[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]
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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.
[[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:
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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,
[email protected] Arlington, VA
epa.gov.
Mark Dow...................... Rm. 214, CM #2, 703- Do.
305-5533; e-mail:
Dow.mark@epamail.epa..
James Tompkins................ Rm. 239, CM #2, 703 Do.
305-5697; e-mail:
tompkins.james@epamai.
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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:
[[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="">50 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="">50 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="">