Pymetrozine - Pesticide Tolerance Filing 9/98
[Federal Register: October 7, 1998 (Volume 63, Number 194)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Tolerance Petitions
AGENCY: Environmental Protection Agency (EPA).
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-831, must
be received on or before November 6, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, Crystal Mall (CM) #2, 1921 Jefferson Davis Highway,
Comments and data may also be submitted electronically by following
the instructions under "SUPPLEMENTARY INFORMATION." No Confidential
Business Information (CBI) 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
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. 119 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
Product Manager telephone number Address
Leonard Cole.................. Rm. 209, CM #2, 703- 1921 Jefferson
305-5412; e-mail: Davis Hwy,
cole.leonard@epamail. Arlington, VA
Mark Dow...................... Rm. 214, CM #2, 703- Do.
James Tompkins................ Rm. 239, CM #2, 703 Do.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various raw 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 grantinig of the
petition. Additional data may be needed before EPA rules on the
The official record for this notice, as well as the public version,
has been established for this notice of filing under document control
number PF-831 (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".
Electronic comments can be sent directly to EPA at:
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 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the document control number (PF-831) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: September 29, 1998.
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. 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.
2. Norvartis Crop Protection
EPA has received a pesticide petition (PP 8F4984) from Norvartis
Crop Protection, P.O. Box 18300 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
Pymetrozine in or on the raw agricultural commodity cotton at 0.4
parts per million (ppm), and on cotton gin by-products at 3.0 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-215944 in plants is
understood for the purposes of the proposed tolerance. Studies in rice,
tomatoes, cotton and potatoes gave similar results. Identified
metabolic pathways have demonstrated that pymetrozine is the residue of
concern for tolerance setting purposes.
2. Analytical method--i. Crops. Novartis has submitted two
analytical methods for the determination of pymetrozine and its major
crop metabolite, in crop substrates. For both methods, the limit of
detection (LOD) is 1.0 nanogram (ng) and the limit of quantitation
(LOQ) of 0.02 ppm. Samples are extracted using acetonitrile: 0.05M
sodium borate and an aliquot is taken for each method. The aliquots
were cleaned up with solid-phase and/or liquid-liquid partitions and
analyzed by high preformance liquid chromatography (HPLC) with column-
switching and Ultra violet (UV) detection. Both methods have undergone
independent laboratory validation. The pymetrozine Analytical Method is
proposed as the tolerance enforcement method.
ii. Livestock. Novartis has submitted an analytical methods for the
determination of pymetrozine in eggs, milk and poultry, dairy and goat
tissues. The LOD for the analytical method is 1.0 ng and the LOQ is
0.01 ppm. Samples are extracted using acetonitrile:water, cleaned up
with solid-phase and liquid-liquid partitions, and analyzed for
pymetrozine by HPLC with column switching and UV detection.
Novartis has also submitted an analytical method for the
determination of the major livestock metabolite of pymetrozine in dairy
and goat tissues and milk. This method also accounts for a phosphate
conjugate, which is a significant metabolite found only in milk. The
LOD for the metabolite method is 1.5 ng and the is LOQ of 0.01 ppm.
Samples are extracted using methanol:water. Milk samples are heated to
hydrolyze the phosphate conjugate, and all samples are cleaned up with
solid-phase partitions and analyzed by HPLC with UV detection. The
parent Analytical Method has successfully undergone independent
3. Magnitude of residues --i. Cotton. The maximum residues of
pymetrozine detected in samples of undelinted cottonseed from cotton
supporting the maximum proposed application rate of 3 x 0.086 lbs.
active ingredient/Acre (ai/A) = 0.258 lbs. ai/A (residue program
performed at 1 x 0.099 lbs. ai/A + 2 x 0.132 lbs. ai/A = 0.363 lbs. ai/
A) harvested with a 21-day pre-harvest interval (PHI) were 0.32 ppm.
The maximum residues of the major metabolite GS-23199 detected in
samples of undelinted cottonseed resulting from cotton treated as
described above and harvested with a 21-day PHI were 0.04 ppm.
The maximum residues of pymetrozine detected in samples of cotton
gin trash from cotton supporting the maximum proposed application rate
of 3 x 0.086 lbs. ai/A = 0.258 lbs. ai/A (residue program performed at
1 x 0.099 lbs. ai/A + 2 x 0.132 lbs. ai/A = 0.363 lbs. ai/A) harvested
with a 21-day PHI were 2.4 ppm. The maximum residues of GS-23199
detected in samples of cotton gin trash resulting from cotton treated
as described above and harvested with a 21-day PHI were 0.31 ppm.
The maximum residues of pymetrozine detected in samples of
cottonseed hulls from cotton supporting the maximum proposed
application rate of 3 x 0.086 lbs. ai/A = 0.258 lbs. ai/A (residue
program performed at 1 x 0.099 lbs. ai/A + 2 x 0.132 lbs. ai/A = 0.363
lbs. ai/A) harvested with a 21-day PHI were 0.08 ppm. No residues of
GS-23199 were detected in samples of cottonseed hulls.
No detectable residues of either pymetrozine or GS-23199 were found
in samples of cottonseed meal or refined oil from cotton supporting the
maximum proposed application rate of
3 x 0.086 lbs. ai/A = 0.258 lbs. ai/A (residue program performed at 1 x
0.099 lbs. ai/A + 2 x 0.132 lbs. ai/A = 0.363 lbs. ai/A) harvested with
a 21-day PHI.
ii. Livestock. A 3-level dairy feeding study was conducted using
pymetrozine as the test substance. Holstein dairy cows were dosed daily
with pymetrozine at levels equivalent to 0 (Control), 1.0 ppm, 3.0 ppm
and 10 ppm. These rates represent 1.6, 5 and 16 times the maximum
contribution to the diet that could be expected from cotton. This study
was designed to provide data concerning the level of residues of
pymetrozine, and CGA-313124, in milk and tissues which could occur as a
result of feeding crops treated with pymetrozine to dairy cows. The
results are used to estimate the transfer of residues from the diet to
the tissues and milk of livestock.
No detectable residues of pymetrozine or CGA-313124 were observed
in samples of liver, kidney, perirenal fat, omental fat, round muscle,
or tenderloin muscle from cows dosed with 10 ppm (16 x ) pymetrozine.
No detectable residues of pymetrozine were observed in samples of milk
from cows dosed with 10 ppm (16 x ), 3 ppm (5 x ), or 1 ppm 1.6 x )
pymetrozine at any sampling interval. Detectable residues of CGA-313124
occurred only in milk samples from 80 x dosed cows at a maximum level
of 0.05 ppm.These results indicate that there is no need to establish a
meat and milk tolerance.
B. Toxicological Profile
1. Acute toxicity. Pymetrozine has low acute toxicity. The oral
LD50 in rats is >5,820 milligram/kilograms (mg/kg) for males
and females, combined. The rat dermal LD50 is > 2,000 mg/kg
and the rat inhalation LC50 is > 1.8 mg/liter (L) air.
Pymetrozine is not a skin sensitizer in guinea pigs and does not
produce dermal irritation in rabbits. It produces minimal eye
irritation in rabbits. End-use water-dispersible granule formulations
of pymetrozine have similar low acute toxicity profiles.
2. Genotoxicty. Pymetrozine has low acute toxicity. The oral
LD50 in rats is > 5,820 mg/kg for males and females,
combined. The rat dermal LD50 is > 2,000 mg/kg and the rat
inhalation LC50 is > 1.8 mg/L air. Pymetrozine is not a skin
sensitizer in guinea pigs and does not produce dermal irritation in
rabbits. It produces minimal eye irritation in rabbits. End-use water-
dispersible granule formulations of pymetrozine have similar low acute
3. Reproductive and developmental toxicity. In a teratology study
in rats, pymetrozine caused decreased body weights (bwts) and food
consumption in females given 100 and 300 mg/kg/day during gestation.
This maternal toxicity was accompanied by fetal skeletal anomalies and
variations consistent with delayed ossification. The no-observed-
adverse-effect-level (NOAEL) for maternal and fetal effects in rats was
30 mg/kg/day. A teratology in rabbits showed that pymetrozine caused
maternal death and reduced body weight gain and food consumption at 125
mg/kg/day highest dose tested (HDT). Maternal toxicity was accompanied
by embryo- and feto-toxicity (abortion in one female and total
resorptions in two females). Body weight and food consumption
decreases, early resorptions and postimplantation losses were also
observed in maternal rabbits given 75 mg/kg/day. There was an increased
incidence of fetal skeletal anomalies and variations at these
maternally toxic doses. The NOAEL for maternal and fetal effects in
rabbits was 10 mg/kg/day. Pymetrozine is not teratogenic in rats or
rabbits. In a 2-generation reproduction study in rats, parental body
weight and food consumption were decreased, liver and spleen weights
were reduced and histopathological changes in liver, spleen and
pituitary were observed at 2,000 ppm HDT. Liver hypertrophy was
observed in parental males at 200 ppm (approximately 10-40 mg/kg/day).
Reproductive parameters were not affected by treatment with
pymetrozine. The NOAEL for reproductive toxicity is 2,000 ppm
(approximately 110-440 mg/kg/day). Offspring bwts were slightly reduced
at 2,000 and 200 ppm and eye opening was slightly delayed in pups at
2,000 ppm. Effects on offspring were secondary to parental toxicity.
The NOAEL for toxicity to adults and pups is 20 ppm (approximately 1-4
4. Subchronic toxicity. Pymetrozine was evaluated in 13-week
subchronic toxicity studies in rats, dogs and mice. Liver, kidneys,
thymus and spleen were identified as target organs. The NOAEL was 500
ppm (33 mg/kg/day) in rats and 100 ppm (3 mg/kg/day) in dogs. In mice,
increased liver weights and microscopical changes in the liver were
observed at all doses tested. The NOAEL in mice was <1,000 ppm (198 mg/
kg/day). No dermal irritation or systemic toxicity occurred in a 28-day
repeated dose dermal toxicity study with pymetrozine in rats given
1,000 mg/kg/day. Minimum direct dermal absorption (1.1%) of pymetrozine
was detected in rats over a 21 hour period of dermal exposure. Maximum
radioactivity left on or in the skin at the application site and
considered for potential absorption was 11.9%.
5. Chronic toxicity. Based on chronic toxicity studies in the dog
and rat, a reference dose (RfD) of 0.0057 mg/kg/day is proposed for
pymetrozine. This RfD is based on a NOAEL of 0.57 mg/kg/day established
in the chronic dog study and an uncertainty factor of 100 to account
for interspecies extrapolation and interspecies variability. Minor
changes in blood chemistry parameters, including higher plasma
cholesterol and phospholipid levels, were observed in the dog at the
lowest-observed-effect level (LOEL) of 5.3 mg/kg/day. The NOAEL
established in the rat chronic toxicity study was 3.7 mg/kg/day, based
on reduced bwt gain and food consumption, hematology and blood
chemistry changes, liver pathology and biliary cysts.z.
6. Animal metabolism. The metabolism of pymetrozine (CGA-215944) in
the rat is well understood. Metabolism involves oxidation of the 5-
methylene group of the triazine ring yielding 4,5-dihydro-5-hydroxy-6-
359009). Oxidation of the methyl substituent of the triazine ring led
triazin-3(2H)-one (CGA-313124) which was further oxidized to the
corresponding carboxylic acid, 4,5-dihydro-6-carboxy-4-[(3-
pyridinylmethylene)amino]-1,2,4-triazin-3(2H)-one. Hydrolysis of the
enamino bridge yielded 4-amino-6-methyl-1,2,4-triazin-3,5(2H,4H)-dione
(CGA-294849). This was further degraded to 6-methyl-1,2,4-triazin-
3,5(2H,4H)-dione (metabolite). Hydrolysis of the enamino bridge of CGA-
215944 produced CGA-215525 which undergoes either acylation (CGA-
259168) or deamination yielding 4,5-dihydro-6-methyl-1,2,4-triazin-
3(2H)-one (CGA-249257). Hydrolysis of the enamino bridge also formed 3-
pyridinecarboxaldehyde (CGA-300407), nicotinic acid (CGA-180777),
nicotinamide (CGA-180778), 3-pyridinemethanol (CGA-128632) and 1,6-
dihydro-1-methyl-6-oxo-3-pyridinecarboxamide. Identified metabolic
pathways in animals and plants are similar.
7. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent compound. Metabolites of pymetrozine are
considered to be of equal or lesser toxicity than the parent.
8. Endocrine disruption. Pymetrozine does not belong to a class of
chemicals known or suspected of having adverse
effects on the endocrine system. There is no evidence that pymetrozine
has any effect on endocrine function in developmental and reproduction
studies. Furthermore, histological investigation of endocrine organs in
chronic dog, rat and mouse studies did not indicate that the endocrine
system is targeted by pymetrozine.
C. Aggregate Exposure
1. Dietary exposure-- Food/Water. Dietary exposure to pymetrozine
was estimated based on tolerance level residues on fruiting vegetables,
tuberous and corm vegetables, cucurbits, cotton, hops (import/
domestic), associated dairy products and drinking water. Maximum
expected exposure to the U.S. population (48 States, all seasons) was
calculated to be 6.66% of the RfD described as 0.0057 mg/kg/bwt/day.
Maximum expected exposure to the most sensitive population subgroup,
non-nursing infants was calculated to be 14.4% of the RfD. The above
values were determined by using tolerance level values for each
appropriate crop with an assumption of 100% market share (most
conservative scenario). In addition, the drinking water component was
evaluated using the Generic expected environmental concentration
(GENEEC) surface water model (worst case scenario) and the resulting
calculated value was then incorporated into the crop and animal aspect
of the diet and is included in the above values. There is a reasonable
certainty that no harm will result from exposure to dietary residues
(including drinking water) of pymetrozine. There are no proposed
residential uses of pymetrozine, therefore the potential for non-
occupational exposure to the general population is not significant.
2. Non-dietary exposure. There are no other uses currently
registered for pymetrozine. The proposed uses involve application of
pymetrozine to crops grown in an agricultural environment. There are no
proposed uses which would be expected to result in residential exposure
of pymetrozine. Therefore, there is no potential for non-occupational
exposure to the general population.
D. Cumulative Effects
The potential for cumulative effects of pymetrozine and other
substances that have a common mechanism of toxicity has also been
considered. Pymetrozine belongs to a new chemical class known as
pyridine azomethines. It exhibits a unique mode of action which can be
characterized as nervous system inhibition of feeding behavior. It does
not have a general toxic or paralyzing effect on insects, but
selectively interferes with normal feeding activities by affecting
nervous system regulation of fluid intake. There is no reliable
information to indicate that toxic effects produced by pymetrozine
would be cumulative with those of any other chemical including another
pesticide. Therefore, Novartis believes it is appropriate to consider
only the potential risks of pymetrozine in an aggregate risk
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions and
the proposed RfD described above, the aggregate exposure to pymetrozine
will utilize 6.66% 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 exposure over a
lifetime will not pose appreciable risks to human health. Therefore,
Novartis concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to pymetrozine residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of pymetrozine, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered.
In a teratology study in rats, developmental toxicity anomalies and
variations associated was observed only at maternally toxic doses.
Similarly, in a rabbit teratology study, was observed only at
maternally toxic doses. The NOAELs in the rat and rabbit teratology
studies were 30 and 10 mg/kg/day, respectively. In the 2-generation
reproduction study, there were no effects on reproductive parameters.
Offspring bwts were slightly reduced and eye opening was slightly
delayed at dose levels producing parental toxicity. The NOAEL for
parental and offspring toxicity was 20 ppm (approximately 1-4 mg/kg/
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 requirements, the database
relative to pre- and post-natal effects for children is complete.
Further, for pymetrozine, the NOAEL of 0.57 from the chronic feeding
study in dogs, which was used to calculate the RfD (0.0057 mg/kg/day),
is already lower than the developmental NOAELs (30 and 10 mg/kg/day)
from the teratogenicity studies in rats and rabbits by a factor of more
than 10 fold. In the pymetrozine rat reproduction study, the mild
nature of the effects observed (decreased bwt) at the systemic LOEL
(10-40 mg/kg/day) and the fact that the effects were observed at a dose
that is more than 10 times greater than the NOAEL in the chronic dog
study (0.57 mg/kg/day) suggest that there is no additional sensitivity
for infants and children. Therefore, it is concluded that an additional
uncertainty factor is not warranted to protect the health of infants
and children and that an RfD of 0.0057 mg/kg/day based on the chronic
dog study is appropriate for assessing aggregate risk to infants and
children from pymetrozine.
Using the exposure assumptions (residues at proposed tolerance
levels on all crops and a 100% market share), the percent of the RfD
that will be utilized by aggregate exposure to residues of pymetrozine
is 3.83% for nursing infants less than 1 year old, 14.4% for non-
nursing infants and 10.17% for children 1-6 years old. Therefore, based
on the completeness and reliability of the toxicity database, Novartis
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to pymetrozine
F. International Tolerances
There are no Codex maximum levels established for residues of
pymetrozine. (Leonard Cole)
[FR Doc. 98-26783 Filed 10-6-98; 8:45 am]
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