[Federal Register Volume 63, Number 34 (Friday, February 20, 1998)]
[Notices]
[Pages 8635-8644]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4187]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-791; FRL-5768-9]
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 agricultural commodities.
DATES: Comments, identified by the docket control number PF-791, must
be received on or before March 23, 1998.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information 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 by 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: By mail: James A. Tompkins, Product
Manager (PM) 25, Registration Division, (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Rm. 239, 1921 Jefferson
Davis Hwy., Arlington, VA., (703) 305-5697; e-mail:
Tompkins.jim@epamail.epa.gov.
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
agricultural 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-791 (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.
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
[[Page 8636]]
pests, Reporting and recordkeeping requirements.
Dated: February 12, 1998.
Donald R. Stubbs,
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 parts per billion (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="" milligrams/kilograms/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 hr 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 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
[[Page 8637]]
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:="" ------------------------------------------------------------------------="" exposure="" (mg/kg="" bw/="" population="" subgroup="" 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="" 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="" [[page="" 8638]]="" 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
six-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.="" 2.="" e.i.="" du="" pont="" de="" nemours="" &="" company="" pp="" 6f4706="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 6f4706)from="" e.i.="" du="" pont="" de="" nemours="" &="" company,="" barley="" mill="" plaza,="" p.o.="" box="" 80038,="" willimington,="" 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="" a="" tolerance="" for="" residues="" of="" rimsulfuron:="" n-((4,6-="" dimethoxypyrimidin-2-yl)="" aminocarbonyl)="" -3-="" (ethylsulfonyl)="" -2-="" pyridinesulfonamide="" in="" or="" on="" the="" raw="" agricultural="" commodity="" tomato="" fruit="" at="" 0.10="" parts="" per="" million.="" 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.="" with="" the="" initial="" establishment="" of="" rimsulfuron="" tolerances="" in="" field="" corn="" and="" potatoes,="" the="" epa="" determined="" that="" the="" nature="" of="" plant="" residues="" was="" adequately="" understood="" for="" the="" purposes="" establishing="" those="" tolerances.="" a="" metabolism="" study="" on="" tomatoes="" was="" conducted="" at="" the="" following="" use="" rates:="" ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------="" ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------="" tomatoes="" grown="" in="" field..........="" 72="" g="" active="" ingredient="" per="" hectare="" (approx.="" 1="" oz.="" ai="" per="" acre,="" maximum="" proposed="" use="" rate).="" tomatoes="" grown="" in="" greenhouse.....="" 172,="" 350,="" and="" ca.="" 700="" g="" ai="" per="" hectare="" (2.5,="" 5,="" and="" 10="" oz.="" ai="" per="" acre="" or="" up="" to="" 10="" times="" the="" proposed="" maximum="" use="" rate).="" ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------="" [[page="" 8639]]="" no="" residues="" of="" rimsulfuron="" or="" any="" metabolite="" were="" detected="" in="" any="" tomato="" fruit,="" immature="" or="" mature.="" detection="" limits="" for="" the="" study="" were="" 0.004="" ppm="" for="" the="" field-grown="" samples="" and="" 0.013="" ppm="" for="" the="" greenhouse-="" grown="" samples.="" this="" study="" conclusively="" shows="" that="" application="" of="" rimsulfuron="" to="" tomatoes,="" when="" used="" in="" accordance="" with="" the="" proposed="" label="" directions,="" will="" not="" result="" in="" detectable="" residue="" of="" rimsulfuron="" or="" its="" metabolites="" in="" tomato="" fruit.="" therefore,="" the="" nature="" of="" rimsulfuron="" residues="" (i.e.,="" their="" absence)="" has="" been="" established="" for="" tomato="" fruit,="" the="" only="" raw="" agricultural="" commodity="" established="" for="" tomatoes.="" 2.="" analytical="" method.="" adequate="" analytical="" methodology,="" high-="" pressure="" liquid="" chromatography="" with="" uv="" detection,="" is="" available="" for="" enforcement="" purposes.="" the="" method="" is="" ``analytical="" method="" for="" the="" quantitiation="" of="" dpx-e9636="" (rimsulfuron)="" in="" various="" crop="" matrices="" and="" their="" processed="" fractions'',="" dupont="" report="" no.="" amr="" 3424-95,="" epa="" mrid="" no.="" 43979002.="" the="" method="" involves="" liquid="" chromatography="" utilizing="" eluent="" and="" column="" switching="" with="" uv/vis="" detection="" at="" 254="" nm.="" the="" limit="" of="" quantitation="" for="" rimsulfuron="" in="" tomatoes="" is="" 0.05="" ppm.="" epa="" offers="" enforcement="" methodology="" to="" anyone="" interested="" in="" pesticide="" enforcement="" when="" requested="" by="" mail="" from:="" calvin="" furlow,="" public="" response="" and="" program="" resources="" branch,="" field="" operations="" division="" (7506c),="" office="" of="" pesticide="" programs,="" environmental="" protection="" agency,="" 401="" m="" st.,="" sw.,="" washington,="" dc="" 20460.="" office="" location="" and="" telephone="" number:="" rm.="" 1130a,="" cm#2,="" 1921="" jefferson="" davis="" hwy.,="" arlington,="" va="" 22202.="" 3.="" magnitude="" of="" residues.="" --i.="" plant="" residues.="" magnitude="" of="" residues="" of="" rimsulfuron="" in="" tomato="" fruit="" were="" determined="" following="" application="" of="" rimsulfuron="" at="" the="" proposed="" maximum="" annual="" use="" rate="" of="" 1.0="" oz="" ai/acre="" (1="" x="" ),="" and="" at="" twice="" that="" rate="" (2="" x="" ).="" an="" additional="" test="" was="" conducted="" at="" an="" exaggerated="" rate="" of="" 5.0="" oz="" ai/acre="" (5="" x="" )="" in="" an="" attempt="" to="" generate="" quantifiable="" residues="" in="" tomato="" fruit="" (rac)="" for="" a="" processing="" study.="" seventeen="" tests,="" each="" containing="" one="" control="" and="" two="" treatment="" plots,="" were="" established="" in="" california,="" florida,="" indiana,="" maryland,="" and="" pennsylvania.="" row-crop="" tomato="" samples="" were="" collected="" approximately="" 45="" days="" following="" the="" final="" application;="" staked="" tomatoes="" were="" collected="" immediately="" following="" the="" final="" application.="" tomato="" samples="" were="" analyzed="" using="" the="" procedures="" described="" in="" dupont="" method="" no.="" amr="" 3424-="" 95,="" analytical="" method="" for="" the="" quantitation="" of="" dpx-e9636="" in="" various="" crop="" matrices="" and="" their="" processed="" fractions.="" the="" overall="" mean="" percent="" recovery="" of="" 52="" control="" tomato="" samples="" fortified="" at="" either="" 0.05="" or="" 0.10="" ppm="" was="" 86%,="" with="" a="" relative="" standard="" deviation="" of="" 4%.="" results="" of="" freezer="" storage="" stability="" study="" indicate="" that="" rimsulfuron="" is="" stable="" up="" to="" 6="" months="" in="" tomatoes="" stored="" at="" -20c="" +/-="" 5c.="" no="" quantifiable="" residues=""><0.05 ppm)="" of="" rimsulfuron="" were="" found="" in="" any="" of="" the="" tomato="" samples="" treated="" at="" 1.0,="" 2.0,="" and="" 5.0="" oz="" ai/acre.="" a="" processing="" study="" was="" not="" necessary="" since="" all="" 1="" x="" and="" 5="" x="" samples="" did="" not="" have="" rimsulfuron="" present="" with="" a="" limit="" of="" quantitation="" of="" 0.05="" ppm.="" data="" generated="" from="" this="" study="" support="" the="" use="" of="" rimsulfuron="" on="" tomatoes="" at="" a="" maximum="" seasonal="" use="" rate="" of="" 1.0="" oz="" ai/acre="" with="" a="" minimum="" preharvest="" interval="" of="" 45="" days.="" study="" results="" also="" support="" the="" petition="" for="" a="" 0.10="" ppm="" tolerance="" of="" rimsulfuron="" on="" tomatoes.="" ii.="" animal="" residues.="" epa="" determined,="" upon="" granting="" field="" corn="" and="" potato="" tolerances,="" that="" there="" is="" no="" reasonable="" expectation="" of="" residues="" occurring="" in="" meat,="" milk,="" poultry,="" or="" eggs="" from="" these="" tolerances.="" tomato="" fruit="" and="" its="" processed="" commodities="" (i.e.,="" tomato="" paste="" and="" puree)="" are="" not="" considered="" by="" the="" epa="" to="" be="" animal="" feed="" items.="" further,="" no="" residues="" would="" be="" available="" to="" enter="" animal="" feed="" based="" on="" results="" from="" the="" tomato="" metabolism="" study="" and="" magnitude="" or="" residue="" study="" discussed="" above.="" therefore,="" there="" remains="" a="" reasonable="" expectation="" that="" no="" residue="" of="" rimsulfuron="" will="" occur="" in="" meat,="" milk,="" poultry,="" or="" eggs="" from="" all="" rimsulfuron="" tolerances,="" current="" (field="" corn="" and="" potatoes)="" and="" proposed="" (tomatoes).="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" technical="" rimsulfuron="" has="" been="" placed="" in="" acute="" toxicology="" category="" iii="" based="" on="" overall="" results="" from="" several="" studies.="" this="" compound="" was="" placed="" in="" toxicology="" category="" iii="" for="" acute="" dermal="" toxicity="">50 > 2,000 mg/kg; rabbits) and eye irritation
(effects reversible within 72 hours; rabbits). Acute oral toxicity
(LD50 > 5,000 mg/kg; rats), acute inhalation toxicity
(LC50 > 5.4 mg/L, rats) and skin irritation (no observed
irritation; rabbits) results were assigned toxicology category IV.
Technical rimsulfuron is not a dermal sensitizer.
2. Genotoxicty. Technical rimsulfuron was negative for genotoxicity
in a battery of in vitro and in vivo tests. These tests included the
following: mutagenicity in bacterial (Ames test) and mammalian (CHO/
HGPRT assay) cells; in vitro cytogenetics (chromosomal aberration in
human lymphocytes); in vivo cytogenetics (bone marrow micronucleus
assay in mice); and unscheduled DNA synthesis in rat primary
hepatocytes.
3. Reproductive and developmental toxicity. A two-generation
reproduction study was conducted in rats with dietary technical
rimsulfuron concentrations of 0, 50, 3,000 or 15,000 ppm. The study was
negative for reproductive toxicity and there was no indication that
offspring were more susceptible to rimsulfuron administration than
parents. The NOEL was 3,000 ppm (or 165 to 264 mg/kg/day for P1 and F1
males and females and their offspring). This was based on the following
effects at 15,000 ppm (830 to 1,316 mg/kg/day): lower food consumption
and/or food efficiency in P1 males and females and F1 females;
decreased mean body weights and/or body weight gain by P1 and F1 males
and females; lower mean body weights and increased incidence of small
body size for F2 pups during lactation.
A developmental study was conducted in rats administered technical
rimsulfuron by gavage at 0, 200, 700, 2,000 or 6,000 mg/kg/day. There
were no systemic or developmental effects observed up to and including
the highest dose tested. The NOEL was therefore > 6,000 mg/kg/day.
A developmental study was conducted in rabbits administered
technical rimsulfuron by gavage at 0, 25, 170, 500 or 1,500 mg/kg/day.
The NOELs for maternal and offspring toxicity were 170 and 500 mg/kg/
day, respectively. The maternal NOEL was based on reduced body weight
and mortality at higher doses. These maternal effects precluded any
evaluation of adverse effects in fetuses at 1,500 mg/kg/day; however,
there were no systemic or developmental effects observed among fetuses
at 500 mg/kg/day and below.
4. Subchronic toxicity. A 90-day study in mice was conducted at
dietary concentrations of 0, 50, 375, 1,500 or 7,500 ppm. The NOELs
were 375 ppm (56.0 mg/kg/day) for male mice and 7,500 ppm (1,575 mg/kg/
day) for female mice. The NOEL for males was based on slight reductions
in mean body weight gain and food efficiency at 1,500 ppm (228 mg/kg/
day).
Technical rimsulfuron was administered in the diets of rats at 0,
50, 1,500, 7,500 or 20,000 ppm for 90 days. The NOEL was 1,500 ppm (102
and 120 mg/kg/day for males and females, respectively) based on reduced
mean body weights and body weight gains and increased relative liver
weights at
[[Page 8640]]
7,500 ppm (495 and 615 mg/kg/day for males and females, respectively).
Dogs were administered technical rimsulfuron in their diets at 0,
250, 5,000 or 20,000 ppm for 90 days. The NOEL was 250 ppm (9.63 and
10.6 mg/kg/day for males and females, respectively). This was based on
slight increases in liver and/or kidney weights, increased urine volume
and decreased urine osmolarity at 5,000 ppm (193 and 189 mg/kg/day for
males and females, respectively).
5. Chronic toxicity. An 18-month mouse study was conducted with
dietary concentrations of 0, 25, 250, 2,500 or 7,500 ppm technical
rimsulfuron. This product was not oncogenic in mice. The systemic NOEL
was 2,500 ppm (351 and 488 mg/kg/day for males and females,
respectively) based on decreased mean body weights in both sexes and
increased incidence of spontaneous, age-related artery and tunica
degeneration in the testes for this mouse strain at the highest dose
tested, 7,500 ppm (1,127 and 1,505 mg/kg/day for males and females,
respectively). The latter was observed in the absence of any effect on
spermatogenesis. An increased incidence of dilation and cysts in the
glandular stomach of males was also observed at 7,500 ppm.
A 2-year chronic toxicity/oncogenicity study was conducted in rats
fed diets that contained 0, 25, 300, 3,000 or 10,000 ppm technical
rimsulfuron. This product was not oncogenic in rats. The systemic NOELs
were 300 ppm (11.8 mg/kg/day) for males and 3,000 ppm (163 mg/kg/day)
for females. The NOELs were defined by decreased body weight gain and
increased relative liver weights at 3,000 ppm (121 mg/kg/day) and
10,000 ppm (569 mg/kg/day) for males and females, respectively.
Technical rimsulfuron was administered for one year to dogs at
dietary concentrations of 0, 50, 2,500 or 10,000 ppm. The NOELs were 50
ppm (1.6 mg/kg/day) for males and 2,500 ppm (86.5 mg/kg/day) for
females. The NOEL for males was based on the following effects observed
at 2,500 ppm (81.8 mg/kg/day): increased absolute liver and kidney
weights; and increased incidence of seminiferous tubule degeneration
and increased numbers of spermatid giant cells present in the
epididymides. The NOEL for females was based on the following effects
observed at 10,000 ppm (358.5 mg/kg/day): decreased body weight and
body weight gain; increased serum cholesterol levels and alkaline
phosphatase activity, increased absolute liver weight and increased
relative liver and kidney weights.
6. Animal metabolism. The metabolism of rimsulfuron in animals
(rat, goat and hen) is adequately understood and is similar among the
species evaluated. Rimsulfuron was rapidly eliminated via urinary and
fecal excretion in the rat. Approximately 60 to 70% of the administered
dose to rats was excreted within 24 hours. There were no volatile
metabolites detected and unmetabolised rimsulfuron was the major
component in the urine (42 - 55%) and feces (5 - 16%). The major
metabolic pathway in rats involved a contraction of the sulfonylurea
bridge followed by dealkylation, hydroxylation and/or conjugation
reactions. Cleavage of the sulfonylurea bridge was observed; however,
it was considered to be a minor pathway. Elimination of administered
rimsulfuron was similarly rapid for the goat and hen. Tissue residue
levels were generally less than 0.3% of the administered dose for the
rat, goat and hen. There was no evidence of accumulation of rimsulfuron
or its metabolites in tissues of any of the species or in milk and
eggs.
7. Metabolite toxicology. Common metabolic pathways for rimsulfuron
were demonstrated in the rat, goat and hen as well as plants (corn,
tomatoes and potatoes). When evaluated for acute toxicity and
mutagenicity, two of the major metabolites, i.e., one resulting from
contraction of the sulfonylurea bridge and one from the cleavage of
this bridge, were found to be of low toxicity and were negative in the
Ames test. The existing metabolism studies indicate that the
metabolites formed are unlikely to accumulate in humans or in animals
that may be exposed to these residues in the diet. The fact that no
quantifiable residues were found in treated crops further indicates
that exposures to and accumulation of metabolites are unlikely. Because
of the above, toxicology studies on metabolites were not required.
C. Aggregate Exposure
1. Dietary exposure -- Residue of concern. When tolerances were
established on field corn and potatoes, EPA determined that the residue
of concern was rimsulfuron. The metabolism study conducted on tomatoes
(see Plant Metabolism Section) showed no residues of rimsulfuron are
present in the tomato fruit. Therefore, the residue of concern
continues to be rimsulfuron.
2. Food. For the general U.S. population, acute dietary exposure
assessments were not considered relevant for rimsulfuron for the
following reasons: rimsulfuron presents very low acute toxicity based
on animal testing; and no detectable residues have been demonstrated in
edible portions of treated crops.
The Agency has conducted chronic dietary exposure assessments for
rimsulfuron and the results are summarized below. The Reference Dose
(RfD) is based on a NOEL of 1.6 mg/kg/day established in the 1-year
feeding study with dogs and combines an uncertainty factor of 100. EPA
calculated the RfD to be 0.016 mg/kg/day. The theoretical maximum
residue contribution (TMRC) for these tolerances for the overall U.S.
population is 1.47 x 10-4 mg/kg/day or 0.92% of the RfD
based on current (field corn and potatoes) tolerances and would be 2.21
x 10-4, or 1.4% of the RfD when the proposed tolerance on
tomatoes is included.
For infants and children, the TMRC for the most exposed subgroup,
children (1 to 6 years old), is 2.37 x 10-4 mg/kg/day,
respectively, or 1.95% of the RfD based on current (field corn and
potatoes) tolerances and would be 4.37 x 10-4 mg/kg/day,
or 2.73% of the RfD, when the proposed tomato tolerance is included. As
with calculations for the general US population, these values assume
the residues are at the established tolerance level and that 100
percent of the crop is treated.
3. Drinking water. Another potential dietary source of exposure of
the general population to residues of pesticides is residues in
drinking water. There have been no field studies or monitoring programs
conducted to assess rimsulfuron residues in groundwater or drinking
water. Several factors indicate very low potential that rimsulfuron
will be present in raw or finished drinking water: low use rate (1 oz
a.i./acre), rapid hydrolysis (half-life < 7="" days),="" short="" half-lives="" under="" field="" conditions="" (7-18="" days),="" absence="" of="" leaching="" in="" field="" soil="" dissipation="" studies.="" water="" solubility="" for="" rimsulfuron="" is="" as="" follows:="" [[page="" 8641]]="" ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------="" ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------="" unbuffered="" water:...........................="">< 10="" ppm="" buffers:....................................="" ph="" 5="" 135="" ppm="" ..........................................="" ph="" 7="" 7,300="" ppm="" ..........................................="" ph="" 9="" 5,560="" ppm="" (rapidly="" decomposes="" at="" ph="" 9);="">oc is less than 100.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Computer modeling, taking into account use rate, physical
properties, and degradation rates, predicts low probability of
rimsulfuron being present in ground- or drinking water. Given that only
2.73% of the RfD is attained by the TMRC for the population sub-group
with the highest theoretical dietary exposure (children 1-6 years old;
see above), there is ample allowance for safe exposure to rimsulfuron
via drinking water.
4. Non-dietary exposure. Rimsulfuron is not registered for any use
which could result in non-occupational, or non-dietary exposure to the
general population.
D. Cumulative Effects
Rimsulfuron belongs to the sulfonylurea class of crop protection
chemicals. Other structurally similar compounds in this class are
registered herbicides. However, the herbicidal activity of
sulfonylureas is due to the inhibition of acetolactate synthase (ALS),
an enzyme found only in plants. This enzyme is part of the biosynthesis
pathway leading to the formation of branched chain amino acids. Animals
lack ALS and this biosynthetic pathway. This lack of ALS contributes to
the relatively low toxicity of sulfonylurea herbicides in animals.
There is no reliable information that would indicate or suggest that
rimsulfuron has any toxic effects on mammals that would be cumulative
with those of any other chemical.
E. Safety Determination
1. U.S. population. Based on the completeness and reliability of
the toxicology database and using the conservative assumptions
presented earlier, EPA has established an RfD of 0.016 mg/kg/day. This
was based on the NOEL for the 1-year dog study of 1.6 mg/kg/day and
employed a 100-fold uncertainty factor. It has been concluded that the
aggregate exposure for existing crops (corn and potatoes) would utilize
0.92% of the RfD and that the addition of tomatoes would increase
utilization to 1.4% 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 rimsulfuron
residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of rimsulfuron, data
from the previously discussed developmental and multigeneration
reproductive toxicity studies were considered.
Developmental studies are designed to evaluate adverse effects on
the developing organism resulting from pesticide exposure during pre-
natal development. Reproduction studies provide information relating to
reproductive and other effects on adults and offspring from pre-natal
and post-natal exposures to the pesticide. The studies with rimsulfuron
demonstrated no evidence of developmental toxicity at exposures below
those causing maternal toxicity. This indicates that developing animals
are not more sensitive to the effects of rimsulfuron administration
than adults.
FFDCA section 408 provides that EPA may apply an additional
uncertainty 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 current toxicological data
requirements, the database for rimsulfuron relative to pre- and post-
natal effects for children is complete. In addition, the NOEL of 1.6
mg/kg/day in the 1-year dog study and upon which the RfD is based is
much lower than the NOELs defined in the reproduction and developmental
toxicology studies. Conservative assumptions utilized to estimate
aggregate dietary exposures of infants and children to rimsulfuron
demonstrated that only 1.95% of the RfD was utilized for current
tolerances (corn and potatoes) and the addition of tomatoes would only
increase utilization to 2.73% of the RfD for the highest exposed group.
Based on these exposure estimates and the fact that the current
database demonstrates that the developing offspring or young animals
are not uniquely susceptible to rimsulfuron administration, the extra
10-fold uncertainty factor is not warranted for these groups.
Therefore, it may be concluded that there is reasonable certainty that
no harm will result to infants and children from aggregate exposures to
rimsulfuron.
F. International Tolerances
The following international tolerances (or Maximum Residue Levels,
MRL's) exist:
----------------------------------------------------------------------------------------------------------------
Country Tolerance in ppm Crop
----------------------------------------------------------------------------------------------------------------
Australia 0.05 Tomatoes
Austria 0.1 Corn, Potato
Belgium 0.05 Corn
Bulgaria 0.5 Corn-Fodder
Canada 0.1 Corn, Potato
Croatia 0.1 Fodder
Czech. Rep. 0.05 Corn, Grain, Potato
Germany 0.05 Corn, Potato
Hungary 0.2 Corn
Italy 0.10 Corn, Potato, Tomatoes
Romania 0.05 Corn, Potato
[[Page 8642]]
Slovakia 0.05 Corn, Grain
Spain 0.05 Corn, Tomatoes
United States 0.1 Corn, Potato
----------------------------------------------------------------------------------------------------------------
3. Monsanto Company
PP 2E4118 and 7F4886
EPA has received a pesticide petitions (PP 2E4118 and 7F4886) from
Monsanto Company, 700 14th St.,NW., Suite 1100, Washington, D.C. 20005,
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 to establish
an exemption from the requirement of a tolerance for glyphosate [(N-
phosphonomethyl) glycine] in or on the imported raw agricultural
commodities barley grain at 20 parts per million (ppm); barley, bran
and pearled barley at 60 ppm; cereal grains group (except wheat, corn,
oats, grain sorghum, and barley at 0.1 ppm; canola, seed at 10 ppm;
canola, meal at 25 ppm; legume vegetables (succulent or dried) group
(except soybeans) at 5 ppm. (PP 2E4118) and in or on the raw
agricultural commodities beets, sugar, tops (leaves) at 10 ppm; beets,
sugar, root at 10 ppm; and beets, sugar, pulp, dried at 25 ppm (PP
7F4886). 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 residue in plants is
adequately understood and consists of the parent, glyphosate and its
metabolite AMPA (aminomethyl-phosphonic acid). Only glyphosate parent
is to be regulated in plant and animal commodities since the metabolite
AMPA is not of toxicological concern in food.
2. Analytical method. Adequate methodology High Pressure Liquid
Chromatograpy (HPLC) with fluorometric detection is available for
enforcement purposes, and the methodology has been published in the
Pesticide Analytical Manual (PAM), Vol. II. This method has a limit of
detection (0.05 ppm) that allows monitoring of food with residues at or
above the levels set in these tolerances.
3. Magnitude of residues. The submitted residue data adequately
support the proposed tolerances on Barley, grain (20 ppm); Barley, bran
and pearled barley (60 ppm); Canola, seed (10 ppm); Canola, meal (25
ppm); and Legume vegetables (succulent or dried) group (except
soybeans) (5 ppm), Sugar beet roots at 10 ppm, Sugar beet tops at 10
ppm and Sugar beet dried pulp at 25 ppm. Any secondary residues
occurring in liver or kidney of cattle, goats, horses, and sheep and
liver and kidney of poultry will be covered by existing tolerances.
B. Toxicological Profile
1. Acute toxicity. A rat acute oral study with a combined
LD50 of > 5000 mg/kg.
A rabbit acute dermal LD50 of > 5000 mg/kg.
A primary eye irritation study in the rabbit which showed severe
irritation for glyphosate acid. However, glyphosate is normally
formulated as one of several salts and eye irritation studies on the
salts showed essentially no irritation.
A primary dermal irritation study which showed essentially no
irritation.
A primary dermal sensitization study which showed no sensitization.
2. Genotoxicty. A number of mutagenicity studies were conducted and
were all negative. These studies included: chromosomal aberration in
vitro (no aberrations in Chinese hamster ovary cells were caused with
or without S9 activation); DNA repair in rat hepatocyte; in vivo bone
marrow cytogenic test in rats; rec-assay with B. subtilis; reverse
mutation test with S. typhimurium; Ames test with S. typhimurium; and
dominant-lethal mutagenicity test in mice.
3. Reproductive and developmental toxicity. An oral developmental
toxicity study with rats given doses of 0, 300, 1,000 and 3,500 mg/kg/
day with a maternal no observable effect level (NOEL) of 1,000 mg/kg/
day based on clinical signs of toxicity, body weight effects and
mortality, and a fetal NOEL of 1,000 mg/kg/day based on reduced body
weights and delayed sternebrae maturation at the highest dose tested of
3,500 mg/kg/day.
An oral developmental toxicity study with rabbits given doses of 0,
75, 175 and 350 mg/kg/day with a maternal of NOEL of 175 mg/kg/day
based on clinical signs of toxicity and mortality, and a fetal NOEL of
350 mg/kg/day based on no developmental toxicity at any dose tested.
A 3-generation reproduction study with rats fed dosage levels of 0,
3, 10 and 30 mg/kg/day with a NOEL for systemic and reproductive/
developmental parameters of 30 mg/kg/day based on no adverse effects
noted at any dose level.
A 2-generation reproduction study with rats fed dosage levels of 0,
100, 500 and 1,500 mg/kg/day with a NOEL for systemic and developmental
parameters of 500 mg/kg/day based on body weight effects, clinical
signs of toxicity in adult animals and decreased pup bodyweights, and a
reproductive NOEL of 1,500 mg/kg/day.
4. Subchronic toxicity. A 90-day feeding study in rats fed dosage
levels of 0, 1,000, 5,000 and 20,000 ppm with a NOEL of 20,000 ppm
based on no effects even at the highest dose tested.
A 90-day feeding study in mice fed dosage levels of 0, 5,000,
10,000 and 50,000 with a NOEL of 10,000 ppm based on body weight
effects at the high dose.
A 90-day feeding study in dogs given glyphosate, via capsule, at
doses of 0, 200, 600 and 2,000 mg/kg/day with a NOEL of 2,000 mg/kg/day
based on no effects even at the highest dose tested.
5. Chronic toxicity. A 12-month oral study in dogs given
glyphosate, via capsule, at doses of 0, 20, 100 and 500 mg/kg/day with
a NOEL of 500 mg/kg/day based on no adverse effects at any dose level.
A 26-month chronic/feeding oncogenicity study with rats fed dosage
levels of 0, 3, 10 and 31 mg/kg/day (males) and 0, 3, 11 and 34 mg/kg/
day (females) with a systemic NOEL of 31 mg/kg/day (males) and 34 mg/
kg/day (females) based on no carcinogenic or other adverse effects at
any dose level.
A 24-month chronic/feeding oncogenicity study with rats fed dosage
levels of 0, 89, 362 and 940 mg/kg/day (males) and 0, 113, 457 and
1,183 mg/kg/day (females) with a systemic NOEL of 362 mg/kg/day based
on body weight
[[Page 8643]]
effects in the female and eye effects in males. There was no
carcinogenic response at any dose level.
6. Carcinogenicity. A mouse oncogenicity study with mice fed dosage
levels of 0, 150, 750 and 4,500 mg/kg/day with a NOEL of 750 mg/kg/day
based on body weight effects and microscopic liver changes at the high
dose. There was no carcinogenic effect at the highest dose tested of
4,500 mg/kg/day.
Glyphosate is classified as a Group E (evidence of non-
carcinogenicity for humans), based upon lack of convincing
carcinogenicity evidence in adequate studies in two animal species.
This classification is based on the following findings: (1) There were
no tumor findings in the chronic testing that were determined to be
compound related; (2) glyphosate was tested up to the limit dose on the
rat and up to levels higher than the limit dose in mice; and (3) there
is no evidence of genotoxicity for glyphosate.
7. Animal metabolism. The nature of the residue in animals is
adequately understood and consists of the parent, glyphosate and its
metabolite AMPA (aminomethyl-phosphonic acid).
8. Metabolite toxicology. Only glyphosate parent is to be regulated
in plant and animal commodities since the metabolite AMPA is not of
toxicological concern in food.
9. Endocrine disruption. The toxicity studies required by EPA for
the registration of pesticides measure numerous endpoints with
sufficient sensitivity to detect potential endocrine-modulating
activity. No effects have been identified in subchronic, chronic or
developmental toxicity studies to indicate any endocrine-modulating
activity by glyphosate. In addition, negative results were obtained
when glyphosate was tested in a dominant-lethal mutation assay. While
this assay was designed as a genetic toxicity test, agents that can
affect male reproduction function will also cause effects in this
assay. More importantly, the multi-generation reproduction study in
rodents is a complex study design which measures a broad range of
endpoints in the reproductive system and in developing offspring that
are sensitive to alterations by chemical agents. Glyphosate has been
tested in two separate multi-generation studies and each time the
results demonstrated that glyphosate is not a reproductive toxin.
C. Aggregate Exposure
1. Dietary exposure -- Food. For purposes of assessing the
potential exposure under these tolerances, dietary exposure was
estimated based on the Theoretical Maximum Residue Contribution (TMRC)
from the all present tolerances for glyphosate and the additional
exposure that could result if the proposed tolerances are established
on barley grain at 20 ppm, barley bran and pearled barley at 60 ppm,
canola seed at 10 ppm, canola meal at 25 ppm, legume vegetables
(succulent or dried) group (except soybeans) at 5 ppm, sugar beet roots
at 10 ppm, sugar beet tops at 10 ppm and sugar beet dried pulp at 25
ppm. The TMRC is obtained by multiplying the tolerance level residue
for each food commodity by the consumption data which estimates the
amount of those products eaten by various population subgroups. In
conducting this exposure assessment, very conservative assumptions were
made -- 100% of these crops will contain glyphosate residues and those
residues would be at the level of the tolerance -- which result in an
overestimate of human exposure. Thus, in making a safety determination
for these tolerances, EPA is taking into account this conservative
exposure assessment.
Secondary residues in animal commodities may occur from these uses
through the feeding of barley grain and canola meal to livestock. Since
these proposed tolerances do not arise from changes in U.S.
registrations involving the use of glyphosate herbicides on barley,
canola, or legume vegetables, it has been concluded that livestock feed
items derived from these crops are not likely to enter channels of
trade in the United States. Based on these considerations and the
results of animal feeding studies and the amount of glyphosate residues
expected in animal feeds, EPA has concluded that there is no reasonable
expectation that such secondary residues of glyphosate will exceed
existing tolerances in edible animal products.
2. Drinking water. In examining aggregate exposure, FQPA directs
EPA to consider available information concerning exposures from the
pesticide residue via drinking water. The lifetime health advisory and
maximum contaminant level (MCL), for glyphosate are both 700 parts per
billion in the EPA Office of Drinking Water`s ``Drinking Water Health
Advisory; Pesticides.'' The MCL represents the level at which no known
or anticipated adverse health effects will occur, allowing for an
adequate margin of safety, and is based on the reference dose (RfD).
Environmental Fate data for glyphosate indicate little potential for
the chemical to migrate to drinking. Glyphosate is not highly mobile
and not persistent in a soil or water environment. Because the Agency
lacks sufficient water-related exposure data to complete a
comprehensive drinking water risk assessment for many pesticides, EPA
has commenced and nearly completed a process to identify a reasonable
yet conservative bounding figure for the potential contribution of
water related exposures to the aggregate risk posed by a pesticide. In
developing the bounding figure, EPA estimated residue levels in water
for a number of specific pesticides using various data sources. The
Agency then applied the estimated residue levels, in conjunction with
appropriate toxicological endpoints (RfDs or acute dietary NOELs) and
assumptions about body weight and consumption, to calculate, for each
pesticide, the increment of aggregate risk contributed by consumption
of contaminated water. While EPA has not yet pinpointed the appropriate
bounding figure for consumption of contaminated water, the ranges the
Agency is continuing to examine are all below the level that would
cause glyphosate to exceed the RfD if the tolerances being considered
in this document were granted. The Agency has therefore concluded that
the potential exposures associated with glyphosate in water, even at
higher levels the Agency may consider a conservative upper bound, would
not prevent the Agency from determining that there is a reasonable
certainty of no harm if the tolerance is granted.
3. Non-dietary exposure. Glyphosate is registered for use on non-
food sites such as around ornamental, shade trees, shrubs, walks,
driveways, flowerbeds, home lawns, farmsteads including building
foundations, along and in fences, in dry ditches and canals, along
ditchbanks, farm roads, shelterbelts, forestry, Christmas trees, and
industrial sites and other non-crop or industrial areas such as
airports, lumber yards, manufacturing sites, utility substations,
parking areas, petroleum tank farms, and pumping station.
Margins of Exposure (MOEs) are determined for non-dietary exposure
based on toxicological endpoints and measured or estimated exposures.
Since glyphosate is a class E chemical (evidence of non-carcinogenicity
for humans), the 21 day dermal study lacked any observable effects at
the limit dose, and no adverse effects were observed in developmental
toxicity studies in rats up to 1,000 mg/kg/day and rabbits up to 175
mg/kg/day, no toxicological endpoints are applicable. Because available
data indicated no evidence of significant toxicity via the dermal or
inhalations routes, MOEs were not calculated and risk
[[Page 8644]]
assessments are not required for non-occupational (residential uses).
D. Cumulative Effects
EPA does not have, at this time, available data to determine
whether glyphosate has a common mechanism of toxicity with other
substances or how to include it in a cumulative risk assessment. Unlike
other pesticides for which EPA has followed a cumulative risk approach
based on common mechanism of toxicity, glyphosate does not produce a
toxic metabolite which is common to other substances. For the purposes
of this tolerance action, therefore EPA has assumed that glyphosate
does not have a common mechanism of toxicity with other substances. A
condition of the registrations associated with these tolerances will be
that the registrant will provide common mechanism data in a timely
manner when and if the Agency asks for it. After EPA develops
methodologies for more fully applying common mechanism of toxicity
issues to risk assessments, the Agency will develop a process to
reexamine those tolerance decisions made earlier.
E. Safety Determination
1. U.S. population --i. Acute dietary exposure. Based on the
available acute toxicity data, glyphosate does not pose any acute
dietary risks, and an acute dietary risk assessment is not required.
ii. Chronic dietary exposure. Using the TAS Exposure 1 software and
1977-78 consumption data, a chronic dietary exposure estimate was based
on 100% of the crops treated and all residues at tolerance levels to
provide the TMRC. Based this assessment the combined new proposed
tolerances contribute dietary exposure equal to 0.36% of the RfD for
U.S. population and 0.69% of the RfD for non- nursing infants under 1
year old. Total estimated dietary exposure from glyphosate residues in
food, taking into account both existing and these proposed uses will be
1.4% of the RfD for the overall U.S. population and 3.1% of the RfD for
non- nursing infants, the most highly exposed population subgroup. An
additional risk assessment for residential uses was not required
because of no evidence of significant toxicology via dermal or
inhalation routes. Even though an appropriate bounding figure for
consumption of contaminated water has not been determined, the ranges
being examine are all below the level that would cause glyphosate to
exceed the RfD. Generally there is no concern for exposures below 100
percent of the RfD. Therefore, based on the completeness and
reliability of the toxicity data and the conservative exposure
assessment, there is reasonable certainty that no harm will occur from
aggregate exposure to glyphosate.
2. Infants and children. FFCDA section 408 provides that an
additional tenfold margin of exposure (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 unless it is determined
that a different margin of exposure (safety) will be safe for infants
and children. Monsanto believes that reliable data support using the
standard margin of exposure (usually 100 x for combined inter- and
intra-species variability) without the additional tenfold margin of
exposure when a complete data base under existing guidelines exists and
when the nature of the findings from these studies do not raise
concerns regarding the adequacy of the standard margin of exposure.
The toxicological database for evaluating pre- and post-natal
toxicity for glyphosate is considered to be complete at this time. Risk
to infants and children for glyphosate was determined by the use of two
developmental toxicity studies in rats and rabbits and a two-generation
reproduction study in rats. The developmental toxicity studies
evaluates the potential for adverse effects on the developing organism
resulting from exposure during prenatal development. The reproduction
study provides information relating to effects from exposure to the
chemical on the reproductive capability of both (mating) parents and on
systemic toxicity, in addition to information on prenatal development.
The results of these studies indicate that glyphosate does not produce
birth defects and is not a reproductive toxin.
In the rabbits, no developmental toxicity was observed at the
highest dose tested (HDT) where significant maternal toxicity occurred
(death and clinical signs at 350 mg/kg/day, highest dose tested HDT).
Because no developmental toxicity was observed at any dose level, the
developmental NOEL is considered to be 350 mg/kg/day. In the rat
developmental toxicity study, severe maternal (systemic) and
developmental toxicity was noted at 3,500 mg/kg/ day HDT. The HDT in
this study was 3.5 times higher than the limit dose that is currently
required by the guidelines. The maternal and developmental (pup) NOEL
was 1,000 mg/kg/day. No effects on reproductive parameters were
observed.
In the rat 2-generation reproduction study, parental toxicity was
observed at 1,500 mg/kg/day as soft stools, decreased food consumption
and body weight gain; therefore, the systemic NOEL is considered to be
500 mg/kg/day. Developmental (pup) toxicity was also only exhibited at
1,500 mg/kg/day as decreased body weight gain of the F1a,
F2a, and F2b male and female pups during the
second and third weeks of lactation. Glyphosate did not affect the
ability of rats to mate, conceive, carry or deliver normal offspring at
any dose level.
The RfD is based on the NOEL for maternal toxicity in the rabbit
developmental study. No developmental effects were noted in the study.
In the rat developmental study, effects were noted only at doses 20-
fold higher than the NOEL used for the RfD. No pre- or post-natal
effects were seen in any study in the absence of maternal toxicity. In
the rat reproduction study, developmental effects were noted at doses 5
times higher than the NOEL used for the RfD. The Agency does not
believe the effects seen in these studies are of such concern to
require an additional safety factor. Accordingly, the Agency believes
the RfD has an adequate margin of protection for infants and children.
The dietary exposure from current and proposed uses of glyphosate
ranges from 1% of the RfD for nursing infants (less than 1 year old) to
3% for non-nursing infants and children 1 to 6 years old. Monsanto has
concluded that there is reasonable certainty that no harm will occur to
infants and children from aggregate exposure to glyphosate.
F. International Tolerances
Codex MRLs have been established for residues of glyphosate in or
on Barley Grain at 20 ppm, Dry Peas at 5 ppm, Dry Beans at 2 ppm, and
Rape (Canola) Seed at 10 ppm. The proposed tolerances will achieve
harmonization with these existing MRLs. The increase in U.S. tolerances
on legume vegetables up to 5 ppm was recommended in 1993 in the
glyphosate Reregistration Eligibility Decision.
The proposed U. S. tolerances are also consistent with the MRLs
presently established for these commodities by other trade partner
countries such as Canada, the European Union, and Japan.
[FR Doc. 98-4187 Filed 2-19-98; 8:45 am]
BILLING CODE 6560-50-F
