[Federal Register Volume 62, Number 242 (Wednesday, December 17, 1997)]
[Notices]
[Pages 66083-66091]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-32936]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-782; FRL-5759-1]
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-782, must
be received on or before January 16, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7502C), 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 to: docket@epamail.epa.gov. Follow 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:
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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-mail: Davis Hwy,
[email protected] Arlington, VA
.epa.gov.
James Tompkins (PM 25)........ Rm. 239, CM #2, 703- Do.
305-5697, e-mail:
tompkins.james@epamai.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment 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-782] (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 or ASCII file
format. All comments and data in electronic form must be identified by
the docket control number [PF-782] 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: December 3, 1997.
Peter Caulkins,
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.
[[Page 66084]]
1. DowElanco
PP 6F4772
EPA has received a pesticide petition (PP 6F4772) 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 establishing a tolerance for
residues of fluroxypyr methylheptyl ester (MHE) and its only
significant metabolite fluroxypyr, free and conjugated, all expressed
as fluroxypyr in or on the raw agricultural commodities wheat, barley,
and oats as follows: 0.5 parts per million (ppm) (grain), 10 ppm (straw
and forage), 20 ppm (hay), and 0.5 ppm (aspirated grain fractions,
wheat). Because residues of fluroxypyr MHE or fluroxypyr, free or
conjugated, may occur in animal feeds derived from wheat, barley, and
oats, the following meat and milk tolerances are also being proposed:
0.1 ppm (meat, fat, milk, and meat byproducts except for kidney) and
0.5 ppm (kidney). The proposed analytical method is based on gas
chomatography (GC) with mass spectral (MS) detection. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of fluroxypyr MHE in plants
(wheat) and animals (goats and poultry) is adequately understood for
the purposes of this tolerance. A rotational crop study showed no
carryover of significant fluroxypyr MHE related residues in
representative test crops except for cereal grains for which tolerances
are being proposed.
2. Analytical method. There is a practical method (GC with MS
detection) for measuring levels of fluroxypyr MHE in or on food with a
limit of detection that allows monitoring of food with residues at or
above the levels set for the proposed tolerances. Fluroxypyr has been
tested through the FDAs Multiresidue Methodology, Protocols C, D. and
E. The results have been published in the FDA Pesticide Analytical
Manual, Volume I.
3. Magnitude of residues. Magnitude of residue studies were
conducted for wheat, barley, and oats. Residues of fluroxypyr MHE did
not concentrate in process fractions in samples treated at a 7.5 X
application rate.
B. Toxicological Profile
1. Acute toxicity. Fluroxypyr MHE has low acute toxicity. The rat
oral LD50 is >5000 mg/kg, the rabbit dermal LD50
is >2000 mg/kg, and the rat inhalation LC50 is >1.0 mg/l
(1,000 mg/cubic meter), the maximum attainable concentration. In
addition, fluroxypyr MHE is not a skin sensitizer in guinea pigs, has
no dermal irritation in rabbits, and shows mild ocular irritation in
rabbits. The end use formulation of fluroxypyr MHE has a similar low
acute toxicity profile.
2. Genotoxicity. Short term assays for genotoxicity consisting of a
bacterial reverse mutation assay (Ames test), an in vitro assay for
cytogenetic damage using the Chinese hamster ovary cells, an in
vitrochromosomal aberration assay using rat lymphocytes, and an in vivo
cytogenetic assay in the mouse bone marrow (micronucleus test) have
been conducted with fluroxypyr MHE. DowElanco believes that these
studies show a lack of genotoxicity. In addition, short term assays for
genotoxicity consisting of an Ames metabolic activation test, point
mutations at the HGPRT-Locus of Chinese hamster ovary cells, in vivo
and in vitro chromosomal aberrations in the Chinese hamster ovary
cells, unscheduled DNA synthesis in human embryonic cells, and an assay
in mouse lymphoma cells have been conducted with fluroxypyr. DowElanco
believes that the weight of evidence also indicates a lack of
genotoxicity.
3. Reproductive and developmental toxicity. Developmental studies
in rats and rabbits were conducted with both fluroxypyr MHE and
fluroxypyr. Studies with fluroxypyr MHE showed maternal and fetal no
observed effect levels (NOELs) of 300 milligram/kilogram (mg/kg/day)
(rat) and 500 mg/kg/day (rabbit). Studies with fluroxypyr showed no
observed adverse effect levels (NOAELs) in the rat of 250 mg/kg/day for
maternal effects and 500 mg/kg/day for fetal effects and a NOEL in the
rabbit of 250 mg/kg/day for both maternal and fetal effects. DowElanco
believes that these studies show that fluroxypyr and fluroxypyr MHE are
not teratogenic nor will they interfere with in utero development. Two
multi-generation reproduction studies were conducted with fluroxypyr in
rats. The first in Wistar rats showed no effect on fertility or
reproductive performance and had a NOAEL of 500 mg/kg/day (highest dose
tested). The second study in Sprague-Dawley rats showed a parental NOEL
for systemic effects of 100 mg/kg/day in male rats and 500 mg/kg/day in
female rats. The NOEL for reproductive effects was 750 mg/kg/day for
males and 1,000 mg/kg/day for females (highest dose tested). The NOEL
for neonatal effects was 500 mg/kg/day.
4. Subchronic toxicity. Fluroxypyr MHE showed a NOEL of 1,000 mg/
kg/day in a 90-day rat dietary study and a 21-day rabbit dermal study.
Ninety day feeding studies with fluroxypyr showed NOELs of 80 mg/kg/day
(Wistar rats), 700 mg/kg/day (Fischer 344 rats), 1342 mg/kg/day (male
mice), and 1,748 mg/kg/day (female mice). In a 4-week dietary, range
finding study with fluroxypyr in dogs the NOEL was >50 mg/kg/day.
5. Chronic toxicity. Based on chronic testing with fluroxypyr in
the mouse, dog, and rat (two studies), a reference dose (RfD) of 0.8
mg/kg/day is proposed for fluroxypyr and fluroxypyr MHE. The RfD has
incorporated a 100-fold safety factor to the NOEL found in the rat
chronic test. NOELs found in the chronic dietary studies are as
follows: 150 mg/kg/day (dog), 300 mg/kg/day (mouse), 80 mg/kg/day
(Wistar rats), 100 mg/kg/day (male Fischer 344 rats), and 500 mg/kg/day
(female Fischer 344 rats).
6. Animal metabolism. Both fluroxypyr and fluroxypyr MHE have been
evaluated in rat metabolism studies. In summary, these studies show
that fluroxypyr MHE is rapidly hydrolyzed and the fate of the
hydrolysis products, fluroxypyr and 1-methylheptanol, are independent
of whether they were given as the ester or the acid. Fluroxypyr, per
se, was extensively absorbed and rapidly excreted principally unchanged
in the urine. 1-Methylheptanol also was rapidly absorbed and rapidly
eliminated. Repeated administration of fluroxypyr MHE was not
associated with accumulation in tissues. Also, the metabolism and
pharmacokinetics of methylheptanol are comparable to that of the
methylheptyl portion of fluroxypyr MHE.
7. Metabolite toxicology. Administration of fluroxypyr, as the acid
or methylheptyl ester, in a variety of toxicological studies has
produced similar effects. The principal response to sufficiently high
dosages, whether administered over the short-term or, in some cases,
over a lifetime, was nephrosis. Fluroxypyr is an organic acid that is
actively excreted into the urine by the kidney. Thus, the target organ
and dose response relationship for fluroxypyr toxicity are entirely
consistent with the data on the toxicokinetics of fluroxypyr.
Metabolism studies have shown that fluroxypyr MHE is rapidly and
completely hydrolyzed to fluroxypyr acid and methylheptanol.
[[Page 66085]]
8. Carcinogenicity. Using the Guidelines for Carcinogen Risk
Assessment published September 24, 1986 (51 FR 33992), it is proposed
that fluroxypyr and fluroxypyr MHE be classified as Group E for
carcinogenicity (no evidence of carcinogenicity) based on the results
of carcinogenicity studies in two species. DowElanco believes that
there was no evidence of carcinogenicity in an 18-month mouse feeding
study and a 24-month rat feeding study at all dosages tested. The NOELs
shown in the mouse and rat oncogenicity studies were 1,000 and 320 mg/
kg/day, respectively. A maximum tolerated dose was achieved at the top
dosage level tested in both of these studies based on excessive renal
toxicity. Thus, the doses tested are adequate for identifying a cancer
risk. Accordingly, DowElanco believes that a cancer risk assessment is
not needed.
9. Endocrine effects. There is no evidence to suggest that
fluroxypyr and fluroxypyr HME have an effect on any endocrine system.
C. Aggregate Exposure
1. Dietary exposure--i. Food. An over estimation of dietary
exposure from use of fluroxypyr MHE on wheat, barley, oats is
determined by basing the TMRC on the conservative assumptions that all
cereal grain commodities will have tolerance level residues of
fluroxypyr and that 100% of the wheat, barley, and oat crops grown in
the U.S. are treated with fluroxypyr MHE. The TMRC is obtained by
multiplying the tolerance residue levels by the consumption data which
estimates the amount of crops and related foodstuffs consumed by
various population subgroups. There are no other established U.S.
tolerances or exemption from tolerances for fluroxypyr MHE and no other
registered uses for fluroxypyr MHE on food or feed crops in the United
States. The use of a tolerance level and 100% of crop treated clearly
results in an overestimate of human exposure and a safety determination
for the use of fluroxypyr MHE on wheat, barley, and oats that is based
on a conservative exposure assessment.
ii. Drinking water. Another potential source of dietary exposure
are residues in drinking water. Based on the available environmental
studies conducted with fluroxypyr MHE and fluroxypyr wherein the
properties of these materials show little persistence in the soil
environment, there is no anticipated exposure to residues of fluroxypyr
MHE and fluroxypyr in drinking water. In addition, there is no
established Maximum Concentration Level for residues of fluroxypyr MHE
and fluroxypyr in drinking water.
2. Non-dietary exposure. There are no other uses currently
registered for fluroxypyr MHE and fluroxypyr. The proposed use on
wheat, barley, and oats involves application of fluroxypyr MHE to crops
grown in an agriculture environment. Thus, the potential for non-
occupational exposure to the general population is not expected to be
significant.
D. Cumulative Effects
The potential for cumulative effects of fluroxypyr MHE and
fluroxypyr and other substances that have a common mechanism of
toxicity is also considered. There is no reliable information to
indicate that toxic effects produced by fluroxypyr MHE and fluroxypyr
would be cumulative with those of any other pesticide chemical. Thus,
it is appropriate to consider only the potential risks of fluroxypyr
MHE and fluroxypyr in an aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions and
the proposed RfD, the dietary exposure to fluroxypyr MHE use on wheat,
barley, and oats will utilize 0.2% of the RfD for the U.S. population.
EPA generally has no concern for exposures below 100% of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. Since there are no anticipated residues in drinking water
or from other non-occupational sources and no reliable information
exists on cumulative effects due to common mechanism of toxicity, the
aggregate exposure to fluroxypyr MHE is adequately represented by the
dietary route. Thus, DowElanco believes that there is reasonable
certainty that no harm will result from aggregate exposure to
fluroxypyr MHE residues on wheat, barley, and oats.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fluroxypyr MHE, data
from developmental toxicity studies in rats and rabbits and a 2-
generation reproduction study in the rat are considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development. Reproduction studies provide information relating
to effects from exposure to the pesticide on the reproductive
capability and potential systemic toxicity of mating animals and on
various parameters associated with the well-being of pups.
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 for fluroxypyr MHE relative to pre- and post-natal effects for
children is complete. Further, for fluroxypyr MHE, the NOEL in the
chronic feeding studies which was used to calculate the RfD (0.8 mg/kg/
day) is already lower than the NOELs from the developmental studies in
rats and rabbits by a factor of more than three.
Concerning the reproduction studies in rats, the pup effects shown
at the highest dose tested (1,000 mg/kg/day) were attributed to
maternal toxicity. Therefore, DowElanco concludes that an additional
uncertainty factor is not needed and that the RfD at 0.8 mg/kg/day is
appropriate for assessing risk to infants and children.
As noted above for the general U.S. population, aggregate exposure
for infants and children will result from the dietary (i.e. not
drinking water or non-occupational) route of exposure. In addition,
there is no reliable information that shows cumulative effects based on
a common mechanism of toxicity for infants and children. Using the
conservative exposure assumptions previously described, the percent RfD
utilized by the aggregate dietary exposure to residues of fluroxypyr
MHE on wheat, barley, and oats is 0.6% for children 1 to 6 years old,
the most sensitive population subgroup. Thus, based on the completeness
and reliability of the toxicity data and the conservative exposure
assessment, DowElanco believes that there is a reasonable certainty
that no harm will result to infants and children from aggregate
exposure to fluroxypyr MHE residues on wheat, barley, and oats.
F. International Tolerances
There are no Codex maximum residue levels established for residues
of fluroxypyr MHE and fluroxypyr on any food or feed crop. (J. Miller)
2. E.I. du Pont de Nemours and Company
PP 1F4032
EPA has received a pesticide petition (PP 1F4032) from E.I. du Pont
de Nemours and Company, Barley Mill Plaza, Walker's Mill Bldg. 37,
Wilmington, DE 19880-0038, proposing
[[Page 66086]]
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 ethametsulfuron in or on the raw agricultural commodity
canola at 0.1 ppm. EPA has determined that the petition contains data
or information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
ethametsulfuron methyl is adequately understood. The unmetabolized
parent compound was the major residue found in a canola metabolism
study up to 30 days after application. The principal route of metabolic
breakdown of ethametsulfuron methyl in canola is dealkylation from the
triazine ring. The initial step in the metabolic breakdown is
deethylation to form O-deethyl ethametsulfuron methyl. Further
metabolism forms N-demethyl-O-deethyl ethametsulfuron methyl and more
minor polar metabolites. For purposes of establishing the proposed
tolerance, the parent compound ethametsulfuron methyl is the only
residue of concern.
The available metabolism studies indicate that total radioactive
residues found in mature seeds, when rapeseed was treated at a rate
equivalent to the proposed application rate, ranged from 0.008 to 0.012
ppm. These terminal residues may consist of the parent compound, O-
deethyl ethametsulfuron methyl, O-deethyl-N-demethyl ethametsulfuron
methyl and other minor metabolites.
2. Analytical method. Analytical methods are available to measure
the parent compound in oil seeds, and in oil seed processing fractions.
The quantification of ethametsulfuron methyl is by normal phase high
performance liquid chromatography (HPLC) using a photoconductivity
detector. The Limit of Quantitation (LOQ) for the analytical method is
0.02 ppm.
3. Magnitude of residues--i. Magnitude of the residue in plants.
The results of the seed analyses from canola/seed show that no
detectable residues of ethametsulfuron methyl were found in canola/seed
harvested 60 to 137 days after treatment at exaggerated rates of 3X of
the normal application rate.
ii. Magnitude of the residue in processed commodities. Analyses of
canola processed fractions (whole seed, pressed cake, desolventized
meal, crude oil, pressed oil, solvent extracted oil, degummed oil,
refined washed oil, refined bleached oil, and deodorized oil) show that
levels of ethametsulfuron methyl were found to be less than 0.02 ppm,
the limit of quantitation of the method in all of the fractions
evaluated. All of the processed fractions were obtained from seed
harvested 92 days after application at proposed use rates and
exaggerated rates.
B. Toxicological Profile
1. Acute toxicity. Based on EPA criteria, ethametsulfuron methyl is
relatively non-toxic, and be categorized as Toxicity Category IV (oral
and inhalation routes) and Category III (dermal exposure).
LD50s are >5,000 mg/kg for acute oral toxicity in rats,
>2,000 mg/kg for acute dermal toxicity in rabbits, and >5.7 mg/L for
acute inhalation toxicity in rats. For technical grade active
ingredient, primary eye irritation in rabbits is classified as Tox Cat
II. For formulated product, primary eye irritation in rabbits is
classified as Tox Cat IV. Primary dermal irritation in rabbits is
classified as Tox Cat IV. Dermal sensitization in guinea pigs is
classified as ``Not a skin sensitizer.''
2. Genotoxicity. This compound was negative in the following tests
that have been conducted to determine the genotoxic and mutagenic
potential of ethametsulfuron methyl: Mutagenicity assays conducted in
bacteria (Ames test) and in cultured Chinese Hamster Ovary cells; a
test that measures the induction of chromosomal aberrations in bone
marrow cells isolated from rats treated with ethametsulfuron methyl;
micronuclei induction in bone marrow cells from mice; and negative in a
text that measures DNA damage in cultured rat liver cells. Based on the
weight of these data, E.I du Pont concludes that ethametsulfuron methyl
is neither genotoxic or mutagenic.
3. Reproductive and developmental toxicity. A 2-generation, four
litter reproduction study with CD rats treated with dietary levels of
0, 250, 5,000, 20,000 ppm of ethametsulfuron methyl failed to reveal
any evidence suggestive of an adverse effect on reproductive potential.
A NOEL was indicated at the mid dose level of 5,000 ppm (equivalent to
approx. 433 mg/kg b.w./day, actual intake) based on significantly
(p<0.5) decreased="" body="" weights="" in="" the="" high="" dose="" treated="" f0="" and="" f1="" generation="" males.="" a="" developmental="" toxicity="" study="" of="" ethametsulfuron="" methyl="" in="" rabbits="" indicated="" that="" dams="" administered="" 4,000="" mg/kg="" (highest="" dose="" tested)="" had="" a="" higher="" mortality="" rate,="" lower="" food="" consumption="" and="" body="" weight="" gains,="" increased="" incidences="" of="" gross="" clinical="" signs="" of="" toxicity="" and="" of="" abortions,="" and="" increased="" absolute="" and="" relative="" liver="" weights.="" absolute="" and="" relative="" liver="" weights="" were="" also="" slightly="" greater="" for="" dams="" administered="" 1,000="" mg/kg.="" there="" were="" no="" compound-related="" effects="" observed="" for="" dams="" administered="" 250="" mg/kg.="" dams="" administered="" 4,000="" mg/kg="" also="" had="" a="" decrease="" in="" the="" number="" of="" live="" fetuses.="" this="" was="" related="" to="" an="" increase="" in="" the="" number="" of="" early="" resorptions.="" there="" were="" no="" other="" compound-related="" effects="" on="" the="" dams,="" nor="" were="" there="" any="" effects="" on="" fetal="" weights,="" malformations="" or="" variations="" incidences.="" the="" noels="" for="" this="" study="" were="" 250="" mg/kg="" for="" the="" dams="" and="" 1,000="" mg/kg="" for="" the="" fetus.="" ethametsulfuron="" methyl="" was="" neither="" teratogenic="" in="" rabbits="" nor="" uniquely="" toxic="" to="" the="" conceptus.="" a="" developmental="" toxicity="" study="" was="" also="" conducted="" in="" rats="" treated="" at="" doses="" of="" 0,="" 60,="" 250,="" 1,000,="" or="" 4,000="" mg/kg.="" among="" the="" dams="" of="" the="" groups="" given="" ethametsulfuron="" methyl,="" no="" compound-related="" mortality="" or="" clinical="" abnormalities="" were="" observed.="" for="" the="" treatment="" period,="" the="" high="" dose="" group="" had="" a="" lower="" weight="" gain="" and="" significantly="" decreased="" food="" consumption="" compared="" to="" the="" control="" group.="" no="" other="" significant="" differences="" in="" body="" weight="" changes="" or="" food="" consumption="" were="" observed.="" a="" significant="" trend="" was="" indicated="" for="" mean="" fetal="" weight="" and="" the="" mean="" fetal="" weight="" of="" the="" high="" dose="" group="" was="" lower="" than="" that="" of="" the="" control="" group.="" no="" significant="" differences="" were="" observed="" in="" the="" rates="" of="" malformations="" or="" developmental="" variations.="" under="" the="" conditions="" of="" the="" study,="" the="" apparent="" no="" effect="" level="" for="" the="" dam="" and="" fetus="" was="" 1,000="" mg/="" kg/day.="" thus="" ethametsulfuron="" methyl="" was="" not="" uniquely="" toxic="" to="" the="" conceptus="" nor="" was="" it="" teratogenic="" in="" rats.="" 4.="" subchronic="" toxicity--i.="" rat.="" a="" 90-day="" feeding="" study="" followed="" by="" a="" 1-generation="" reproduction="" phase="" in="" rats="" at="" dietary="" levels="" of="" 0,="" 100,="" 1,000,="" and="" 5,000="" ppm="" of="" ethametsulfuron="" methyl="" failed="" to="" elicit="" any="" signs="" of="" overt="" toxicity="" or="" any="" adverse="" effect="" on="" reproductive="" performance="" at="" levels="" as="" high="" as="" 5,000="" ppm="" (equivalent="" to="" 0.5%="" of="" the="" diet="" or="" approximately="" 409="" mg/kg="" b.w./day,="" actual="" intake).="" the="" no="" observed="" adverse="" effect="" level="" (noael)="" for="" this="" study="" was,="" therefore,="" the="" high="" dose="" level="" of="" 5,000="" ppm.="" ii.="" mouse.="" a="" 90-day="" dietary="" feeding="" study="" in="" cd-1="" mice="" at="" levels="" of="" 0,="" 50,="" 500,="" 2,500="" and="" 5,000="" ppm="" indicated="" a="" no="" observed="" effect="" level="" (noel)="" for="" females="" and="" a="" noael="" for="" males="" set="" at="" [[page="" 66087]]="" the="" high="" dose="" level="" of="" 5,000="" ppm="" (equivalent="" to="" approximate="" 687="" mg/kg="" b.w./day,="" actual="" intake="" for="" males).="" iii.="" dog.="" dietary="" administration="" of="" technical="" ethametsulfuron="" methyl="" to="" dogs="" for="" 90="" days="" at="" levels="" of="" 0,="" 100,="" 3,500="" or="" 10,000="" ppm="" failed="" to="" reveal="" any="" evidence="" of="" treatment-related="" toxicity="" at="" levels="" as="" high="" as="" 10,000="" ppm="" (equivalent="" to="" 1%="" of="" the="" diet="" or="" approximately="" 386="" mg/kg="" b.w./day,="" based="" on="" actual="" intake).="" 5.="" chronic="" toxicity--i.="" rat.="" administration="" of="" ethametsulfuron="" methyl="" to="" sprague-dawley="" rats="" for="" up="" to="" 24="" months="" at="" dietary="" levels="" of="" 0,="" 50,="" 500="" and="" 5,000="" ppm="" revealed="" a="" noael="" for="" in-life="" parameters="" of="" 5,000="" ppm="" (equivalent="" to="" 238.5="" mg/kg="" b.w./day,="" actual="" intake),="" based="" on="" questionable="" toxicological="" significance="" of="" decreased=""><0.05) serum="" sodium="" levels="" in="" both="" the="" 5,000="" ppm="" treated="" males="" and="" females="" during="" the="" first="" 12="" months="" of="" treatment.="" the="" effects="" on="" serum="" sodium="" levels="" in="" the="" high="" dose="" groups="" were="" described="" as="" mild="" (representing="" a="" decrease="" in="" 2-6%="" of="" the="" control="" values)="" and="" occurring="" in="" the="" absence="" of="" any="" associated="" pathological="" changes="" in="" the="" kidney.="" treatment="" with="" the="" test="" material="" at="" dietary="" levels="" as="" high="" as="" 5,000="" ppm="" (equivalent="" to="" 0.5%="" of="" the="" diet)="" failed="" to="" elicit="" any="" evidence="" of="" treatment-related="" neoplastic="" potential.="" ii.="" dogs.="" chronic="" dietary="" administration="" of="" the="" test="" material="" to="" dogs="" at="" levels="" of="" 0,="" 250,="" 3,000="" and="" 15,000="" ppm="" for="" 1-year="" indicated="" a="" noel="" of="" 3,000="" ppm,="" equivalent="" to="" approximately="" 87="" mg/kg="" b.w./day="" actual="" intake,="" based="" on="" compound-related="" effects="" expressed="" in="" the="" 15,000="" ppm="" treated="" group="" as="" decreased="" body="" weight="" gain="" and="" food="" efficiency="" values="" in="" the="" males.="" significantly="" decreased="" serum="" sodium="" levels="" in="" both="" sexes="" at="" the="" high="" dose="" treated="" level="" were="" not="" associated="" with="" any="" evidence="" of="" renal="" pathology.="" in="" the="" absence="" of="" any="" collaborative="" clinical="" or="" pathological="" findings="" differences="" in="" organ="" weights="" relative="" to="" body="" or="" brain="" weight="" were="" considered="" to="" be="" of="" doubtful="" biological="" significance.="" iii.="" mouse.="" administration="" of="" the="" test="" material="" to="" cd-1="" mice="" at="" dietary="" levels="" of="" 0,="" 25,="" 500,="" and="" 5,000="" ppm="" for="" the="" period="" of="" up="" to="" 78="" weeks="" failed="" to="" reveal="" any="" overt="" signs="" of="" treatment-related="" toxicity="" of="" dietary="" levels="" of="" up="" to="" 5,000="" ppm="" (equivalent="" to="" 818="" mg/kg="" bwt/day,="" actual="" intake).="" although="" a="" direct="" effect="" of="" treatment="" on="" body="" weights="" or="" weight="" gains="" could="" not="" be="" established,="" overall="" body="" weight="" gain="" in="" the="" 5,000="" ppm="" treated="" male="" mice="" was="" depressed="" (non-significant,="" p="">0.05)
by 10% when compared to the controls. There was no evidence of any
treatment-related oncogenic potential.
6. Animal metabolism. When administered via oral gavage to rats,
ethametsulfuron methyl was rapidly metabolized and excreted in the
urine and feces. Within 3 days, greater than 90% of the administered
dose was excreted by male rats and greater than 80% was excreted by
females. Approximately 50% of the administered dose was excreted as
unchanged ethametsulfuron methyl. The remainder was converted
predominately to N-demethyl ethametsulfuron methyl and O-deethyl
ethametsulfuron methyl, which are considered by by-products of
cytochrome P450-mediated reactions. Less than 0.02% of the administered
dose remained in the carcass or tissues. There was no significant or
preferential accumulation of ethametsulfuron methyl or its metabolites
in any tissue. Because of the short excretion half-life, repeated daily
exposures are not expected to result in significant body burdens of
ethametsulfuron methyl.
7. Metabolite toxicology. There is no evidence that the metabolites
of ethametsulfuron methyl as identified as either the plant or animal
metabolism studies are of any toxicological significance.
8. Endocrine effects. No special studies investigating potential
estrogenic or endocrine effects of ethametsulfuron methyl have been
conducted. However, the standard battery of required toxicology studies
have been completed. 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. Based on these studies there is no evidence to suggest that
ethametsulfuron methyl has an effect on the endocrine system.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Based on the residue data and the
proposed single-crop use, potential for dietary exposure of
ethametsulfuron methyl from food sources is extremely low. Residue
studies have shown no residues above the LOQ (residues <0.02 ppm)="" in="" any="" canola="" seed="" samples="" evaluated,="" including="" the="" canola="" oil="" processed="" fractions.="" no="" dietary="" exposure="" is="" anticipated="" from="" secondary="" residues="" in="" meat="" or="" milk.="" although="" canola="" meal="" is="" considered="" a="" minor="" feedstuff="" for="" cattle="" and="" poultry="" (representing="" a="" maximum="" of="" 15%="" of="" an="" animal's="" diet),="" field="" residue="" studies="" showed="" ethametsulfuron="" methyl="" residues="" were="" all="" below="" the="" loq=""><0.02 ppm)="" in="" all="" of="" the="" canola="" racs="" and="" processed="" fractions,="" including="" meal,="" even="" when="" the="" crop="" was="" treated="" at="" 2-3x="" the="" proposed="" maximum="" use="" rate.="" direct="" human="" consumption="" of="" canola="" as="" a="" food="" commodity="" in="" the="" united="" states="" is="" extremely="" low.="" canola="" is="" a="" minor="" crop="" in="" the="" u.s.,="" and="" the="" only="" canola="" fraction="" used="" as="" a="" food="" product="" is="" the="" refined="" canola="" oil.="" a="" dietary="" risk="" evaluation="" (dres)="" was="" conducted="" to="" determine="" the="" theoretical="" maximum="" residue="" contribution="" of="" ethametsulfuron="" methyl="" in="" the="" diet="" as="" a="" result="" of="" agricultural="" use="" on="" canola.="" unfortunately,="" consumption="" data="" for="" canola="" oil="" does="" not="" exist="" in="" the="" 1977-1979="" food="" consumption="" database="" used="" in="" epa's="" dres="" system,="" since="" at="" that="" time,="" canola="" oil="" was="" not="" a="" significant="" part="" of="" the="" u.s.="" diet.="" since="" 1977="" more="" canola="" oil="" is="" used="" in="" u.s.="" homes,="" although="" total="" production="" and="" usage="" are="" still="" minor="" when="" compared="" to="" other="" edible="" oils="" such="" as="" soybean="" oil.="" conservative="" assumptions="" were="" used="" to="" estimate="" canola="" consumption="" in="" the="" united="" states.="" the="" usda's="" oilseed="" analysis="" division="" has="" indicated="" that="" an="" average="" of="" 1.1="" billion="" pounds="" of="" canola="" oil="" was="" used="" in="" the="" united="" states="" annually="" over="" the="" past="" 5="" years.="" the="" dietary="" exposures="" that="" might="" occur="" by="" way="" of="" canola="" oil="" consumption="" can="" be="" estimated="" by="" taking="" the="" average="" annual="" use="" of="" canola="" oil="" in="" the="" united="" states="" (includes="" both="" domestically="" produced="" and="" imported="" canola="" oils)="" and="" dividing="" it="" by="" the="" approximate="" us="" population="" of="" 266.3="" million="" people.="" this="" provides="" a="" per-capita="" consumption="" estimate="" for="" the="" general="" population.="" using="" this="" approach,="" total="" canola="" oil="" consumption="" on="" a="" grams="" per="" kg="" body="" weight="" per="" day="" was="" calculated="" by="" dividing="" by="" the="" average="" days="" in="" a="" year="" and="" average="" body="" weight="" of="" a="" person="" (60="" kg).="" the="" 60="" kg="" value="" is="" used="" by="" the="" us="" epa="" as="" part="" of="" their="" ``food="" factor''="" system,="" and="" is="" also="" supported="" by="" taking="" the="" average="" weight="" of="" children="" between="" the="" ages="" of="" 6="" months="" to="" 19="" years="" (36="" kg)="" and="" the="" average="" weight="" of="" adults="" of="" 70="" kg="" and="" assuming="" a="" 69="" year="" life="" span="" (as="" proposed="" in="" the="" review="" draft="" of="" the="" us="" epa's="" exposure="" factors="" handbook).="" using="" these="" assumptions,="" canola="" oil="" consumption="" was="" calculated="" to="" be="" 0.088="" g/kg="" bw/="" day.="" while="" this="" method="" provides="" a="" useful="" approximation="" of="" canola="" consumption,="" this="" is="" clearly="" a="" conservative="" estimate="" for="" risk="" assessment="" purposes,="" since="" this="" estimate="" assumes="" that="" all="" of="" the="" canola="" oil="" used="" in="" the="" us="" is="" indeed="" ingested.="" in="" reality,="" not="" all="" the="" oil="" that="" is="" used="" in="" cooking="" or="" deep-fat="" frying="" is="" consumed="" but="" instead,="" is="" discarded="" or="" recycled.="" another="" indication="" that="" the="" consumption="" value="" of="" 0.088="" g/kg="" bw/day="" is="" an="" over-estimate="" is="" from="" the="" usda's="" 1989-1992="" food="" survey="" (not="" yet="" included="" in="" the="" epa's="" dres="" system),="" [[page="" 66088]]="" which="" indicates="" canola="" oil="" consumption="" is="" 0.00023="" g/kg/day="" for="" the="" general="" u.s.="" population.="" using="" the="" consumption="" estimate="" of="" 0.088="" g="" canola="" oil/="" kg="" bw/day="" for="" the="" general="" us="" population,="" and="" assuming="" that="" 100%="" of="" the="" canola="" crop="" is="" treated="" with="" ethametsulfuron="" methyl="" and="" all="" canola="" consumed="" contains="" residues="" at="" the="" proposed="" tolerance="" level="" of="" 0.1="" ppm,="" the="" theoretical="" maximum="" residue="" contribution="" of="" ethametsulfuron="" methyl="" in="" the="" diet="" is="" calculated="" to="" be="" 0.00001="" mg/kg/day="" or=""><0.01% of="" the="" rfd="" of="" 0.87="" mg/kg/="" day.="" ii.="" drinking="" water.="" another="" potential="" source="" of="" dietary="" exposure="" to="" pesticides="" are="" residues="" in="" drinking="" water.="" there="" is="" no="" established="" maximum="" concentration="" level="" (mcl)="" for="" ethametsulfuron="" methyl="" in="" water.="" based="" on="" the="" low="" use="" rate="" of="" ethametsulfuron="" methyl,="" and="" a="" use="" pattern="" that="" is="" not="" widespread="" (since="" the="" only="" proposed="" use="" is="" on="" a="" minor="" crop),="" dupont="" does="" not="" anticipate="" residues="" of="" ethametsulfuron="" in="" drinking="" water="" and="" exposure="" from="" this="" route="" is="" unlikely.="" 2.="" non-dietary="" exposure.="" ethametsulfuron="" methyl="" is="" not="" registered="" for="" any="" use="" which="" could="" result="" in="" non-occupational,="" non-dietary="" exposure="" to="" the="" general="" population.="" ethametsulfuron="" methyl="" is="" a="" herbicide="" with="" proposed="" use="" only="" on="" canola.="" there="" are="" no="" other="" food="" uses,="" nor="" are="" there="" any="" residential="" or="" non-crop="" uses="" of="" this="" active="" ingredient.="" therefore,="" the="" only="" potential="" for="" non-occupational="" aggregate="" exposure="" would="" come="" from="" dietary="" intake.="" d.="" cumulative="" effects="" ethametsulfuron="" methyl="" belongs="" to="" the="" sulfonylurea="" class="" of="" compounds.="" other="" compounds="" in="" this="" class="" are="" registered="" herbicides.="" however,="" the="" herbicidal="" activity="" of="" the="" sulfonylureas="" is="" due="" to="" the="" inhibition="" of="" acetolactase="" 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="" the="" sulfonylurea="" compounds="" in="" animals.="" there="" is="" no="" evidence="" to="" indicate="" or="" suggest="" that="" ethametsulfuron="" methyl="" has="" any="" toxic="" effects="" on="" mammals="" that="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemicals.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" most="" sensitive="" species="" chronic="" noel="" of="" 87="" mg/kg="" and="" a="" reference="" dose="" (rfd)="" of="" 0.87="" mg/kg/day,="" the="" proposed="" use="" of="" ethametsulfuron="" methyl="" on="" canola="" is="" expected="" to="" utilize="" 0.001%="" of="" the="" rfd="" for="" the="" general="" u.s.="" population.="" generally,="" exposures="" below="" 100="" percent="" 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="" risk="" to="" human="" health.="" thus,="" dupont="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" ethametsulfuron="" methyl="" resulting="" from="" proposed="" agricultural="" use="" on="" canola.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" ethametsulfuron="" methyl,="" data="" were="" considered="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit,="" and="" a="" multi-generation="" reproduction="" study="" in="" rats.="" the="" developmental="" toxicity="" studies="" demonstrated="" that="" even="" at="" the="" high="" oral="" doses="" used="" in="" these="" studies="" (up="" to="" 4,000="" mg/kg="" in="" rabbits="" and="" rats),="" no="" teratogenic="" effects="" were="" found="" in="" either="" species="" nor="" was="" the="" compound="" found="" to="" be="" uniquely="" toxic="" to="" the="" conceptus.="" the="" 2-generation="" reproduction="" study="" in="" rats="" treated="" at="" dietary="" levels="" as="" high="" as="" 20,000="" ppm="" on="" a="" daily="" basis="" throughout="" 2="" generations="" (equivalent="" to="" 1,582="" mg/kg/day="" for="" males="" and="" 1817="" mg/kg/day="" for="" females),="" showed="" no="" evidence="" of="" effects="" on="" reproductive="" performance="" in="" the="" adults,="" or="" evidence="" of="" gross="" or="" histopathological="" effects="" in="" the="" adult="" or="" weanling="" rats="" in="" any="" test="" group.="" this="" study="" indicates="" that="" ethametsulfuron="" methyl="" is="" not="" a="" reproductive="" toxicant.="" as="" mentioned="" previously,="" canola="" oil="" is="" a="" very="" minor="" component="" of="" the="" diet,="" and="" thus="" had="" not="" been="" included="" as="" part="" of="" the="" 1977-79="" food="" survey="" used="" in="" epa's="" dres="" system.="" dupont="" is="" not="" aware="" of="" specific="" food="" survey="" data="" concerning="" consumption="" of="" canola="" oil="" by="" infants="" and="" children.="" however,="" the="" 1977-79="" food="" survey="" database="" does="" provide="" consumption="" data="" for="" other="" edible="" oils="" for="" each="" of="" the="" population="" subgroups,="" including="" infants="" and="" children.="" this="" data="" indicate="" that="" non-="" nursing="" infants="" consume="" more="" soybean="" and="" coconut="" oil="" than="" any="" of="" the="" other="" 22="" population="" subgroups,="" specifically="" consuming="" 4.2="" times="" more="" soybean="" oil="" and="" 49.1="" times="" more="" coconut="" oil="" than="" the="" consumption="" by="" the="" general="" us="" population.="" the="" data="" also="" show="" that="" children="" 1-6="" consume="" more="" corn,="" cottonseed,="" peanut="" and="" sunflower="" oil="" than="" any="" other="" subgroup="" listed,="" to="" a="" maximum="" of="" 2="" times="" more="" than="" the="" general="" u.s.="" population.="" using="" these="" data="" and="" making="" the="" most="" conservative="" assumption="" to="" extrapolate="" to="" canola="" oil,="" we="" can="" estimate="" that="" infants="" and="" children="" consume="" 49="" times="" more="" canola="" oil="" than="" does="" the="" u.s.="" population,="" and="" calculate="" an="" approximate="" daily="" consumption="" of="" 4.3="" g="" canola="" oil/kg="" body="" weight.="" if="" we="" use="" the="" additional="" conservative="" assumptions="" that="" all="" the="" canola="" oil="" consumed="" contains="" ethametsulfuron="" methyl="" residues="" at="" tolerance="" levels="" of="" 0.1="" ppm,="" we="" calculate="" that="" the="" maximum="" theoretical="" residue="" concentration="" of="" ethametsulfuron="" methyl="" in="" the="" infants'="" and="" children's="" diets="" would="" be="" 0.00049="" mg/kg/day="" or=""><0.05% of="" the="" rfd.="" as="" indicated="" above,="" dupont="" concludes="" that="" infants="" and="" children="" have="" a="" low="" potential="" for="" ethametsulfuron="" methyl="" exposure="" because="" of="" both="" the="" low="" level="" of="" canola="" oil="" in="" the="" diet,="" and="" the="" absence="" of="" detectable="" residues="" in="" field-treated="" canola.="" the="" toxicology="" profile="" of="" ethametsulfuron="" methyl="" demonstrates="" low="" mammalian="" toxicity,="" and="" results="" from="" the="" developmental="" and="" reproduction="" studies="" indicate="" that="" there="" is="" no="" additional="" sensitivity="" for="" infants="" and="" children.="" therefore,="" dupont="" concludes="" that="" an="" additional="" safety="" (uncertainty)="" factor="" is="" not="" warranted="" and="" the="" rfd="" of="" 0.87="" mg/kg="" body="" weight/day,="" which="" utilizes="" a="" 100-fold="" safety="" factor,="" is="" appropriate="" to="" assure="" a="" reasonable="" certainty="" of="" no="" harm="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" ethametsulfuron="" methyl.="" f.="" international="" tolerances="" ethametsulfuron="" methyl="" and="" its="" end-use="" product="" muster="" are="" registered="" only="" in="" canada="" on="" canola/rape="" and="" mustard="" with="" a="" mrl="" value="" of="" 0.1="" ppm.="" a="" codex="" tolerance="" for="" ethametsulfuron="" methyl="" has="" not="" been="" established.="" (jim="" tompkins)="" 3.="" monsanto="" pp="" 7f4840="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 7f4840)="" from="" monsanto,="" suite="" 1100,="" 700="" 14th="" st.,="" nw.,="" washington,="" dc="" 2005,="" 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="" sulfosulfuron="" 1-(4,6-dimethoxypyrimidin-2-yl)-3-[(2-="" ethanesulfonyl-imdazo[1,2-a]pyridine-3-yl)sulfony]urea="" in="" or="" on="" the="" raw="" agricultural="" commodities.="" the="" proposed="" analytical="" method="" involves="" hydrolyzing="" sulfosulfuron="" and="" its="" imadazopyridine-containing="" metabolites="" under="" acidic="" conditions="" to="" the="" common="" chemophore,="" ethyl="" sulfone.="" ethyl="" sulfone="" is="" then="" separated="" and="" quantitated="" by="" high="" performance="" liquid="" chromatography="" (hplc)="" with="" fluorescence="" detection.="" epa="" has="" determined="" that="" the="" petition="" [[page="" 66089]]="" 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.="" metabolism="" of="" sulfosulfuron="" in="" plants="" is="" negligible.="" the="" nature="" of="" the="" major="" sulfosulfuron="" residues="" in="" wheat="" matrices="" depends="" primarily="" on="" the="" mode="" of="" application="" with="" reliance="" upon="" metabolism="" in="" the="" soil.="" postemergence="" applications="" result="" in="" residues="" that="" are="" mostly="" made="" up="" of="" parent="" compound,="" with="" small="" amounts="" of="" five="" to="" six="" metabolites="" that="" together="" make="" up="" less="" than="" 15%="" of="" the="" total="" radioactive="" residue.="" preemergence="" application="" result="" in="" soil="" degradation="" of="" the="" parent="" compound="" followed="" by="" uptake="" primarily="" of="" the="" imidazopyridine="" ring-="" containing="" metabolites="" and="" small="" amounts="" of="" the="" parent="" compound.="" the="" pyrimidine="" ring-containing="" metabolites="" under="" these="" conditions="" are="" tightly="" bound="" to="" the="" soil,="" resulting="" in="" negligible="" uptake="" of="" these="" residues.="" little="" further="" metabolism="" of="" the="" imidazopyridine="" metabolites="" takes="" place="" in="" the="" plant.="" the="" predominant="" residues="" resulting="" from="" preemergence="" applications="" were="" sulfonamide="" (22%="" trr)="" and="" guanidine="" (18.3%="" trr).="" in="" both="" cases,="" translocation="" of="" residue="" to="" the="" grain="" is="" negligible.="" the="" highest="" residues="" are="" observed="" following="" postemergence="" applications="" and="" the="" residues="" are="" primarily="" parent="" compound.="" in="" rotational="" crops,="" residues="" were="" low,="" with="" the="" trr's="" not="" exceeding="" 0.01="" ppm="" in="" most="" crops.="" the="" most="" abundant="" metabolite="" was="" sulfonamide,="" with="" low="" levels="" of="" a="" sulfonamide-sugar="" conjugate="" and="" parent="" compound="" also="" observed.="" 2.="" analytical="" method.="" the="" primary="" crop="" (wheat)="" residue="" and="" the="" secondary="" (animal="" products)="" residues="" are="" analyzed="" as="" total="" residue="" by="" hydrolyzing="" sulfosulfuron="" and="" its="" imadazopyridine-containing="" metabolites="" under="" acidic="" conditions="" to="" the="" common="" chemophore,="" ethyl="" sulfone.="" ethyl="" sulfone="" is="" then="" separated="" and="" quantitated="" by="" high="" performance="" liquid="" chromatography="" (hplc)="" with="" fluorescence="" detection.="" 3.="" magnitude="" of="" residues.="" epa="" has="" received="" a="" pesticide="" petition="" from="" monsanto="" company="" proposing="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" residues="" of="" the="" herbicide="" sulfosulfuron="" in="" or="" on="" the="" following:="" ------------------------------------------------------------------------="" commodity="" part="" per="" million="" (ppm)="" ------------------------------------------------------------------------="" wheat="" grain="" 0.01="" ppm="" (limit="" of="" quantitation="" 0.008="" ppm)="" straw="" 0.1="" ppm="" hay="" 0.3="" ppm="" forage="" 3.0="" ppm="" animal="" products="" milk="" 0.004="" ppm="" fat="" 0.004="" ppm="" meat="" 0.004="" ppm="" muscle="" 0.004="" ppm="" meat="" by-products="" 0.1="" ppm="" kidney="" 0.1="" ppm="" liver="" 0.1="" ppm="" ------------------------------------------------------------------------="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" a="" rat="" acute="" oral="" study="" with="" an="">50
of >5,000 mg/kg, EPA Category IV. A rabbit acute dermal study with an
LD50 of >5,000 mg/kg, EPA Category IV. A rat inhalation
study with and LC50 of >3.0 mg/l, the highest concentration
generated, EPA Category IV. A primary eye irritation study in the
rabbit showing moderate eye irritation, EPA Category III. A primary
dermal irritation study in the rabbit showing essentially no
irritation, EPA Category IV. A dermal sensitization study in the guinea
pig showing no potential for sensitization. Acute and subchronic
neurotoxicity studies in rats demonstrating no neurotoxicity potential.
Sulfosulfuron has a low order of acute toxicity.
2. Genotoxicity. An in vitro Ames/Salmonella mutagenicity assay in
five commonly used strains was negative for mutagenic potential.
An in vitro CHO/HGPRT Gene Mutation assay was negative for
mutagenicity up to the limit of solubility.
An in vitro chromosomal aberration test in cultured mammalian cells
demonstrated the induction of chromosomal aberrations only under
conditions of prolonged incubation at high dose levels that exceeded
the solubility of the test material. The mechanism responsible for this
induction and the biological relevance of the effect is not clear.
Other, more relevant, chromosomal aberration tests (see below) were
negative.
An in vitro chromosome aberration study in human lymphocytes was
negative for chromosomal aberrations.
An in vivo bone marrow micronucleus assay in the mouse was negative
for chromosomal effects.
The weight of evidence demonstrates that sulfosulfuron does not
produce significant genotoxic or mutagenic effects.
3. Reproductive and developmental toxicity. A developmental study
in the rat demonstrated no signs of maternal or developmental toxicity
up to the maximum dose level of 1,000 mg/kg/day. The NOEL was
considered to be 1,000 mg/kg/day.
A developmental study in the rabbit demonstrated no signs of
maternal or developmental toxicity up to the maximum dose level of
1,000 mg/kg/day. The NOEL was considered to be 1,000 mg/kg/day.
A 2-generation reproduction study in the rat demonstrated a
subchronic toxicity NOEL of 5,000 ppm based on body weight and food
consumption decreases, urinary bladder calculi formation and minor
bladder and kidney pathology. There were no effects on reproduction or
fertility up to 20,000 ppm, the highest dose tested. Sulfosulfuron
demonstrates no reproductive effects in rats and no teratogenic or
developmental effects in rats and rabbits.
4. Subchronic toxicity. A 28-day dermal study in the rat with a
NOEL of at least 1,000 mg/kg/day, the highest dose tested. A 90-day
feeding study in the rat resulted in only mild body weight/weight gain
effects at 20,000 ppm, the highest dose tested. The NOEL for both males
and females was considered to be 6,000 ppm. A 90-day feeding study in
the dog demonstrated subchronic toxicity, primarily in the urinary
bladder, secondary to urinary crystal formation and urolithiasis at
dose levels of 300 and 1,000 mg/kg/day in females and at 1,000 mg/kg/
day in males. The NOEL was considered to be 100 mg/kg/day in females
and 300 mg/kg/day in males. Sulfosulfuron has a low order of subchronic
toxicity, related only to the precipitation of test material in the
urinary bladder of dogs at high doses.
5. Chronic toxicity. A 1-year study in the dog demonstrated
toxicity in the urinary bladder secondary to urinary crystal and
calculus formation at 500 mg/kg/day in a single male animal. Urinary
crystal formation was observed in females at 500 mg/kg/day with no
subsequent pathology. The NOEL was considered to be 100 mg/kg/day for
male and female dogs.
A combined chronic toxicity/oncogenicity study in the rat
demonstrated chronic toxicity, primarily in the urinary bladder, in
males and females at 5,000 and females at 20,000 mg/kg/day. The NOEL
for chronic toxicity was considered to be 500 ppm or 24.4 mg/kg/day.
This is the
[[Page 66090]]
lowest NOEL and is used in the calculation of the Reference Dose (RfD).
An 18-month oncogenicity study in the mouse demonstrated chronic
toxicity, primarily in the urinary bladder, of male mice at 3,000 and
7,000 ppm. No chronic toxicity was observed in females. The NOEL for
chronic toxicity was considered to be 700 ppm for male mice and 7,000
ppm for female mice. Sulfosulfuron demonstrates chronic toxicity
related only to the formation of crystals and calculi of the compound
in the urinary bladders of mice, rats and dogs.
6. Carcinogenicity. An 18-month oncogenicity study in the mouse
demonstrated a small increase in the incidence of benign mesenchymal
tumors of the urinary bladder submucosa in male mice with urinary
bladder calculi at 7,000 ppm. However, these tumors are reportedly
unique to Swiss-derived mice and were considered to be of biological
relevance only to the mouse by a Independent Working Group on Mouse
Mesenchymal Tumors convened by the International Life Sciences
Institute (ILSI).
A combined chronic toxicity/oncogenicity study in the rat (same as
above) demonstrated a urinary bladder transitional cell carcinoma and a
urinary bladder transitional cell papilloma in two females at 5,000 mg/
kg/day, probably secondary to urinary system calculi formation and
(chronic) irritation.
The low incidences of oncogenicity observed in the oncogenicity
studies conducted with sulfosulfuron are either considered to be
relevant to the mouse only or a secondary threshold effect related to
chronic irritation resulting from bladder stone formation at high
doses. Sulfosulfuron is not considered to be a primary oncogen.
Using the Guidelines for Carcinogenic Risk Assessment published
September 24, 1986, Monsanto believes that the EPA would classify
sulfosulfuron as a Group ``C'' carcinogen, without quantitative risk
assessment, i.e., using the margin of exposure (MOE) approach for risk
assessment. Under the proposed guidelines published April 10, 1996,
however, Monsanto believes that sufosulfuron should be included in the
``Not Likely Human Carcinogen'' category based upon mechanistic
considerations. To quote the 1996 EPA guideline document discussing a
similar effect in a rat study:
``A major uncertainty is whether the profound effects of (substance
5) may be unique to the rat. Even if (substance 5) produced stones in
humans, there is only limited evidence that humans with bladder stones
develop cancer. Most often human bladder stones are either passed in
the urine or lead to symptoms resulting in their removal.''
In either case, a Margin of Exposure assessment or reference dose
(RfD) approach would be utilized. Since the chronic NOEL for male rats
is lower than the oncogenic NOEL for female rats (24 mg/kg/day vs 30
mg/kg/day), the male rat chronic NOEL was used with a 100 fold safety
factor for a reference dose of 0.24 mg/kg/day, for the quantitation of
human risk.
7. Animal metabolism. An animal metabolism study was conducted in
the rat using sulfosulfuron radiolabeled in both the pyrimidine and
iminodazopyridine rings to detect possible cleavage of the sulfonylurea
bond. Following oral dosing of sulfosulfuron, absorption was found to
be greater at low doses (>90%) than at the higher doses ( 40%).
Sulfosulfuron was readily excreted, mostly unchanged, with urinary
excretion the major route of elimination at low doses and fecal
excretion the major route at high doses. Greater than 90% of the dose
was excreted 3 days after administration. Expiration as carbon dioxide
or volatiles was not a significant route of elimination. Metabolism of
sulfosulfuron in the rat occurred to only a limited extent with
demethylation and pyrimidine ring hydroxylation as the major metabolic
routes, yielding desmethyl-sulfosulfuron and 5-hydroxy-sulfosulfuron as
the major metabolites. There was no evidence of bio-retention of
sulfosulfuron or its metabolites; tissue and blood levels were
negligible, with no individual tissue showing levels exceeding 0.2% of
the dose.
8. Metabolite toxicology. Dietary residues are comprised almost
entirely of parent sulfosulfuron and the imidazopyridine-containing
metabolites sulfonamide and guanidine. Specific toxicology data is not
available on these metabolites, but the structures do not suggest any
specific toxicologic concern and the level of dietary exposure is low.
These metabolites are not considered to present a significant
toxicological risk.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Estimates of dietary exposure to
residues of sulfosulfuron utilized the proposed tolerance-level
residues for wheat grain (0.01 ppm) and for the following animal
products: milk (0.004 ppm), fat (0.004 ppm), meat (0.004 ppm) and meat
by-products (0.1 ppm, including kidney and liver). One-hundred percent
market share was assumed as well as the assumption that no loss of
residue would occur due to processing and cooking. A Reference Dose
(RfD) of 0.24 mg/kg/day was assumed based on the low NOEL from the
chronic/oncogenicity study in rats ( 24 mg/kg/day) with a
safety factor of 100. Since the present label lists only wheat or
fallow as approved rotations, no residues were entered for rotational
crops. Using these conservative assumptions, dietary residues of
sulfosulfuron contribute only 0.000149 mg/kg/day (0.006% of the RfD)
for children 1-6 years, the most sensitive sub-population. For the U.S.
Population as a whole, the exposure was only 0.000048 mg/kg/day (0.02%
of the RfD).
ii. Drinking water. Given the low use rates, rapid soil
degradation, strong soil binding characteristics and low soil mobility
of sulfosulfuron, the risk of significant ground and surface water
contamination and exposure via drinking water is considered to be
negligible. Assuming that 10% of the RfD is allocated to drinking water
exposure (0.024 mg/kg/day), and the average, 70 kg human consumes 2
liters of water per day, a Maximum Allowable Concentration value for
drinking water of 0.84 mg/l is proposed for sulfosulfuron.
2. Non-dietary exposure. Sulfosulfuron is proposed for a variety of
non-crop uses including roadsides, fencerows, industrial sites, parks,
apartment complexes, schools and other public areas. Exposure
assessments have been made for mixer/loaders and applicators in these
situations (occupational exposure) and the cumulative (amortized) daily
exposure from both these activities has been estimated to be less than
0.5 g/kg/day, or approximately 0.2% of the RfD. The non-
occupational exposure in these locations to the casual passer-by would
be expected to be orders of magnitude less. The exposure in either
instance does not present a significant exposure risk.
D. Cumulative Effects
Sulfosulfuron falls into the common category of sulfonylurea (SU)
herbicides; however there is no information to suggest that any of the
SU's have a common mechanism of mammalian toxicity or even produce
similar effects. It is not appropriate to combine exposures in this
case, and Monsanto is considering only the potential risk of
sulfosulfuron in its aggregate exposure assessment.
E. Safety Determination
1. U.S. population. As presented above, the exposure of the U.S.
General population to sulfosulfuron is low, and the risks, based on
comparisons to the reference dose, are negligible. Margins
[[Page 66091]]
of safety are expected to be considerable. Monsanto concludes that
there is a reasonable certainty that no harm will result to the U.S.
Population from aggregate exposure to sulfosulfuron residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of sulfosulfuron,
Monsanto considered data from developmental toxicity studies in the rat
and rabbit and a two-generation reproduction study in rats. No
developmental or reproductive effects were observed up to the highest
dose tested in each of the three studies. The Observed NOEL's were
1,000 mg/kg/day, 1,000 mg/kg/day and 20,000 ppm, respectively. Using
the same conservative assumptions that were made previously for the
dietary exposure analysis for the U.S. General population, the percent
of the RfD utilized by pre-adult sub-populations are: all infants-
0.03%; nursing infants-0.005%; non-nursing infants-0.04%; children, 1-6
years-0.06%; children, 7-12 years-0.04%. Monsanto concludes that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to sulfosulfuron residues.
F. International Tolerances
There are currently no international (Codex) tolerances established
for sulfosulfuron. Sulfosulfuron is currently registered on wheat in
Switzerland, Poland, the Czech Republic, Slovakia and South Africa.
Petitions for tolerances for sulfosulfuron in/on wheat have been
submitted in Canada, Australia and the European Union. (Jim Tompkins)
[FR Doc. 97-32936 Filed 12-16-97; 8:45 am]
BILLING CODE 6560-50-F
