[Federal Register Volume 64, Number 164 (Wednesday, August 25, 1999)]
[Notices]
[Pages 46382-46389]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21548]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-882; FRL-6093-7]
Notice of Filing a Pesticide Petition to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food
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 docket control number PF-882, must be
received on or before September 24, 1999.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION'' section. To
ensure proper receipt by EPA, it is imperative that you identify docket
control number PF-882 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: By mail: James A. Tompkins,
Registration Support Branch, Registration Division (7505C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460; telephone number: (703) 305-5697; and e-mail
address: tompkins.james@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer, or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed in the ``FOR FURTHER INFORMATION
CONTACT'' section.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically.. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-882. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business
[[Page 46383]]
information (CBI). This official record includes the documents that are
physically located in the docket, as well as the documents that are
referenced in those documents. The public version of the official
record does not include any information claimed as CBI. The public
version of the official record, which includes printed, paper versions
of any electronic comments submitted during an applicable comment
period, is available for inspection in the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA, from 8:30 a.m. to 4 p.m.,
Monday through Friday, excluding legal holidays. The PIRIB telephone
number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-882 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
E-mail to: opp-docket@epa.gov,'' or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 5.1/
6.1 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-882. Electronic comments may
also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified in the ``FOR FURTHER INFORMATION
CONTACT'' section.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemical 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 this petition contains 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.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: August 10, 1999.
James Jones,
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. Entek Corporation
PP 9F5095
EPA has received a pesticide petition (PP 9F5095) from Entek
Corporation, 6835 Deerpath Road, Suite E, Elkridge, MD 21075 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR 180 by revising the existing
tolerance regulation for glyphosate to allow application of glyphosate
(in its acid form) on raw agricultural commodities (RAC). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue in plants is
adequately understood and consists of the parent, glyphosate and its
metabolite, aminomethylphosphonic acid (AMPA). Only the glyphosate
parent is to be regulated in plant and animal commodities since the
metabolite AMPA is not of toxicological concern in food.
2. Analytical method. Glyphosate food residues can be measured
using high pressure liquid chromatography
[[Page 46384]]
(HPLC) with fluorometric detection. This method is adequate for
enforcement purposes; the methodology has been published in the
pesticide analytical manual (PAM), Vol II. The method has a limit of
detection (L0D) of 0.05 parts per million (ppm), which allows
monitoring of food with residues at or above the tolerance levels.
3. Magnitude of residues. Adequate data concerning glyphosate
residues on RAC has previously been submitted to the Agency.
Accordingly, the available residue data for glyphosate support the
proposed revision of the tolerance expression for glyphosate. As noted
above, this revision will permit glyphosate residues from the
application of glyphosate in the acid form. In addition, any secondary
residues occurring in liver, or kidney of cattle, goats, horses, and
sheep, and liver and kidney of poultry will be covered by existing
tolerances.
B. Toxicological Profile
1. Acute toxicity. Glyphosate is practically non-toxic by the oral
route of exposure since the acute oral LD50 for glyphosate
is greater than 5,000 milligrams/kilograms (mg/kg).
2. Genotoxicty. Glyphosate was evaluated in the standard battery of
mutagenicity screening tests and all assays were negative. The
individual genotoxicity studies are: in vitro chromosomal aberration
(no aberrations in Chinese hamster ovary cells were caused, with or
without S9 activation); DNA repair in rat hepatocytes; in vivo bone
marrow cytogenic test in rats; rec-assay with B. subtilis; reverse
mutation test with S. typhimurium; Ames Test with S. typhimurium; and
the dominant-lethal mutagenicity test in mice.
3. Reproductive and developmental toxicity. Developmental toxicity
studies were conducted with glyphosate in the rat and mouse. In the rat
study, test animals were orally given doses of 0, 300, 1,000 and 3,500
mg/kg/day of glyphosate. The maternal no-observable adverse effect
level (NOAEL) is 1,000 mg/kg/day based on clinical signs of toxicity,
body weight effects and mortality and the fetal NOAEL is 1,000 mg/kg/
day based on reduced body weights and delayed sternebrae maturation at
the highest dose tested (HDT), 3,500 mg/kg/day.
In the rabbit study, test animals were orally given doses of 0, 75,
175 and, 350 mg/kg/day of glyphosate. The maternal NOAEL is 175 mg/kg/
day based on clinical signs of toxicity and mortality and the fetal
NOAEL is 350 mg/kg/day based on no developmental toxicity at any dose
tested.
Two studies evaluating the reproductive effects of glyphosate were
conducted in the rat. In a 3-generation study, rats were fed dosage
levels of 0, 3, 10, and 30 mg/kg/day of glyphosate. The NOAEL for
systemic and reproductive/developmental parameters is 30 mg/kg/day
based on no-adverse effects noted at any dose level.
In a 2-generation reproduction study, rats were fed dosage levels
of 0, 100, 500, and 1,500 mg/kg/day of glyphosate. The NOAEL for
systemic and developmental parameters is 500 mg/kg/day based on body
weight effects, clinical signs of toxicity in adult animals and
decreased pup body weights and a reproductive NOAEL of 1,500 mg/kg/day.
4. Subchronic toxicity. Subchronic (90-day) feeding studies were
conducted with the rat, mouse, and dog. In the rat study, the test
animals were fed dosage levels of 0, 1,000, 5,000, and 20,000 ppm of
glyphosate. The NOAEL is 20,000 ppm based on no-effects at the HDT.
In the mouse study, the test animals were fed dosage levels of 0,
5,000, 10,000, and 50,000 ppm of glyphosate. The NOAEL is 10,000 ppm
based on body weight effects at the HDT.
In the dog study, the test animals were given glyphosate, via
capsule, at doses of 0, 200, 600, and 2,000 mg/kg/day. The NOAEL is
2,000 mg/kg/day based on no-effects at the HDT.
5. Chronic toxicity/carcinogenicity. In a 12-month oral study, dogs
were given glyphosate, via capsule, at doses of 0, 20, 100, and 500 mg/
kg/day. The NOAEL is 500 mg/kg/day based on no-adverse effects at any
dose level.
In a 26-month chronic feeding/oncogenicity study, rats were fed
glyphosate at dosage levels of 0, 3, 10, and 31 mg/kg/day (males) and
0, 3, 11, and 34 mg/kg/day (females). The NOAEL is 31 mg/kg/day (males)
and 34 mg/kg/day (females) based on no carcinogenic or other adverse
effects at any dose level.
In a 24-month chronic feeding/oncogenicity study, rats were fed
glyphosate at dosage levels of 0, 89, 362, and 940 mg/kg/day (males)
and 0, 113, 457, and 1,183 mg/kg/day (females). The systemic NOAEL is
362 mg/kg/day based on body weight effects in the female and eye
effects in males. There was no carcinogenic response at any dose level.
In a mouse oncogenicity study, mice were fed glyphosate at dosage
levels of 0, 150, 750, and 4,500 mg/kg/day with a NOAEL of 750 mg/kg/
day based on body weight effects and microscopic liver changes at the
HDT. There was no carcinogenic effect at the HDT of 4,500 mg/kg/day.
Glyphosate is classified as a Group E (evidence of non-
carcinogenicity for humans). This classification is based on the
following findings:
i. There were no treatment related tumor findings in three state-
of-the-art long-term bioassays.
ii. Glyphosate was tested up to the limit dose in the rat and up to
levels higher than the limit dose in mice.
iii. There is no evidence of genotoxicity for glyphosate.
6. Animal metabolism. The nature of the residue in animals is
adequately understood and consists of the parent, glyphosate and its
metabolite AMPA.
7. Metabolite toxicology. Only glyphosate parent is regulated in
plant and animal commodities since the metabolite AMPA is not of
toxicological concern.
8. Endocrine disruption. The toxicity studies required by EPA for
the registration of pesticides measure numerous endpoints with
sufficient sensitivity to detect potential endocrine modulating
activity. No effects have been identified in subchronic, chronic or
developmental toxicity studies to indicate any endocrine modulating
activity by glyphosate. In addition, negative results were obtained
when glyphosate was tested in a dominant-lethal assay. While this assay
was designed as a genetic toxicity test, agents that can affect male
reproduction function will also cause effects in this assay. More
importantly, the multi-generation reproduction study in rodents is a
complex study design which measures a broad range of endpoints in the
reproductive system and in developing offspring that are sensitive to
alterations by chemical agents. Glyphosate has been tested in two
separate multi-generation studies and each time the results
demonstrated that glyphosate is not a reproductive toxin.
C. Aggregate Exposure
1. Dietary exposure--Food. Dietary exposure was estimated using the
Theoretical Maximum Residue Contribution (TMRC) from all present
tolerances. The TMRC is obtained by multiplying the tolerance level
residue for each food commodity by consumption data which estimates the
amount of those products eaten by various population subgroups. In
conducting this exposure assessment, very conservative assumptions are
made: 100% of these crops will contain glyphosate residues and the
residues will be at the tolerance level.
[[Page 46385]]
2. Drinking water. In examining aggregate exposure, the Food
Quality Protection Act (FQPA) directs EPA to consider available
information concerning exposures from the pesticide residue via
drinking water. The lifetime health advisory and maximum contaminant
level (MCL) for glyphosate are both 700 parts per billion (ppb) in the
EPA Office of Drinking Water's ``Drinking Water Health Advisory -
Pesticides.'' The MCL represents the level at which no known or
anticipated adverse health effects will occur allowing for an adequate
margin of safety and is based on the reference dose (RfD).
Environmental fate data for glyphosate shows little potential for the
chemical to migrate to drinking water. In addition, glyphosate is not
highly mobile and not persistent in soil or water.
Because the Agency lacks sufficient water-related exposure data to
complete a comprehensive water risk assessment for many pesticides, EPA
has commenced and nearly completed a process to identify a reasonable
yet conservative boundary figure for the potential contribution of
water-related exposures to the aggregate risk posed by a pesticide.
In developing a boundary figure, EPA estimated residue levels in
water for a number of specific pesticides using various data sources.
The Agency then applied the estimated residue levels, in conjunction
with appropriate toxicological endpoints RfDs or acute dietary NOAELs
and assumptions about body weight and consumption, to calculate, for
each pesticide, the increment of aggregate risk contributed by
consumption of contaminated water. While EPA has not yet pinpointed the
appropriate bounding figure for consumption of contaminated water, the
ranges the Agency is continuing to examine are all below the level that
would cause glyphosate to exceed the RfD if the change in the tolerance
expression being considered in this document is granted. The Agency has
therefore concluded that the potential exposures associated with
glyphosate in water, even at higher levels the Agency may consider a
conservative upper bound, would not prevent the Agency from determining
that there is a reasonable certainty of no harm if the proposed
tolerance revision is granted.
3. Non-dietary exposure. Glyphosate is registered for use on
several non-food sites such as around ornamentals, shade trees, shrubs,
walks, driveways, flowerbeds, home lawns, farmstead including building
foundations, along and in fences, in dry ditches and canals, along
ditch banks, farm roads, shelter belts, forestry, Christmas trees, and
industrial sites and other non-crop or industrial areas such as
airports, lumber yards, manufacturing sites, utility substations,
parking areas, petroleum tank farms and pumping stations. Margins of
Exposure (MOEs) are determined for non-dietary exposure based on
toxicological endpoints and measured or estimated exposures. Since
glyphosate is not a carcinogen, the 21-day dermal study lacked any
observable effects at the limit dose; and no adverse effects were
observed in developmental toxicity studies in rats up to 1,000 mg/kg/
day and rabbits up to 175 mg/kg/day, no toxicological endpoints are
applicable. Because available data indicate no evidence of significant
toxicity via the dermal or inhalation routes, MOE's were not calculated
and risk assessments are not required for non-occupational residential
uses.
D. Cumulative Effects
EPA does not have, at this time, available data to determine
whether glyphosate has a common mechanism of toxicity with other
substances or how to include it in a cumulative risk assessment. Unlike
other pesticides for which EPA has followed a cumulative risk approach
based on common mechanism of toxicity, glyphosate does not produce a
toxic metabolite which is common to other substances.
For the purposes of this tolerance action, EPA has assumed that
glyphosate does not have a common mechanism of toxicity with other
substances. A condition of the registrations associated with these
tolerances will be that registrants will provide common mechanism data
in a timely manner when and if the Agency asks for it. After EPA
develops methodologies for more fully applying common mechanism of
toxicity issues to risk assessments, the Agency will develop a process
to reexamine those tolerance decisions made earlier.
E. Safety Determination
1. U.S. population--i. Acute dietary exposure. Based upon available
data, glyphosate does not pose any acute dietary risk and an acute
dietary risk assessment is not required
ii. Chronic dietary exposure. Using the TAS Exposure I software and
1977-78 food consumption data, a chronic dietary exposure estimate has
been performed based on 100% of the crops treated and all residues at
tolerance levels. Based on this assessment, the total dietary exposure
from glyphosate residues is 1.4% of the RfD for the overall U.S.
population and 3.1% of the RfD for non-nursing infants, the most highly
exposed population subgroup. As noted above, an additional risk
assessment for residential uses was not required because there is no
evidence of significant toxicity via dermal or inhalation exposure
routes. Even though an appropriate bounding figure for consumption of
contaminated water has not been determined, the ranges being examined
are all below the level that would cause glyphosate to exceed the RfD.
Generally, there is no concern for exposures below 100% of the RfD.
Therefore, based on the completeness and reliability of the toxicology
data and the conservative exposure assessment employed, there is a
reasonable certainty that no harm will occur from aggregate exposure to
glyphosate.
2. Infants and children. FFDCA section 408 provides than an
additional tenfold MOE (safety) for infants and children in the case of
threshold effects may be needed to account for prenatal, and postnatal
toxicity and the completeness of the data base unless it is determined
that a different MOE (safety) will be safe for infants and children.
Reliable data support using the standard MOE (usually 100x for combined
interspecies and intraspecies variability), without the additional
tenfold MOE, when a complete data base under current guidelines exists
and when the nature of the findings from these studies do not raise
concerns regarding the adequacy of the standard MOE.
The toxicological data base for evaluating prenatal and postnatal
toxicity for glyphosate is considered to be complete at this time. Risk
to infants and children for glyphosate was determined by using two
developmental toxicity studies in rats and rabbits and a 2-generation
reproduction study in rats. The developmental toxicity studies evaluate
the potential for adverse effects on the developing organism resulting
from exposure during prenatal development. The reproduction study
provides information relating to effects from exposure to the chemical
on the reproductive capability of both (mating) parents and on systemic
toxicity, in addition to information on prenatal development. The
results of these studies indicate that glyphosate does not produce
birth defects and is not a reproductive toxin.
In the rabbit, no developmental toxicity was observed at the HDT
where significant maternal toxicity occurred (death and clinical signs
at 350 mg/kg/day). Because no developmental toxicity was observed at
any dose level, the developmental toxicity NOAEL is considered to be
350 mg/kg/day. In the rat developmental toxicity study, severe
[[Page 46386]]
maternal (systemic) and developmental toxicity was noted at 3,500 mg/
kg/day, the HDT. It is important to note that the HDT in this study was
3.5 times higher than the limit dose currently required by EPA
guidelines. The maternal and developmental (pup) NOAEL was 1,000 mg/kg/
day. No effects on reproductive parameters were observed.
In the rat 2-generation study, prenatal toxicity was observed at
1,500 mg/kg day as soft stools, decreased food consumption, and body
weight gain; therefore, the systemic NOAEL is considered to be 500 mg/
kg/day. Developmental (pup) toxicity was only exhibited at 1,500 mg/kg/
day as decreased body weight gain of the F1a, F2a, and F2b male, and
female pups during the second and third weeks of lactation. Glyphosate
did not affect the ability of rats to mate, conceive, carry or deliver
normal offspring at any dose level.
The RfD is based on the NOAEL for maternal toxicity in the rabbit
developmental toxicity study. No developmental effects were noted in
the study; effects were noted only at doses 20-fold higher than the
NOAEL used for the RfD. No prenatal or postnatal effects were seen in
any study in the absence of maternal toxicity. In the rat reproduction
study, developmental effects were noted at doses 5 times higher than
the NOAEL used for the RfD. The Agency does not believe the effects
seen in these studies are of such concern to require an additional
safety factor. Accordingly, the Agency believes the RfD has an adequate
margin of protection for infants and children. The dietary exposure
from current uses of glyphosate range from 1% of the RfD for nursing
infants (less than 1-year old) to 3% for non-nursing infants and
children 1 to 6 years old. Therefore, there is reasonable certainty
that no harm will occur to infants and children from aggregate exposure
to glyphosate.
F. International Tolerances
Codex MRLs have been established for residues of glyphosate in or
on several raw agricultural commodities.
2. Novartis Crop Protection, Inc.
PP 4F4336 and PP 5F4469
EPA has received pesticide petitions (PP 4F4336 and PP 5F4469) from
Novartis Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419
proposing, pursuant to section 408(d) of FFDCA, 21 U.S.C. 346a(d), to
amend 40 CFR 180.481 by extending time-limited tolerances for residues
of prosulfuron, 1-(4-methoxy-6-methyl-triazin-2-yl)-3-[2-(3,3,3-
trifluoropropyl)-phenylsulfonyl]-urea in or on the RAC cereal grains
group (except rice and wild rice) grain at 0.01 ppm; cereal grains
group (except rice and wild rice) forage at 0.10 ppm; cereal grains
group (except rice and wild rice) fodder at 0.01 ppm; cereal grains
group (except rice and wild rice) straw at 0.02 ppm; cereal grains
group (except rice and wild rice) hay at 0.20 ppm; milk at 0.01 ppm;
and meat, fat, kidney, liver and meat byproducts of cattle, goats,
hogs, horses, and sheep at 0.05 ppm until December 31, 2001. 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 prosulfuron in corn is well
understood. Significant pathways involve oxidation of the phenyl ring
to give 5-hydroxy prosulfuron, which is followed by sugar conjugation.
Hydrolytic cleavage of the sulfonylurea bridge occurs for both
prosulfuron and 5-hydroxy prosulfuron yielding the corresponding
sulfonamide and triazine amine moieties. The sulfonamide metabolites
are subsequently conjugated with sugars. Demethylation of the triazine
amine results in the formation of the corresponding hydroxy triazine,
which is further hydrolyzed at the amino group to form the dihydroxy
triazine.
2. Analytical method. Novartis Crop Protection, Inc has submitted
practical analytical methods for the detection and measurement of
residue levels of prosulfuron in or on RAC and processed commodities of
cereal grains, and for meat, milk and eggs. The LOD for prosulfuron is
0.8 ng injected and the limit of quantitation (LOQ) is 0.01 ppm for
crop commodities, processed fractions and milk, and 0.05 ppm for meat
and eggs. The method is based on commodity-specific cleanup procedures
followed by determination by high performance liquid chromatography
with ultraviolet (UV) detection.
3. Magnitude of residues. Complete, full geography residue
programs, including processing, have been conducted on corn, wheat and
grain sorghum. A three-level dairy animal feeding study to determine
the transfer of residues of prosulfuron from animal feed commodities to
meat and milk has also been conducted.
B. Toxicological Profile
1. Acute toxicity. Studies conducted with the technical material of
prosulfuron:
i. Rat acute oral toxicity study with a LD50 of 949 mg/
kg for males and 546 mg/kg for females.
ii. Rabbit acute dermal toxicity study with a LD50 >
2,000 mg/kg.
iii. Rat acute inhalation toxicity study with a LC50 >
5.4 milligrams per liter (mg/L).
iv. Rabbit eye irritation study showing slight irritation (Category
III).
v. Rabbit dermal irritation study showing no irritation (Category
IV).
vi. Guinea pig dermal sensitization study with the Buehler's method
showing negative findings Guinea pig dermal sensitization study with
the maximization method showing negative findings.
2. Genotoxicty. No genotoxic activity is expected of prosulfuron
under in vivo or physiological conditions. The compound has been tested
in a bacterial reverse gene mutation assay with and without metabolic
activation using different S. typhimurium and E. coli stains; in a
mammalian gene mutation study using V79 cells; in an in vitro mammalian
cytogenetic test using Chinese hamster ovary cells with and without
metabolic activation; in a micronucleus test in mice; and in a DNA-
repair using freshly isolated rat liver hepatocytes. All these tests
were negative for mutagenicity.
3. Reproductive and developmental toxicity. FFDCA section 408
provides that EPA may apply an additional safety factor for infants and
children in the case of threshold effects to account for prenatal and
postnatal toxicity and the completeness of the data base. While the
final review of some of additional developmental data has not yet been
completed, based on the current toxicological data requirements, the
data base on prosulfuron relative to prenatal and postnatal effects for
children is considered to be complete.
In assessing the potential for additional sensitivity of infants
and children to residues of prosulfuron, Novartis considered data from
teratogenicity studies in the rat and the rabbit and a 2-generation
reproduction studies in the rat. The teratogenicity studies are
designed to evaluate adverse effects on the developing embryo as a
result of chemical exposure during the period of organogenesis.
Reproduction studies provide information on effects from chemical
exposure on the reproductive capability of mating animals and systemic
and developmental toxicity from in-utero exposure.
[[Page 46387]]
In the rat teratology study, prosulfuron was administered at dose
levels of 0, 5, 50, 200 and 400 mg/kg during days 6 to 15 of gestation.
Evidence of maternal toxicity (decreased body weight gain and reduced
food consumption) and developmental toxicity (increased incidence of
skeletal variations that was not significantly different from the
historical control) was found at the maximum tolerated dose of 400 mg/
kg. There was no evidence of teratogenicity at any dose, and the
maternal and developmental no observed adverse effect levels (NOAELs)
were established at 200 mg/kg.
Prosulfuron was administered to rabbits at dose levels of 0, 1, 10,
and 100 mg/kg during days 7 to 19 of pregnancy. Maternal toxicity
(decreased body weight gain and reduced food consumption) was observed
in the 100 mg/kg dose group. There was no evidence of teratogenicity at
any dose.
Since a range-finding rabbit teratology study had seen additional
clinical findings and fetotoxicity at maternally toxic doses
( 150 mg/kg) but not in the definitive study at up to 100
mg/kg, a second rabbit teratology study was conducted at doses of 0,
20, 100, and 200 mg/kg/day. Maternal toxicity was observed at 200 mg/
kg. The developmental NOAEL was 100 mg/kg and the maternal NOAEL was 20
mg/kg in this study. There was no evidence of teratogenicity at any
dose.
Prosulfuron was administered to rats at dose levels of 0, 0.67,
13.3, 136, or 278 (males), and 0, 0.76, 15.3, 152, or 311 mg/kg/day
(females) throughout two consecutive generations. The reproductive and
systemic NOAELs of 13.3 mg/kg/day were based on decreased mean body
weights and body weight gain observed at 136 mg/kg/day for both pups
and parental animals. No treatment- related effects on reproductive
performance (i.e., to produce, deliver or raise litters), litter sizes,
viability of pups and necropsy findings in parental animals and
offspring were noted up to the highest dose level.
Based on all these teratology and reproduction studies, the lowest
NOAEL for developmental toxicity is estimated to be 13.3 mg/kg while
the lowest NOAEL in the subchronic and chronic studies is 1.84 mg/kg/
day (from the dog chronic study). Therefore, no additional sensitivity
for infants and children to prosulfuron is suggested by the data base.
4. Subchronic toxicity. The liver was identified as a target organ
at high doses in the rat, mouse and dog as indicated by slightly
increased liver enzymes and liver weights. No histomorphologic
correlates of liver damage was noted in the 90-day studies except in
the mouse study where centrilobular hypertrophy was found in males at
feeding levels 1,750 ppm and in females at levels
3,500 ppm. Effects of prosulfuron on the hematopoietic
system (anemia) were noted in the dog at feeding levels
1,500 ppm and myocardial lesions were found in the 3,000 ppm animals in
the 90-day study. Myocardial vacuolative degeneration was observed in
male mice fed prosulfuron for 90 days at levels 3,500 ppm
and in females at 7,000 ppm.
In general, NOAELs for target organ effects were established at
doses that were much higher than overall study NOAELs, which were based
on other indicators of toxicity such body weight gain.
5. Chronic toxicity. Prosulfuron was fed to dogs at dosages of 0,
0.33, 1.95, 18.6 or 41.0 mg/kg/day (males) and 0, 0.31, 1.84, 20.2, or
48.8 mg/kg/day (females) for 1-year. The NOAEL was 1.84 mg/kg/day based
on hematologic and clinical chemistry effects and incidence of
lipofuscin accumulation in the liver at 18.6 mg/kg/day.
In an 18-month mouse carcinogenicity study, prosulfuron was
administered at dose levels of 0, 1.71, 81.4, 410 or 832 mg/kg/day
(males), and 0, 2.11, 100, 508 or 1,062 mg/kg/day (females). There was
no evidence of carcinogenic effects up to 1,062 mg/kg/day, the HDT. The
NOAEL was 1.71 mg/kg/day in males, and 100 mg/kg/day in females based
on increased incidence/severity of centrilobular hepatocellular
hypertrophy. A 2-year chronic feeding/carcinogenicity study in rats fed
dosages of 0, 0.4, 7.9, 79.9 or 160.9 (males), and 0, 0.5, 9.2, 95.7 or
205.8 mg/kg/day (females) was conducted. There was uncertain evidence
of carcinogenicity with slight increases in the incidence of mammary
gland adenocarcinomas in females at 95.7 and 205.8 mg/kg/day, slight
increase in incidence of benign testicular interstitial cell tumors at
79.9 and 160.9 mg/kg/day (significant trend only). A systemic NOAEL of
7.9 mg/kg/day was based on decreased body weight and body weight gain,
hematopoietic effects (males), and possibly increased serum GGT and
decreased liver, kidney and adrenal weights (females) at 79.9 mg/kg/
day.
6. Carcinogenicity. The HED RfD/Peer Review Committee (PRC)
classified this chemical as a Class D oncogen based on the conclusion
that there was uncertain evidence of carcinogenicity. No relevant
treatment-related oncogenic potential was observed in rats and mice.
The slightly increased incidence of testicular interstitial cell tumors
in male rats at 79.9 mg/kg/day and the slightly increased
incidence of mammary gland adenocarcinoma in females at
95.7 mg/kg/day was not significant when the increased survival in these
groups was considered. Furthermore, the overall incidence of mammary
tumors was essentially identical in all groups including the control.
There was no evidence of carcinogenicity in mice and dosages in both
studies were sufficient for identifying a cancer risk. In the absence
of carcinogenicity, it is appropriate that a RfD approach be used for
quantitation of human risks.
7. Animal metabolism. Prosulfuron is rapidly absorbed from the
gastrointestinal tract of rats and is rapidly excreted. Approximately
90% of the administered dose is excreted during the first 48 hours,
predominately via urine. Tissue residues are low. Prosulfuron is
metabolized primarily via hydroxylation at side chain and phenyl ring
positions and O-demethylation of the triazyl methoxy group. Minor
pathways include unsaturation of the trifluoropropyl side chain,
hydrolysis of the phenylsulfonylurea bridge and oxidative/hydrolytic
cleavage of the triazine ring system.
In the goat, the orally administered prosulfuron is quickly
eliminated primarily via the urine as prosulfuron. The metabolism of
prosulfuron in the goat follows a similar pathway as observed in the
rat although not as extensive. Accordingly, the biotransformation is
limited to oxidation of the triazinyl methyl, O-demethylation of the
triazinyl methoxy group and hydrolytic cleavage of the sulfonylurea
bridge. The majority of the residues were accounted for as prosulfuron,
the triazine amine, which results from bridge hydrolysis (CGA-150829)
and the triazinyl hydroxymethyl metabolite (CGA-273437). In the hen,
metabolism is similar to that observed in the rat and goat. The major
residues found in edible tissues and eggs were prosulfuron, and the
triazine amine (CGA-150829) and the sulfonamide (CGA-159902) which
results from hydrolysis of the sulfonylurea bridge. In conclusion, the
major metabolic pathways in the rat, goat, and hen are similar.
7. Metabolite toxicology. Metabolic pathways of prosulfuron in
plants and animals are comparable and no (detectable) residues are
found in or on crops. All relevant plant metabolites are observed in
the animals and are thus toxicologically covered. The remaining plant
metabolites are toxicologically insignificant. Therefore, no analytical
method for metabolite determination is necessary for routine residue
monitoring. For enforcement purposes
[[Page 46388]]
(e.g., high overdose or application too close to harvest) parent
prosulfuron is the appropriate compound for analytical monitoring.
8. Endocrine disruption. Prosulfuron does not belong to a class of
chemicals known for having significant adverse effects on the endocrine
system. Developmental toxicity studies in rats and rabbits and
reproduction study in rats gave no indication that prosulfuron might
have any effects on endocrine function related to development and
reproduction. The subchronic and chronic studies also showed no
evidence of a long-term effect related to the endocrine system.
C. Aggregate Exposure
1. Dietary exposure. Acute and Chronic dietary exposure assessments
were conducted for prosulfuron using tolerance values published in 40
CFR part 180.481. In both assessments it was assumed that 100% of all
corn and cereal grains were treated with prosulfuron (100% market
share). The exposure analyses was conducted using food consumption data
from USDA's 1994-96 Continuing Survey of Intake by Individuals (CSFII)
and Novigen Sciences, Inc. Dietary Exposure Evaluation Model (DEEMTM).
Chronic exposure was compared to a RfD of 0.02 mg/kg based on a NOAEL
of 1.84 mg/kg in a dog feeding study and a 100-fold uncertainty factor.
This exposure analysis showed that the U.S. population had an exposure
of less than 1% of the chronic RfD. The most sensitive sub-population
was children (1-6 years old) with a chronic exposure of 2.4%.
Acute exposure was compared to an acute RfD of 0.1 mg/kg, which was
based on a NOAEL of 10 mg/kg from an acute neurotoxicity study in the
rat and a 100-fold uncertainty factor. The most sensitive sub-
population was all infants with an exposure of 2.2% of the acute RfD.
The U.S. population showed an exposure of 1.5% of the RfD.
These results show that there is more than a reasonable certainty
of no harm, through exposure to prosulfuron residues in the diet.
ii. Drinking water--estimated surface drinking water
concentrations. The GENEEC estimated surface water concentrations of
prosulfuron were 1.86 ppb on the Peak Day-0 and 1.40 ppb on the average
56-day. According to the EPA ``OPP's Interim Approach for Addressing
Drinking Water Exposure,'' the average 56-day value is divided by three
when correcting for overestimation of the GENEEC model. This resulted
in a corrected potential drinking water exposure via surface water of
1.40 ppb / 3 =0.4667 ppb.
These concentrations were not adjusted for the estimated market
share, regional soil characteristics or percentage of use area. The
Peak Day-0 estimate, 1.86 ppb, was used in the acute exposure analysis
and the corrected 56-day drinking water concentration of 0.4667 ppb was
used in the chronic exposure analysis.
iii. Estimated ground water concentrations. The SCI-GROW estimated
ground water concentration for the prosulfuron uses of 0.406585 ppb
contributed little to the overall exposure. The estimated
concentrations were not adjusted for the estimated market share or
percentage of use area.
2. Drinking water levels of concern--i. Acute exposure. The
estimated ground and surface water concentrations of prosulfuron
contributed little to the potential acute human exposure. The acute
drinking water levels of concern (DWLOCacute) for
prosulfuron were based on the acute RfD, a MOE, the 99.9th percentile
of the acute dietary exposure for U.S. population subgroups and the
body weight - daily water consumption of each respective subgroup. The
acute RfD of prosulfuron was 10 mg/kg/day based on the findings from
the acute neurotoxicity rat study. The lowest MOE for any pesticide is
100 and this was used as a conservative approach. The dietary exposure
estimates for subgroups of the U.S. population included the U.S.
population all seasons, all infants (<1-year), nursing="" infants="">< 1-="" year),="" non-nursing="" infants="">< 1-year),="" children="" (1-6="" years)="" and="" children="" (7-12="" years).="" the="" dietary="" exposure="" estimates="" for="" all="" the="" subgroups="" were="" less="" than="" 0.0023="" mg/kg/bodyweight/day.="" the="" calculated="">acute values for these respective subgroups were 3447,
987, 980 and 978 ppb.
The estimated ground water concentration (0.406585 ppb) and the
peak day-0 surface water concentration (1.86 ppb) of prosulfuron did
not exceed the DWLOCacute values. Therefore, there is
reasonable certainty that the residues of prosulfuron in the drinking
water would not result in unacceptable levels of acute aggregate human
health risk, and that such exposure would not exceed the exposure
allowable by the risk cup.
ii. Chronic exposure. The estimated ground and surface water
concentrations of prosulfuron contributed little to the potential
chronic human exposure. The chronic (non-cancer) drinking water levels
of concern (DWLOCchronic) for prosulfuron were based on the
chronic RfD, any estimated residential exposure, the chronic dietary
exposure for select U.S. population subgroups and the body weight -
daily water consumption of each respective subgroup. The chronic RfD
for prosulfuron was 0.02 mg/kg/bwt/day based on the findings of a
chronic dog study. There was no estimated residential exposure from the
prosulfuron uses. The potential chronic dietary exposure estimates were
calculated for the same subgroups selected for the acute exposure
analysis. These potential chronic dietary values included 0.00172 mg/
kg/bwt/day for the United States all seasons and < 0.0005="" for="" the="" remaining="" subgroups="" (non-nursing="" infants="">< 1-year,="" children="" 1-6="" years,="" and="" children="" 7-12="" years).="" the="" calculated="">chronic values
for the respective subgroups were 694, 198, 195 and 197 ppb.
The GENEEC estimated concentration of prosulfuron in surface water
at the average 56-day was 1.40 ppb. According to EPA ``OPP's Interim
Approach for Addressing Drinking Water Exposure,'' the average 56-day
value is divided by three when correcting for overestimation of the
GENEEC model. This resulted in a corrected surface drinking water
concentration of 1.40 ppb/3 = 0.4667 ppb.
The estimated ground water concentration (0.406585 ppb) and the
corrected average 56-day surface water concentration (0.4667 ppb) of
prosulfuron did not exceed the DWLOCchronic values.
Therefore, there is reasonable certainty that the residues of
prosulfuron in the drinking water would not result in unacceptable
levels of chronic aggregate human health risk, and that such exposure
would not exceed the exposure allowable by the risk cup.
3. Non-dietary exposure. Non-dietary exposure to prosulfuron is
considered negligible as the chemical is registered for agricultural
use only. For workers handling this chemical, acceptable MOE (in the
range of thousands) have been obtained for both acute and chronic
scenarios.
D. Cumulative Effects
Consideration of a common mechanism of toxicity is not appropriate
at this time since there is no information to indicate that toxic
effects produced by prosulfuron would be cumulative with those of any
other types of chemicals. Furthermore, the triazine containing
sulfonyl-urea is a new type of herbicide and no compound in this
general chemical class currently has a significant market share.
Consequently, it is considered appropriate to only
[[Page 46389]]
include the potential exposure to prosulfuron in an aggregate risk
assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data base for prosulfuron, Novartis has calculated aggregate
exposure levels for this chemical. The calculation shows that less than
1% of the RfD will be utilized for the U.S. population based on chronic
toxicity endpoints. 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. Novartis concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to prosulfuron residue.
2. Infants and children. No adverse effects on the ability to
produce, deliver or rear offspring was observed in a 2-generation study
in rats. Likewise, teratogenicity studies in rats and rabbits did not
reveal any teratogenic, embryotoxic or fetotoxic potential of
prosulfuron. The lowest observed adverse effect level (LOAEL) for
developmental toxicity was established in the rat reproduction study at
13.3 mg/kg, which is higher than the chronic NOAEL of 1.84 mg/kg, on
which the RfD is based.
Using the same conservative exposure assumptions as employed for
the determination in the general population, Novartis has calculated
that the percent of the RfD that will be utilized by aggregate exposure
to residues of prosulfuron is only 2.4% for children (1-6 years old),
the most impacted sub-population. Therefore, based on the completeness
and reliability of the toxicity data base and the conservative exposure
assessment, Novartis concludes that there is a reasonable certainty
that no harm will result to infants and children from aggregate
exposure to prosulfuron residues.
F. International Tolerances
No Codex MRLs have been established for residues of prosulfuron.
[FR Doc. 99-21548 Filed 8-24-99; 8:45 am]
BILLING CODE 6560-50-F
