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Bifenthrin - Pesticide Tolerance Petition 10/98

[Federal Register: October 7, 1998 (Volume 63, Number 194)]
[Notices]
[Page 53902-53911]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07oc98-1037]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-831; FRL-6026-3]
Notice of Filing of Pesticide Tolerance 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-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,
Arlington, VA.
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
table below:
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                                   Office location/
        Product Manager            telephone number          Address
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Leonard Cole..................  Rm. 209, CM #2, 703-    1921 Jefferson
                                 305-5412; e-mail:       Davis Hwy,
                                 cole.leonard@epamail.   Arlington, VA
                                 epa.gov.
Mark Dow......................  Rm. 214, CM #2, 703-    Do.
                                 305-5533; e-mail:
                                 Dow.mark@epamail.epa.
                                 gov.
James Tompkins................  Rm. 239, CM #2, 703     Do.
                                 305-5697; e-mail:
                                 tompkins.james@epamai
                                 l.epa.gov.
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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
petition.
    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:
    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 5.1/6.1 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
requirements.
    Dated: September 29, 1998.
James Jones,
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.
1. FMC Corporation
PP 8F5014
    EPA has received a pesticide petition (PP 8F5014) from FMC
Corporation, 1735 Market Street, Philadelphia, PA 19103 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 Bifenthrin: (2-methyl [1,1'-biphenyl]-3-yl)methyl 3-(2-
chloro-3,3,3-trifluoro-1-propenyl)-2,2 dimethylcyclopropanecarboxylate
in or on the raw agricultural commodity corn, grain (sweet) at 0.05 and
corn, forage at 3.0 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 bifenthrin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radiolabelled bifenthrin in various crops all showing
similar results. The residue of concern is the parent compound only.
    2. Analytical method. There is a practical method for detecting and
measuring levels of bifenthrin in or on food with a limit of detection
that allows monitoring of food with residues at or above the levels set
in these tolerances (Gas Chromatography with Electron Capture Detection
(GC/ECD) analytical method P-2132M, PP 0E3921, MRID 41658601).
    3. Magnitude of residues. Field residue trials meeting EPA study
requirements have been conducted at the maximum label rate for the crop
sweet corn. Results from these trials demonstrate that the proposed
bifenthrin tolerances on corn, sweet (k+cwhr) at 0.05 ppm and on corn,
forage at 3.0 ppm will not be exceeded when the product is applied
following the proposed use directions.
B. Toxicological Profile
    1. Acute toxicity. For the purposes of assessing acute dietary
risk, FMC has used the maternal No-Observed-Adverse-Effects-Level
(NOAEL) of 1.0 milligram/kilogram/day (mg/kg/day) from the oral
developmental toxicity study in rats. The maternal Lowest Effect Level
(LEL) of this study of 2.0 mg/kg/day was based on tremors from day 7-17
of dosing. This acute dietary endpoint is used to determine acute
dietary risks to all population subgroups.
    2. Genotoxicty. The following genotoxicity tests were all negative:
gene mutation in Salmonella (Ames); chromosomal aberrations in Chinese
hamster ovary and rat bone marrow cells; Hypoxanthine guanine
phophoribosyl transferase (HGPRT) locus mutation in mouse lymphoma
cells; and unscheduled DNA synthesis in rat hepatocytes.
    3. Reproductive and developmental toxicity. i. In the rat
reproduction study, parental toxicity occurred as decreased body weight
at 5.0 mg/kg/day with a NOAEL of 3.0 mg/kg/day. There were no
developmental (pup) or reproductive effects up to 5.0 mg/kg/day
(highest dose tested).
    ii. Post-natal sensitivity. Based on the absence of pup toxicity up
to dose levels which produced toxicity in the parental animals, there
is no evidence of special post-natal sensitivity to infants and
children in the rat reproduction study.
    4. Subchronic toxicity. Short- and intermediate-term toxicity. The
maternal NOAEL of 1.0 mg/kg/day from the oral developmental toxicity
study in rats is also used for short- and intermediate-term Margins of
Exposure (MOE) calculations (as well as acute, discussed in (1) above).
The maternal LEL of this study of 2.0 mg/kg/day was based on tremors
from day 7-17 of dosing.
    5. Chronic toxicity. i. The Referenced Dose (RfD) has been
established at 0.015 mg/kg/day. This RfD is based on a 1-year oral
feeding study in dogs with a NOAEL of 1.5 mg/kg/day, based on
intermittent tremors observed at the Lowest Observed Effects Level
(LOEL) of 3.0 mg/kg/day; an uncertainty factor of 100 is used.
    ii. Bifenthrin is classified as a Group C chemical (possible human
carcinogen) based upon urinary bladder tumors in mice; assignment of a
Q* has not been recommended.
    6. Animal metabolism. The metabolism of bifenthrin in animals is
adequately understood. Metabolism studies in rats with single doses
demonstrated that about 90% of the parent compound and its hydroxylated
metabolites are excreted.
    7. Metabolite toxicology. The Agency has previously determined that
the metabolites of bifenthrin are not of toxicological concern and need
not be included in the tolerance expression.
    8. Endocrine disruption. No special studies investigating potential
estrogenic or other endocrine effects of bifenthrin have been
conducted. However, no evidence of such effects were reported in the
standard battery of required toxicology studies which have been
completed and found acceptable. Based on these studies, there is no
evidence to suggest that bifenthrin has an adverse effect on the
endocrine system.
C. Aggregate Exposure
    1. Dietary exposure. -- Food. Tolerances have been established for
the residues of bifenthrin, in or on a variety of raw agricultural
commodities. Tolerances, in support of registrations, currently exist
for residues of bifenthrin on hops; strawberries; corn (field, seed,
and pop) grain, forage, and fodder; cottonseed; and from the associated
meat, milk and meat by-products from livestock commodities of cattle,
goats, hogs, horses, sheep, and poultry. Additionally, time-limited
tolerances associated with emergency exemptions were established for
broccoli, cauliflower, raspberries, cucurbits and canola. A pending
tolerance for artichokes also exists. For the purposes of assessing the
potential dietary exposure for these existing and pending tolerances as
well as the existing time-limited tolerances under FIFRA section 18
emergency exemptions, FMC has utilized available information on
anticipated residues, monitoring data and percent crop treated as
follows:
    i. Acute exposure and risk. Acute dietary exposure risk assessments
are performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1 day or single exposure. For the purposes of assessing acute
dietary risk for bifenthrin, the maternal NOAEL of 1.0 mg/kg/day from
the oral developmental toxicity study in rats was used. The maternal
LEL of this study of 2.0 mg/kg/day was based on tremors from day 7-17
of dosing. This acute dietary endpoint was used to determine acute
dietary risks to all population subgroups. Available information on
anticipated residues, monitoring data and percent crop treated was
incorporated into a Tier 3 analysis, using Monte Carlo modeling for
commodities that may be consumed in a single serving. These assessments
show that the MOE are significantly greater than the EPA standard of
100 for all subpopulations. The 95th percentile of exposure for the
overall U. S. population was estimated to be 0.001105 mg/kg/day (MOE of
905); 99th percentile 0.002064 mg/kg/day (MOE of 484); and 99.9th
percentile 0.003955 mg/kg/day (MOE of 253). The 95th percentile of
exposure for all infants < 1 year old was estimated to be 0.002234 mg/
kg/day (MOE of 448); 99th percentile 0.004459 mg/kg/day (MOE of 224);
and 99.9th percentile 0.006945 mg/kg/day (MOE of 144). The 95th
percentile of exposure for nursing infants < 1 year old was estimated
to be 0.00061 mg/kg/day (MOE of 1,639); 99th percentile 0.001376 mg/kg/
day (MOE of 727); and 99.9th percentile 0.002009 mg/kg/day (MOE of
498). The 95th percentile of exposure for non-nursing infants < one
year old was estimated to be 0.002804 mg/kg/day (MOE of 357); 99th
percentile 0.004831 mg/kg/day (MOE of 207); and 99.9th percentile
0.007236 mg/kg/day (MOE of 138). The 95th percentile of exposure for
children 1 to 6 years old (the most highly exposed population subgroup)
was estimated to be 0.002377 mg/kg/day (MOE of 421); 99th percentile
0.003483 mg/kg/day (MOE of 287); and 99.9th percentile 0.00628 mg/kg/
day (MOE of 159). Therefore, FMC concludes that the acute dietary risk
of bifenthrin, as estimated by the dietary risk assessment, does not
appear to be of concern.
    ii. Chronic exposure and risk. The acceptable RfD is based on a
NOAEL of 1.5 mg/kg/day from the chronic dog study and an uncertainty
factor of 100 is 0.015 mg/kg/day. The endpoint effect of concern were
tremors in both sexes of dogs at the LEL of 3.0 mg/kg/day. A chronic
dietary exposure/risk assessment has been performed for bifenthrin
using the above RfD. Available information on anticipated residues,
monitoring data and percent crop treated was incorporated into the
analysis to estimate the anticipated residue contribution (ARC). The
ARC is generally considered a more realistic estimate than an estimate
based on tolerance level residues. The ARC are estimated to be 0.000384
mg/kg body weight (bwt)/day and utilize 2.6% of the RfD for the overall
U. S. population. The ARC for non-nursing infants (<1 year) and
children 1-6 years old (subgroups most highly exposed) are estimated to
be 0.000837 mg/kg bwt/day and 0.001265 mg/kg bwt/day and utilizes 5.6%
and 8.4% of the RfD, respectively. Generally speaking, the EPA has no
cause for concern if the total dietary exposure from residues for uses
for which there are published and proposed tolerances is less than 100%
of the RfD. Therefore, FMC concludes that the chronic dietary risk of
bifenthrin, as estimated by the dietary risk assessment, does not
appear to be of concern.
    2. Drinking water. Laboratory and field data have demonstrated that
bifenthrin is immobile in soil and will not leach into groundwater.
Other data show that bifenthrin is virtually insoluble in water and
extremely lipophilic. As a result, FMC concludes that residues reaching
surface waters from field runoff will quickly adsorb to sediment
particles and be partitioned from the water column. Further, a screening
evaluation of leaching potential of a typical pyrethroid was conducted using
EPA's Pesticide Root Zone Model (PRZM3). Based on this screening assessment, the
potential concentrations of a pyrethroid in groundwater at depths of 1
and 2 meters are essentially zero (<0.001 parts per billion (ppb)).
Surface water concentrations for pyrethroids were estimated using PRZM3
and Exposure Analysis Modeling System (EXAMS) using standard EPA cotton
runoff and Mississippi pond scenarios. The maximum concentration
predicted in the simulated pond was 0.052 ppb. Concentrations in actual
drinking water would be much lower than the levels predicted in the
hypothetical, small, stagnant farm pond model since drinking water
derived from surface water would normally be treated before
consumption. Based on these analyses, the contribution of water to the
dietary risk estimate is negligible. Therefore, FMC concludes that
together these data indicate that residues are not expected to occur in
drinking water.
    3. Non-dietary exposure. Analyses were conducted which included an
evaluation of potential non-dietary (residential) applicator, post-
application and chronic dietary aggregate exposures associated with
bifenthrin products used for residential flea infestation control and
agricultural/commercial applications. The aggregate analysis
conservatively assumes that a person is concurrently exposed to the
same active ingredient via the use of consumer or professional flea
infestation control products and to chronic level residues in the diet.
    In the case of potential non-dietary health risks, conservative
point estimates of non-dietary exposures, expressed as total systemic
absorbed dose (summed across inhalation and incidental ingestion
routes) for each relevant product use category (i.e., lawn care) and
receptor subpopulation (i.e., adults, children 1 - 6 years and infants
< 1 year) are compared to the systemic absorbed dose NOAEL for
bifenthrin to provide estimates of the MOEs. Based on the toxicity
endpoints selected by EPA for bifenthrin, inhalation and incidental
oral ingestion absorbed doses were combined and compared to the
relevant systemic NOAEL for estimating MOEs.
    In the case of potential aggregate health risks, the above
mentioned conservative point estimates of inhalation and incidental
ingestion non-dietary exposure (expressed as systemic absorbed dose)
are combined with estimates (arithmetic mean values) of chronic average
dietary (oral) absorbed doses. These aggregate absorbed dose estimates
are also provided for adults, children 1 - 6 years and infants < 1
year. The combined or aggregated absorbed dose estimates (summed across
non-dietary and chronic dietary) are then compared with the systemic
absorbed dose NOAEL to provide estimates of aggregate MOEs.
    The non-dietary and aggregate (non-dietary + chronic dietary) MOEs
for bifenthrin indicate a substantial degree of safety. The total non-
dietary (inhalation + incidental ingestion) MOEs for post-application
exposure for the lawn care product evaluated was estimated to be
>51,000 for adults, 1,900 for children 1-6 years old and 1,800 for
infants < 1 year. The aggregate MOE (inhalation + incidental oral +
chronic dietary, summed across all product use categories) was
estimated to be 2,479 for adults, 559 for children 1-6 years old and
712 for infants (<1 year). It can be concluded that the potential non-
dietary and aggregate (non-dietary + chronic dietary) exposures for
bifenthrin are associated with substantial margins of safety.
D. Cumulative Effects
    In consideration of potential cumulative effects of bifenthrin and
other substances that may have a common mechanism of toxicity, to our
knowledge there are currently no available data or other reliable
information indicating that any toxic effects produced by bifenthrin
would be cumulative with those of other chemical compounds; thus only
the potential risks of bifenthrin have been considered in this
assessment of its aggregate exposure. FMC intends to submit information
for the EPA to consider concerning potential cumulative effects of
bifenthrin consistent with the schedule established by EPA published in
the Federal Register of August 4, 1997 (62 FR 42020) (FRL 5734-6) and
other EPA publications pursuant to the Food Quality Protection Act
(FQPA).
E. Safety Determination
    1. U.S. population. Based on a complete and reliable toxicology
database, the acceptable RfD is 0.015 mg/kg/day, based on a NOAEL of
1.5 mg/kg/day from the chronic dog study and an uncertainty factor of
100. Available information on anticipated residues, monitoring data and
percent crop treated was incorporated into an analysis to estimate the
Anticipated Residue Contribution (ARC) for 26 population subgroups. The
ARC is generally considered a more realistic estimate than an estimate
based on tolerance level residues. The ARC are estimated to be 0.000384
mg/kg bwt/day and utilize 2.6% of the RfD for the overall U. S.
population. The ARC for non-nursing infants (<1 year) and children 1-6
years old (subgroups most highly exposed) are estimated to be 0.000837
mg/kg bwt/day and 0.001265 mg/kg bwt/day and utilizes 5.6% and 8.4% of
the RfD, respectively. Generally speaking, the EPA has no cause for
concern if the total dietary exposure from residues for uses for which
there are published and proposed tolerances is less than 100% of the
RfD. Therefore, FMC concludes that the chronic dietary risk of
bifenthrin, as estimated by the aggregate risk assessment, does not
appear to be of concern.
    For the overall U.S. population, the calculated MOE at the 95th
percentile was estimated to be 905; 484 at the 99th percentile; and 253
at the 99.9th percentile. For all infants < one year old, the
calculated MOE at the 95th percentile was estimated to be 448; 224 at
the 99th percentile; and 144 at the 99.9th percentile. For nursing
infants < 1 year old, the calculated MOE at the 95th percentile was
estimated to be 1,639; 727 at the 99th percentile; and 498 at the
99.9th percentile. For non-nursing infants < 1 year old, the calculated
MOE at the 95th percentile was estimated to be 357; 207 at the 99th
percentile; and 138 at the 99.9th percentile. For the most highly
exposed population subgroup, children 1 - 6 years old, the calculated
MOE at the 95th percentile was estimated to be 421; 287 at the 99th
percentile; and 159 at the 99.9th percentile. Therefore, FMC concludes
that there is reasonable certainty that no harm will result from acute
exposure to bifenthrin.
    2. Infants and children. --i. General. In assessing the potential
for additional sensitivity of infants and children to residues of
bifenthrin, FMC considered data from developmental toxicity studies in
the rat and rabbit, and a 2-generation reproductive study in the rat.
The developmental toxicity studies are designed to evaluate adverse
effects on the developing organism resulting from pesticide exposure
during prenatal development to one or both parents. Reproduction
studies provide information relating to effects from exposure to the
pesticide on the reproductive capability of mating animals and data on
systemic toxicity. FFDCA section 408 provides that EPA may apply an
additional margin of safety for infants and children in the case of
threshold effects to account for pre- and post-natal toxicity and the
completeness of the database.
    ii. Developmental toxicity studies. In the rabbit developmental
study, there were no developmental effects observed in the fetuses
exposed to bifenthrin. The maternal NOAEL was 2.67 mg/kg/day based on
head and forelimb twitching at the LOEL of 4 mg/kg/day. In the rat
developmental study, the maternal NOAEL was 1 mg/kg/day, based on
tremors at the LOEL of 2 mg/kg/day. The developmental (pup) NOAEL was
also 1 mg/kg/day, based upon increased incidence of hydroureter at the
LOEL 2 mg/kg/day. There were 5/23 (22%) litters affected (5/141 fetuses
since each litter only had one affected fetus) in the 2 mg/kg/day
group, compared with zero in the control, 1, and 0.5 mg/kg/day groups.
According to recent historical data (1992-1994) for this strain of rat,
incidence of distended ureter averaged 11% with a maximum incidence of
90%.
    iii. Reproductive toxicity study. In the rat reproduction study,
parental toxicity occurred as decreased body weight at 5.0 mg/kg/day
with a NOAEL of 3.0 mg/kg/day. There were no developmental (pup) or
reproductive effects up to 5.0 mg/kg/day (highest dose tested).
    iv. Pre- and post-natal sensitivity. --a. Pre-natal. Since there
was not a dose-related finding of hydroureter in the rat developmental
study and in the presence of similar incidences in the recent
historical control data, the marginal finding of hydroureter in rat
fetuses at 2 mg/kg/day (in the presence of maternal toxicity) is not
considered a significant developmental finding. Nor does it provide
sufficient evidence of a special dietary risk (either acute or chronic)
for infants and children which would require an additional safety
factor.
    b. Post-natal. Based on the absence of pup toxicity up to dose
levels which produced toxicity in the parental animals, there is no
evidence of special post-natal sensitivity to infants and children in
the rat reproduction study.
    v. Conclusion. Based on the above, FMC concludes that reliable data
support use of the standard 100-fold uncertainty factor, and that an
additional uncertainty factor is not needed to protect the safety of
infants and children. As stated above, aggregate exposure assessments
utilized significantly less than 1% of the RfD for either the entire U.
S. population or any of the 26 population subgroups including infants
and children. Therefore, it may be concluded that there is reasonable
certainty that no harm will result to infants and children from
aggregate exposure to bifenthrin residues.
F. International Tolerances
    There are no Codex, Canadian, or Mexican residue limits for
residues of bifenthrin in or on corn, sweet.          (Mark Dow)
2. Norvartis Crop Protection
PP 8F4984
    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
Prymetrozine 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
laboratory validation.
    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
toxicity profiles.
    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
mg/kg/day).
    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-
methyl-4-[(3-pyridinylmethylene)amino]-1,2,4-triazin-3(2H)-one (CGA-
359009). Oxidation of the methyl substituent of the triazine ring led
to 4,5-dihydro-6-(hydroxymethyl)-4-[(3-pyridinylmethylene)amino]-1,2,4-
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
assessment.
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/
day).
    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
residues.
F. International Tolerances
    There are no Codex maximum levels established for residues of
pymetrozine.         (Leonard Cole)
3. Zeneca Ag. Products
PP 5F1625/5H5088
    EPA has received pesticide petitions PP 5F1625 and 5H5088 from
Zeneca Ag Products, 1800 Concord Pike, P.O. Box 15458, Wilmington,
Delaware 19850-5458, proposing pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act, (FFDCA) 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues of the
herbicide paraquat (1,1-dimethyl-4,4'-bypyridinium) derived from the
corn harvest-aid application of the dichloride salt (calculated as the
cation) in or on the raw agricultural commodities corn, pop, grain at
0.05 part per million (ppm); corn, field, grain at 0.05 ppm; corn,
field, forage at 3.0 ppm; corn, pop, forage at 3.0 ppm; corn, field,
stover at 10.0 ppm; corn, pop, stover at 10 ppm; and corn, flour at 0.1
ppm.
    An adequate analytical method (spectrophotometric method) has been
accepted and published in the Pesticide Analytical Manual (PAM Vol. II)
for the enforcement of tolerances in plant commodities. 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 qualitative nature of the residue in
plants is adequately understood based on studies depicting the
metabolism of paraquat in carrots and lettuce following pre-emergence
treatments and in potatoes and soybeans following desiccant treatment.
The residue of concern in plants is the parent, paraquat; the current
tolerance expression for plant commodities, as defined in 40 CFR
180.205(a) and (b).
    2. Analytical method. An adequate analytical method (spectrometric
method) has been accepted and published in the The Pesticide Analytical
Manual (PAM Vol. II) for the enforcement of tolerances in plant
commodities.
    3. Magnitude of residues. Paraquat residues on corn forage ranged
from <0.025 to 3 ppm and on corn fodder ranged from 0.025 to 6 ppm
following preemergence and post-directed applications as described for
MRID 41151523 and 41151506. Residue data submitted in tolerance
petition PP 5F1625 (MRID 00114426) for corn harvest-aid use of paraquat
indicate that corn grain residues would not exceed the established
tolerance of 0.05 ppm when applied broadcast postemergence at 0.5 lbs
ai/A with a 7-day pre-harvest interval. Residue data submitted in
tolerance petition PP 5F1625 (MRID 00114426) for corn harvest-aid use
of paraquat indicate that corn fodder (stover) residues range from 1.3
to 10.0 ppm when applied broadcast postemergence at 0.5 lbs ai/A with a
7-day pre-harvest interval. These data support a corn forage tolerance
of 3 ppm and a corn stover tolerance of 10 ppm.
B. Toxicological Profile
    1. Acute Toxicity. Acute toxicity studies conducted with the 45.6%
paraquat dichloride technical concentrate give the following results:
oral LD50 in the rat of 344 mg/kg (males) and 283 mg/kg
(females) (Category II); dermal LD50 in the rat of
≤ 2,000 mg/kg for males and females (Category III); the
primary eye irritation study showed corneal involvement with clearing
within 17 days (Category II); and dermal irritation of slight erythema
and edema at 72 hours (Category IV). Paraquat is not a dermal
sensitizer. Acute inhalation studies conducted to EPA guideline with
aerosolized sprays result in LD50 of 0.6 to 1.4
μg paraquat cation/Liter (L) (Category I). However, since
paraquat dichloride has no measurable vapor pressure; and hydraulic spray
droplets are too large to be respirable, inhalation exposure is not a
concern in practice.
    2. Genotoxicity. Paraquat dichloride was not mutagenic in the Ames
test using Salmonella typhinurium strains TA1535, TA1538, TA98, and
TA100; the chromosomal aberrations in the bone marrow test system; or
in the dominant lethal mutagenicity study with CD-1 mice. Additionally,
paraquat dichloride was negative for unscheduled DNA synthesis in rat
hepatocytes in in vitro and in vivo. Paraquat was weakly positive in
the mouse lymphoma cell assay only in the presence of metabolic
activation. Paraquat dichloride was weakly positive in mammalian cells
(lymphocytes) and positive in the sister chromatid exchange (SCE) assay
in Chinese hamster lung fibroblasts. Paraquat is non-mutagenic.
    3. Reproductive and developmental toxicity. A 3-generation
reproduction study in rats fed diets containing 0, 25, 75, and 150 ppm
which correspond to 0, 1.25, 3.75 or 7.5 mg of paraquat cation/kg/day,
respectively. Paraquat, at all levels tested, had no effect on body
weight gain, food consumption and utilization, fertility and length of
gestation of the F0 F1 and F2 parents.
The NOAEL and LOEL for systemic toxicity are 25 ppm (1.25 mg/kg/day)
and 75 ppm (3.75 mg/kg/day), respectively, expressed as paraquat
cation. The NOAEL for reproductive toxicity is ≥150 ppm (7.5
mg/kg/day; HDT) expressed as paraquat cation, as there were no
reproductive effects observed.
    Two developmental toxicity studies were conducted in rats given
gavage doses of 0, 1, 5, and 10 mg/kg/day and 0, 1, 3, and 8 mg/kg/day,
respectively, expressed as paraquat cation. In the first study, the
NOAEL for maternal toxicity was 1 mg/kg/day based on clinincal signs of
toxicity and decreased body weight gain at 5 mg/kg/day (the LOEL). The
NOAEL for developmental toxicity was set at 5 mg/kg/day based on
delayed ossification of the forelimb and hindlimb digits. In the
second, study, the maternal and developmental NOAEL is 8 mg/kg/day
(HDT) as there were no effects observed at any dose level even though
the animals were examined more carefully in the manus and pes
assessment. Based on both studies the overall NOAEL for maternal and
developmental toxicity is at least 3 mg/kg/day.
    Two developmental toxicity studies were conducted in mice given
gavage doses of 0, 1, 5, and 10 mg/kg/day and 0, 7.5, 15, or 25 mg/kg/
day paraquat ion, respectively. Both the maternal and developmental
NOAEL's are at 15 mg/kg/day in the second study. The maternal LOEL of
25 mg paraquat cation/kg/day is based on death, decreases in body
weight and body weight gain, and other clinical signs. The
developmental LOEL is 25 mg/kg/day. In the first study there was a
statistically significant effect on "partial ossification" of the 4th
sternebra at 10 mg/kg/day (HDT). However, it is not believed the
ossification pattern of the 4th sternebra was affected by paraquat as
evidenced by the lack of increase in "4th sternebra - not ossified."
    Additionally there were no statistically significant skeletal
abnormalities seen in the second study. The developmental/maternal
NOAEL should be based on the second study and is 15 mg/kg/day. Paraquat
dichloride is not a developmental toxin.
    4. Subchronic toxicity. A 90 day feeding study in dogs fed doses of
0, 7, 20, 60 or 120 ppm with a NOAEL of 20 ppm based on long effects
such as alveolitis and alveolar collapse seen at the LOEL of 60 ppm.
    A 21 day dermal toxicity study in rabbits exposed dermally to doses
of 0, 1.5, 3.4, 7.8 or 17.9 mg/kg/day with a NOAEL of 1.15 mg/kg/day
and a LOEL of 2.6 mg/kg/day based on dermal irritation.
    A 21 day inhalation toxicity study in rats were exposed to
respirable aerosols of paraquat at doses of 0, 0.01, 0.1, 0.5 and 1.0
μg/L with a NOAEL of 0.01 μg/L and a LOEL of 0.10
μg/L based on histopathological changes to the epithelium of
the larynx and nasal discharge.
    5. Chronic toxicity. In a 12-month feeding study in dogs fed dose
levels of 0, 15, 30, or 50 ppm, expressed as paraquat cation. These
levels corresponded to 0, 0.45, 0.93 or 1.51 mg of paraquat cation/kg/
day, respectively, in male dogs or 0, 0.48, 1.00 or 1.58 mg of paraquat
cation/kg/day, respectively for female dogs. There was a dose-related
increase in the severity and extent of chronic pneumonitis in the mid-
dose and high-dose male and female dogs. This effect was also noted in
the low-dose male group, but was minimal when compared with the male
controls. The systemic NOAEL is 15 ppm (0.45 mg/kg/day for males and
0.48 mg/kg/day for females, expressed as paraquat cation). The systemic
LOEL is 30 ppm (0.93 mg/kg/day for males and 1.00 mg/kg/day for females,
expressed as paraquat cation).
    In a 2-year chronic feeding/carcinogenicity study, rats were fed
doses of paraquat dichloride at 0, 25, 75, or 150 ppm which
corresponded to 0, 1.25, 3.75, or 7.5 mg of paraquat cation/kg/day.
Paraquat enhanced the development of ocular lesions in all of the
treated groups. The predominant lesions detected opthalmoscopically
were lenticular opacities and cataracts. At test week 103, dose-related
statistically significant (P<0.001) increases in the incidence of
ocular lesions were observed only in the mid-dose and high-dose male
and female groups. Based on these findings, the NOAEL (approximate) and
the LOEL for systemic toxicity, for both sexes, are 25 ppm (1.25 mg/kg/
day) and 75 ppm (3.75 mg/kg/day), respectively.
    In another 2-year chronic feeding/carcinogenicity study, rats were
dosed at 0, 6, 30, 100 or 300 ppm, expressed as paraquat dichloride
(nominal concentrations), equivalent to 0, 0.25, 1.26, 4.15, or 12.25
mg/kg/day, respectively (males) and 0, 0.30, 1.5, 5.12 or 15.29 mg/kg/
day respectively (females), expressed as paraquat dichloride. The
incidence of ocular changes were low and not caused by paraquat in this
study. The systemic NOAEL is 100 ppm of paraquat dichloride (4.15 and
5.12 mg/kg/day, for males and females, respectively); or 3.0 mg/kg/day
(males) and 3.7 mg/kg/day (females), expressed as paraquat cation. The
systemic LOEL is 300 ppm of paraquat dichloride (12.25 and 15.29 mg/kg/
day, for males and females, respectively); or 9.0 mg/kg/day (males) and
11.2 mg/kg/day (females), expressed as paraquat cation.
    A chronic feeding/carcinogenicity study in rats fed dose levels of
0, 25, 75 or 150 ppm, expressed as paraquat cation (nominal
concentrations). These doses corresponded to 0, 1.25, 3.75, or 7.5 mg
paraquat cation/kg/day, respectively. There was uncertain evidence of
carcinogenicity (squamous cell carcinomas in the head region; ears,
nasal cavity, oral cavity and skin) in males at 7.5 mg/kg/day (HDT)
with a systemic NOAEL of 1.25 mg/kg/day. Upon submission of additional
data to EPA, the incidence of pulmonary adenomas and carcinomas was
well within historical ranges and it was determined that paraquat was
not carcinogenic in the lungs and the head region of the rat.
    In another chronic feeding/carcinogenicity study, rats were fed
dose levels of 0, 6, 30, 100 or 300 ppm, expressed as paraquat
dichloride. There were no carcinogenic findings in this study at the
highest dose tested. In a two year chronic feeding/oncogenicity study,
SPF Swiss derived mice were fed paraquat dichloride at dose levels of
0, 12.5, 37.5, or 100/125 ppm, expressed as paraquat cation. These
rates correspond to 0, 1.87, 5.62, and 15 mg/kg/day as cation. Because
no toxic signs appeared after 35 weeks of dosing, the 100 ppm level was
increased to 125 ppm at week 36. There were no carcinogenic effects
observed in this study.
    The systemic NOAEL for both sexes is 12.5 ppm (1.87 mg/kg/day) and
the systemic LOEL is 37.5 ppm (5.6 mg/kg/day), each expressed as
paraquat cation based on renal tubular degeneration in males and weight
loss and decreased food intake in females.
    Paraquat is classified Category E for carcinogenicity (no evidence
of carcinogenicity in animal studies).
    6. Animal metabolism. The qualitative nature of the residue in
animals is adequately understood based on the combined studies
conducted with ruminants (goats and cows), swine, and poultry. The
residue of concern in eggs, milk, and poultry and livestock tissues is
the parent, paraquat.
    7. Metabolite toxicology. The nature of residues in plants and
animals is adequately understood. The residue of concern in eggs, milk,
poultry, livestock, and in crops is the parent paraquat. There are no
metabolites.
    8. Endocrine disruption. EPA is required to develop a screening
program to determine whether certain substances (including all
pesticides and inerts) "may have an effect produced by a naturally
occurring estrogen, or such other endocrine effect ." The Agency is
currently working with interested stakeholders, including other
government agencies, public interest groups, industry and research
scientist in developing a screening and testing program and a priority
setting scheme to implement this program. Congress has allowed 3 years
from passage of FQPA (August 3, 1999) to implement this program. At
that time, EPA may require further testing of this active ingredient
and end use products for endocrine disrupter effects.
C. Aggregate Exposure
    In examining aggregate exposure, FQPA directs EPA to take into
account available information concerning exposures from the pesticide
residue in food and all other exposures for which there is reliable
information. These other sources of exposure including drinking water,
and non-occupational exposures, e.g., to pesticides used in and around
the home. For estimating acute and chronic risks the Agency considers
aggregate exposures from the diet and from drinking water. Exposures
from uses in and around the home that may be short term, intermediate
or other duration may also be aggregated as appropriate for specific
chemicals.
    1. Dietary exposure. The Residue Chemistry data base for paraquat
is substantially complete, and the nature of the residues in plants and
animals is adequately understood. The residue of concern is the parent,
paraquat; the current tolerance expression for plants and animal
commodities, as defined in 40 CFR 180.205(a) and (b), is adequate. The
Reference Dose (RfD) for chronic dietary assessments is 0.0045 mg/kg/
day, based on a NOAEL of 0.45 mg/kg/day from a 1 year dog study and the
addition of a standard uncertainty factor of 100.
    2. Food. --i. Chronic dietary assessment. A chronic dietary
exposure analysis was performed using current and reassessed tolerance
level residues, contributions from the proposed use as a corn harvest
aid, and 100% crop treated information to estimate the Theoretical
Maximum Residue Contribution (TMRC) for the general population and 22
subgroups. The resulting TMRC for the general U.S. population from all
established uses is 0.001669 mg/kg/day (37% of the RfD). For children
ages 1-6, the most highly exposed subgroup, the resulting TMRC is
0.003679 mg/kg/day (82% of the RfD). A refined chronic dietary
assessment using percent crop treated data provided a more accurate
estimate of exposure, called the Anticipated Residue Contribution
(ARC). The resulting ARC for the general population is 0.00037 mg/kg/
day (8.0% of the RfD), and 0.001 mg/kg/day (22% of the RfD) for
children ages one to six.
    ii. Acute dietary assessment. EPA has determined that current data
on paraquat shows no acutedietary endpoint of concern. Therefore, an
acute dietary risk assessment is not required for paraquat.
    3. Drinking water. Paraquat is not expected to be a contaminant of
groundwater. Paraquat dichloride binds strongly to soil clay particles
and it did not leach from the surface in terrestrial field dissipation
studies. There were, however, detections of paraquat in drinking water
wells from 2 states cited in the Pesticides in Ground Water Database
(1991). These detections are not considered to be representative of
normal paraquat use. Therefore, paraquat is not expected to be a
groundwater contaminant or concern based on normal use patterns.
    Due to its persistent nature, paraquat could potentially be found
in surface water systems associated with soil particles carried by erosion,
however, paraquat is immobile in most soils, and at very high
application rates (50-1,000X), there was no desorption of paraquat from
soils. Therefore, based on paraquat's normal use patterns and unique
environmental fate characteristics, exposures to paraquat in drinking
water are not expected to be obtained from surface water sources.
    4. Non-dietary exposure. Paraquat dichloride has no residential or
other non-occupational uses that might result in non-occupational, non-
dietary exposure for the general population. Paraquat products are
Restricted Use, for use by Certified Applicators only, which means the
general public cannot buy or use paraquat products.
D. Cumulative Effects
    In assessing the potential risk from cumulative effects of paraquat
and other chemical substances, the Agency has considered structural
similarities that exist between paraquat and other bipyridylium
compounds such as diquat dibromide. Examination of the toxicology
databases of paraquat and diquat dibromide, indicates that the two
compounds have clearly different target organs. Based on available
data, the Agency does not believe that the toxic effects produced by
paraquat would be cumulative with those of diquat dibromide.
E. Safety Determination
    1. U.S. population. Based on the information provided in this
notice, EPA has determined that for the aggregate exposure assessment
the only exposure route of concern for paraquat is chronic dietary. The
toxicology database for paraquat is considered by EPA to be complete
and reliable. Using the conservative assumptions presented earlier, EPA
has established an RfD of 0.0045 mg/kg/day. This was based on the NOAEL
for the 1-year dog study of 0.45 mg/kg/day and employed a 100-fold
uncertainty factor. Results of this aggregate exposure assessment,
which includes EPA's reassessment of tolerances for existing crops and
the addition of corn harvest aid, utilize a maximum of 22% of the RfD.
Generally, exposures below 100% of the RfD are of no concern because it
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risk to human health. Thus,
there is reasonable certainty that no harm will result from aggregate
exposures to paraquat residues.
    2. Infants and children. EPA has determined that the established
tolerances for paraquat, with amendments and changes as specified in
this notice, meet the safety standards under the FQPA amendments to
section 408(b)(2)(C) for infants and children. The safety determination
for infants and children considers the factors noted above for the
general population, but also takes into account the possibility of
increased dietary exposure due to specific consumption patterns of
infants and children, as well as the possibility of increased
susceptibility to the toxic effects of paraquat residues in this
population subgroup.
    In determining whether or not infants and children are particularly
susceptible to toxic effects from paraquat residues, EPA considered the
completeness of the database for developmental and reproductive
effects, the nature and severity of the effects observed, and other
information.
    Based on the current data requirements, paraquat has a complete
database for developmental and reproductive toxicity. In the
developmental studies effects were seen (delayed ossification in the
forelimb and hindlimb digits) in the fetuses only at the same or higher
dose levels than effects in the mother. In the reproduction study, no
effects on reproductive performance were seen. Also because the NOAELs
from the developmental and reproduction studies were equal to or
greater than the NOAEL used for establishing the reference dose, EPA
concludes that it is unlikely that there is additional risk concern for
immature or developing organisms. Finally, the Agency has no
epidemiological information suggesting special sensitivity of infants
and children to paraquat. Therefore, the Agency finds that the
uncertainty factor (100X) routinely used in RfD calculations is
adequately protective of infants and children, and an additional
uncertainty factor is not warranted for paraquat.
    Zeneca estimates that paraquat residues in the diet of non-nursing
infants (less than 1 year) account for 18% of the RfD and 22% of the
RfD for children aged 1-6 years. Further, residues in drinking water
are not expected. Therefore, the Zeneca has determined that there is
reasonable certainty that dietary exposure to paraquat will not cause
harm to infants and children.
F. International Tolerances
    Codex maximum residue levels (MRL) are established for residues of
paraquat for corn grain at 0.1 ppm. The proposed tolerances for corn
grain at 0.05 ppm differ from the Codex MRL's based on field residue
data generated in the United States for this use (Pesticide Petitions
5F1625 and 5H5088 for corn grain. Differences in use patterns and pre-
harvest intervals may account for the differences between the Codex
MRLs and the tolerance values generated from the pesticide residue
trials in the United States.        (Jim Tompkins)
[FR Doc. 98-26783 Filed 10-6-98; 8:45 am]
BILLING CODE 6560-50-F