 mg/kg/day with an
MOE of 204. Thus, there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to esfenvalerate
residues published in the Federal Register at 62 FR 63019 (November 26,
1997) (FRL-5754-6).
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. There are some minimal differences between the section 408
tolerances and certain Codex MRL values for specific commodities. These
differences could be caused by differences in methods to establish
tolerances, calculate animal feed, dietary exposure, and as a result of
different agricultural practices. Therefore, some harmonization of
these maximum residue levels may be required.
3. Novartis Crop Protection, Inc.
PP 7E4920
EPA has received a pesticide petition (PP 7E4920) from Novartis
Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419, 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 inert
tolerances for residues of cloqiontocet-mexyl (acteic acid, [5-chloro-
8-quinolinyl)oxy]-,1-methylhexylester; CGA-185072) in or on the raw
agricultural commodities wheat grain at 0.02 ppm and wheat straw at
0.05 ppm. The proposed analytical method involves homogenization,
filtration, partition, and cleanup with analysis by high performance
liquid chromotography using UV detection. 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
[[Page 18418]]
the data supports granting of the petition. Additional data may be
needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of CGA-185072 in wheat has been
investigated. Total residues in all crop samples are low. Metabolism
involves primarily rapid hydrolysis of the parent to the resulting acid
followed by conjugation.
2. Analytical method. Novartis has submitted practical analytical
methods for the determination of CGA-185072 and its major plant
metabolite CGA-153433 in wheat raw agricultural commodities (RACs).
CGA-185072 is extracted from crops with acetonitrile, cleaned up by
solvent partition and solid phase extraction and determined by column
switching HPLC with UV detection. CGA-153433 is extracted from crops
with an acetone-buffer (pH=3) solution, cleaned up by solvent partition
and solid phase extraction, and determined by HPLC with UV detection.
The limits of quantification (LOQ) for the methods are 0.02 ppm for
CGA-185072 in forage and grain, 0.05 ppm for CGA-185072 in straw, and
0.05 ppm for CGA-153433 in forage, straw and grain.
3. Magnitude of residues. Twelve residue trials were conducted from
1989-1992 in the major spring wheat growing areas of Manitoba, Alberta
and Saskatchewan, which share compatible crop zones with the major
spring wheat growing areas of the U.S. (MT, ND, SD, MN). Nine trials
were conducted in 1989-91 with a tank mix of CGA-184927 (a.i.) and the
CGA-185072 safener as separate EC formulations and three trials in 1992
were conducted with CGA-184927 and the CGA-185072 safener as a pre-pack
EC formulation. All trials had a single post-emergence application of
CGA-185072 at a rate of 20 g a.i./Ha. At PHIs of 55-97 days, no
detectable residues of CGA-185072 or its metabolite CGA-153433 were
found in mature grain or straw from these trials. Separate decline
studies (3) on green forage showed no detectable residues of CGA-185072
or CGA-153433 at 3 days after application. Freezer storage stability
studies indicated reasonable stability of both analytes for a period of
one year, with CGA-185072 declining to 83% in grain and 67% in straw
after two years, while CGA-153433 was stable for at least two years.
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD50 values
for cloquintocet-mexyl are greater than 2,000 mg/kg for rats of both
sexes, respectively. Its acute inhalation LC50 in the rat is
greater than 0.94 mg/liter , the highest attainable concentration.
Cloquintocet-mexyl is slightly irritating to the eyes, minimally
irritating to the skin of rabbits, but was found to be sensitizing to
the skin of the guinea pig. This technical would carry the EPA signal
word ``Caution''.
2. Genotoxicty. The mutagenic potential of cloquintocet-mexyl was
investigated in six independent studies covering different end points
in eukaryotes and prokaryotes in vivo and in vitro. These tests
included: Ames reverse mutation with Salmonella typhimurium and Chinese
hamster V79 cells; chromosomal aberrations using human lymphocytes and
the mouse micronucleus test; and DNA repair using rat hepatocytes and
human fibroblasts. Cloquintocet-mexyl was found to be negative in all
these tests and, therefore, is considered devoid of any genotoxic
potential at the levels of specific genes, chromosomes or DNA primary
structure.
3. Reproductive and developmental toxicity. Dietary administration
of cloquintocet-mexyl over two generations at levels as high as 10,000
ppm did not affect mating performance, fertility, or litter sizes, but
a slightly reduced body weight development of adults and pups was noted
at this level. The target organ was kidney in adults and pups. The
treatment had no effect on reproductive organs. The developmental and
reproductive NOEL was 5,000 ppm, corresponding to a mean daily intake
of 350 mg/kg cloquintocet-mexyl.
In a developmental toxicity study in rats, the highest dose level
of 400 mg/kg resulted in reduced body weight gain of the dams and signs
of retarded fetal development. No teratogenic activity of the test
article was detected. The NOEL for dams and fetuses was 100 mg/kg/day.
In a developmental toxicity study in rabbits, mortality was
observed in dams at dose levels of 300 mg/kg. No teratogenic effects
were noted. Fetuses showed signs of slightly retarded development. The
NOEL for both dams and fetuses was 60 mg/kg/day.
4. Subchronic toxicity. In a 90-day study, rats fed 6,000 ppm
exhibited reduced body weight gain and one male died with acute
nephritis and inflamed urinary bladder. Reduced liver and kidney
weights were observed in males fed 1,000 and 6,000 and in females fed
6,000 ppm. Target organs were identified to be kidney and urinary
bladder. The NOEL was 150 ppm (9.66 mg/kg in males and 10.2 mg/kg in
females).
In a 90-day study in beagle dogs, a level of 40,000 ppm resulted in
deterioration of general condition so that the feeding level was
reduced in a stepwise fashion to 15,000 ppm. Anemia was noted at 15,000
ppm and the feeding level of 1,000 ppm. The NOEL of 100 ppm was
equivalent to a mean daily intake of 2.9 mg/kg in males and females.
5. Chronic toxicity. In a 12-month feeding study in dogs, 15,000
ppm resulted in inappetence and body weight loss. As a result, this
feeding level was adjusted to 10,000 ppm after 2-weeks. Animals fed
this level exhibited anemia and an elevation in blood urea levels. The
kidney was considered the target organ. The NOEL of 1,500 ppm was
equivalent to a mean daily intake of 43.2 mg/kg in males and 44.8 mg/kg
in females.
Lifetime dietary administration of cloquintocet-mexyl to mice
resulted in reduced body weights in both sexes at 5,000 ppm. Overall
body weight gain was reduced by 17% to 22% in males and females,
respectively, indicating the MTD was achieved or exceeded.
Histopathological examination revealed chronic inflammation of the
urinary bladder. There was no indication of any tumorigenic response
due to treatment. The NOEL of 1,000 ppm was equivalent to a mean daily
dose of 111 mg/kg in males and 102 mg/kg in females.
A top feeding level of 2,000 ppm was selected, based on the 90-day
study, for the lifetime feeding study in the rat. This feeding level
was well-accepted, but produced hyperplasia of the thymus in males and
hyperplasia of the thyroid in females. There was no increase in tumors
of any type and the total number of tumor- bearing animals showed no
dose-related trends. The NOEL of 100 ppm was equivalent to a mean daily
dose of 3.77 mg/kg in males and 4.33 mg/kg in females.
6. Animal metabolism. In rats, approximately 50% of an oral dose of
cloquintocet-mexyl was rapidly absorbed through the gastrointestinal
tract and excreted via urine and bile. The administered dose was
excreted independent of sex and was essentially complete within 48
hours. 95% of the excreted dose was associated with one metabolite, an
acid residue of cloquintocet-mexyl, CGA-153433. Simultaneous
administration of the cloquintocet-mexyl and clodinafop-propargyl did
not alter the rate of excretion of cloquintocet-mexyl or its metabolite
pattern.
7. Metabolite toxicology. At the present time there is no evidence
which affords an association of the toxicities noted with the highest
feeding levels of cloquintocet-mexyl with its primary metabolite, CGA-
153433.
[[Page 18419]]
8. Endocrine disruption. A special study was conducted to
investigate a histological finding of hyperplasia of thyroid gland
epithelium noted in the female rat in the standard lifetime combined
chronic toxicity and carcinogenicity study. This study was a 28-day
oral gavage study with a 28-day recovery period at dose levels as high
as 400 mg/kg/day or approximately 4,000 ppm. No effect was noted on the
level of thyroid hormones at any of the treatment levels. Although
thyroid hyperplasia and an accompanying increase in pituitary
basophilic cells were noted at the end of 28-days, these effects were
reversible in the recovery period.
C. Aggregate Exposure
1. Dietary exposure. Cloquintocet-mexyl is intended to be used as a
safener for the post emergence herbicide, clodinafop-propargyl, used in
wheat. The use rate is very low (formulated at a 1:4 ratio of safener
to active ingredient). Results from plant metabolism and residue
studies show that residues of the safener cloquintocet-mexyl or its
metabolites are below the detection limit in wheat grains and other
wheat byproducts including green wheat used for forage. Tolerances in
wheat and wheat products are being proposed at the detection limit of
0.02 ppm (LOQ) for the parent active ingredient in wheat grain and 0.05
ppm (LOQ) in wheat straw. For cloquintocet, similar tolerances will be
proposed in wheat grain (0.02 ppm) and wheat straw (0.05 ppm).
i. Chronic. The RfD of 0.0377 mg/kg/day was derived from the male
NOEL of 3.77 mg/kg/day. Based on the assumption that 100% of all wheat
used for human consumption would contain residues of cloquintocet-mexyl
and anticipated residues would be at the level of \1/2\ the LOQ, the
potential dietary exposure was calculated using the TAS
exposure program based on the food survey from the year of 1977-1978.
Calculations were made for anticipated residues using \1/2\ the LOQ or
0.01 ppm. Calculated on the basis of the assumptions above, the chronic
dietary exposure of the U.S. population to cloquintocet-mexyl would
correspond to 0.000014 mg/kg/day or 0.04% of its RfD. MOE against NOEL
in the most sensitive species is 269,286-fold.
Using the same conservative exposure assumptions, the percent of
the RfD that will be utilized is 0.01% for nursing infants less than 1-
year old, 0.03% for non-nursing infants, 0.08% for children 1-6 years
old and 0.06% for children 7-12 years old. It is concluded that there
is a reasonable certainty that no harm will result to infants and
children from exposure to residues of cloquintocet-mexyl.
ii. Acute. Using the same computer software package used for the
calculation of chronic dietary exposure, the acute dietary exposure was
calculated for the general population and several sub-populations
including children and women of child bearing age. The USDA Food
Consumption Survey of 1989-1992 was used, however, instead of the 1977-
1978 survey used for the chronic assessment. MOEs were calculated
against the NOEL of 2.9 mg/kg found in a 90-day dietary toxicity study
in dogs, which is the lowest NOEL observed in a short term or
reproductive toxicity study. NOELs from reproductive or developmental
toxicity studies were significantly higher and there was no evidence
that cloquintocet-mexyl has any potency to affect these endpoints.
The exposure model predicted that 99.9% of the general population
will be exposed to less than 0.000104 mg/kg cloquintocet-mexyl per day,
which corresponds to a MOE of almost 27,944 when compared to the NOEL
of 2.9 mg/kg. Children 1-6 years constitute the sub-population with the
highest predicted exposure. Predicted acute exposure for this subgroup
is less than 0.000134 mg/kg/day, corresponding to a MOE of at least
21,721 for 99.9% of the individuals.
2. Drinking water. Other potential sources of exposure of the
general population to residues of pesticides are residues in drinking
water. Results of studies have shown that cloquintocet-mexyl or its
degradation products do not have any leaching potential. Accordingly,
there is no risk of groundwater contamination with cloquintocet-mexyl
or its metabolites. Thus, aggregate risk of exposure to cloquintocet-
mexyl does not include drinking water. Cloquintocet-mexyl is not
intended for uses other than the agricultural use on wheat. Thus, there
is no potential for non-occupational exposure.
The Maximum Contaminant Level Goal (MCLG) calculated for
cloquintocet-mexyl according to EPA's procedure leads to an exposure
value substantially above levels that are likely to be found in the
environment under proposed conditions of use.
MCLG = RfD x 20% x 70 kg/2 L
MCLG = 0.0377 mg/kg x 0.2 x 70 kg/2 L
MCLG = 0.264 ppm = 264 ppb
3. Non-dietary exposure. Exposure to cloquintocet-mexyl for the
mixer/loader/ground boom/aerial applicator was calculated using the
Pesticide Handlers Exposure Database (PHED). It was assumed that the
product would be applied 10-days per year by ground boom application to
a maximum of 300 acres per day by the grower, 450 acres per day by the
commercial groundboom applicator, and 741 acres per day for the aerial
applicator at a maximum use rate of 28 grams active ingredient (7 grams
of cloquintocet-mexyl) per acre. For purposes of this assessment, it
was assumed that an applicator would be wearing a long-sleeved shirt
and long pants and the mixer/loader would, in addition, wear gloves.
Daily doses were calculated for a 70 kg person assuming 100% dermal
penetration.
The results indicate that large margins of safety exist for the
proposed experimental use of cloquintocet-mexyl. The use pattern of
cloquintocet indicates that the NOEL(1,000 mg/kg/day) from the 28-day
rat dermal study is appropriate for comparison to mixer/loader-
applicator exposure. The chronic NOEL of 3.77 mg/kg/day from the 2-year
feeding study in rats is used to examine longer term exposure.
For short-term exposure, MOEs for cloquintocet ranged from 2.4E+05
for commercial open mixer-loader to 2.5E+06 for commercial groundboom
enclosed-cab applicator. For chronic exposure, MOEs ranged from 3.2E+04
for commercial open mixer-loader to 3.5E+05 for commercial groundboom
enclosed-cab applicator. Aerial application of cloquintocet results in
short-term MOEs of 1.4E+05 for the mixer-loader and 2.5E+05 for pilots.
Chronic MOEs are 2.0E+04 for the mixer-loader and 3.4E+04 for the
pilot. Based on this assessment, occupational exposure to cloquintocet-
mexyl results in acceptable MOEs.
In reality, the proposed label for the end use product containing
the active ingredient plus cloquintocet-mexyl will require more
restrictive personal protective equipment for applicators and other
handlers, resulting in additional margins of safety.
D. Cumulative Effects
Novartis has considered the potential for a cumulative exposure
assessment for effects of cloquintocet-mexyl and other substances with
the same mechanism of toxicity. It is concluded that such a
determination would be inappropriate at this time because of the unique
role of cloquintocet-mexyl as a product specific safener.
E. Safety Determination
1. U.S. population. Using the same conservative exposure
assumptions as described for chronic and acute dietary exposure,
aggregrate exposure of the
[[Page 18420]]
U.S. population to cloquintocet-mexyl would correspond to 0.000014 mg/
kg/day or 0.04% of its RfD. The chronic MOE against the NOEL in the
most sensitive species is 269,286-fold. EPA generally has 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. Therefore, it
is concluded that there is a reasonable certainty that no harm will
result from aggregate exposure to residues of cloquintocet-mexyl.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of cloquintocet-mexyl,
data from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from chemical exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to a chemical on
the reproductive capability of mating animals and data on systemic
toxicity.
The highest dose level of 400 mg/kg/day in a developmental toxicity
study in rats resulted in reduced body weight gain of the dams and
signs of retarded fetal development. No teratogenic activity due to the
test article was detected. The NOEL for dams and fetuses was 100 mg/kg/
day. Although mortality was observed in rabbit dams at the dose level
of 300 mg/kg/day, no teratogenic effects were noted. The NOEL for both
dams and fetuses was 60 mg/kg/day.
Dietary administration of cloquintocet-mexyl over 2-generations at
levels as high as 10,000 ppm did not affect mating performance,
fertility, or litter sizes in rats, but a slightly reduced body weight
development of adults and pups was noted at this level. The target
organ was kidney in adults and pups. The treatment had no effect on
reproductive organs. The developmental and reproductive NOEL was 5,000
ppm, corresponding to a mean daily intake of 350 mg/kg cloquintocet-
mexyl.
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 for children is
complete. Further, for cloquintocet-mexyl, the NOEL of 3.77 mg/kg/day
from the combined chronic/oncogenicity study in rats, which was used to
calculate the RfD, is already lower than the NOEL's of 100 and 60 mg/
kg/day for the rat and rabbit developmental toxicity studies,
respectively. Further, the developmental and reproductive NOEL of 350
mg/kg/day from the cloquintocet-mexyl reproduction study is nearly 100
times greater than the NOEL for the combined chronic/oncogenicity rat
study. These data would indicate there is no additional sensitivity of
infants and children to cloquintocet-mexyl. Therefore, it is concluded
that an additional uncertainty factor is not warranted to protect the
health of infants and children from the use of cloquintocet-mexyl.
Using the conservative exposure assumptions described above, it is
concluded that the percentage of the RfD that will utilized by
aggregate exposure to residues of cloquintocet-mexyl for its proposed
use as a safener for clodinafop-propargyl on wheat is 0.01% for nursing
infants less than 1-year old, 0.03% for non-nursing infants, 0.08% for
children 1-6 years old and 0.06% for children 7-12 years old.
Therefore, based on the completeness and reliability of the toxicity
data and the conservative nature of the exposure assessment, it is
concluded that there is a reasonable certainty that no harm will result
to infants and children from exposure to residues of cloquintocet-
mexyl.
F. International Tolerances
Cloquintocet-mexyl is used as a safener for the herbicide,
clodinafop-propargyl. There are no Codex Alimentarius Commission
(CODEX) maximum residue levels (MRLs) established for residues of
cloquintocet-mexyl in or on raw
[FR Doc. 98-9395 Filed 4-14-98; 8:45 am]
BILLING CODE 6560-50-F
