[Federal Register Volume 63, Number 194 (Wednesday, October 7, 1998)]
[Notices]
[Pages 53902-53911]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-26783]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[PF-831; FRL-6026-3]


Notice of Filing of Pesticide Tolerance Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

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.

[[Page 53903]]

    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:

------------------------------------------------------------------------
                                   Office location/
        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
                                 epa.gov.
Mark Dow......................  Rm. 214, CM #2, 703-    Do.
                                 305-5533; e-mail:
                                 D[email protected].
gov.
James Tompkins................  Rm. 239, CM #2, 703     Do.
                                 305-5697; e-mail:
                                 tompkins.james@epamai
l.epa.gov.
------------------------------------------------------------------------


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:
    [email protected]


    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:

[[Page 53904]]

 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

[[Page 53905]]

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.

[[Page 53906]]

    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

[[Page 53907]]

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

[[Page 53908]]

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

[[Page 53909]]

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 g 
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 
g/L with a NOAEL of 0.01 g/L and a LOEL of 0.10 
g/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

[[Page 53910]]

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

[[Page 53911]]

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