[Federal Register Volume 63, Number 37 (Wednesday, February 25, 1998)]
[Notices]
[Pages 9519-9528]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4803]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-790; FRL-5768-4]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-790, must
be received on or before March 27, 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, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Following the instructions under
``SUPPLEMENTARY INFORMATION.'' No confidential business information
should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 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/e- Address
mail address
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George LaRocca (PM 21)........ Rm. 204, CM #2, 703- 1921 Jefferson
305-6100, e-mail: Davis Hwy,
[email protected] Arlington, VA
l.epa.gov.
James A. Tompkins (PM 25)..... Rm. 239, CM #2, 703- Do.
305-5697, e-mail:
tompkins.james@epamai.
Hoyt Jamerson (PM 05)......... Rm. 268, CM #2, 703- Do.
308-9368, e-mail:
[email protected]
.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various 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 docket control
number PF-790 (including comments and data submitted electronically as
described below). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The
official record is located at the address in ``ADDRESSES'' at the
beginning of this document.
[[Page 9520]]
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 docket control number (insert docket number) 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: February 11, 1998.
Peter Caulkins,
Acting 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. DowElanco
PP 1F3935
EPA has received a pesticide petition (PP 1F3935) from DowElanco,
9330 Zionsville Road, Indianapolis, IN 46268-1054 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 triclopyr, (3,5,6-trichloro-2-pyridinyl)oxyacetic acid and
its metabolites 3,5,6-trichloro-2-pyridinol (TCP) and 2-methoxy-3,5,6-
trichloropyridine (TMP) in or on the raw agricultural commodity fish at
3.0 parts per million (ppm), and shellfish at 5.0 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. Analytical method. Adequate methodology is available for the
enforcement of tolerances for triclopyr residues of concern. Gas
chromatography methods are available for the determination of triclopyr
residues of concern. Residues of triclopyr, 3,5,6-trichloro-2-
pyridinol, and 2-methoxy-3,5,6-trichloropyridine can be separately
determined. The limits of quantitation are 0.01 - 0.05 ppm in fish and
shellfish, depending on the compound being analyzed. The water method
has a limit of quantitation of 0.1 ppb.
2. Magnitude of residues. In field studies, triclopyr and its
metabolites in water have half-lives of 0.5 - 15 days. Triclopyr
residues in lake water treated at the maximum label rate were below 0.5
ppm within 3 - 14 days. In pond water where whole ponds were treated at
the maximum label rate, residues were below 0.5 ppm by 28 days after
treatment. After 42 days in both lakes and ponds, residues were non-
detectable (<0.010 ppm)="" to="" 0.013="" ppm.="" residues="" of="" triclopyr="" and="" its="" metabolites="" 3,5,6-trichloro-2-="" pyridinol="" and="" 2-methoxy-3,5,6-trichloropyridine="" reach="" a="" maximum="" concentration="" in="" fish="" at="" 3-14="" days="" after="" treatment="" of="" water,="" and="" total="" residues="" of="" triclopyr="" and="" its="" metabolites="" were="" detectable="" in="" the="" edible="" flesh="" at="" a="" maximum="" level="" of="" 3.0="" ppm="" in="" fish="" and="" 5.0="" ppm="" in="" shellfish.="" residues="" in="" fish="" and="" shellfish="" decline="" as="" residues="" in="" water="" dissipate.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" the="" developmental="" no-effect="" level="" (noel)="" of="" 30="" milligram/kilogram/day="" (mg/kg/day)="" from="" a="" rabbit="" developmental="" study="" was="" recommended="" for="" the="" acute="" dietary="" risk="" assessment.="" at="" the="" lowest="" effect="" level="" (lel)="" of="" 100="" mg/kg/day,="" there="" were="" embryotoxic="" and="" fetotoxic="" effects="" associated="" with="" significant="" maternal="" toxicity,="" including="" death.="" acute="" exposure="" assessment="" will="" evaluate="" risk="" to="" pregnant="" females="" age="" 13="" and="" older.="" 2.="" short-="" and="" intermediate-term="" toxicity.="" based="" on="" the="" available="" data,="" short-="" and="" intermediate-term="" dermal="" and="" inhalation="" risk="" assessments="" are="" not="" required.="" a="" systemic="" noel="" of="" 1,000="" mg/kg/day,="" the="" highest="" dose="" tested="" (hdt),="" was="" determined="" in="" a="" 21-day="" dermal="" toxicity="" study="" in="" rabbits.="" the="">50 from the acute inhalation study
in rats was determined to be > 2.6 mg/L (Toxicity Category III).
3. Chronic toxicity. The Reference Dose (RfD) for triclopyr is 0.05
mg/kg/day. This RfD is based on a 2-generation reproductive toxicity
study in rats with a NOEL of 5.0 mg/kg/day using an uncertainty factor
of 100. At the next higher dose level of 25 mg/kg/day, an increased
incidence of slight degeneration of the proximal tubules of the kidneys
was observed in some P1 and P2 parents of both sexes. Chronic exposure
assessment will evaluate risk using this RfD.
4. Carcinogenicity. Environmental Protection Agency's Cancer Peer
Review Committee (CPRC) concluded that triclopyr should be classified
as a ``Group D chemical'' - not classifiable as to human
carcinogenicity. A cancer risk assessment is not required.
5. Animal metabolism. Disposition and metabolism of 14C-
triclopyr in rats demonstrated that triclopyr was well absorbed after
oral administration. Excretion was relatively rapid with a majority of
radioactivity eliminated in the urine by 24 hours. At the high dose of
60 mg/kg, urinary elimination of 14C-triclopyr was decreased
due to apparent saturation of renal elimination mechanisms. Fecal
elimination of 14C-triclopyr was a minor route of excretion,
as was elimination via exhaled air. Unmetabolized parent chemical
represented >90% of urinary radioactivity, with the remainder accounted
for by the metabolite 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), and
possible glucuranide and/or sulfate conjugates of 3,5,6-TCP. Plasma
elimination following intravenous administration of 14C-
triclopyr was consistent with a one-compartment model with an
elimination half-life of 3.6 hour and zero-order kinetics from 0-12
hours at the 60 mg/kg dose.
6. Bioequivalency. Toxicology studies conducted with triclopyr have
been performed using both the free acid or the triethylamine salt from
of triclopyr. Bioequivalency of the two chemical forms of triclopyr has
been addressed through the conduct of special studies with the
triethylamine from of triclopyr. These studies, which included data on
comparative disposition, plasma half-life, tissue distribution,
hydrolytic cleavage under physiological and environmental conditions
for triclopyr triethylamine salt were found to adequately address the
issue of Bioequivalency. In addition, subchronic toxicity studies
supported the pharmacokinetics data in demonstrating bioequivalence.
Therefore, studies conducted with any one from of triclopyr can be used
to support the toxicology database as a whole.
7. Endocrine Effects. An evaluation of the potential effects on the
endocrine systems of mammals has not been
[[Page 9521]]
determined; However, no evidence of such effects were reported in the
chronic or reproductive toxicology studies described above. There was
no observed pathology of the endocrine organs in these studies. There
is no evidence at this time that triclopyr causes endocrine effects.
C. Aggregate Exposure
1. Dietary exposure. The RfD for triclopyr is based upon the 2-
generation reproduction toxicity study in rats with a NOEL of 5.0 mg/
kg/day, the lowest dose tested. An uncertainty factor of 10 for
interspecies differences in response and an uncertainty factor of 10
for intraspecies differences in response was applied. Thus, the RfD for
triclopyr was established at 0.05 mg/kg/day by the RfD Peer Review
Committee on September 4, 1996.
A chronic dietary exposure analysis was performed using tolerance
level residues and 100 percent crop treated information to estimate the
Theoretical Maximum Residue Contribution (TMRC) for the general
population and 22 subgroups. Existing tolerances, including the
proposed tolerances for fish and shellfish, result in a TMRC that
represents 1.25% of the RfD for the U.S. general population. The
highest subgroup, Non-Nursing Infants (<1 year="" old)="" occupies="" 2.65%="" of="" the="" rfd.="" the="" chronic="" analysis="" for="" triclopyr="" is="" a="" worse="" case="" estimate="" of="" dietary="" exposure="" with="" all="" residues="" at="" tolerance="" level="" and="" 100="" percent="" of="" the="" commodities="" assumed="" to="" be="" treated="" with="" triclopyr.="" based="" on="" the="" risk="" estimates="" calculated="" in="" this="" analysis,="" the="" chronic="" dietary="" risk="" from="" the="" uses="" currently="" registered="" is="" not="" of="" concern.="" since="" the="" toxicological="" endpoint="" to="" which="" exposure="" is="" being="" compared="" in="" the="" acute="" dietary="" risk="" analysis="" is="" a="" developmental="" noel="" (30="" mg/kg/day),="" females="" (13+="" years)="" are="" the="" sub="" population="" of="" particular="" interest.="" the="" margin="" of="" exposure="" (moe)="" is="" a="" measure="" of="" how="" close="" the="" high="" end="" exposure="" comes="" to="" the="" noel="" (the="" highest="" dose="" at="" which="" no="" effects="" were="" observed="" in="" the="" laboratory="" test),="" and="" is="" calculated="" as="" the="" ratio="" of="" the="" noel="" to="" the="" exposure="" (noel/exposure="MOE.)" generally,="" acute="" dietary="" margins="" of="" exposure="" greater="" than="" 100="" tend="" to="" cause="" no="" dietary="" concern.="" the="" high="" end="" moe="" value="" of="" 1,639="" is="" above="" the="" acceptable="" level="" and="" demonstrates="" no="" acute="" dietary="" concern.="" an="" acute="" dietary="" exposure="" analysis="" was="" performed="" using="" tolerance="" level="" residues="" and="" 100="" percent="" crop="" treated="" to="" estimate="" the="" high="" end="" exposure="" for="" the="" general="" population="" and="" females="" (13+,="" pregnant,="" non-="" nursing).="" the="" high="" end="" exposure="" was="" assumed="" to="" be="" the="" upper="" 0.5%="" of="" consumers,="" that="" is,="" the="" 99.5="" percentile.="" the="" resulting="" exposure="" estimates="" and="" margins="" of="" exposure="" are="" as="" follows:="" ----------------------------------------------------------------------------------------------------------------="" population="" subgroup="" exposure="" (mg/kg="" bw/day)="" moe="" ----------------------------------------------------------------------------------------------------------------="" u.s.="" population="" 0.01359="" 2208="" females="" 0.01831="" 1639="" ----------------------------------------------------------------------------------------------------------------="" these="" high="" end="" moe="" values="" are="" above="" the="" acceptable="" level="" and="" demonstrate="" no="" acute="" dietary="" concerns.="" 2.="" drinking="" water.="" the="" use="" of="" triclopyr="" as="" described="" on="" the="" label="" allows="" only="" slight="" additional="" exposure="" of="" triclopyr="" to="" humans.="" the="" proposed="" labeling="" requires="" that="" the="" product="" not="" be="" applied="" within="" one-="" quarter="" mile="" of="" a="" potable="" water="" intake="" and="" that="" treated="" water="" not="" be="" used="" for="" domestic="" purposes="" until="" the="" residue="" level="" is="" demonstrated="" to="" be="" at="" or="" below="" 0.5="" ppm="" as="" determined="" by="" laboratory="" analysis="" or="" immunoassay.="" the="" basis="" for="" these="" restrictions="" is="" a="" series="" of="" aquatic="" dissipation="" studies="" conducted="" in="" lakes="" and="" ponds.="" in="" these="" studies,="" triclopyr="" was="" applied="" to="" lakes="" and="" ponds="" at="" the="" maximum="" concentration="" of="" 2.5="" ppm="" triclopyr="" in="" water.="" triclopyr="" residues="" in="" the="" lakes="" at="" one-="" quarter="" mile="" from="" the="" treatment="" areas="" were="" well="" below="" 0.1="" ppm="" throughout="" the="" study,="" with="" a="" maximum="" reported="" value="" of="" 0.058="" ppm.="" within="" the="" treatment="" area,="" triclopyr="" residues="" of="" less="" than="" 0.5="" ppm="" were="" reported="" at="" 3="" -="" 14="" days="" after="" treatment="" in="" the="" lake="" minnetonka="" and="" lake="" seminole="" studies.="" in="" seven="" test="" ponds="" treated="" with="" triclopyr="" at="" a="" water="" concentration="" of="" 2.5="" ppm,="" total="" residues="" of="" triclopyr="" were="" less="" than="" 0.5="" ppm="" by="" 28="" days="" after="" application,="" with="" the="" highest="" residue="" value="" being="" 0.193="" ppm.="" at="" 42="" days="" after="" treatment,="" total="" residues="" in="" both="" treated="" lakes="" and="" ponds="" ranged="" from="" non-detectable="" to="" 0.013="" ppm.="" if="" the="" proposed="" labeling="" is="" followed="" precisely,="" that="" is,="" potable="" water="" is="" not="" collected="" within="" one-quarter="" mile="" of="" a="" treated="" area,="" there="" will="" be="" little="" contribution="" from="" water="" to="" the="" ``risk="" cup''="" for="" triclopyr.="" if="" drinking="" water="" is="" collected="" from="" the="" treatment="" area="" when="" water="" analysis="" indicates="" triclopyr="" residues="" are="" 0.5="" ppm="" or="" less,="" the="" risk="" is="" still="" acceptable="" on="" an="" acute="" basis.="" on="" a="" chronic="" basis,="" the="" value="" of="" 0.013="" ppm,="" found="" to="" be="" the="" highest="" triclopyr="" residue="" at="" 42="" days="" after="" treatment="" in="" all="" studies,="" uses="" only="" 0.9%="" of="" the="" rfd="" for="" females="" (13+,="" pregnant,="" not="" nursing)="" and="" 2.6%="" of="" the="" rfd="" for="" children="" (1-6="" years).="" for="" a="" worst="" case="" estimate="" of="" potential="" drinking="" water="" exposure,="" the="" water="" residue="" at="" the="" proposed="" allowable="" water="" level="" at="" 0.5="" ppm="" was="" utilized.="" when="" this="" residue="" level="" is="" considered,="" the="" following="" analysis="" indicates="" no="" level="" of="" concern="" for="" acute="" exposure:="" for="" a="" 60="" kg="" pregnant="" female="" consuming="" 2="" liters="" a="" day="" (acute)="" (0.5="" mg/l="" x="" 2="" l/day)="" 60="" kg="0.0167" mg/kg/day="" moe="NOEL" exposure="(30" mg/kg/day)="" (0.0167="" mg/kg/day)="1796" for="" a="" 60="" kg="" pregnant="" female="" consuming="" 2="" liters="" a="" day="" (chronic)="" (0.013="" mg/kg/day="" x="" 2="" l/day)="" 60="" kg="0.00043" mg/kg/day="" %="" rfd="(0.00043" mg/kg/day="" x="" 100)="" (0.05="" mg/kg/day)="0.9" %="" for="" a="" 10="" kg="" child="" consuming="" 1="" liter="" a="" day="" (acute)="" (0.5="" mg/l="" x="" 1="" l/day)="" 10="" kg="0.05" mg/kg/day="" moe="(30" mg/kg/day)="" (0.05="" mg/kg/day)="600" for="" a="" 10="" kg="" child="" consuming="" 1="" liter="" a="" day="" (chronic)="" (0.013="" mg/l="" x="" 1="" l/day)="" 10="" kg="0.0013" mg/kg/day="" %="" rfd="(0.0013" mg/kg/day="" x="" 100)="" (0.05="" mg/kg/day)="2.6" %="" 3.="" non-dietary="" exposure.="" there="" are="" potential="" exposures="" to="" homeowners="" during="" usual="" use-patterns="" associated="" with="" triclopyr.="" these="" involve="" application="" of="" triclopyr-containing="" products="" by="" means="" of="" aerosol="" cans,="" pump="" spray="" bottles,="" squeeze="" bottles,="" ``weed="" sticks,''="" hose-end="" sprayers,="" power="" sprayers,="" paint="" brush,="" rotary="" and="" drop="" spreaders.="" it="" is="" unlikely="" that="" power="" sprayers="" will="" be="" used="" by="" homeowners;="" this="" is="" an="" application="" method="" requiring="" special="" applicator="" equipment="" more="" apt="" to="" be="" used="" by="" agricultural="" or="" commercial="" applicator.="" homeowner="" exposure="" will="" not="" be="" significant="" for="" the="" following="" reasons:="" the="" [[page="" 9522]]="" percent="" ai="" in="" products="" for="" homeowner="" use="" is="" less="" than="" that="" for="" agricultural="" or="" industrial="" use;="" the="" areas="" treated="" are="" usually="" limited="" in="" size;="" all="" products="" are="" intended="" for="" outdoor="" use="" which="" is="" likely="" to="" reduce="" the="" concentration="" in="" the="" environment="" by="" allowing="" dissipation="" in="" the="" outdoor="" air;="" the="" application="" methods="" recommended="" or="" commonly="" used="" by="" homeowners="" are="" not="" expected="" to="" provide="" significant="" exposure.="" additionally,="" no="" toxicological="" endpoints="" of="" concern="" have="" been="" identified="" by="" epa="" for="" dermal="" exposure="" to="" triclopyr,="" therefore,="" no="" exposure="" assessment="" is="" required="" for="" this="" exposure;="" an="" inhalation="" exposure="" assessment="" is="" also="" not="" required="" and="" no="" chronic="" use="" pattern="" is="" expected="" for="" homeowner="" use="" of="" triclopyr="" products.="" there="" is="" a="" potential="" for="" post-application="" exposure="" to="" swimmers="" following="" applications="" to="" aquatic="" sites="" that="" may="" be="" used="" for="" recreational="" purposes.="" there="" are="" no="" triclopyr-specific="" exposure="" data="" to="" assess="" swimmer="" exposure.="" however,="" an="" assessment="" was="" conducted="" using="" information="" provided="" in="" epa's="" dermal="" exposure="" assessment:="" principles="" and="" applications.="" the="" dermal="" permeability="" constant="" (kp)="" was="" calculated="" to="" be="" 6.5="" x="">-8 mg/cm2/hr. The assessment of
swimmer exposure was based on a 6-year old boy having a body weight of
21.9 kg and a surface area of 0.88 m2. The swimming period
was assumed to be 3 hours on the day of treatment in water containing
2.5 ppm triclopyr.
Total dermal exposure (mg) = 3 hr/day x 0.88 m2 x
104 cm2/m2 x 6.5 x 10-8
mg/cm2/hr = 1.716 x 10-3 mg/day
Oral absorption could also account for a portion of the exposure.
It was assumed that 1% of the water in residence in the mouth while
breathing will be swallowed.
Oral exposure = 3 hr/day x 0.05 L/hr x 2.5 mg/L = 0.375 mg/day
Combining the dermal exposure and oral exposure for a 21.9 kg
child, the swimming exposure for one day was estimated to be 0.377 mg/
day 21.9 kg = 0.017 mg/kg/day. Compared to the acute NOEL of
30 mg/kg/day, an MOE of 1,765 was obtained. No dermal or inhalation
endpoint has been established for triclopyr, so this represents a very
conservative estimate of the risk due to swimming in triclopyr-treated
waters.
D. Cumulative Effects
The potential for cumulative effects of triclopyr and other
substances that have a common mechanism of toxicity was considered. The
mammalian toxicity of triclopyr is well defined. However, the
biochemical mechanism of toxicity of this compound is not known. No
reliable information exists to indicate that toxic effects produced by
triclopyr would be cumulative with those of other similar compounds.
Therefore, consideration of a common mechanism of toxicity with other
compounds is not appropriate. Thus, only the potential risks of
triclopyr are considered in the aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Because of the toxicological characteristics of
triclopyr (no dermal endpoint of concern), post-application exposure
assessment was not necessary. Residential exposure is considered to be
negligible. Swimming in treated water was shown to be a minimal risk.
Therefore, residential and swimming exposure were not considered in the
aggregate risk calculation.
For the population subgroup of concern, pregnant females age 13 and
older, an MOE of 857 was estimated for the acute aggregate dietary risk
(food + water) from exposures to triclopyr residues.
MOE = (30 mg/kg/day) / (0.0183 + 0.0167) mg/kg/day = 857
Using the TMRC exposure assumptions described above, the percentage
of the RfD that will be utilized by aggregate exposures (food + water)
to residues of triclopyr ranges from 2.1% to 5.3% for the U.S.
population. The major identifiable subgroup with the highest aggregate
exposure is non-nursing infants <1 year="" old.="" the="" water="" exposure="" value="" used="" the="" highest="" water="" residue="" concentration="" at="" 42="" days="" after="" treatment="" of="" lakes="" and="" ponds="" (the="" longest="" sampling="" time="" interval="" common="" to="" all="" studies),="" 0.013="" ppm,="" in="" the="" calculations="" below:="" total="" u.s.="" population="" (dietary="" +="" drinking="" water)="" (0.00062="" +="" 0.00043)="" mg/kg/day="" x="" 100="" (0.05="" mg/kg/day)="2.1%" rfd="" non-nursing="" infants="" (dietary="" +="" drinking="" water)="" (0.00133="" +="" 0.0013)="" mg/kg/day="" x="" 100="" (0.05="" mg/kg/day)="5.3%" rfd="" determination="" of="" safety="" for="" u.s.="" population="" based="" on="" the="" current="" state="" of="" knowledge="" for="" this="" chemical,="" the="" rfd="" approach="" accurately="" reflects="" the="" exposure="" of="" the="" u.s.="" population,="" infants="" and="" children="" to="" triclopyr.="" 2.="" infants="" and="" children.="" studies="" cited="" earlier="" in="" this="" document="" indicate="" that="" triclopyr="" is="" not="" a="" selective="" developmental="" toxicant,="" and="" an="" additional="" uncertainty="" factor="" for="" infants="" and="" children="" is="" unnecessary.="" this="" decision="" is="" based="" on="" the="" following="" data.="" since="" the="" developmental="" and="" reproductive="" noels="" were="" either="" the="" same="" or="" greater="" than="" the="" maternal="" or="" parental,="" it="" is="" unlikely="" that="" there="" is="" additional="" risk="" concern="" for="" immature="" or="" developing="" organisms="" which="" is="" not="" reflected="" by="" the="" risk="" assessment="" utilizing="" the="" established="" reference="" dose.="" the="" effects="" noted="" for="" the="" rfd="" noel="" are="" parental="" effects,="" not="" developmental.="" f.="" international="" tolerances="" there="" are="" no="" established="" or="" proposed="" codex="" mrls="" for="" triclopyr="" residues.="" therefore,="" there="" are="" no="" issues="" of="" compatibility="" with="" respect="" to="" u.s.="" tolerances="" and="" codex="" mrls.="" (pm="" 25)="" 2.="" dupont="" agricultural="" products="" pp="" 4f3003,="" 4f3120,="" 0f3852="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 4f3003,="" 4f3120,="" 0f3852)="" from="" dupont="" agricultural="" products,="" po="" box="" 80038,="" wilmington,="" de="" 19880-="" 0038.="" 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="" tolerances="" for="" residues="" of="" esfenvalerate="" (asana="" xl="" insecticide),="" ((s)-cyano-(3-phenoxyphenyl)="" methyl="" (s)-4-chloro-alpha-="" (1-methylethyl)="" benzeneacetate)="" in="" or="" on="" the="" raw="" agricultural="" commodities="" sorghum,="" sugarbeets="" and="" head="" lettuce="" (see="" section="" a3="" for="" specific="" tolerance="" levels).="" the="" proposed="" analytical="" method="" involves="" homogenization,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" high="" performance="" liquid="" chromatography="" using="" ultra="" violet="" (uv)="" detection.="" epa="" has="" determined="" that="" the="" petition="" contains="" data="" or="" information="" regarding="" the="" elements="" set="" forth="" in="" section="" 408(d)(2)="" of="" the="" ffdca;="" however,="" epa="" has="" not="" fully="" evaluated="" the="" sufficiency="" of="" the="" submitted="" data="" at="" this="" time="" or="" whether="" the="" data="" supports="" granting="" of="" the="" petition.="" additional="" data="" may="" be="" needed="" before="" epa="" rules="" on="" the="" petition.="" a.="" residue="" chemistry="" 1.="" plant="" and="" animal="" metabolism.="" the="" metabolism="" and="" chemical="" nature="" of="" residues="" of="" fenvalerate="" in="" plants="" and="" animals="" are="" adequately="" understood.="" the="" fate="" of="" fenvalerate="" has="" been="" extensively="" studied="" using="" radioactive="" tracers="" in="" plant="" and="" animal="" metabolism/nature="" of="" the="" residue="" studies="" previously="" submitted="" to="" the="" agency.="" these="" studies="" have="" demonstrated="" that="" the="" parent="" compound="" is="" the="" only="" residue="" of="" toxicological="" significance.="" epa="" has="" concluded="" that="" the="" qualitative="" nature="" of="" [[page="" 9523]]="" the="" residue="" is="" the="" same="" for="" both="" fenvalerate="" and="" esfenvalerate.="" 2.="" analytical="" method.="" there="" is="" a="" practical="" analytical="" method="" utilizing="" electron-capture="" gas="" chromatography="" with="" nitrogen="" phosphorous="" detection="" available="" for="" enforcement="" with="" a="" limit="" of="" detection="" that="" allows="" monitoring="" food="" with="" residues="" at="" or="" above="" tolerance="" levels.="" the="" limit="" of="" detection="" for="" updated="" method="" is="" the="" same="" as="" that="" of="" the="" current="" pam="" ii,="" which="" is="" 0.01="" ppm.="" 3.="" magnitude="" of="" residues.="" fenvalerate="" is="" a="" racemic="" mixture="" of="" four="" isomers="" (s,s;="" r,s;="" s,r;="" and="" r,r).="" technical="">
(esfenvalerate) is enriched in the insecticidally active S,S-isomer
(84%). Tolerance expressions are proposed for esfenvalerate based on
the sum of all isomers. Tolerance of 5 parts per million (ppm) for head
lettuce, 5.0 ppm for sorghum grain, 10.0 ppm for sorghum forage, 10.0
ppm for sorghum fodder, 0.03 ppm for whole eggs, 0.03 ppm for poultry
meat, 0.3 ppm for poultry fat, 0.3 ppm for poultry meat by-products
(except liver), and 0.03 ppm for poultry liver, 5 ppm for sugarbeet
tops, 0.5 ppm for sugarbeet roots and 2.5 ppm sugarbeet pulp are
proposed. Magnitude of residue studies support the proposed tolerance.
B. Toxicological Profile
1. Acute toxicity. A battery of acute toxicity studies places
technical esfenvalerate in Toxicity Category II for acute oral toxicity
(rat LD50 87.2 mg/kg), Category III for acute dermal (rabbit
LD50 >2,000 mg/kg) and primary eye irritation (mild
irritation in rabbits), and Category IV for primary skin irritation
(minimal skin irritation in rabbits that reversed within 72 hours after
treatment). Acute inhalation on technical grade a.i. waived due to
negligible vapor pressure. A dermal sensitization test on esfenvalerate
in guinea pigs showed no sensitization.
2. Genotoxicty. Esfenvalerate was not mutagenic in reverse mutation
assays in S. typhimurium and E. Coli and did not induce mutations
Chinese hamster V79 cells or chromosome aberrations in Chinese hamster
ovary cells. Esfenvalerate did not induce micronuclei in bone marrow of
mice given up to 150 mg/kg intraperitoneally. Esfenvalerate did not
induce unscheduled DNA synthesis in HeLa cells. Other genetic
toxicology studies submitted on racemic fenvalerate indicate that the
mixture containing equal parts of the four stereoisomers is not
mutagenic in bacteria. The racemic mixture was also negative in a mouse
host mediated assay and in a mouse dominant lethal assay.
3. Reproductive and developmental toxicity. Esfenvalerate was
administered to pregnant female rats by gavage in a pilot developmental
study at doses of 0, 1, 2, 3, 4, 5, and 20 mg/kg/day and a main study
at 0, 2.5, 5, 10, and 20 mg/kg/day. Maternal clinical signs (abnormal
gait and mobility) were observed at 2.5 mg/kg/day and above. A maternal
NOEL of 2 mg/kg/day was established on the pilot study. The
developmental NOEL was >20 mg/kg/day.
Esfenvalerate was administered by gavage to pregnant female rabbits
in a pilot developmental study at doses of 0, 2, 3, 4, 4.5, 5, and 20
mg/kg/day and a main study at does of 0, 3, 10, and 20 mg/kg/day.
Maternal clinical signs (excessive grooming) were observed at 3 mg/kg/
day and above. A maternal NOEL of 2 mg/kg/day was established on the
pilot study. The developmental NOEL was > 20 mg/kg/day.
A two-generation feeding study with esfenvalerate was conducted in
the rat at dietary levels of 0, 75, 100, and 300 ppm. Skin lesions and
minimal (non biologically significant) parental body weight effects
occurred at 75 ppm. The NOEL for reproductive toxicity was 75 ppm (4.2-
7.5 mg/kg/day) based on decreased pup weights at 100 ppm.
4. Subchronic toxicity. Two 90-day feeding studies with
esfenvalerate were conducted in rats - one at 50, 150, 300, and 500 ppm
esfenvalerate, and a second at 0, 75, 100, 125, and 300 ppm to provide
additional dose levels. The NOEL was 125 ppm (6.3 mg/kg/day) based on
clinical signs (jerky leg movements) observed at 150 ppm (7.5 mg/kg/
day) and above. A 90-day feeding study in mice was conducted at 0, 50,
150, and 500 ppm esfenvalerate with a NOEL of 150 ppm (30.5 mg/kg)
based on clinical signs of toxicity at 500 ppm (106 mg/kg). Three-month
subchronic study in dogs was satisfied by one-year oral study in dogs,
in which the NOEL was 200 ppm (5 mg/kg/day). A 21-day dermal study in
rabbits with fenvalerate conducted at 100, 300, and 1,000 mg/kg/day
with an NOEL of 1,000 mg/kg/day.
5. Chronic toxicity. In a one-year study, dogs were fed 0, 25, 50,
or 200 ppm esfenvalerate with no treatment related effects at any
dietary level. The NOEL was 200 ppm (5 mg/kg/day). An effect level for
dietary administration of esfenvalerate for dogs of 300 ppm had been
established earlier in a three week pilot study used to select dose
levels for the chronic dog study.
One chronic study with esfenvalerate and three chronic studies with
fenvalerate have been conducted in mice.
In an 18-month study, mice were fed 0, 35, 150, or 350 ppm
esfenvalerate. Mice fed 350 ppm were sacrificed within the first two
months of the study after excessive self-trauma related to skin
stimulation and data collected were not used in the evaluation of the
oncogenic potential of esfenvalerate. The NOEL was 35 ppm (4.29 and
5.75 mg/kg/day for males and females, respectively) based on lower body
weight and body weight gain at 150 ppm. Esfenvalerate did not produce
carcinogenicity. In a 2-year feeding study, mice were administered 0,
10, 50, 250 or 1,250 ppm fenvalerate in the diet. The NOEL was 10 ppm
(1.5 mg/kg/day) based on granulomatous changes (related to fenvalerate
only, not esfenvalerate) at 50 ppm (7.5 mg/kg/day). Fenvalerate did not
produce carcinogenicity. In an 18-month feeding study, mice were fed 0,
100, 300, 1,000, or 3,000 ppm fenvalerate in the diet. The NOEL is 100
ppm (15.0 mg/kg/day) based on fenvalerate-related microgranulomatous
changes at 300 ppm (45 mg/kg/day). No compound related oncogenicity
occurred. Mice were fed 0, 10, 30, 100, or 300 ppm fenvalerate for 20
months. The NOEL was 30 ppm (3.5 mg/kg/day) based on red blood cell
effects and granulomatous changes at 100 ppm (15 mg/kg/day).
Fenvalerate was not carcinogenic at any concentration.
In a two-year study, rats were fed 1, 5, 25, or 250 ppm
fenvalerate. A 1,000 ppm group was added in a supplemental study to
establish an effect level. The NOEL was 250 ppm (12.5 mg/kg/day). At
1,000 ppm (50 mg/kg/day), hind limb weakness, lower body weight, and
higher organ-to-body weight ratios were observed. Fenvalerate was not
carcinogenic at any concentration. (A conclusion that fenvalerate is
associated with the production of spindle cell sarcomas at 1,000 ppm
was retracted by EPA).
EPA has classified esfenvalerate in Group E - evidence of
noncarcinogenicity for humans.
6. Animal metabolism. After oral dosing with fenvalerate, the
majority of the administered radioactivity was eliminated in the
initial 24 hours. The metabolic pathway involved cleavage of the ester
linkage followed by hydroxylation, oxidation, and conjugation of the
acid and alcohol moieties.
7. Metabolite toxicology. The parent molecule is the only moiety of
toxicological significance appropriate for regulation in plant and
animal commodities.
8. Other potential toxicology considerations - endocrine effects.
[[Page 9524]]
Estrogenic effects have not been observed in any studies conducted on
fenvalerate or esfenvalerate. In subchronic or chronic studies there
were no lesions in reproductive systems of males or females. In the
recent reproduction study with esfenvalerate, full histopathological
examination of the pituitary and the reproductive systems of males and
females was conducted. There were no compound-related gross or
histopathological effects. There were also no compound-related changes
in any measures of reproductive performance including mating,
fertility, or gestation indices or gestation length in either
generation. There have been no effects on offspring in developmental
toxicity studies. EPA is required to develop an endocrine disrupter
screening program by August 3, 1999. EPA will decide whether further
testing of esfenvalerate is required at that time.
C. Aggregate Exposure
1. Dietary exposure. Tolerances have been established for the
residues of fenvalerate/esfenvalerate, in or on a variety of
agricultural commodities. In addition, pending tolerance petitions
exist for use of esfenvalerate on sugarbeets, sorghum, head lettuce,
celery, pistachios, and a number of other minor use commodities. For
purposes of assessing dietary exposure, chronic and acute dietary
assessments have been conducted using all existing and pending
tolerances for esfenvalerate. EPA recently reviewed the existing
toxicology data base for esfenvalerate and selected the following
toxicological endpoints. For acute toxicity, EPA established a NOEL of
2.0 mg/kg/day from rat and rabbit developmental studies based on
maternal clinical signs at higher concentrations. An MOE of 100 was
required. For chronic toxicity EPA established the RfD for
esfenvalerate at 0.02 mg/kg/day. This RfD was also based on a NOEL of
2.0 mg/kg/day in the rat developmental study with an uncertainty factor
of 100. Esfenvalerate is classified as a Group E. There is no evidence
of carcinogenicity in either rats or mice.
2. Food. A chronic dietary exposure assessment was conducted using
Novigen's DEEm (Dietary Exposure Estimate Model). Anticipated residues
and adjustment for percent crop treated were used in the chronic
dietary risk assessment. The percentages of the Reference Dose (RfD)
utilized by the most sensitive sub-population, children 1-6 yrs., was
4.6% based on a daily dietary exposure of 0.000911 mg/kg/day. Chronic
exposure for the overall Us population was 1.9% of the RfD based on a
dietary exposure of 0.000376 mg/kg/day. This assessment has been
approved by EPA and included pending tolerances and all food tolerances
for incidental residues from use in food handling establishments. EPA
has no concern for exposures below 100% of the RfD because the RfD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health.
Esfenvalerate is classified as a Group E carcinogen - no evidence of
carcinogenicity in rats or mice. Therefore, a carcinogenicity risk
analysis is not required.
Potential acute exposures from food commodities were estimated
using a Tier 3 (Monte Carlo) Analysis and appropriate processing
factors for processed food and distribution analysis. This analysis
used field trial data to estimate exposure and federal and market
survey information to derive the percent of crop treated. EPA
considered these data reliable and used the upper end estimate of
percent crop treated in order to not underestimate any significant
subpopulation. Regional consumption information was taken into account.
The Margins of Exposure (MOEs) for the most sensitive sub-population
(children 1-6 yr.) were 202 and 103 at the 99th, and
99.9th percentile of exposure, respectively, based on daily
exposures of 0.009908 and 0.019445 mg/kg/day. The MOEs for the general
population are 355 and 171 at the 99th and 99.9th
percentile of exposure, respectively, based on daily exposure estimates
of 0.005635 and 0.011717 mg/kg/day. The EPA has stated there is no
cause for concern if total acute exposure calculated for the
99.9th percentile yields an MOE of 100 or larger. This acute
dietary exposure estimate is considered conservative and EPA considered
the MOEs adequate in a recent final rule (62 FR 63019).
3. Drinking water. Esfenvalerate is immobile in soil and will not
leach into groundwater. Due to the insolubility and lipophilic nature
of esfenvalerate, any residues in surface water will rapidly and
tightly bind to soil particles and remain with sediment, therefore not
contributing to potential dietary exposure from drinking water. A
screening evaluation of leaching potential of a typical pyrethroid was
conducted using EPA's Pesticide Root Zone Model (PRZM). Based on this
screening assessment, the potential concentrations of a pyrethroid in
ground water at depths of 1 and 2 meters are essentially zero (much
less than 0.001 parts per billion).
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 parts per billion.
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 be treated before
consumption. Chronic drinking water exposure was estimated to be
0.000001 mg/kg/day for both the U.S. general population and for non-
nursing infants. Less than 0.1% of the RfD was occupied by both
population groups.
Using these values, the contribution of water to the acute dietary
risk estimate was estimated for the U.S. population to be 0.000019 mg/
kg/day at the 99th percentile and 0.000039 mg/kg/day at the
99.9th percentile resulting in MOEs of 105,874 and 51,757,
respectively. For the most sensitive subpopulation, non-nursing infants
less than 1 year old, the exposure is 0.000050 mg/kg/day and 0.000074
mg/kg/day at the 99th and 99.9th percentile,
respectively, resulting in MOEs of 39,652, and 27,042, respectively.
Therefore there is reasonable certainty of no harm from drinking water.
4. Non-dietary exposure. Esfenvalerate is registered for non-crop
uses including spray treatments in and around commercial and
residential areas, treatments for control of ectoparasites on pets,
home care products including foggers, pressurized sprays, crack and
crevice treatments, lawn and garden sprays, and pet and pet bedding
sprays. For the non-agricultural products, the very low amounts of
active ingredient they contain, combined with the low vapor pressure
(1.5 x 10-9 mm Mercury at 25 deg. C.) and low dermal
penetration, would result in minimal inhalation and dermal exposure.
To assess risk from (nonfood) short and intermediate term exposure,
EPA has recently selected a toxicological endpoint of 2.0 mg/kg/day,
the NOEL from the rat and rabbit developmental studies. For dermal
penetration/absorption, EPA selected 25% dermal absorption based on the
weight-of-evidence available for structurally related pyrethroids. For
inhalation exposure, EPA used the oral NOEL of 2.0 mg/kg/day and
assumed 100% absorption by inhalation. Individual non-dietary risk
exposure analyses were conducted using a flea infestation scenario that
included pet spray, carpet
[[Page 9525]]
and room treatment, and lawn care, respectively. The total potential
short- and intermediate-tern aggregate non-dietary exposure including
lawn, carpet, and pet uses are: 0.000023 mg/kg/day for adults, 0.00129
mg/kg/day for children 1-6 years and 0.00138 mg/kg/day for infants less
than one year old. EPa concluded (62 FR 63019) that the potential non-
dietary exposure for esfenvalerate are associated with substantial
margins of safety.
5. Aggregate exposure - dietary and non-dietary exposure. EPA has
concluded that aggregate chronic exposure to esfenvalerate from food
and drinking water will utilize 1.9% of the RfD for the U.S. population
based on a dietary exposure of 0.000377 mg/kg/day. The major
identifiable subgroup with the highest aggregate exposure are children
1-6 years old. EPA generally has no concern for exposures below 100% of
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health.
The acute aggregate risk assessment takes into account exposure
from food and drinking water. The potential acute exposure from food
and drinking water to the overall U.S. population provides an acute
dietary exposure of 0.011756 mg/kg/day with an MOE of 170. This acute
dietary exposure estimate is considered conservative, using anticipated
residue values and percent crop-treated data in conjunction with Monte
Carlo analysis.
Short- and intermediate-term aggregate exposure takes into account
chronic dietary food and water (considered to be a background exposure
level) plus indoor and outdoor residential exposure. The potential
short- and intermediate-term aggregate risk for the U.S. population is
an exposure of 0.0082 mg/kg/day with an MOE of 244.
It is important to acknowledge that these MOEs are likely to
significantly underestimate the actual MOEs due to a variety of
conservative assumptions and biases inherent in the exposure assessment
methods used for their derivation. Therefore, it can be concluded that
the potential non-dietary and dietary aggregate exposures for
esfenvalerate are associated with a substantial degree of safety. EPA
has previously determined (62 FR 63019) that there was reasonable
certainty that no harm will result from aggregate exposure to
esfenvalerate residues. Head lettuce was included in that risk
assessment.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity''. In a recent Final Rule on esfenvalerate
(62 FR 63019) EPA concluded, ``Available information'' in this context
might include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments. For
most pesticides, although the Agency has some information in its files
that may turn out to be helpful in eventually determining whether a
pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning common mechanism of toxicity
in a meaningful way. EPA has begun a pilot process to study this issue
further through the examination of particular classes of pesticides.
The Agency hopes that the results of this pilot process will increase
the Agency's scientific understanding of this question such that EPA
will be able to develop and apply scientific principles for better
determining which chemicals have a common mechanism of toxicity and
evaluating the cumulative effects of such chemicals. The Agency
anticipates, however, that even as its understanding of the science of
common mechanisms increases, decisions on specific classes of chemicals
will be heavily dependent on chemical specific data, much of which may
not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed). Although esfenvalerate is
similar to other members of the synthetic pyrethroid class of
insecticides, EPA does not have, at this time, available data to
determine whether esfenvalerate has a common method of toxicity with
other substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
esfenvalerate does not appear to produce a toxic metabolite produced by
other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that esfenvalerate has a common mechanism of
toxicity with other substances.
E. Safety Determination
Both the chronic and acute toxicological endpoints are derived from
maternal NOEL's of 2.0 mg/kg/day in developmental studies in rats and
rabbits. There were no fetal effects. In addition, no other studies
conducted with fenvalerate or esfenvalerate indicate that immature
animals are more sensitive than adults. Therefore, the safety factor
used for protection of adults is fully appropriate for the protection
of infants and children; no additional safety factor is necessary as
described below.
1. U.S. population. A chronic dietary exposure assessment using
anticipated residues, monitoring information, and percent crop treated
indicated the percentage of the Reference Dose (RfD) utilized by the
General Population to be 1.9%. There is generally no concern for
exposures below 100% of the RfD because the RfD represents the level at
or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health.
For acute exposure, a Margin of Exposure (MOE) of greater than 100
is considered an adequate MOE. A Tier 3 acute dietary exposure
assessment found the General Population to have MOE's of 355 and 171 at
the 99th and 99.9th percentile of exposure,
respectively. These values were generated using actual field trial
residues and market share data for percentage of crop treated. These
results depict an accurate exposure pattern at an exaggerated daily
dietary exposure rate.
Short- and intermediate-term aggregate exposure risk from chronic
dietary food and water plus indoor and outdoor residential exposure for
the U.S. population is an exposure of 0.0082 mg/kg/day with an MOE of
244. Therefore, there is a reasonable certainty that no harm will
result from chronic dietary, acute dietary, non-dietary, or aggregate
exposure to esfenvalerate residues.
2. Infants and children. FFDCA section 408 provides that EPA shall
[[Page 9526]]
apply an additional tenfold margin of safety for infants and children
unless EPA determines that a different margin of safety will be safe
for infants and children. EPA has stated that reliable data support
using the standard MOE and uncertainty factor (100 for combined inter-
and intra-species variability) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor. In a
recent Final Rule (62 FR 63019), EPA concluded that reliable data
support use of the standard 100-fold uncertainty factor for
esfenvalerate, and that an additional uncertainty factor is not needed
to protect the safety of infants and children. This decision was based
on: no evidence of developmental toxicity at a doses up to 20 mg/kg/day
(ten times the maternal NOEL) in prenatal developmental toxicity
studies in both rats and rabbits; offspring toxicity only at dietary
levels which were also found to be toxic to parental animals in the two
generation reproduction study; and no evidence of additional
sensitivity to young rats or rabbits following pre- or postnatal
exposure to esfenvalerate.
A chronic dietary exposure assessment found the percentages of the
RfD utilized by the most sensitive sub-population to be 4.6% for
children 1-6 yr based on a dietary exposure of 0.000912 mg/kg/day. The
% RfD for nursing and non-nursing infants was 1.1% and 2.7%,
respectively. The Agency has no cause for concern if RfD are below
100%.
The most sensitive sub-population, children 1-6 year, had acute
dietary MOEs of 202 and 103 at the 99th and
99.9th percentile of exposure, respectively. Nursing infants
had MOEs of 195 and 146 at the 99th, and 99.9th
percentile of exposure, respectively. Non-nursing infants had MOEs of
304 and 158 at the 99th and 99.9th percentile of
exposure, respectively. The Agency has no cause for concern if total
acute exposure calculated for the 99.9th percentile yields a
MOE of 100 or larger.
EPA has recently concluded that the potential short- or
intermediate-term aggregate exposure of esfenvalerate from chronic
dietary food and water plus indoor and outdoor residential exposure to
children (1-6 years old) is 0.0113 mg/kg/day with an MOE of 177. For
infants (less than 1 year old) the exposure is 0.0098 mg/kg/day with an
MOE of 204. There is reasonable certainty that no harm will result to
infants and children from aggregate exposure to esfenvalerate residues
(62 FR 63019).
F. International Tolerances
Codex maximum residue levels (MRL's) have been established for
residues of fenvalerate on a number of crops that also have U.S.
tolerances. There is a Codex MRL of 2 ppm fenvalerate on head lettuce.
Thus any imported head lettuce is expected to have lower residue values
than the proposed section 408 tolerance of 5 ppm esfenvalerate on head
lettuce. There are also some minimal differences between the section
408 tolerances and certain Codex MRl values for other commodities.
These differences could be caused by differences in methods to
establish tolerances, calculate animal feed, dietary exposure, and as a
result of different agricultural practices. Therefore, some
harmonization of these maximum residue levels will be required. (PM
13)
3. Interregional Research Project No. 4 (IR-4)
PP 5E4598
EPA has received a pesticide petition (PP) from the Interregional
Research Project No. 4 (IR-4), New Jersey Agricultural Experiment
Station, P.O. Box 231, Rutgers University, New Brunswick, NJ 08903,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.472 by extending
the effective date for the time-limited tolerance established for
indirect or inadvertant combined residues of the insecticide
imidacloprid in or on the raw agricultural commodity cucurbit vegetable
crop group at 0.2 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 nature of the imidacloprid residue in
plants and livestock is adequately understood. The residues of concern
are combined residues of imidacloprid and it metabolites containing the
6-chloropyridinyl moiety, all calculated as imidacloprid.
2. Analytical method. The analytical method is a common moiety
method for imidacloprid and its metabolites containing the 6-
chloropyridinyl moiety using a permanganate oxidation, silyl
derivatization, and capillary GC-MS selective ion monitoring. This
method has successfully passed a petition method validation in EPA
labs. There is a confirmatory method specifically for imidacloprid and
several metabolites utilizing GC/MS HPLC-UV which has been validated by
the EPA as well. Imidacloprid and its metabolites are stable for at
least 24 months in the commodities when frozen.
B. Toxicological Profile
1. Acute toxicity. The acute oral LD50 values for
imidacloprid technical ranged from 424 - 475 milligram (mg)/kilogram
(kg) body weight (bwt) in the rat. The acute dermal LD50 was
greater than 5,000 mg/kg in rats. The 4-hour rat inhalation
LC50 was > 69 mg/meter3 (m3) air (aerosol). Imidacloprid was
not irritating to rabbit skin or eyes. Imidacloprid did not cause skin
sensitization in guinea pigs.
2. Genotoxicty. Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, both using in vitro and in vivo test systems show
imidacloprid to be non-genotoxic.
3. Reproductive and developmental toxicity. A 2-generation rat
reproduction study gave a no-observed-effect level (NOEL) of 100 ppm (8
mg/kg/bwt). Rat and rabbit developmental toxicity studies were negative
at doses up to 30 mg/kg/bwt and 24 mg/kg/bwt, respectively.
4. Subchronic toxicity. 90-day feeding studies were conducted in
rats and dogs. The NOEL's for these tests were 14 mg/kg bwt/day (150
ppm) and 5 mg/kg bwt/day (200 ppm) for the rat and dog studies,
respectively.
5. Chronic toxicity. A 2-year rat feeding/carcinogenicity study was
negative for carcinogenic effects under the conditions of the study and
had a NOEL of 100 ppm (5.7 mg/kg/ bwt in male and 7.6 mg/kg/bwt female)
for noncarcinogenic effects that included decreased body weight gain in
females at 300 ppm and increased thyroid lesions in males at 300 ppm
and females at 900 ppm. A 1-year dog feeding study indicated a NOEL of
1,250 ppm (41 mg/kg/bwt). A 2-year mouse carcinogenicity study that was
negative for carcinogenic effects under conditions of the study and had
a NOEL of 1,000 ppm (208 mg/kg/day).
6. Plant and animal metabolism. The nature of the imidacloprid
residue in plants and livestock is adequately understood. The residues
of concern are combined residues of imidacloprid and
[[Page 9527]]
it metabolites containing the 6-chloropyridinyl moiety, all calculated
as imidacloprid.
7. Endocrine disruption. The toxicology database for imidacloprid
is current and complete. Studies in this database include evaluation of
the potential effects on reproduction and development, and an
evaluation of the pathology of the endocrine organs following short- or
long-term exposure. Bayer has concluded that these studies revealed no
primary endocrine effects due to imidacloprid.
C. Aggregate Exposure
Imidacloprid is a broad-spectrum insecticide with systemic and
contact toxicity characteristics with both food and non-food uses.
Imidacloprid is currently registered for use on various food crops,
tobacco, turf, ornamentals, buildings for termite control, and cats and
dogs for flea control. These potential exposures are addressed below:
1. Dietary exposure. For purposes of assessing the potential acute
and chronic dietary exposure, Bayer has estimated exposure based on the
Theoretical Maximum Residue Contribution (TMRC). The TMRC is obtained
by using a model which multiplies the tolerance level residue for each
commodity by consumption data. The consumption data, based on the
National Food Consumption Survey data base, estimates the amount of
each commodity and products derived from the commodities that are eaten
by the U.S. population and various population subgroups.
2. Food --i. Acute. For acute dietary exposure the model calculates
a margin of exposure (MOE) by dividing the estimated human exposure
into the NOEL from the appropriate animal study. Commonly, EPA finds
MOEs lower than 100 to be unacceptable. The EPA has determined that a
NOEL of 24 mg/kg/day from a developmental toxicity study in rabbits
should be used to assess acute toxicity.
The MOE for imidacloprid derived from previously established
tolerances and pending tolerances, including IR-4's cucurbit petition,
would be 366 for the U.S. population (48 states), 323 for non-nursing
infants, 101 for children (ages 1-6 years), 420 for children (ages 7-12
years), 622 for males 13+ years, and 554 for females 13+ years at the
99.9 percentile. These MOEs do not exceed the EPA's level of concern
for acute dietary exposure.
ii. Chronic. For purposes of assessing the potential chronic
dietary exposure, the model uses the reference dose (RfD) which the EPA
has determined to be 0.057 mg/kg/day. This is based on the 2-year rat
feeding/carcinogenic study with a NOEL of 5.7mg/kg/bwt and 100-fold
uncertainty factor. In conducting this exposure assessment, very
conservative assumptions (100% of all commodities contain imidacloprid
residues and those residues are at the level of the tolerance) result
in a large overestimate of human exposure.
3. Drinking water. The EPA has determined that imidacloprid is
persistent and could potentially leach into groundwater. However, there
is no established Maximum Contamination Level (MCL) or health advisory
levels established for imidacloprid in drinking water. EPA's
``Pesticides in Groundwater Database'' has no entry for imidacloprid.
In addition, Bayer is not aware of imidacloprid being detected in any
wells, ponds, lakes, streams, etc. from its use in the U.S. In studies
conducted in 1995, imidacloprid was not detected in 17 wells on potato
farms in Quebec, Canada. Therefore, Bayer concludes that contributions
to the dietary burden from residues of imidacloprid in water would be
inconsequential.
4. Non-dietary exposure --i. Residential Tur. Bayer has conducted
an exposure study to address the potential exposures of adults and
children from contact with imidacloprid treated turf. The population
considered to have the greatest potential exposure from contact with
pesticide treated turf soon after pesticides are applied are young
children. Margins of safety (MOS) of 7,587 - 41,546 for 10-year-old
children and 6,859 - 45,249 for 5-year-old children were estimated by
comparing dermal exposure doses to the imidacloprid no-observable
effect level of 1,000 mg/kg/day established in a 15-day dermal toxicity
study in rabbits. The estimated safe residue levels of imidacloprid on
treated turf for 10-year-old children ranged from 5.6 - 38.2
g/cm2 and for 5-year-old children from 5.1 - 33.5
g/cm2. This compares with the average imidacloprid
transferable residue level of 0.080 g/cm2 present
immediately after the sprays have dried. These data indicate that
children can safely contact imidacloprid-treated turf as soon after
application as the spray has dried.
ii. Termiticide. Imidacloprid is registered as a termiticide. Due
to the nature of the treatment for termites, exposure would be limited
to that from inhalation and was evaluated by EPA's Occupational and
Residential Exposure Branch's (OREB) and Bayer. Data indicate that the
Margins of Safety for the worst case exposures for adults and infants
occupying a treated building who are exposed continuously (24 hours/
day) are 8.0 x 107 and 2.4 x 108,
respectively - and exposure can thus be considered negligible.
iii. Tobacco Smoke. Studies have been conducted to determine
residues in tobacco and the resulting smoke following treatment.
Residues of imidacloprid in cured tobacco following treatment were a
maximum of 31 ppm (7 ppm in fresh leaves). When this tobacco was burned
in a pyrolysis study only 2 percent of the initial residue was
recovered in the resulting smoke (main stream plus side stream). This
would result in an inhalation exposure to imidacloprid from smoking of
approximately 0.0005 mg per cigarette. Using the measured subacute rat
inhalation NOEL of 5.5 mg/m3, it is apparent that exposure to
imidacloprid from smoking (direct and/or indirect exposure) would not
be significant.
iv. Pet Treatment. Human exposure from the use of imidacloprid to
treat dogs and cats for fleas has been addressed by EPA's Occupational
and Exposure Branch (OREB) who have concluded that due to the fact that
imidacloprid is not an inhalation or dermal toxicant and that while
dermal absorption data are not available, imidacloprid is not
considered to present a hazard via the dermal route.
D. Cumulative Effects
No other chemicals having the same mechanism of toxicity are
currently registered, therefore, Bayer concludes that there is no risk
from cumulative effects from other substances with a common mechanism
of toxicity.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data, it can be concluded that total aggregate exposure to
imidacloprid from all current uses including those currently proposed
will utilize little more than 14.3% of the RfD for the U.S. population
from food, water and non-occupational sources. EPA generally has no
concerns 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. In addition,
the MOEs for all population groups does not exceed the EPA's level of
concern for acute dietary exposure. Thus, Bayer concludes that there is
a reasonable certainty that no harm will result from aggregate exposure
to imidacloprid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of
[[Page 9528]]
infants and children to residues of imidacloprid, the data from
developmental studies in both rat and rabbit and a 2-generation
reproduction study in the rat have been considered. The developmental
toxicity studies evaluate potential adverse effects on the developing
animal resulting from pesticide exposure of the mother during prenatal
development. The reproduction study evaluates effects from exposure to
the pesticide on the reproductive capability of mating animals through
two generations, as well as any observed systemic toxicity.
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 effects and the completeness of the
toxicity database. Based on current toxicological data requirements,
the toxicology database for imidacloprid relative to pre- and post-
natal effects is complete. Further for imidacloprid, the NOEL of 5.7
mg/kg/bwt from the 2-year rat feeding/ carcinogenic study, which was
used to calculate the RfD (discussed above), is already lower than the
NOELs from the developmental studies in rats and rabbits by a factor of
4.2 to 17.5 times. Since a 100-fold uncertainty factor is already used
to calculate the RfD, it is surmised that an additional uncertainty
factor is not warranted and that the RfD at 0.057 mg/kg/bwt/day is
appropriate for assessing aggregate risk to infants and children.
Using the conservative exposure assumptions described above under
aggregate exposure, Bayer has determined from a chronic dietary
analysis that the percent of the RfD utilized by aggregate exposure to
residues of imidacloprid ranges from 9.3% for nursing infants up to
32.2% for children (1-6 years). EPA generally has no concern for
exposure below 100 percent of the RfD. In addition, the MOEs for all
infant and children population groups do not exceed EPA's level of
concern for acute dietary exposure. Therefore, based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, Bayer concludes that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to the residues of imidacloprid, including all
anticipated dietary exposure and all other non-occupational exposures.
F. International Tolerances
No Codex Maximum Residue Levels (MRLs) have been established for
residues of imidacloprid on any crops at this time. (PM 05)
[FR Doc. 98-4803 Filed 2-24-98; 8:45 am]
BILLING CODE 6560-50-F
