[Federal Register Volume 62, Number 133 (Friday, July 11, 1997)]
[Notices]
[Pages 37234-37246]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-18256]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-748; FRL-5728-7]
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-748, must
be received on or before August 11, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7506C), Information Resources and Services
Division, Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, 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. 1132 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:
[[Page 37235]]
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Office location/
Product Manager telephone number Address
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Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:[email protected] Arlington, VA
amail.epa.gov.
George LaRocca (PM 13)........ Rm. 204, CM #2, 703- Do.
305-6100, e-mail:
larocca.george@epamai.
James Tompkins (PM 25)........ Rm. 229, CM #2, 703- Do.
305-7830, e-mail:
tompkins.james@epamai.
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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 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 granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-748] (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 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [PF-748] and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: July 1, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. 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 6G3306
EPA has received a pesticide petition (PP) 6G3306 from DowElanco,
9330 Zionsville Road, Indianapolis, IN 46268 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 renewing a temporary tolerance for
the combined residues of herbicide triclopyr (3,5,6-trichloro-2-
pyridinyl)oxyacetic acid and its metabolites 3,5,6-trichloro-2-
pyridinol and 2-methoxy-3,5,6-trichloropyridine in or on the raw
agricultural commodities fish and shellfish at 0.2 part per million
(ppm). An allowable residue level of 0.5 ppm in potable water is also
being renewed. The proposed analytical method is gas chromatography.
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. Triclopyr Uses
Triclopyr as the triethylamine salt solution is currently
registered for use on rights-of-way, industrial sites, non-crop areas,
forest sites, rangeland, permanent grass pastures, roadsides, fence
rows, ornamental turf, non-irrigation ditchbanks, and rice. It is
recommended for the selective control of unwanted woody plants and
annual and perennial broadleaf weeds on these sites.
Triclopyr is to be experimentally used for the selective control of
aquatic weeds such as alligatorweed, Eurasian watermilfoil, parrot's
feather, pickerelweed, purple loosestrife, and water hyacinth growing
in lakes, ponds, reservoirs, and wetlands. It will also be tested for
the control of woody brush and herbaceous weeds growing in wetlands and
the banks and shores of aquatic sites. Application timing will coincide
with the seasons of the year when the target species are actively
growing. The maximum rates for triclopyr are 2 gallons per acre for the
treatment of floating or emerged weeds, 3 gallons per acre for
treatment of woody plants, and 2.5 ppm in water for treatment of
submersed weeds.
B. 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 detection limits range from 0.01 to 10 ppm depending on
the compound being analyzed.
2. Magnitude of residues. In field studies, triclopyr in water has
a half-life of 0.5 - 3.5 days. Triclopyr residues were below 0.5 ppm
after 3 days. The metabolite, 3,5,6-trichloro-2-pyridinol was not
detected within the treatment area. Within the treatment area,
triclopyr was detected at <0.01 -="" 0.03="" ppm="" in="" water="" collected="" 21="" days="" after="" application.="" the="" average="" concentration="" did="" not="" exceed="" 0.5="" ppm="" at="" 600="" ft="" from="" the="" border="" of="" the="" treated="" area.="" residues="" of="" triclopyr="" and="" its="" metabolites="" 3,5,6-trichloro-2-pyridinol="" and="" 2-methoxy-3,5,6-="" trichloropyridine="" were="" detectable="" only="" at="" the="" limit="" of="" detection,="" 0.01="" ppm="" and="" non-detectable="" after="" day="" eight="" in="" fish="" flesh.="" shellfish="" residues="" were="" [[page="" 37236]]="" greater,="" with="" less="" than="" 0.1="" ppm="" remaining="" in="" the="" edible="" portion="" after="" two="" weeks="" of="" treatment.="" c.="" toxicology="" profile="" 1.="" acute="" toxicity.="" acute="" toxicity="" studies="" conducted="" with="" the="" triethylamine="" salt="" of="" triclopyr="" indicate="" low="" toxicity="" with="" the="" exception="" of="" eye="" irritation.="" the="" acute="" oral="">50, in rats
with the triethylamine salt of triclopyr is 2,574 mg/kg (males) or
1,847 mg/kg (females) (Toxicity Category III.) The acute dermal LD, in
rabbits using the triethylamine salt of triclopyr was > 2,000 mg/kg
(Toxicity Category III.) The acute inhalation LD50, in rats
was > 2.6 mg/L (maximum attainable concentration) with a Toxicity
Category of III. In a primary eye irritation study in rabbits the
triethylamine salt of triclopyr was found to be corrosive, with corneal
involvement present through day 21 post-dose. The triethylamine salt of
triclopyr was found to be non-irritating to the skin of white rabbits.
In dermal sensitization studies in guinea pigs, sensitization was
observed with the triethylamine salt of triclopyr.
2. Genotoxicity. The genotoxic potential of triclopyr has been
evaluated in a range of assays in vivo and in vitro. These assays
demonstrate triclopyr is non-mutagenic in vivo and in vitro.
Mutagenicity data included gene mutation assays with E. coli and S.
typhimurium (negative); DNA damage assays with B. subtillis (negative);
an unscheduled DNA synthesis with rat hepatocytes (negative), a
chromosomal aberration test in Chinese hamster cells and rat cells
(negative) and dominant lethal assays in rats and mice (negative).
3. Reproductive and developmental toxicity. A developmental
toxicity study in rats fed dosage levels of 0, 30, 100, and 300 mg/kg/
day, with a maternal lowest observed effect level (LOEL) = 300 mg/kg
based on the increased incidence of salivation and mortality and a
maternal no-observed effect level (NOEL) = 100 mg/kg. Developmental
toxicity was evident in this study at the 300 mg/kg dose level, and
included decreased mean fetal body weight, increased fetal and litter
incidence of skeletal anomalies and an increase in the number of
fetuses with unossified sternebrae. The developmental LOEL = 300 mg/kg-
based on decreased mean fetal weight, increased fetal and fitter
incidence of skeletal anomalies, and increased fetal incidence of
unossified sternebrae. The developmental NOEL = 100 mg/kg.
A developmental toxicity study in rabbits fed dosage levels of 0,
10, 30, and 100 mg/kg/day with a maternal LOEL = 100 mg/kg based on the
decreased body weight gain, decreased food efficiency, and increased
liver and kidney weight. The maternal NOEL = 30 mg/kg. Developmental
toxicity was evident at the 100 mg/kg dose level in the form of reduced
number of litters, reduced number of corpora lutea, reduced number of
total implants, reduced total live fetuses, increased embryonic deaths
and deaths/dam, and increased pre-implantation loss. The developmental
LOEL =100 mg/kg based an the decreased number of live implants,
decreased live fetuses, and increased embryonic deaths. The
developmental NOEL = 30 mg/kg.
A 2-generation reproduction study in rats fed dosages of 0, 5, 25,
and 250 mg/kg/day with a Parental Systemic Toxicity NOEL = 5 mg/kg/day
(males and females); the parental Systemic Toxicity LOEL = 25 mg/kg/
day, based on increased incidence of proximal tubular degeneration in
male and female Pl and P2 rats. The Reproductive/
Systemic Toxicity NOEL = 25 mg/kg/day; the Reproductive/Systemic
Toxicity LOEL = 250 mg/kg/day, based on decreased litter size,
decreased body weight and weight gain, and decreased survival in the
F1 and F2 litters.
4. Subchronic toxicity. A subchronic oral toxicity study in rats
receiving dietary concentrations of triclopyr at doses of 0, 5, 20, 50,
or 250 mg/kg/day for 13 weeks with a systemic NOEL was 5 mg/kg/day, and
the systemic LOEL of 20 mg/kg/day, based on histopathological changes
in the kidneys of both sexes.
A 183-day toxicity study in dogs receiving dietary doses of
triclopyr technical at 0, 0.1, 0.5, or 2.5 mg/kg/day with decreased
rate of phenolsulfanthalein (PSP) excretion was observed in dogs
receiving 2.5 mg/kg/day triclopyr. This effect is a result of
competition between triclopyr and PSP for renal excretion, and is not
toxicologically relevant. The systemic NOEL is 2.5 mg/kg/day and the
systemic LOEL is > 2.5 mg/kg/day in both sexes.
5. Chronic toxicity. In a 1-year dietary toxicity study, triclopyr
was administered to dogs at doses of 0, 0.5, 2.5, or 5.0 mg/kg/day.
There were no significant effects of treatment on mortality, clinical
signs, body weight, or food consumption in male and female dogs at any
dose level treated. Increases in urea nitrogen and creatinine were
observed at 2.5 and 5.0 mg/kg/day; these changes in clinical chemistry
values do not represent a toxic response to the test chemical, but a
physiologic response of the dog, based on the limited ability of the
dog to excrete organic acids at higher plasma concentrations. The lack
of histopathologic alterations in the kidneys of both sexes is
supportive of this conclusion. The systemic NOEL is 5.0 mg/
kg/day for both sexes; the systemic LOEL is >5.0 mg/kg/day.
In a chronic toxicity/carcinogenicity study, triclopyr was
administered in the diet to mice at dose levels of 0, 50 ppm, 250 ppm,
or 1,250 ppm. There were no compound-related tumors observed in mice.
The LOEL was considered to be 143 mg/kg/day in male mice and 135 mg/kg/
day in female mice, based on the decreased body weight gain. The NOEL
is considered to be 28.6 mg/kg/day in male mice, and 26.5 mg/kg/day in
female mice.
In a chronic toxicity/carcinogenicity study, triclopyr was
administered to Fischer 344 rats for 2 years at dose levels of 0, 3,
12, or 36 mg/kg/day. Mortality in treated groups of male rats was lower
than that in the control group. Cumulative mortality was 50%, 32%, 26%,
and 36% for control, low, mid, and high dose level male rats. Red cell
count, hemoglobin, and hematocrit in male rats was numerically
decreased at the high dose at 6, 12, and 24 months. Statistical
significance was achieved for the decrease in red cells at 12 months,
for hemoglobin at 6 months, and for hematocrit at 6 and 22 months.
Absolute and relative kidney weight was significantly increased (10-
13%) at the high dose in male rats, with an apparent dose-related trend
at 12 months. Female rats showed an increased incidence of pigmentation
of the proximal descending tubule at all dose levels compared to
control, while male rats in the 6-month satellite group showed
increased incidence of proximal tubule degeneration at the 12 and 36
mg/kg/day dose levels compared to control. There were no significant
increasing trends in tumor incidence for rats.
As a result of the August 9, 1995 meeting of the Health Effects
Division Carcinogenicity Peer Review Committee, triclopyr was
classified as a Group D chemical (not classifiable as to human
carcinogenicity).
6. Animal metabolism. Disposition and metabolism of 14C-
triclopyr was investigated in rats at a low oral dose (3 mg/kg),
repeated low oral doses ( 3 mg/kg x 14 days), and a high dose (60 mg/
kg.) Comparison of disposition data in intravenously dosed and orally
dosed rats demonstrated that triclopyr was well absorbed after oral
administration. Excretion was relatively rapid at the low dose, with a
majority of radioactivity eliminated in the urine by 24 hours. At 60
mg/kg, urinary elimination of 14C-triclopyr derived
radioactivity was decreased in rats from 0-12 hours, due to apparent
saturation of renal
[[Page 37237]]
elimination mechanisms. Fecal elimination of 14C-Triclopyr
derived radioactivity was a minor route of excretion, as was
elimination via exhaled air. No significant effect was observed on
metabolism or disposition of 14C-triclopyr from repeated low
oral dosing.
Urinary metabolites of 14C-triclopyr were isolated and
identified by HPLC and GC/MS. 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.
7. Bioequivalency. Toxicology studies conducted with triclopyr have
been performed using either the free acid or the triethylamine salt
form of triclopyr. Bioequivalency of the two chemical forms of
triclopyr has been addressed through the conduct of special studies
with the triethylamine form 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 pharmacokinetic data in demonstrating bioequivalence.
Therefore, studies conducted with any one form of triclopyr can be used
to support the toxicology database as a whole.
D. Aggregate Exposure
1. Dietary exposure--i. Food. The Reference Dose (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% crop treated information to estimate the
Theoretical Maximum Residue Contribution (TMRC) for the general
population and 22 subgroups. Existing tolerances result in a TMRC which
represents 0.81% 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%="" of="" the="" commodities="" assumed="" to="" be="" treated="" with="" triclopyr.="" based="" on="" the="" risk="" estimates="" calculated="" in="" this="" analysis,="" it="" appears="" that="" 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)="" is="" 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="" 2,500="" is="" above="" the="" acceptable="" level="" and="" demonstrates="" no="" acute="" dietary="" concern.="" an="" acute="" dietary="" exposure="" analysis="" was="" performed="" using="" tolerance="" level="" residues="" and="" 100%="" 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/kgbw/day)="" moe="" ------------------------------------------------------------------------="" u.s.="" population="" 0.00230="" 13050="" females="" 0.00184="" 16277="" ------------------------------------------------------------------------="" these="" high="" end="" moe="" values="" are="" above="" the="" acceptable="" level="" and="" demonstrate="" no="" acute="" dietary="" concerns.="" ii.="" drinking="" water.="" the="" use="" of="" triclopyr="" in="" the="" proposed="" eup="" does="" not="" add="" any="" additional="" exposure="" of="" triclopyr="" to="" humans.="" the="" only="" additional="" source="" that="" needs="" to="" be="" considered="" is="" drinking="" water.="" the="" proposed="" eup="" labeling="" requires="" that="" the="" product="" not="" be="" applied="" within="" one="" mile="" of="" a="" potable="" water="" intake,="" and="" treated="" water="" is="" not="" to="" be="" used="" for="" domestic="" purposes="" for="" 21="" days="" after="" application.="" the="" basis="" for="" these="" restrictions="" is="" a="" study="" conducted="" at="" lake="" seminole,="" ga.="" in="" this="" study,="" triclopyr="" was="" not="" detected="" one="" mile="" downstream="" from="" the="" treated="" area="" for="" up="" to="" 42="" days="" after="" treatment.="" within="" the="" treatment="" area,="" triclopyr="" was="" detected="" at=""><0.01 -="" 0.03="" ppm="" in="" water="" collected="" 21="" days="" after="" application.="" at="" 1="" hour="" after="" application,="" water="" from="" the="" treated="" area="" contained="" 2.6="" ppm="" of="" triclopyr,="" and="" was="" below="" the="" temporary="" tolerance="" level="" of="" 0.5="" ppm="" at="" 3="" days="" after="" treatment.="" if="" the="" proposed="" labeling="" is="" followed="" precisely,="" that="" is,="" potable="" water="" is="" not="" collected="" within="" one="" mile="" of="" a="" treated="" area,="" triclopyr="" residues="" will="" not="" be="" detected=""><0.01 ppm),="" and="" there="" will="" be="" no="" contribution="" from="" water="" to="" the="" ``risk="" cup''="" for="" triclopyr.="" if="" water="" is="" collected="" from="" the="" treated="" area="" 21="" days="" after="" treatment="" and="" used="" in="" drinking="" water="" supplies,="" the="" maximum="" residue="" of="" 0.03="" ppm="" in="" the="" lake="" seminole="" study="" would="" increase="" the="" amount="" of="" the="" rfd="" used="" for="" non-="" nursing="" infants=""><1 yr="" old)="" from="" 2.6="" %="" to="" 7.0="" %="" for="" chronic="" exposure.="" for="" a="" worst="" case="" estimate="" of="" potential="" drinking="" water="" exposure,="" the="" water="" residue="" data="" from="" the="" treated="" area="" in="" the="" lake="" seminole="" study="" was="" utilized.="" it="" was="" assumed="" that="" potable="" water="" was="" collected="" from="" the="" treatment="" area="" during="" the="" 21="" days="" following="" the="" application.="" the="" data="" were="" integrated="" over="" the="" time="" period="" to="" find="" an="" ``average''="" value,="" which="" calculated="" to="" be="" 0.2="" ppm.="" when="" this="" residue="" level="" is="" considered,="" the="" following="" analysis="" demonstrates="" the="" risk="" is="" minimal.="" acute="" noel="" (pregnant="" females)="30" mg/kg/day;="" acute="" noel="" (children="" 1-6="" years);="" chronic="" noel="" (all="" population="" subgroups)="5" mg/kg/day="" time="" weighted="" concentration="" during="" the="" mitigation="" period="0.2" ppm="2.0" x="">1 mg/L
For a 10 kg child consuming 1 liter a day (Acute):
(2.0 X 10-1 mg/L X 1 L/day) / 10 kg = 2.0 X 10-
2 mg/kg/day MOE = NOEL/Exposure = 5 mg/kg/day / 2.0 X 10-
2 mg/kg/day MOE = 250
For a 10 kg child consuming 1 Liter a day (Chronic):
Percent of RfD = (2.0 X 10-2 mg/kg/day / 0.05) X 100 =
40%
For a 60 Kg pregnant female consuming 2 Liters a day (Acute):
(2.0 x 10-1 mg/L X 2 L/day) / 60 kg = 6.7 X 10-
3 mg/kg/day
MOE = 30 mg/kg/day / 6.7 X 10-3 mg/kg/day = 4478
For a 60 kg pregnant female consuming 2 Liters a day (Chronic):
Percent of RfD = (6.7 X 10-3 mg/kg/day / 0.05) x 100 =
13.4%
2. 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
[[Page 37238]]
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 a.i., 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.
E. 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 well known.
No reliable information exists to indicate that toxic effects produced
by triclopyr would be cumulative with those of any other chemical
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.
F. 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. Therefore, residential exposure was not considered in the
aggregate risk calculation. The water exposure value used the time
weighted concentration during the mitigation period = 0.2 ppm = 2.0 X
10-1 mg/L in the calculations below for drinking water
exposure. The high end (99.5 percentile) exposure from the acute
dietary analysis is used for the populations below.
13+ pregnant females Dietary + Drinking water
0.0018 mg/kg/day + 6.7 X 10-3 mg/kg/day = 8.5 X 10-
3 mg/kg/day
Acute MOE = 30 mg/kg/day / 8.5 X 10-3 mg/kg/day = 3529
Non-nursing infants Dietary + Drinking water
0.006 mg/kg/day + 0.02 mg/kg/day = 2.6 X 10-2 mg/kg/day
Acute MOE = 5 mg/kg/day / 2.6 X 10-2 mg/kg/day = 192
Children (1-6 years), Dietary + Drinking Water
0.0035 mg/kg/day + 0.02 mg/kg/day = 2.35 X 10-2 mg/kg/
day
Acute MOE = 5 mg/kg/day/2.35 X 10-2 mg/kg/day = 213
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 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. Even using the time weighted concentration during the
mitigation period for drinking water risk is minimal.
G. 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.
H. 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. (James Tompkins)
2. DowElanco
PP 4F4379, 8F3600, and 8H5551
EPA has received pesticide petitions (PP) 4F4379 (sweet corn and
popcorn) and 8F3600 and 8H5551 (sugar beets) 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 the herbicide clopyralid in or on the raw agricultural
commodities (RACs) sweet corn, fodder at 10.0 ppm; sweet corn, forage
and cannery waste at 3.0 ppm; sweet corn, grain at 1.0 ppm and kernel
plus cob with husks removed (K + CWHR) at 0.5 ppm; and pop corn, fodder
at 10.0 ppm, and pop corn, grain at 1.0 ppm; and revising the tolerance
for residues of the herbicide clopyralid in or on the raw agricultural
commodities sugar beet, roots at 1.0 ppm and sugar beet, tops at 1.0
ppm and on the processed agricultural commodity (PAC) sugar beet,
molasses at 8.0 ppm. The proposed analytical method is available for
enforcement purposes.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended,
DowElanco has submitted the following summary of information, data and
arguments in support of their pesticide petition. This summary was
prepared by DowElanco and EPA has not fully evaluated the merits of the
petition. EPA edited the summary to clarify that the conclusions and
arguments were the petitioners and not necessarily EPAs and to remove
certain extraneous material.
A. Residue Chemistry
1. Plant metabolism. The metabolism in plants is adequately
understood. No metabolites of significance were detected in plant
metabolism studies.
2. Analytical method. There is a practical analytical method for
detecting and measuring levels of clopyralid in or on food with a limit
of quantitation (LOQ) of 0.05 ppm that allows monitoring of food with
residues at or above the levels set in these tolerances. EPA has
provided information on this method to FDA. The method is available to
anyone who is interested in pesticide residue enforcement.
3. Magnitude of residues-- i. Sugar beets. Tolerances for residues
of the herbicide clopyralid in or on the following raw agricultural
commodities, sugar beet roots and tops and the processed agricultural
commodity molasses, were established on August 12, 1988 (53 FR 33488,
33489) at 0.5, 0.5, and 7.0 parts per million (ppm), respectively,
based upon residue data generated by Craven Laboratories. The validity
of these data were in question and DowElanco repeated the residue
studies. The last of the required residue data were submitted to the
Agency in June 1994. The range of the residues
[[Page 37239]]
found for sugar beet, roots was to no detected residues above the LOQ
of the method - 0.7 ppm; sugar beet, tops; was to no detected residues
above the LOQ of the method - 0.9 ppm; and the residues in the
processed agricultural commodities when clopyralid was applied at the
maximum labeled rate were 0.5, 0.09, and 6.3 ppm for pulp, sugar and
molasses respectively. The proposed revised tolerances would adequately
cover these anticipated residues.
ii. Sweet corn. Clopyralid was applied at the maximum label rate
and residues were detected at the following ppm ranges: Grain, 0.087 -
0.12; Forage, 0.34 - 2.0; Ears (K + CWHR), 0.029 - 0.23 and Cannery
Waste; no residues were detected above the LOQ of the method. The
proposed tolerances would adequately cover these anticipated residues.
iii. Pop corn. Clopyralid was applied at the maximum label rate and
residues were detected at the following ppm ranges; Grain: 0.03 - 0.91,
Fodder: No detectable residues above the LOQ of the method - 0.60, and
Forage 0.14 - 1.2, The proposed tolerances would adequately cover these
anticipated residues.
B. Toxicological Profile
1. Acute toxicity. Clopyralid has low acute toxicity. The rat oral
LD50 is 5,000 mg/kg or greater for males and females. The
rabbit dermal LD50 is greater than 2,000 mg/kg and the rat
inhalation LC50 is greater than 1.0 mg/L air (the highest
attainable concentration). In addition, clopyralid is not a skin
sensitizer in guinea pigs and is not a dermal irritant. Technical
clopyralid is an ocular irritant but ocular exposure to the technical
material would not normally be expected to occur to infants or children
or the general public. End use formulations of clopyralid have similar
low acute toxicity profiles and most have low ocular toxicity as well.
Therefore based on the available acute toxicity data, clopyralid does
not pose any acute dietary risks.
2. Genotoxicity. Clopyralid is not genotoxic. The following studies
have been conducted and all were negative for genotoxic responses. Ames
bacterial mutagenicity assay (with and without exogenous metabolic
activation); Host-Mediated assay In vivo cytogenetic test, rat; In vivo
cytogenetic test, mouse; In vivo dominant lethal test, rat; In vitro
unscheduled DNA synthesis assay in primary rat hepatocyte cultures; In
vitro mammalian cell gene mutations assay in Chinese hamster ovary cell
cultures (with and without exogenous metabolic activation).
3. Reproductive and developmental toxicity. Developmental toxicity
was studied using rats and rabbits. The developmental study in rats
resulted in a developmental NOEL of >250 mg/kg/day (a maternally toxic
dose) and a maternal toxicity NOEL of 75 mg/kg/day. A 1974 study in
rabbits revealed no evidence of developmental or maternal toxicity at
250 mg/kg/day; thus the developmental and maternal NOEL was >250 mg/kg/
day. A more recent study in rabbits (1990) resulted in developmental
and maternal NOELs of 110 mg/kg/day based on maternal toxicity at 250
mg/kg/day. Based on all of the data for clopyralid, there is no
evidence of developmental toxicity at dose levels that do not result in
maternal toxicity. In a 2-generation reproduction study in rats, pups
from the high dose group which were fed diets containing clopyralid had
a slight reduction in body weight during lactation and an increase in
liver weights in F1a and F1b weanlings. The NOEL for parental systemic
toxicity was 500 mg/kg/day. There was no effect on reproductive
parameters at >1,500 mg/kg/day nor was there an adverse effect on the
morphology, growth or viability of the offspring; thus, the
reproductive NOEL is >1500 mg/kg/day.
4. Subchronic toxicity. The following studies have been conducted
using clopyralid. In a rat 90-day feeding study, Fischer 344 rats were
fed diets containing clopyralid at doses of 5, 15, 50, or 150 mg/kg/day
with no adverse effects attributed to treatment. In a second study,
Fischer 344 rats were fed diets containing clopyralid at doses of 300,
1,500, and 2,500 mg/kg/day. Effects at the highest doses were decreased
food consumption accompanied by decreased body weights and weight gains
in both males and females. Slightly increased mean relative liver and
kidney weights were noted in males of all doses and in females at the
top 2 doses. Because there were no other effects, the kidney and liver
weight effects were judged as being adaptive rather than directly
toxic. The no-observed-adverse-effect level (NOAEL) was 1,500 mg/kg/day
for males and females. The no-observed-effect level (NOEL) was 300 mg/
kg/day for females. In a mouse 90-day feeding study, B6C3F1 mice were
fed diets containing clopyralid at doses of 200, 750, 2,000 or 5,000
mg/kg/day. A slight decrease in body weight occurred at the top dose in
both sexes. The liver was identified as the target organ based on
slight increases in liver weights and minimal microscopic alterations
at the higher dose levels. The liver changes were considered to be
reversible and adaptive. The NOEL for males was 2,000 mg/kg/day and for
females was 750 mg/kg/day. In a 180-day feeding study, beagle dogs were
fed diets containing clopyralid at doses of 15, 50, or 150 mg/kg/day;
there were no adverse effects. In a second dietary study, dogs also
were fed diets containing clopyralid at doses of 15, 50, or 150 mg/kg/
day; the only effect was an increase in the mean relative liver weight
in females at the 150 mg/kg/day. In a 21-day dermal study, clopyralid
was applied by repeated dermal application to New Zealand White rabbits
at dose levels up to 1,000 mg/kg/day. Treatment produced no systemic
effects.
5. Chronic toxicity. In a chronic toxicity and oncogenicity study,
Sprague-Dawley rats were fed diets containing clopyralid at doses of 5,
15, 50 or 150 mg/kg/day. The only effect was a trend toward a decreased
body weight of female rats receiving the 150 mg/kg/day dose with a NOEL
of 50 mg/kg/day. In a second study clopyralid was fed to Fischer 344
rats in the diet at doses of 15, 150, or 1,500 mg/kg/day. The effects
were confined almost entirely to the 1,500 mg/kg/day dose groups and
included slightly decreased food consumption and body weights, slightly
increased liver and kidney weights and macroscopic and microscopic
changes in the stomach. No tumorigenic response was present. The NOEL
for this study was 150 mg/kg/day. B6C3F1 mice were maintained for 2
years on diets formulated to provide targeted dose levels of 10, 500,
or 2,000 mg/kg/day. The only evidence of toxicity was body weight
depression in males dosed at 2,000 mg/kg/day. There was no evidence of
tumorigenic response at any dose level. Based on the chronic toxicity
data, EPA has established the RfD for clopyralid at 0.5 milligrams
(mg)/kilogram (kg)/day. The RfD for clopyralid is based on a 2-year
chronic oncogenicity study in rats with a no-observed-effect level
(NOEL) of 50 mg/kg/day and an uncertainty (or safety) factor of 100.
Thus, it would not be necessary to require the application of an
additional uncertainty factor above the hundredfold factor already
applied to the NOEL.
6. Carcinogenicity. Using its Guidelines for Carcinogen Risk
Assessment published September 24, 1986 (51 FR 33992), clopyralid would
be classified as Group E for carcinogenicity (no evidence of
carcinogenicity) based on the results of the carcinogenicity studies.
There was no evidence of carcinogenicity in 2-year feeding studies in
mice and rats at the dosage levels tested. The doses tested are
adequate for identifying a cancer
[[Page 37240]]
risk. Thus, a cancer risk assessment would not be appropriate.
7. Animal metabolism. Disposition and metabolism of clopyralid were
tested in male and female rats at a dose of 5 mg/kg (oral). The
majority of a radioactive dose was excreted in 24 hours of all dose
groups. Fecal elimination was minor. Detectable levels of residual
radioactivity were observed in the carcass and stomach at 72 hours
post-dose. HPLC and TLC analysis of urine and fecal extracts showed no
apparent metabolism of clopyralid.
8. Metabolite toxicity. There are no clopyralid metabolites of
toxicological significance.
9. Endocrine effects. There is no evidence to suggest that
clopyralid has an effect on any endocrine system.
C. Aggregate Exposure
1. From food and feed uses. For purposes of assessing the potential
dietary exposure under these tolerances, exposure is estimated based on
the TMRC from the existing and pending tolerances for clopyralid on
food crops. The TMRC is obtained by multiplying the tolerance level
residues by the consumption data which estimates the amount of those
food products eaten by various population subgroups. Exposure of humans
to residues could also result if such residues are transferred to meat,
milk, poultry or eggs. The following assumptions were used in
conducting this exposure assessment: 100% of the crops were treated,
the RAC residues would be at the level of the tolerance, certain
processed food residues would be at anticipated (average) levels based
on processing studies and all current and pending tolerances were
included. This results in an overestimate of human exposure and a
conservative assessment of risk. Based on a NOEL of 50 mg/kg/day in a
2-year chronic feeding/oncogenicity study in the rat and a hundredfold
safety factor, the reference dose (RfD) would be 0.5 mg/kg/day.
Consequently, all existing and pending tolerances have a theoretical
maximum residue contribution of 0.005135 mg/kgBW/day and would utilize
less than 2.3% of the RfD.
2. From potable water. Another potential source of dietary exposure
to residues of pesticides are residues in drinking water. There is no
established Maximum Concentration Level for residues of clopyralid in
drinking water. Although there has been limited detections at ppb
levels in some of the specially designed studies under highly
vulnerable test conditions, no ongoing monitoring studies (U.S.
Geological Survey, Selected Water Resources Abstracts, and Pesticides
in Ground Water Database - A Compilation of Monitoring Studies: 1971-
1991 National Summary; U.S. Department of Agriculture, AGRICOLA
database; and, U.S. Department of Commerce, National Technical
Information Service) have reported residues of clopyralid in ground or
surface waters.
Based on the physical and chemical characteristics of clopyralid,
such as water solubility and its stability under hydrolysis and
photolysis, it has potential for downward movement through the soil
profile. However, the behavior of the compound under field conditions
demonstrates fairly rapid degradation and limited downward movement.
Degradation based on 20 field dissipation sites indicated an average
half-life of 34 days. Degradation is driven primarily by microbial
processes. Downward movement through the soil profile was generally
confined to the upper 18 inches of the soil profile. Validated computer
modeling also predicted the maximum depth of residues to be 18-inches,
with no detections predicted at 6 months after application. Because the
laboratory derived physical/chemical properties of clopyralid indicate
a potential for downward movement, lysimeter studies were conducted. In
a U.S. study, undisturbed soil columns (lysimeters), 8 inches in
diameter, and 3 feet deep, were treated with 950 g ae/ha (about 5 X
labeled use rates) in actual field conditions. Residues of clopyralid
in soil as well as soil-solution (leachate) were collected in the
closed system. The average depth of movement for the majority of
clopyralid (center of mass) was 11 inches, and no detectable residues
were observed in the leachate. In a European study, lysimeters 1 - 3
ft. diameter, and 3 ft. deep, were treated with 120 and 240 g ae/ha in
actual field conditions. The average center of mass was 12 inches. No
detectable residues were observed in the lysimeters. The amount of
14C in leachate accumulated over 2 years in the degraded
loess and silty sand lysimeters, was only 0.6% and 0.3% of applied,
respectively. The leachate concentrations of 14C-labeled
clopyralid in degraded loess and silty sand throughout the first 10-16
months of the study ranged from 0.002-0.14 g/l (ppb) and
0.003-0.02 ppb, respectively. A second European lysimeter study with
silty sand lysimeters treated with 120 g ae/ha revealed a 2-year
cumulative clopyralid leachate of only 0.1% of applied (0.04 ppb).
These studies demonstrate that in lysimeter test systems, under field
environmental conditions, clopyralid rapidly dissipates through
mineralization to carbon dioxide. Also the very low levels observed in
leachate demonstrate that there is very little potential for clopyralid
to leach through soil and to contaminate ground water.
In summary, these data on potential water exposure indicate
insignificant additional dietary intake of clopyralid and any exposure
is more than offset for in the conservative dietary risk evaluation.
Therefore, it is concluded that there is a reasonable certainty of no
harm even at potential upper limit exposures to clopyralid from
drinking water.
3. From non-dietary uses. There is only one non-dietary use
registered under the Federal Insecticide, Fungicide and Rodenticide
Act. The use is for weed control in residential turf. Potential
exposures for children from non-occupational uses is therefore limited
to turf re-entry and this exposure is low.
4. Short-term or intermediate-term. The data for clopyralid does
not indicate any evidence of significant toxicity by the dermal and
inhalation routes. Consequently, there is no concern for short-term or
intermediate-term residential risk. Therefore, a short-term or
intermediate-term residential risk assessment would not be required.
5. Chronic. As part of a hazard assessment process an endpoint of
concern is determined for the chronic occupational or residential risk
assessment. However, as indicated, the exposures that would result from
the use of clopyralid are of an intermittent nature. The frequency and
duration of these exposures do not exhibit a chronic exposure pattern.
The exposure does not occur often enough to be considered a chronic
exposure; i.e., a continuous exposure that occurs for a least several
months. Therefore, it would not be appropriate to aggregate exposure
from the residential use with exposure from food and drinking water.
6. Acute. No concern would exist for an acute dietary assessment
for clopyralid because the available data indicates no evidence of
significant toxicity from a one day or single event exposure by the
oral route. Therefore, an acute dietary risk assessment would not be
required.
D. Cumulative Exposure to Substances with Common Mechanism of Toxicity
The potential for cumulative effects of clopyralid and other
substances that have a common mechanism of toxicity was considered. The
mammalian toxicity of clopyralid is well defined. However, no reliable
information exists to indicate that toxic effects produced
[[Page 37241]]
by clopyralid would be cumulative with those of any other chemical
compound. Additionally, clopyralid does not appear to produce a toxic
metabolite produced by other substances. Therefore, consideration of a
common mechanism of toxicity with other compounds is not appropriate at
this time. Thus only the potential exposures to clopyralid were
considered in the aggregate exposure assessment.
E. Determination of Safety
1. U.S. population in general. Based on a NOEL of 50.80 mg/kg/bwt/
day from a 2-year rat feeding study with a decreased mean body weight
gain effect, and using an uncertainty factor of 100 to account for the
interspecies extrapolation and intraspecies variability, a Reference
Dose (RfD) of 0.5 mg/kg bwt/day was used for this assessment of chronic
risk. As indicated, there is no endpoint of concern identified with
acute and short- or intermediate-term exposures. Based on the known
toxicity and exposure data, the proposed and existing tolerances would
utilize approximately 2% of the RfD for the U.S. population. And, as
indicated previously, whatever upper limit might be used for drinking
water exposure, the exposure estimate for clopyralid would not exceed
the RfD. Generally, exposures below 100% of the RfD are of no concern
because the RfD 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 a reasonable certainty that no harm will
result from aggregate exposure to clopyralid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of clopyralid, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat were considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism during prenatal development resulting from
pesticide exposure to one or both parents. Reproduction studies provide
(1) information relating to effects from exposure to the pesticide on
the reproductive capability of mating animals and (2) data on systemic
toxicity.
Developmental toxicity was studied using rats and rabbits. The
developmental study in rats resulted in a developmental NOEL of >250
mg/kg/day (a maternally toxic dose) and a maternal toxicity NOEL of 75
mg/kg/day. A 1974 study in rabbits revealed no evidence of
developmental or maternal toxicity at 250 mg/kg/day; thus the
developmental and maternal NOEL was >250 mg/kg/day. A more recent study
in rabbits (1990) resulted in developmental and maternal NOEL's of 110
mg/kg/day based on severe maternal toxicity at 250 mg/kg/day. Based on
all of the data for clopyralid, there is no evidence of developmental
toxicity at dose levels that do not result in maternal toxicity.
In a 2-generation reproduction study in rats, pups from the high
dose group which were fed diets containing clopyralid had a slight
reduction in body weight during lactation and an increase in liver
weights in F1a and F1b weanlings. The NOEL for parental systemic
toxicity was 500 mg/kg/day. There was no effect on reproductive
parameters at >1500 mg/kg/day nor was there an adverse effect on the
morphology, growth or viability of the offspring; thus, the
reproductive NOEL is >1,500 mg/kg/day.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. These data suggest minimal concern for developmental or
reproductive toxicity and do not indicate any increased pre- or post-
natal sensitivity. Therefore, an additional uncertainty factor is not
necessary to protect the safety of infants and children and that the
RfD at 0.5 mg/kg/day is appropriate for assessing aggregate risk to
infants and children.
The percent of the RfD that will be utilized by the aggregate
exposure from all tolerances to clopyralid will be much less than 10%
for non-nursing infants and for children (1 - 6 years of age).
Therefore, based on the completeness and reliability of the toxicity
data and the conservative exposure assessment, it is concluded that
there is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to clopyralid residues.
F. International Tolerances
There are no Codex maximum residue levels established for
clopyralid. (Joanne Miller)
3. E.I. DuPont Company
PP 4F4391
In the Federal Register of October 25, 1995, (60 FR 54607), EPA
established a time-limited tolerance pursuant to the Federal Food Drug
and Cosmetic Act (FFDCA) for residues of the herbicide pyrithiobac
sodium salt (sodium 2-chloro-6-[(4,6-dimethoxypyrimidin-2-
yl)thio]benzoate) in or on the raw agricultural commodity cottonseed at
0.02 part per million (ppm). The time-limited tolerance expires
September 30, 1997. The tolerance was requested in pesticide petition
(PP) 4F4391 by E. I. DuPont de Nemours and Co., Inc. (DuPont), Barley
Mill Plaza, P.O. Box 80083, Wilmington, DE 19880-0038. The tolerance
was issued as a time-limited tolerance because EPA required additional
residue data on the commodity of cotton gin byproducts. The petitioner
proposes to renew the time-limited tolerance for a 2-year period and
retain the pesticide labeling previously accepted under the Federal
Insecticide Fungicide and Rodenticide Act (FIFRA), as amended, which
bears a restriction against feeding cotton gin byproducts from treated
fields to livestock. DuPont has requested this tolerance extension
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
as amended, 21 U.S.C. 346a(d), by the Food Quality Protection Act of
1996 (Pub. L. 104-170, 110 Stat. 1489). The request addresses the
requirements of the new FFDCA Section 408(d)(2). The time-limited
tolerance would expire on September 30, 1998. An adequately validated
analytical method is available for enforcement purposes. Pursuant to
section 408(d)(2)(A)(i) of the FFDCA, as amended, DuPont has submitted
the following summary of information, data and arguments in support of
its pesticide petition. This summary was proposed by DuPont and EPA has
not yet fully evaluated the merits of the petition. EPA edited the
summary to clarify that the conclusions and arguments presented are
those of the petitioner and not necessarily EPA's and to remove certain
extraneous material.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
pyrithiobac sodium in cotton is adequately understood. Metabolism
studies with pyrithiobac sodium indicate the major metabolic pathway
being o-dealkylation of the parent compound resulting in o-desmethyl
pyrithiobac sodium (O-DPS). O-DPS, both free and conjugated, was the
major metabolite identified in cotton foliage. The results of a
confined crop rotation study with pyrithiobac sodium revealed the
presence of a metabolite 2-chloro-6-sulfobenzoic acid (CSBA) not seen
in the cotton metabolism study. This metabolite appeared to originate
from soil metabolism of pyrithiobac sodium. Since preemergence
applications of pyrithiobac sodium are allowed, crop residues of CSBA
were
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considered a possibility. In consideration of PP 4F4391 CBTS, in
consultation with the HED Metabolism Committee has previously concluded
that for the proposed use on cotton, none of the pyrithiobac sodium
metabolites including O-DPS and CSBA warrant inclusion in the tolerance
regulation, and that the only residue of concern is the parent,
pyrithiobac sodium.
2. Analytical method. There is a adequately validated practical
analytical method available using HPLC-UV with column switching, to
measure levels of pyrithiobac sodium in or on cotton with a limit of
quantitation that allows monitoring of cottonseed at or above tolerance
levels. EPA has provided information on this method to FDA for future
publication in PAM II.
3. Magnitude of residues. Crop field trial residue data from a 60
day PHI study shows that the established pyrithiobac sodium time-
limited tolerance on cottonseed of 0.02 ppm will not be exceeded when
DuPont Staple Herbicide is used as directed. An adequate cottonseed
processing study shows that pyrithiobac sodium does not concentrate in
cottonseed processed commodities; thus no tolerances on these
commodities are required.
B. Toxicological Profile
1. Acute toxicity. Pyrithiobac sodium technical has been placed in
EPA Toxicity Category II for acute eye irritation based on the test
article inducing irritation in the form of corneal opacity, iritis and
conjunctival redness, and discharge in the eyes of rabbits after
receiving ocular doses of 36 mg (0.1 ml). Signs of irritation were
clear within 14 days of treatment. Pyrithiobac sodium has been placed
in Toxicity Category III for acute dermal toxicity based on the test
article being nonlethal and nonirritating at the limit dose of 2,000
mg/kg (highest dose tested). Pyrithiobac sodium has been placed in
Toxicity Category III for acute oral toxicity based on acute oral
LD50s of 3,200 mg/kg for both male and female rats.
Pyrithiobac sodium has been placed in Category IV for the remaining
acute toxicity tests based on the following: a rat acute inhalation
study with an LC50 of >6.9 mg/l; and a primary dermal
irritation test that did not induce a dermal irritation response. A
dermal sensitization test with pyrithiobac sodium technical in guinea
pigs demonstrated no significant effects. Based on these results,
pyrithiobac sodium does not pose an acute dietary or exposure risk.
2. Genotoxicty. Pyrithiobac sodium technical was negative (non-
mutagenic and non-genotoxic) in the following tests: Ames microbial
mutation assay; the hypoxanthine-guanine phosphoribosyl transferase
gene mutation assay using Chinese hamster ovary cells; and induction of
unscheduled DNA synthesis (UDS) in primary rat hepatocytes. Pyrithiobac
sodium was positive in an in vitro assay for chromosome aberrations in
human lymphocytes. It was negative for the induction of micronuclei in
the bone marrow cells of male and female CD-1 mice administered the
test article by oral gavage at 500, 1,000 or 2,000 mg/kg. Based on the
weight of these data, pyrithiobac sodium is neither genotoxic nor
mutagenic.
3. Reproductive and developmental toxicity. A 2-generation, 4
litter reproduction study with CD rats treated at dietary levels of 0,
25, 1,500, 7,500 or 20,000 ppm of pyrithiobac sodium demonstrated a
maternal NOEL of 1,500 ppm (103 mg/kg/day) and a maternal LOEL of 7,500
ppm (508 mg/kg/day), based on decreased body weight gain and food
efficacy. An offspring NOEL of 7,500 ppm (508 mg/kg/day) and LOEL of
20,000 ppm (1,551 mg/kg/day) were also demonstrated based on decreased
offspring body weight. Pyrithiobac sodium was not teratogenic when
administered to rats or rabbits. A developmental toxicity study with
pyrithiobac sodium in rats demonstrated a maternal NOEL of 200 mg/kg
and LOEL of 600 mg/kg due to increased incidence of salivation. A
developmental NOEL of 600 mg/kg and LOEL of 1,800 mg/kg were
demonstrated based on an increased incidence of skeletal variations. A
developmental toxicity study with pyrithiobac sodium in rabbits
demonstrated maternal and developmental NOELs of 300 mg/kg and a
maternal LOEL of 1,000 mg/kg based on mortality, decreased body weight
gain and feed consumption, increased incidence of clinical signs, and
an increase in early resorptions. A developmental LOEL of 1,000 mg/kg
was based on decreased fetal body weight gain. Based on the weight of
these data, pyrithiobac sodium is not considered a reproductive or
developmental hazard. In addition, there were no effects observed in
offspring in the absence of maternal toxicity; therefore, the offspring
were not uniquely susceptible to the effects of compound
administration.
4. Subchronic toxicity. In a 90-day feeding study in rats conducted
with pyrithiobac sodium at dietary levels of 0, 10, 50, 500, 7,000 and
20,000 ppm, the NOEL was 500 ppm (31.8 and 40.5 mg/kg/day, M/F) and the
LOEL was 7,000 ppm (466 and 588 mg/kg/day, M/F) based on decreased body
weight gains and increased rate of hepatic B-oxidation in males. In a
90-day feeding study in mice conducted with pyrithiobac sodium at
dietary levels of 0, 10, 50, 500, 1,500 and 7,000 ppm, the NOEL was 500
ppm (83.1 and 112 mg/kg/day, M/F) and the L0EL was 1,500 ppm (263 and
384 mg/kg/day, M/F) based on increased liver weight and increased
incidence of hepatocellular hypertrophy in males and decreased
neutrophil count in females. In a 90-day feeding study in dogs
conducted with pyrithiobac sodium at dietary levels of 0, 50, 5,000, or
20,000 ppm, the NOEL was 5,000 ppm (165 mg/kg/day) and the LOEL was
20,000 ppm (626 mg/kg/day) based on decreased red blood cell count,
hemoglobin, and hematocrit in females and increased liver weight in
both sexes. In a 21-day dermal study with rats conducted with
pyrithiobac sodium at exposure levels of 0, 50, 500, or 1,200 mg/kg/
day, the dermal irritation NOEL was 500 mg/kg/day and the dermal
irritation LOEL was 1,200 mg/kg/day. There were no systemic effects
observed at this high dose; therefore, the systemic NOEL is considered
to be 1,200 mg/kg/day.
5. Chronic toxicity. A 1-year feeding study in dogs conducted with
pyrithiobac sodium at dietary levels of 0, 100, 5,000, and 20,000 ppm
resulted in a NOEL of 5,000 ppm (143 and 166 mg/kg/day, M/F) and a LOEL
of 20,000 ppm (580 and 647 mg/kg/day, M/F) based on decreases in body
weight gain and increased liver weight. A 78-week oncogenicity study in
mice was conducted with pyrithiobac sodium at dietary levels of 0, 10,
150, 1,500 and 5,000 ppm. The systemic NOEL is 1,500 ppm (217 and 319
mg/kg/day, M/F) and the LEL is 5,000 ppm (745 and 1,101 mg/kg/day, M/
F), based on decreased body weight gain and liver lesions. Kidney
effects were also observed at 5,000 ppm; however, these were present at
low incidence and were of minimal severity and were considered to be of
only minimal biological significance. Increased incidence of foci/focus
of hepatocellular alteration was observed in males fed 5,000 ppm diets.
Increased incidences of hepatocellular neoplasms (adenomas or adenomas
plus carcinomas) were observed only in 150 and 1,500 ppm males. The
incidence of these liver tumors was not significantly increased in the
5,000 ppm males or in females at any dose level; the 5,000 ppm male
tumor incidence was within the historical control range. A 2-year study
in rats was conducted at dietary pyrithiobac sodium levels of 0, 5, 25,
[[Page 37243]]
1,500 or 5,000 ppm for males and 0, 5, 25, 5,000 or 15,000 ppm for
females. The NOEL for systemic effects was 1,500 ppm (58.7 mg/kg/day)
for males and 5,000 ppm (278 mg/kg/day) for females. The LEL was 5,000
ppm (200 mg/kg/day for males)/15,000 ppm (918 mg/kg/day) for females.
The LEL was based on the following: decreased body weight, body weight
gain and food efficiency (for females); mild changes in hematology and
urinalysis, clinical signs indicative of urinary tract dysfunction
(both sexes); increased incidence of focal cystic degereration in the
liver and increased rate of hepatic peroxisome beta-oxidation (males);
and an increased incidence of inflammatory and degenerative microscopic
lesions in the kidney (females). There was evidence of oncogenicity
based on an increased trend for kidney tubular combined adenoma/
carcinoma in male rats and an increased trend for kidney tubular
adenomas in female rats. Although the incidences were low, they were
statistically significant. The highest dose level tested in male rats
(5,000 ppm) was considered adequate for assessment of oncogenic
potential, that in female rats (15,000 ppm) exceeded the Maximum
Tolerated Dose (MTD).
6. Carcinogenicity. In consideration of PP 4F4391 the HED
Carcinogenicity Peer Review Committee has previously concluded that the
available data provide limited evidence of the carcinogenicity of
pyrithiobac sodium in mice and rats and has classified pryithiobac
sodium as a Group C (possible human carcinogen with limited evidence of
carcinogenicity in animals) in accordance with Agency guidelines
published in the Federal Register in 1986 (51 FR 33992, September 24,
1986) and recommend that for the purpose of risk characterization a
low-dose extrapolation model should be applied to the experimental
animal tumor data for quantification for human risk (Q1*). This
decision was based on liver adenomas, carcinomas and combined adenoma/
carcinomas in the male mouse and kidney tubular adenomas, carcinomas
and combined adenoma/carcinomas in the male rat. The unit risk, Q1*
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/day)-1 in
human equivalents based on male kidney tumors.
7. Animal metabolism. Disposition and metabolism of pyrithiobac
sodium were tested in male and female rats using two radiolabeled forms
of pyrithiobac sodium. Either phenyl-labeled or pryimidine-labeled
compounds were administered orally at 5 or 250 mg/kg. In addition, i.v.
administration was evaluated at 5 mg/kg. Essentially all of the dose
was excreted in the urine and feces, with greater than 90% being
excreted within 48 hours. No label was detected in the expired air.
Only minute quantities of radioactivity (at or near the limit of
detection) were detected in the major organs of metabolism and
excretion. This study indicates that pyrithiobac sodium has low
toxicity and does not accumulate within the body. The major compound
eliminated in urine and feces was O-DPS (desmethyl metabolite), formed
by demethylation of the pyrimidine ring. There was evidence that
conjugation with glucuronic acid and 5-hydroxylation of the pyrimidine
ring of pyrithiobac sodium were additional minor routes of metabolism
in the rat.
8. Metabolite toxicology. There is no evidence that the metabolites
of pyrithiobac sodium as identified in either the plant metabolism,
confined crop rotation, or animal metabolism studies are of any
toxicological significance.
9. Neurotoxicity. A 90-day rat neurotoxicity screen battery
conducted with pyrithiobac sodium resulted in a systemic NOEL of 7,000
ppm (466 and 588 mg/kg/day, M/F) and a systemic LOEL of 20,000 ppm
(1,376 and 1,609 mg/kg/day, M/F) based on reduced body weight gain and
food efficiency and increased liver weight. Slight reductions in hind-
leg grip strength and slightly increased foot splay in males were
observed in 20,000 ppm males. However, because these were of small
magnitude, lacked statistical significance and corresponding
histopathology, pyrithiobac sodium was not considered a neurotoxin. The
NOEL for neurotoxicity was 20,000 ppm [highest dose tested (HDT)].
10. Endocrine effects. No special studies investigating potential
estrogenic or other endocrine effects of pyrithiobac sodium have been
conducted. However, the standard battery of required toxicology studies
has been completed and found acceptable. These include an evaluation of
the potential effects on reproduction and development, and an
evaluation of the pathology of the endocrine organs following repeated
or long-term exposure to doses that far exceed likely human exposures.
Based on these studies there is no evidence to suggest that pyrithiobac
sodium has an adverse effect on the endocrine system.
C. Aggregate Exposure
1. Dietary exposure--i. Food. For purposes of assessing the
potential dietary exposure under this tolerance, an estimate of
aggregate exposure is made using the tolerance on cottonseed at 0.02
ppm. The potential exposure is obtained by multiplying the tolerance
level residues by the consumption data which estimates the amount of
cottonseed products translated as cottonseed meal and cottonseed oil
eaten by various population subgroups. Cottonseed is fed to animals,
thus exposure of humans to residues of cottonseed might result if such
residues are transferred to meat, milk, poultry, or eggs. However, in
consideration of PP 4F4391 CBTS has previously concluded that secondary
residues in meat, milk, poultry and eggs are not expected from the use
of cottonseed (undelinted) as an animal feed. There are no other
established tolerances or registered uses for pyrithiobac sodium in the
United States. Based on a NOEL of 58.7 mg/kg/day, from the chronic rat
toxicity study and a hundredfold safety factor, the reference dose
(RfD) is 0.58 mg/kg/day. Assuming residues at tolerance levels and that
100% of the crop is being treated, a theoretical maximum residue
contribution (TMRC) of <0.000001 mg/kg/day="" is="" calculated.="" with="" the="" above="" assumptions="" which="" clearly="" overestimate="" potential="" human="" exposure="" and="" are="" a="" most="" conservative="" assessment="" of="" risk,="" dietary="" (food)="" exposure="" to="" pyrithiobac="" sodium="" will="" utilize="" significantly="" less="" than="" 1%="" of="" the="" rfd="" for="" the="" overall="" us="" population.="" for="" the="" most="" highly="" exposed="" subgroup,="" children="" aged="" 1="" to="" 6="" years,="" the="" tmrc="" is="" 0.000001="" mg/kg/day,="" which="" is="" still="" less="" than="" 1%="" of="" the="" rfd.="" the="" unit="" risk,="">*
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/
day)-1 in human equivalents based on male kidney tumors. Based on this
upper bound potency factor (Q1*), a 70-year life-span, and
the assumption that 100% of the crop is treated with pyrithiobac
sodium, the upper-bound limit of a dietary carcinogenic risk is
calculated in the range of 1 incidence in a billion (1.0 x 10-
9).
ii. Drinking water. Other potential dietary sources of exposure of
the general population to pesticides are residues in drinking water.
There is no Maximum Contaminant Level established for residues of
pyrithiobac sodium. The petitioner has reported to the Environmental
Fate and Groundwater Branch of EPA (EFGWB) the interim results of a
prospective groundwater monitoring study conducted at a highly
vulnerable site. In consideration of this information in support of PP
4F4391 EFGWB has previously concluded by preliminary evaluation, that
pyrithiobac sodium may
[[Page 37244]]
not be stable enough to leach to groundwater at most use sites, even in
sandy soils. All other environmental fate data requirements for
pyrithiobac sodium have been satisfied and based on these studies and
the conditions of use, the potential for finding pyrithiobac sodium
residues in drinking water is minimal.
2. Non-dietary exposure. Pyrithiobac sodium is not registered for
any use which could result in non-occupational, non-dietary exposure to
the general population.
D. Cumulative Effects
Pyrithiobac sodium is based on a new chemical class; there are no
known registered herbicides with similar structure. Therefore, EPA
should consider only the potential risks of pyrithiobac sodium in its
exposure assessment. The herbicidal activity of pyrithiobac sodium is
due to the inhibition of acetolactate synthase (ALS), an enzyme only
found in plants. ALS is part of the biosynthetic pathway leading to the
formation of branched chain amino acids. Animals lack ALS and this
biosynthetic pathway. This lack of ALS contributes to the low toxicity
of pyrithiobac sodium in animals. There is no evidence to indicate or
suggest that pyrithiobac sodium 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 a complete and reliable toxicity
database, the EPA has adopted an RfD value of 0.58 mg/kg/day using the
NOEL of 58.7 mg/kg/day, from the 2-year chronic toxicity study in rats
and a hundredfold safety factor. Using crop tolerance levels and
assuming 100% of the crop being treated a Theoretical Maximum Residue
Contribution (TMRC) was calculated for the overall US population and 22
population subgroups. This analysis concluded that aggregate exposure
to pyrithiobac sodium will utilize significantly less that 1 percent of
the RfD for either the entire U.S. population or any subgroup
population. The TMRC for the most highly exposed subgroup identified as
children aged 1 thru 6 years was 0.000001 mg/kg/day. EPA generally has
no concern for exposure below 100 percent of the RfD because the RfD
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 a reasonable certainty that no harm will result from aggregate
exposure to pyrithiobac sodium residues. The unit risk, Q1*
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/
day)-1 in human equivalents based on male kidney tumors. Based on this
upper bound potency factor (Q1*) and assuming a 70 year
lifetime exposure an upper-bound limit of a dietary carcinogenic risk
is calculated in the range of 1 incidence in a billion (1.0 x 10-
9). This indicates a negligible cancer risk.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of pyrithiobac sodium,
data from the previously discussed developmental and reproduction
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 exposure to the
pesticide. Based on the weight of these data, pyrithiobac sodium was
not a reproductive toxicant. Maternal and developmental effects
(NOEL's, LOEL's) were comparable indicating no increase in
susceptibility of developing organisms. No evidence of endocrine
effects were noted in any study. FFDCA section 408 provides that EPA
may apply an additional safety factor for infants and children in the
case of threshold effects to account for pre and post-natal toxicity
and the completeness of the database. Based on current toxicological
data requirements, the database for pyrithiobac sodium relative to pre-
and post-natal effects for children is complete. The NOEL of 58.7 mg/
kg/day from the 2-year rat study with pyrithiobac sodium, which was
used to calculate the RfD, is lower than any of the NOEL's defined in
the developmental and reproductive toxicity studies with pyrithiobac
sodium. When the weight of these facts is considered an additional
safety factor is not warranted for developmental effects. As stated
above, aggregate exposure assessments utilized significantly less than
1% of the RfD for either the entire U.S. population or any of 22
population subgroups including infants and children. Therefore, it may
be concluded that there is reasonable certainty that no harm will
result to infants and children from aggregate exposure to pyrithiobac
sodium residues.
F. International Tolerances
There are no established Codex MRLs for pyrithiobac sodium on
cottonseed. An established Mexican tolerance for pyrithiobac sodium on
cottonseed is identical to the U.S. tolerance. Compatibility is not a
problem at this time. (James Tompkins)
4. Zeneca AG
PP 5F4588
EPA has received a pesticide petition (PP 5F4588) from Zeneca Ag
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, Delaware
19850-5458, proposing pursuant to section 408(d) of the Federal Food,
Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for combined residues of the insecticide
lambda-cyhalothrin and its epimer in or on the raw agricultural
commodities (RACs) alfalfa forage at 5.0 parts per million (ppm),
alfalfa hay at 6.0 ppm, leaf lettuce at 2.0 ppm, head and stem Brassica
crop subgroup at 0.4 ppm, aspirated grain fractions at 2.0 ppm and
increasing the existing time-limited tolerance for poultry fat to 0.03
ppm. The proposed analytical method is gas liquid chromatography with
an electron capture detector.
Pursuant to section 408 (d) (2) (A) (i) of the FFDCA, as amended,
Zeneca Ag Products has submitted the following summary of information,
data and arguments in support of their pesticide petition. This summary
was prepared by Zeneca and EPA has not fully evaluated the merits of
the petition. EPA edited the summary to clarify that the conclusions
and arguments were the petitioner's and not necessarily EPA's.
A. Residue Chemistry
1. Plant Metabolism. The metabolism of lambda-cyhalothrin in plants
is adequately understood for this use. Any secondary residues occurring
in meat and meat by-products will be covered by the existing tolerances
with the exception of the fat of poultry, which is discussed under
Magnitude of Residues.
2. Analytical method. An adequate analytical method (gas liquid
chromatography with an electron capture detector) is available for
enforcement purposes.
3. Magnitude of residues--i. Alfalfa. Sixteen field trials were
carried out on alfalfa forage and hay in twelve states during 1990 in
the USA. The trials were conducted in the states of Arizona,
California, Iowa, Idaho, Kansas, Michigan, Minnesota, Montana,
Nebraska, New York, South Dakota, and Wisconsin. The number and
geographical distribution of the trials agrees with the recommendation
given in the ``EPA Residue Chemistry Guidance'' (1994).
In these trials, the maximum combined residues of lambda-
cyhalothrin and epimer in or on alfalfa
[[Page 37245]]
forage is 5.0 ppm and alfalfa hay is 6.0 ppm.
ii. Leaf lettuce. Eight field trials were carried out on leaf
lettuce in eight states during 1990 in the USA. The trials were
conducted in Arizona, California, Colorado, Florida, Michigan, New
York, Texas, and Washington. The number and geographical distribution
of the trials agrees with the recommendation given in the ``EPA Residue
Chemistry Guidance'' (1994).
In these trials, the maximum combined residues of lambda-
cyhalothrin and epimer in or on leaf lettuce is 1.8 ppm.
iii. Head and stem Brassica crop subgroup. No additional residue
crop field data were conducted for the head and stem Brassica crop
subgroup. The tolerance request is based on existing data and the
existing time-limited tolerances for combined residues of lambda-
cyhalothrin and epimer in or the Brassica crops, cabbage, and broccoli
at 0.4 ppm.
iv. Aspirated grain fractions. The existing tolerance for wheat
grain dust at 2.0 ppm is being revised to read ``aspirated grain
fractions'' at the same tolerance level. This change reflects Agency
policy to establish grain dust tolerances in terms of aspirated grain
fractions which include a mixture of all aspirated grains for which the
pesticide has a tolerance and is established at the highest current
tolerance for any grain dust.
v. Poultry fat. Alfalfa forage, hay, meal and silage are animal
feed items for beef and dairy cattle. Alfalfa meal is a feed item for
poutry and swine. No feed items are involved with the proposed uses on
leaf lettuce and the head and stem Brassica crop subgroup. Based on
calculated realistic worst case secondary dietary burdens for animal
commodities, the maximum calculated residues expected for the fat of
poultry is 0.0225 ppm compared to the existing tolerance of 0.01 ppm.
B. Toxicological Profile
The following toxicity studies have been conducted to support the
request for a regulation for residues of lambda-cyhalothrin in or on
rice.
1. Acute toxicity. Acute toxicity studies with the technical grade
of the active ingredient lambda-cyahothrin: oral LD50 in the
rat of 79 mg/kg (males) and 56 mg/kg (females), dermal LD50
in the rat of 632 mg/kg (males) and 696 mg/kg females, primary eye
irritation study showed mild irritation and primary dermal irritation
study showed no irritation.
2. Genotoxicity. The following genotoxicity tests were all
negative: a gene mutation assay (Ames), a mouse micronucleus assay, an
in-vitro cytogenetics assay, and a gene mutation study in mouse
lymphoma cells.
3. Reproductive and developmental toxicity. A 3-generation
reproduction study in rats fed diets containing 0, 10, 30, and 100 ppm
with no developmental toxicity observed at 100 ppm, the highest dose
tested. The maternal NOEL (no-observed effect level) and LOEL (lowest
observed effect level) for the study are established at 30 (1.5 mg/kg/
day) and 100 ppm (5 mg/kg/day), respectively, based upon decreased
parental body weight gain. The reproductive NOEL and LOEL are
established at 30 (1.5 mg/kg/day) and 100 ppm (5 mg/kg/day),
respectively, based on decreased pup weight gain during weaning.
A developmental toxicity study in rats given gavage doses of 0, 5,
10, and 15 mg/kg/day with no developmental toxicity observed under the
conditions of the study. The developmental NOEL is greater than 15 mg/
kg/day, the highest dose tested. The maternal NOEL and LOEL are
established at 10 and 15 mg/kg/day, respectively, based on reduced body
weight gain.
A developmental toxicity study in rabbits given gavage doses of 0,
3, 10, and 30 mg/kg/day with no developmental toxicity observed under
the conditions of the study. The maternal NOEL and LOEL are established
at 10 and 30 mg/kg/day, respectively based on decreased body weight
gain. The developmental NOEL is greater than 30 mg/kg/day, the highest
dose tested.
4. Subchronic toxicity. A 90-day feeding study in rats fed doses of
0, 10, 50 and 250 ppm with a NOEL of 50 ppm and a LOEL of 250 ppm based
on body weight gain reduction.
A 21-day study in rabbits exposed dermally to doses of 0, 10, 100,
and 1,000 mg/kg/day, 6 hours/day, 5 days/week with a systemic NOEL
>1,000 mg/kg/kg. There were no clinical signs of systemic toxicity at
any dose level tested.
5. Chronic toxicity. A 12-month feeding study in dogs fed dose (by
capsule) levels of 0, 0.1, 0.5, 3.5 mg/kg/day with a NOEL of 0.1 mg/kg/
day. The LOEL for this study is established at 0.5 mg/kg/day based upon
clinical signs of neurotoxicity.
A 24-month chronic feeding/carcinogenicity study with rats fed
diets containing 0, 10, 50, and 250 ppm. The NOEL was established at 50
ppm and LOEL at 250 ppm based on reduced body weight gain. There were
no carcinogenic effects observed under the conditions of the study.
A carcinogenicity study in mice fed dose levels of 0, 20, 100, or
500 ppm (0, 3, 15, or 75 mg/kg/day) in the diet for 2 years. A systemic
NOEL was established at 100 ppm and systemic LOEL at 500 ppm based on
decreased body weight gain in males throughout the study at 500 ppm.
The Agency has classified lambda-cyhalothrin as a Group D carcinogen
(not classifiable due to an equivocal finding in this study). It is
Zeneca's position that no treatment-related carcinogenic effects were
observed under the conditions of the study.
6. Animal metabolism. Metabolism studies in rats demonstrated that
distribution patterns and excretion rates in multiple oral dose studies
are similar to single-dose studies. Accumulation of unchanged compound
in fat upon chronic administration with slow elimination. Otherwise,
lambda-cyhalothrin was rapidly metabolized and excreted. The metabolism
of lambda-cyhalothrin in livestock is also adequately understood for
the proposed use on alfalfa.
7. Metabolite toxicology. The Agency has previously determined that
the metabolites of lambda-cyhalothrin are not of toxicological concern
and need not be included in the tolerance expression. Given this
determination, it is concluded that there is no need to discuss
metabolite toxicity.
C. Aggregate Exposure
1. Dietary exposure--i Food. For the purposes of assessing the
potential dietary exposure for all existing and pending tolerances for
lambda-cyhalothrin, Zeneca has utilized available information on
anticipated residues and percent crop treated. For all existing and
pending tolerances the Anticipated Residue Contribution (ARC) is
estimated at 0.000310 mg/kg/bwt/day.
ii. Drinking water. Laboratory and field data have demonstrated
that lambda-cyhalothrin and its degradates are immobile in soil and
will not leach into groundwater. Other data show that lambda-
cyhalothrin is virtually insoluble in water and extremely lipophilic.
As a result, residues reaching surface waters from field runoff will
quickly adsorb to sediment particles and be partitioned from the water
column. Together these data indicate that residues are not expected in
drinking water.
2. Non-dietary exposure. Other potential sources of exposure are
from non-occupational sources such as structural pest control and
ornamental plant and lawn use of lambda-cyhalothrin. Zeneca has no data
upon which to estimate exposure from these
[[Page 37246]]
uses. However, given the extremely low vapor pressure of lambda-
cyhalothrin (1.5 x 10-9 millimeters of Hg) and the low use
rates, it is anticipated that inhalation and dermal exposure from these
uses will be insignificant.
D. Cumulative Effects
At this time, Zeneca cannot make a determination based on available
and reliable information that lambda-cyhalothrin and other substances
that may have a common mechanism of toxicity would have cumulative
effects. Therefore for purposes of these tolerances it is appropriate
only to consider the potential risks of lambda-cyhalothrin in an
aggregate exposure assessment.
E. Safety Determination
The acceptable Reference Dose (RfD) based on a NOEL of 0.1 mg/kg/
body weight/day from the chronic dog study and a safety factor of 100
is 0.001 mg/kg/body weight/day. A chronic dietary exposure/risk
assessment has been performed for lambda-cyhalothrin using the above
RfD. Available information on anticipated residues and percent crop
treated was incorporated into the analysis to estimate the Anticipated
Residue Contribution (ARC) for all existing and the proposed
tolerances. The ARC is generally considered a more realistic estimate
than an estimate based on tolerance level residues.
1. US population. The ARC from established tolerances and the
current and pending actions are estimated to be 0.000310 mg/kg/bwt/day
and utilize 31.04 per cent of the RfD for the U.S. population.
2. Infants and children. The ARC for children, aged 1 to 6 years
old, and nonnursing infants (subgroups most highly exposed) utilizes 60
and 67% of the RfD, respectively. Generally speaking, the Agency has no
cause for concern if anticipated residues contribution for all
published and proposed tolerances is less than the RfD.
F. International Tolerances
There are no Codex maximum residue levels [MRL] established for
residues of lambda-cyhalothrin in or on alfalfa hay, forage, leaf
lettuce, or Brassica crop subgroup. (George LaRocca)
[FR Doc. 97-18256 Filed 7-10-97; 8:45 am]
BILLING CODE 6560-50-F
