[Federal Register Volume 63, Number 108 (Friday, June 5, 1998)]
[Notices]
[Pages 30750-30756]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-15014]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-807; FRL-5791-4]
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-807, must
be received on or before July 6, 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. 119, 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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Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:[email protected] Arlington, VA
amail.epa.gov.
Beth Edwards (PM 3)........... Rm. 206, CM #2, 703- Do.
305-5400, e-mail:
edwards.beth@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 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-807] (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 (insert docket number) 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: May 20, 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
[[Page 30751]]
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. Novartis Crop Protection, Inc.
PP 7F4924
EPA has received a pesticide petition (PP 7F4924) from Novartis
Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419-8300
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 to establish
tolerances for Clodinafop-propargyl, Propanoic acid, 2-[4-[(5-chloro-3-
fluoro-2-pyridinyl)oxy]phenoxy]-,2-propynyl ester, in or on the raw
agricultural commodities wheat grain at 0.02 and wheat straw at 0.05
parts per million (ppm). EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of CGA-184927 in wheat is
understood for the purposes of the proposed tolerance. Two studies, one
with the racemic mixture of the R (+) and S (-) forms and the other
with the pure R (+) form (CGA-184927 pyridyloxy labeled), gave similar
results. Metabolism involves hydrolysis of the parent to the resulting
acid followed by conjugation, arylhydroxylation at the 6 position of
the pyridyl ring followed by sugar conjugation, and cleavage of the
pyridinyloxy-phenoxy ether bridge which forms the breakdown products 2-
(4-hydroxyphenoxy) propanoic acid and 2-hydroxy-3-fluoro-5-
chloropyridine.
2. Analytical method. Novartis has submitted practical analytical
methods for the determination of CGA-184927 and its major plant
metabolite CGA-193469 in wheat raw agricultural commodities (RACs).
CGA-184927 is extracted from crops with acetonitrile, cleaned up by
solvent partition and solid phase extraction and determined by column
switching HPLC with ultraviolet detection. CGA-193469 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 quantitation (LOQ) for the methods are 0.02
ppm for CGA-184927 in grain and forage, 0.05 ppm for CGA-184927 in
straw, and 0.05 ppm for CGA-193469 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 US (MT, ND, SD, MN). Nine trials were
conducted in 1989-91 with a tank mix of CGA-184927 and a safener as
separate EC formulations, and three trials in 1992 were conducted with
CGA-184927 and the safener as a pre-pack EC formulation. All trials had
a single post-emergence application of CGA-184927 at a rate of 80 g
a.i./Ha. At PHIs of 66-97-days, no detectable residues of CGA-184927 or
its metabolite CGA-193469 were found in mature grain and straw from
these trials. Separate decline studies (3) on green forage showed no
detectable residues of CGA-184927 or CGA-193469 beyond the 3-days after
application (DAA) interval. A freezer storage stability study indicated
reasonable stability of both analytes for a period of 1-year, with CGA-
184927 showing a decline to 56% in grain and 47% in straw after 2-
years. CGA-193469 remained stable for at least 2-years.
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD50 values
for clodinafop- propargyl are 1829 mg/kg and greater than 2,000 mg/kg
for rats of both sexes, respectively. Its acute inhalation
LC50 in the rat is greater than 2.33 mg/liter, the highest
attainable concentration. Clodinafop-propargyl 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 clodinafop-propargyl was
investigated in 6 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. Clodinafop-propargyl 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 clodinafop-propargyl over 2-generations at levels as high as 1,000
ppm did not affect mating performance, fertility or litter sizes. The
physiological developmental and the survival of the pups during the
last week of the lactation period were slightly reduced at levels equal
to or greater than 500 ppm during the first generation only. Target
organs were liver (adults) and kidney (adults and pups). The treatment
had no effect on reproductive organs. The developmental and
reproductive NOEL was 50 ppm, corresponding to a mean daily intake of
3.3 milligrams/kilogram (mg/kg) clodinafop-propargyl.
In a developmental toxicity study in rats, the highest dose level
of 160 mg/kg resulted in reduced body weight gain of the dams and signs
of retarded fetal body weight and incomplete ossification of vertebrae
and sternebrae. No teratogenic activity of the test article was
detected. The NOEL for dams and fetuses was 40 mg/kg/day.
In a developmental toxicity study in rabbits, mortality was
observed in dams at dose levels of 125 and 175 mg/kg. No teratogenic or
fetotoxic effects were noted. The maternal NOEL was 25 mg/kg/day and
the fetal NOEL was 175 mg/kg/day.
4. Subchronic toxicity. A 90-day feeding study in rats at 1,000 ppm
resulted in reduced body weight gain, increased liver weights,
hematological changes, and increased serum activities of the alkaline
phosphatase. Target organs were liver (increased weight), thymus
(atrophy) and spleen (reduced weight). The changes were reversible
during 4-weeks of recovery. The NOEL was 15 ppm (0.92 mg/kg in males
and 0.94 mg/kg in females).
In a 90-day feeding study in mice, 400 ppm resulted in reduced
activity, one death, markedly increased activities of
aminotransferases, alkaline phosphatase, and albumin concentration,
increased liver weights, hepatocellular hypertrophy, and single cell
necroses in all mice. Other findings included intrahepatic bile duct
proliferation, Kupffer cell hyperplasia and higher incidence of
inflammatory cell infiltration. These findings were considered to be
secondary to the hepatocyte necrosis. The NOEL of 6 ppm was equivalent
to a daily dose of 0.9 mg/kg in males and 1.05 mg/kg in females.
In a 90-day study in beagle dogs, levels of 500 and 1,000 ppm fed
over 1-weeks clearly exceeded a maximum tolerated dose and led to
mortality and severe toxicity. Effects at 50 and 200 ppm were limited
to dermatitis and
[[Page 30752]]
clinical chemistry changes, which were generally mild and transient.
The NOEL of 10 ppm was equivalent to a mean daily intake of 0.36 mg/kg
in males and females.
5. Chronic toxicity. In a 12-month feeding study in dogs, 500 ppm
resulted in transient dermatitis and reduced body weight gain. Two
females were more severely affected and showed inappetence, body weight
loss, tremors and severe dermatitis, and necessitated an interruption
of the treatment in order to avoid mortality. Histopathology revealed
slight hepatocellular hypertrophy in one male and one female. The NOEL
of 100 ppm was equivalent to a mean daily intake of 3.38 mg/kg in males
and 3.37 mg/kg in female.
Lifetime dietary administration of clodinafop-propargyl to mice
resulted in reduced body weights and reduced survival in males treated
at 250 ppm. Severe hepatotoxicity was noted at 100 and 250 ppm in both
sexes. Based on markedly increased liver weights, enhanced serum
activities of hepatic enzymes and hepatocellular necroses, dietary
levels of 100 ppm and 250 ppm clearly exceeded maximum tolerated doses
in males and females, respectively. The increased incidence of benign
liver tumors that occurred in males treated at 250 ppm was, therefore,
considered a toxicologically irrelevant response as the livers of these
animals were damaged significantly and this finding was not
interpretable. The test substance was severely hepatotoxic at 100 and
250 ppm, with males being more sensitive than females. Based on
markedly increased liver weights, enhanced serum activities of hepatic
enzymes, and hepatocellular necroses, dietary levels of 100 ppm and 250
ppm clearly exceeded maximum tolerated doses in males and females,
respectively. The incidence of hepatocellular carcinoma, in these
clearly compromised mice, remained within the historical control range,
although the incidence was slightly increased in comparison to the
concomitant controls. Tumor incidences in females were generally low
and well within the range of the historical controls. The NOEL of 10
ppm was equivalent to a mean daily dose of 1.10 mg/kg in males and 1.25
mg/kg in females.
Dietary treatment of rats with concentrations over 2-years resulted
in initial inappetence in males and reduced body weight development in
both sexes treated at 750 ppm. The main target organ of toxicity was
the liver. Changes in plasma protein and lipid levels, strongly
enhanced serum activities of liver enzymes, increased liver weights,
and severe hepatocellular necroses were observed at dietary doses of
300 and 750 ppm in males and at 750 ppm in females, giving evidence
that these dose levels exceeded a maximum tolerated dose (MTD). Top
dose group males showed higher incidences of prostate adenoma, while
prostate hyperplasia was reduced. The total incidence of proliferative
changes in the prostate remained unchanged. Females treated at the same
high dose had higher incidences of ovary tubular adenoma. Both tumors
also occur spontaneously in the rat strain used. Their slightly
enhanced incidences are likely a consequence of the severe disturbance
of the general physiological balance due to excessive liver toxicity.
There was no progression to a malignant phenotype and the tumors had no
influence on survival. In rats, feeding a dose of 750 ppm to males
showed higher incidences of prostate adenoma, while prostate
hyperplasia was reduced. The total number of tumor-bearing animals
showed no dose-related trends. The NOEL of 10 ppm was equivalent to a
mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in females.
6. Animal metabolism. In rats, clodinafop-propargyl was rapidly
absorbed through the gastrointestinal tract. Absorption through the
skin of rats is considerably slower with 15% of a dermally applied dose
being absorbed within 8-hours. Single doses were excreted more rapidly
by female rats than by males. Most likely due to enzyme induction,
differences were much less pronounced after repeated treatment. Both
sexes excreted clodinafop-propargyl with urine and feces mainly in the
form of its propionic acid derivative, CGA-193469. Simultaneous
administration of the safener, cloquintocet-mexyl, did not alter the
rate of excretion of clodinafop-propargyl or its metabolite pattern.
7. Metabolite toxicology. Clodinafop-propargyl acts as a typical
peroxisome proliferator in the rodent liver which is most likely
induced by its propionic acid derivative metabolite, CGA-193469. Like
other known well-characterized substances with this property, CGA-
193469 caused peroxisome proliferation in vitro in hepatocytes of the
mouse and rat, but not of the Guinea pig, marmoset, or human. There is
ample scientific evidence that exposure to peroxisome proliferators
represents no risk of tumor development in man. Clodinafop-propargyl
is, therefore, not considered to be a carcinogen of relevance to
humans.
8. Endocrine disruption. No special studies investigating potential
estrogenic or endocrine effects of clodinafop-propargyl 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. Although
prostate adenomas and ovarian adenomas were observed to be
statistically increased in rats at the highest feeding level with
clodinafop-propargyl, this feeding level clearly exceeded the MTD and
the livers in these rats were severely compromised. Therefore, these
findings are considered irrelevant.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
exposure under the proposed tolerances for clodinafop-propargyl,
Novartis has estimated aggregate exposure based on the theoretical
maximum residue contribution (TMRC) from the residues of the active
ingredient, clodinafop-propargyl, or metabolites thereof. Residues are
below the detection limit in wheat grains and other wheat products,
including green wheat used for forage. Tolerances in wheat and wheat
products are proposed at the detection limit of 0.02 ppm (LOQ) for the
parent active ingredient in wheat grain. Although wheat commodities may
be fed to poultry or cattle and it is common practice in some areas to
graze cattle on green wheat, tolerances in meat or milk are not
necessary because forage commodities do not contain detectable amounts
of the parent clodinafop-propargyl or its metabolites.
i. Chronic. The RfD of 0.0032 mg/ kg/day is derived from the male
rat NOEL of 0.32 mg/ kg/ day. Based on the assumption that 100% of all
wheat used for human consumption would contain residues of clodinafop-
propargyl and anticipated residues would be at the level of \1/2\ the
LOQ, the potential dietary exposure was calculated using the TAS (TAS
Exposure Analysis, Technical Assessment Systems Inc., Washington, DC.)
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. The proposed tolerance (0.02 ppm) was set at the lowest limit
of detection for the active ingredient in wheat commodities (grain)
because, with the available methodology, there are no detectable
residues of clodinafop-propargyl in wheat or wheat products. Residues
in milk, meat and eggs due to the feeding of wheat grain, green wheat
or other
[[Page 30753]]
feed commodities will not occur and tolerances for milk, meat and eggs
are therefore not required. Calculated on the basis of the assumptions
above, the chronic dietary exposure of the U.S. population to
clodinafop-propargyl would correspond to 0.000014 mg/kg/day or 0.47% of
its RfD. The margin of exposure (MOE) against the NOEL in the most
sensitive species is 22,857-fold.
Using the same conservative exposure assumptions, the percentage of
the RfD that will be utilized is 0.14% for nursing infants less than 1-
year old, 0.34% for non-nursing infants, 1.05% for children 1-6 years
old and 0.77% 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 clodinafop-propargyl.
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 from 1989-1992 was used, however, instead of the
1977/78 survey used for the chronic assessment. Margins of exposure
were calculated against the NOEL of 1 mg/kg found in a 90-day dietary
toxicity study in rats, which is the lowest NOEL observed in a short
term or reproductive toxicity study. NOEL from reproductive or
developmental toxicity studies were significantly higher and there was
no evidence that clodinafop-propargyl has any potency to affect these
endpoints.
The exposure model predicted that 99.9% of the general population
will be exposed to less than 0.000105 mg/kg of clodinafop-propargyl per
day, which corresponds to a MOE of almost 9,529 when compared to the
NOEL of 1 mg/kg. Children 1-6 years constitute the sub-population with
the highest predicted exposure. Predicted acute exposure for this
subgroup is less than 0.000136 mg/kg/day, corresponding to a MOE of at
least 7,362 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. Although clodinafop-propargyl has a slight to medium leaching
potential, the risk of the parent compound to leach to deeper soil
layers is negligible under practical conditions in view of the rapid
degradation of the product and its low application rate. According to
laboratory and field studies there is no risk of ground water
contamination with clodinafop-propargyl or its metabolites. Thus,
aggregate risk of exposure to clodinafop-propargyl does not include
drinking water. Clodinafop-propargyl 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
clodinafop-propargyl 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 = 0.0032 mg/kg x 0.2 x 70 kg/2 L
MCLG = 0.0448 ppm = 44.8 ppb.
3. Non-dietary exposure. Exposure to clodinafop-propargyl 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 ground boom applicator and 741 acres per day by the aerial
applicator at a maximum use rate of 28 grams active ingredient 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. These assumptions were
selected from PHED. 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 use of clodinafop-propargyl.
Based upon the use pattern for clodinafop, the NOEL (50 mg/kg/day) from
the 28-day rat dermal study is appropriate for comparison to mixer/
loader-applicator exposure. The chronic NOEL of 0.32 mg/kg/day from the
2-year feeding study in rats is used to examine longer term exposures.
For short-term exposure, MOEs for clodinafop ranged from 2.9E+03
for commercial open mixer-loader to 3.1E+04 for commercial groundboom
enclosed-cab applicator. For chronic exposure, MOEs ranged from 6.9E+02
for commercial open mixer-loader to 7.4E+03 for commercial groundboom
enclosed-cab applicator. Aerial application of clodinafop results in
short-term MOEs of 1.8E+03 for the mixer-loader and 2.0E+03 for pilots.
Chronic MOEs are 4.2E+02 for the mixer-loader and 4.7E+02 for the
pilot.
In reality, the proposed label will require more restrictive
personal protective equipment for applicators and other handlers,
resulting in additional margins of safety.
D. Cumulative Effects
A cumulative exposure assessment for effects of clodinafop-
propargyl and other substances with the same mechanism of action is not
appropriate because there is ample evidence to indicate that humans are
not sensitive to the effects of clodinafop-propargyl and other
peroxisome proliferators. Thus, the calculations outlined below were
done for clodinafop-propargyl alone.
E. Safety Determination
1. U.S. population. Using the same conservative exposure
assumptions described above, based on the completeness and reliability
of the toxicity data, Novartis calculated that the aggregate risk for
clodinafop-propargyl for chronic dietary exposure of the U.S.
population would correspond to 0.000014 mg/kg/day or 0.47% of its RfD.
The margin of exposure (MOE) against the NOEL in the most sensitive
species is 22,857-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 clodinafop-propargyl.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of clodinafop-
propargyl, 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.
Retarded fetal body weight and incomplete ossification of vertebrae
and sternebrae were observed at a maternally toxic dose of 160 mg/kg/
day in rats; however, no teratogenic activity of the test article was
detected. The NOEL for dams and fetuses was 40 mg/kg/day. Although
mortality was observed in rabbit dams at dose levels of 125 and 175 mg/
kg, no teratogenic or fetotoxic effects were noted. The maternal NOEL
was 25 mg/kg/day and the fetal NOEL was 175 mg/kg/day.
Clodinafop-propargyl fed over 2-generations to rats at levels as
high as 1,000 ppm did not affect mating
[[Page 30754]]
performance, fertility, or litter sizes. Physiological developmental
and the survival of the pups during the last week of the lactation
period were slightly reduced at levels equal to or greater than 500 ppm
during the first generation only. Target organs were liver (adults) and
kidney (adults and pups). The developmental and reproductive NOEL was
50 ppm, corresponding to a mean daily intake of 3.3 mg/kg clodinafop-
propargyl.
Section 408 FFDCA 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. Base on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, for clodinafop-propargyl, the NOEL of 0.32 mg/kg/day
from the combined chronic/oncogenicity rat study, which was used to
calculate the RfD, is already lower than the NOEL's of 40 and 25 mg/kg/
day for the rat and rabbit developmental toxicity studies,
respectively. Further, the developmental and reproductive NOEL of 3.3
mg/kg/day from the clodinafop-propargyl reproduction study is 10- 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 clodinafop-propargyl. Therefore, it is concluded that
an additional uncertainty factor is not warranted to protect the health
of infants and children from the use of clodinafop-propargyl.
Using the conservative exposure assumptions described above, it is
concluded that the percentage of the RfD that will be utilized by
aggregate exposure to residues of clodinafop-propargyl for the proposed
use on wheat is 0.14% for nursing infants less than 1-year old, 0.34%
for non-nursing infants, 1.05% for children 1-6 years old and 0.77% 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 clodinafop-propargyl.
F. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue
levels (MRLs) established for residues of clodinafop-propargyl in or on
raw agricultural commodities. (Joanne Miller)
2. Office of IR-4
PP 8G4964
EPA has received a pesticide petition (PP 8G4964) from Office of
IR-4, P.O. Box 231, New Brunswick, N.J. 08903-0321 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 temporary tolerance
exemption based on no detectable residues in potatoes in 14 field
trials and the limited nature of the EUP program or a temporary
tolerance for residues of the insecticide spinosad in or on the raw
agricultural commodity potatoes at 0.032 ppm which is 2x the limit of
quantitation of the analytical method. The proposed analytical method
involves homogenization, filtration, partition and cleanup with
analysis by high performance liquid chromatography 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 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 spinosad in plants (apples,
cabbage, cotton, tomato, and turnip) and animals (goats and poultry) is
adequately understood for the purposes of these tolerances. A
rotational crop study showed no carryover of measurable spinosad
related residues in representative test crops.
2. Analytical method. There is a practical method (HPLC with UV
detection) for detecting (0.004 ppm) and measuring (0.01 ppm) levels of
spinosad in or on food with a limit of detection that allows monitoring
of food with residues at or above the levels set for these tolerances.
The method has had a successful method tryout in the EPA's
laboratories. Additionally, an Immunoassay has been developed.
3. Magnitude of residues. Magnitude of residue studies were
conducted for potatoes at 14 sites in 7 States. No residues in potatoes
were found in these studies with the lower limit of detection of 0.005
ppm.
B. Toxicological Profile
1. Acute toxicity. Spinosad has low acute toxicity. The rat oral
LD50 is 3,738 mg/kg for males and >5,000 mg/kg for females,
whereas the mouse oral LD50 is >5,000 mg/kg. The rabbit
dermal LD50 is >2,000 mg/kg and the rat inhalation
LC50 is >5.18 mg/l air. In addition, spinosad is not a skin
sensitizer in guinea pigs and does not produce significant dermal or
ocular irritation in rabbits. End use formulations of spinosad that are
water based suspension concentrates have similar low acute toxicity
profiles.
2. Genotoxicty. Short term assays for genotoxicity consisting of a
bacterial reverse mutation assay (Ames test), an in vitro assay for
cytogenetic damage using the Chinese hamster ovary cells, an in vitro
mammalian gene mutation assay using mouse lymphoma cells, an in vitro
assay for DNA damage and repair in rat hepatocytes, and an in vivo
cytogenetic assay in the mouse bone marrow (micronucleus test) have
been conducted with spinosad. These studies show a lack of
genotoxicity.
3. Reproductive and developmental toxicity. Spinosad caused
decreased body weights in maternal rats given 200 mg/kg/day by gavage
highest dose tested (HDT). This was not accompanied by either embryo
toxicity, fetal toxicity, or teratogenicity. The NOELs for maternal and
fetal effects in rats were 50 and 200 mg/kg/day, respectively. A
teratology study in rabbits showed that spinosad caused decreased body
weight gain and a few abortions in maternal rabbits given 50 mg/kg/day
HDT. Maternal toxicity was not accompanied by either embryo toxicity,
fetal toxicity, or teratogenicity. The NOELs for maternal and fetal
effects in rabbits were 10 and 50 mg/kg/day, respectively. The NOEL
found for maternal and pup effects in a rat reproduction study was 10
mg/kg/day. Neonatal effects at 100 mg/kg/day HDT in the rat
reproduction study were attributed to maternal toxicity.
4. Subchronic toxicity. Spinosad was evaluated in 13-week dietary
studies and showed NOELs of 4.9 mg/kg/day in dogs, 6 mg/kg/day in mice,
and 8.6 mg/kg/day in rats. No dermal irritation or systemic toxicity
occurred in a 21-day repeated dose dermal toxicity study in rabbits
given 1,000 mg/kg/day.
5. Chronic toxicity. Based on chronic testing with spinosad in the
dog and the rat, the EPA has set a reference dose (RfD) of 0.0268 mg/
kg/day for spinosad. The RfD has incorporated a 100-fold safety factor
to the NOELs found in the chronic dog study. The NOELs shown in the dog
chronic study were 2.68 and 2.72 mg/kg/day, respectively for male and
female dogs. The NOELs shown in the rat chronic study were 2.4 and 3.0
mg/kg/day, respectively for male and female rats. Using the Guidelines
for Carcinogen Risk Assessment published September 24, 1986 (51 FR
33992) (FRL-2984-1), it is proposed that spinosad be classified as
Group E for
[[Page 30755]]
carcinogenicity (no evidence of carcinogenicity) based on the results
of carcinogenicity studies in two species. There was no evidence of
carcinogenicity in an 18-month mouse feeding study and a 24-month rat
feeding study at all dosages tested. The NOELs shown in the mouse
oncogenicity study were 11.4 and 13.8 mg/kg/day, respectively for male
and female mice. The NOELs shown in the rat chronic/oncogenicity study
were 2.4 and 3.0 mg/kg/day, respectively for male and female rats. A
maximum tolerated dose was achieved at the top dosage level tested in
both of these studies based on excessive mortality. Thus, the doses
tested are adequate for identifying a cancer risk. Accordingly, a
cancer risk assessment is not needed.
6. Animal metabolism. There were no major differences in the
bioavailability, routes or rates of excretion, or metabolism of
spinosyn A and spinosyn D following oral administration in rats. Urine
and fecal excretions were almost completed in 48-hours post-dosing. In
addition, the routes and rates of excretion were not affected by
repeated administration.
7. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent material (spinosyn A and spinosyn D).
Thus, there is no need to address metabolite toxicity.
8. Neurotoxicity. Spinosad did not cause neurotoxicity in rats in
acute, subchronic, or chronic toxicity studies.
9. Endocrine effects. There is no evidence to suggest that spinosad
has an effect on any endocrine system.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure from use of spinosad on cotton gin byproducts as well
as from other existing or pending uses, a conservative estimate of
aggregate exposure is determined by basing the TMRC on the proposed
tolerance levels for spinosad and assuming that 100% of the cotton gin
byproducts and other existing and pending crop uses grown in the U.S.
were treated with spinosad. The TMRC is obtained by multiplying the
tolerance residue levels by the consumption data which estimates the
amount of crops and related foodstuffs consumed by various population
subgroups. The use of a tolerance level and 100% of crop treated
clearly results in an overestimate of human exposure and a safety
determination for the use of spinosad on crops cited in this summary
that is based on a conservative exposure assessment.
2. Drinking water. Another potential source of dietary exposure are
residues in drinking water. Based on the available environmental
studies conducted with spinosad wherein it's properties show little or
no mobility in soil, there is no anticipated exposure to residues of
spinosad in drinking water. In addition, there is no established
Maximum Concentration Level (MCL) for residues of spinosad in drinking
water.
3. Non-dietary exposure. Spinosad is currently registered for use
on cotton with several crop registrations pending all of which involve
applications of spinosad in the agriculture environment. Spinosad is
also currently registered for use on turf and ornamentals at low rates
of application (0.04 to 0.54 lb a.i. per acre). Thus, the potential for
non-dietary exposure to the general population is not expected to be
significant.
D. Cumulative Effects
The potential for cumulative effects of spinosad and other
substances that have a common mechanism of toxicity is also considered.
In terms of insect control, spinosad causes excitation of the insect
nervous system, leading to involuntary muscle contractions, prostration
with tremors, and finally paralysis. These effects are consistent with
the activation of nicotinic acetylcholine receptors by a mechanism that
is clearly novel and unique among known insecticidal compounds.
Spinosad also has effects on the GABA receptor function that may
contribute further to its insecticidal activity. Based on results found
in tests with various mammalian species, spinosad appears to have a
mechanism of toxicity like that of many amphiphilic cationic compounds.
There is no reliable information to indicate that toxic effects
produced by spinosad would be cumulative with those of any other
pesticide chemical. Thus it is appropriate to consider only the
potential risks of spinosad in an aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions and
the proposed RfD described above, the aggregate exposure to spinosad
use on potatoes (using 0.032 ppm residue level) and other existing or
pending crop uses will utilize 20.8% of the RfD for the U.S.
population. No contribution to animal feed from potato was utilized in
this analysis due to the limited scope of the EUP. A more realistic
estimate of dietary exposure and risk relative to a chronic toxicity
endpoint is obtained if average (anticipated) residue values from field
trials are used. Inserting the average residue values in place of
tolerance residue levels produces a more realistic, but still
conservative risk assessment. Based on average or anticipated residues
in a dietary risk analysis, the use of spinosad on potatoes and other
existing or pending crop uses will utilize 4.6% of the RfD for the U.S.
population. 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. Thus, it is clear that there is reasonable
certainty that no harm will result from aggregate exposure to spinosad
residues on potatoes and other existing or pending crop uses.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of spinosad, data from
developmental toxicity studies in rats and rabbits and a 2-generation
reproduction study in the rat are considered. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure during prenatal
development. Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability
and potential systemic toxicity of mating animals and on various
parameters associated with the well-being of pups.
Section 408 FFDCA 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 for spinosad relative to pre- and post-natal effects for
children is complete. Further, for spinosad, the NOELs in the dog
chronic feeding study which was used to calculate the RfD (0.0268 mg/
kg/day) are already lower than the NOELs from the developmental studies
in rats and rabbits by a factor of more than 10-fold.
Concerning the reproduction study in rats, the pup effects shown at
the HDT were attributed to maternal toxicity. Therefore, it is
concluded that an additional uncertainty factor is not needed and that
the RfD at 0.0268 mg/kg/day is appropriate for assessing risk to
infants and children.
Using the conservative exposure assumptions previously described
(tolerance level residues), the % RfD utilized by the aggregate
exposure to residues of spinosad on potatoes and other existing or
pending crop uses is 38.4% for children 1 to 6-years old, the most
sensitive population subgroup. If average or anticipated residues are
used
[[Page 30756]]
in the dietary risk analysis, the use of spinosad on these crops will
utilize 11.3% of the RfD for children 1 to 6-years old. Thus, based on
the completeness and reliability of the toxicity data and the
conservative exposure assessment, it is concluded that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to spinosad residues on cotton gin byproducts
and other existing or pending crop uses.
F. International Tolerances
There are no Codex maximum residue levels established for residues
of spinosad on cotton gin byproducts or any other food or feed crop.
(Beth Edwards).
[FR Doc. 98-15014 Filed 6-4-98; 8:45 am]
BILLING CODE 6560-50-F
