[Federal Register Volume 63, Number 103 (Friday, May 29, 1998)]
[Notices]
[Pages 29401-29409]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-14160]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-806; FRL-5791-2]
Monsanto Company; Pesticide Tolerance Petitions Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-806, must
be received on or before June 29, 1998.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119,
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 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: James A. Tompkins, Registration
Support Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW, Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
239, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA
22202, (703) 305-5697; e-mail: tompkins.james@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: 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.
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-806] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on this proposed rule 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: May 14, 1998.
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. Monsanto Company
PP 8F4937
EPA has received a pesticide petition (PP 8F4937) from Monsanto
Company, 700 14th St., NW., Suite 1100, Washington, DC 20005. proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
for residues of
[[Page 29402]]
halosulfuron-methyl: methyl 5-[(4,6-dimethoxy-2-pyrimidinyl)amino]
carbonyl aminosulfonyl-3-chloro-1-methyl-1H-pyrazole-4-carboxylate in
or on the raw agricultural commodity undelinted cotton seed & cotton
gin by-products at 0.05 parts per million (ppm), rice grain at 0.05
ppm, rice straw at 0.20 ppm, tree nut group (Group 14) nutmeat at 0.05
ppm and hulls at 0.20 ppm, pistachio, nutmeat at 0.05 ppm, pistachio,
hulls at 0.2 ppm.
In addition, Monsanto proposes the establishment of tolerances for
halosulfuron methyl (as parent only) in or on the following raw
agricultural commodities:
Corn, field: grain at 0.05 ppm, forage at 0.2 ppm, and fodder at
0.8 ppm.
Grain, sorghum (milo): grain at 0.05 ppm, forage at 0.05 ppm, and
fodder/stover at 0.10 ppm.
Monsanto also proposes removing 40 CFR 180.479 (b) which reads as
follows:
Indirect or inadvertent tolerances. Tolerances are established for
indirect or inadvertent residues of the herbicide halosulfuron-methyl
and its metabolites determined as 3-chloro-1-methyl-5-
sulfamoylpyrazole-4-carboxylic acid and expressed as parent
equivalents, in or on the following raw agricultural commodities when
present therein as a result of the application of halosulfuron-methyl
to growing crops.
Soybean, forage at 0.5 ppm, soybean, hay at 0.5 ppm, soybean, seed
at 0.5 ppm, wheat, forage at 0.1 ppm, wheat, grain at 0.1 ppm. and
wheat, straw at 0.2 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 metabolism of halosulfuron-methyl as well
as the nature of the residues in plants is adequately understood for
purposes of these tolerances. Metabolism studies were conducted in
three crops, viz.; field corn, sugarcane and soybeans. Metabolism
depends on the mode of application. Preemergent applications result in
rapid soil degradation of halosulfuron-methyl followed by crop uptake
of the resulting pyrazole moiety. The pyrimidine ring binds tightly to
soil and is eventually converted to carbon dioxide by microbial
degradation. In postemergent applications, little metabolism and
translocation take place resulting in unmetabolized parent compound as
the major residue on the directly treated foliar surfaces. Very low
residue levels of the metabolite 3-chloro-1-methyl-5-sulfamoylpyrazole-
4-carboxylic acid (3-CSA) are found in the grain.
2. Analytical method. A practical analytical method, gas
chromatography with an electron- capture detector which detects and
measures total residues (halosulfuron-methyl and metabolites) is
available for enforcement purposes with a limit of detection that
allows monitoring of food with residues at or above the levels set in
these tolerances. This enforcement method has been submitted to the
Food and Drug Administration for publication in the Pesticide
Analytical Manual, Vol. II (PAM II). It has undergone independent
laboratory validation and validation at the Beltsville laboratory. The
Analytical Chemistry section of the EPA concluded that the method is
adequate for enforcement. Analytical method is also available for
analyzing meat by-products which also underwent successful independent
laboratory and Beltsville laboratory validations.
3. Magnitude of residues. In the tree nut residue study, there were
no quantifiable residues found in nut meats using an analytical method
with limit of quantitation (LOQ) of 0.05 ppm. Residues ranging from
<0.05 to="" 0.154="" ppm="" were="" found="" in="" almond="" hulls="" when="" treated="" at="" 1.4="" times="" the="" recommended="" rate.="" there="" were="" no="" detectable="" residues="" found="" in="" cotton="" undelinted="" seed="" as="" well="" as="" from="" the="" resulting="" processed="" commodities="" even="" at="" treatment="" rates="" of="" more="" than="" 5="" times="" the="" maximum="" recommended="" rate="" per="" season.="" no="" quantifiable="" residues="" were="" found="" in="" cotton="" gin="" byproducts.="" the="" residues="" in="" the="" rice="" grain="" and="" rice="" processed="" fractions="" were="" below="" the="" limit="" of="" detection="" of="" 0.02="" ppm="" at="" all="" locations.="" 5="" of="" the="" 18="" sites="" showed="" residues="" in="" rice="" straw="" ranging="" from="" 0.06="" to="" 0.17="" ppm="" while="" 13="" sites="" had="" non-quantifiable="" residues=""><0.05 ppm).="" results="" of="" the="" aquatic="" sediment="" dissipation="" study="" showed="" that="" the="" parent="" and="" major="" metabolite="" residues="" dissipated="" rapidly="" in="" both="" soil="" and="" water="" phases="" with="">50 values of 1.3 and 1.87 days and
DT90 of 6.48 and 12 days from 2 sites, respectively. The
half-life of halosulfuron-methyl in the paddy water phase is calculated
to be 0.87 days following direct application to water. The vertical
mobility is not a major route of dissipation. The residues (parent and
metabolites that are hydrolyzable to 3-CSA) dissipated rapidly in the
upper soil layer but showed no indication of significant downward
movement into the lower soil layers.
B. Toxicological Profile
1. Acute toxicity. Acute toxicological studies placing the
technical-grade halosulfuron-methyl in Toxicity Category III. A 90-day
feeding study in rats resulted in a lowest-observed-effect-level (LOEL)
of 497 milligrams/kilograms/day (mg/kg/day) in males and 640 mg/kg/day
in females, and a no-observed-effect-level (NOEL) of 116 mg/kg/day in
males and 147 mg/kg/day in females.
2. Genotoxicty. Bacterial/mammalian microsomal mutagenicity assays
were performed and found not to be mutagenic. Two mutagenicity studies
were performed to test gene mutation and found to produce no
chromosomal aberrations or gene mutations in cultured Chinese hamster
ovary cells. An in vivo mouse micronucleus assay did not cause a
significant increase in the frequency of micronucleated polychromatic
erythrocytes in bone marrow cells. A mutagenicity study was performed
on rats and found not to induce unscheduled DNA synthesis in primary
rat hepatocytes.
3. Reproductive and developmental toxicity. A developmental
toxicity study in rats resulted in a developmental LOEL of 750 mg/kg/
day, based on decreases in mean litter size and fetal body weight, and
increases in resorptions, resorptions/dam, post-implantation loss and
in fetal and litter incidences of soft tissue and skeletal variations,
and a developmental NOEL of 250 mg/kg/day. Maternal LOEL was 750 mg/kg/
day based on increased incidence of clinical observations, reduced body
weight gains, and reduced food consumption and food efficiency. The
maternal NOEL was 250 mg/kg/day.
A developmental toxicity study in rabbits resulted in a
developmental LOEL of 150 mg/kg/day, based on decreased mean litter
size and increases in resorptions, resorptions/dam and post-
implantation loss, and a developmental NOEL of 50 mg/kg/day. The
maternal LOEL was 150 mg/kg/day based on reduced body weight gain and
reduced food consumption and food efficiency. The maternal NOEL was 50
mg/kg/day.
A dietary 2-generation reproduction study in rats resulted in
parental toxicity at 223.2 mg/kg/day in males and 261.4 mg/kg/day in
females in the form of decreased body weights, decreased body weight
gains, and reduced food consumption during the premating period. Very
slight effects were noted in body weight of the offspring at this dose.
This effect was
[[Page 29403]]
considered to be developmental toxicity (developmental delay) rather
than a reproductive effect. No effects were noted on reproductive or
other developmental toxicity parameters. The systemic/ developmental
toxicity LOEL was 223.2 mg/kg/day in males and 261.4 mg/kg/day in
females; the systemic/developmental toxicity NOEL was 50.4 mg/kg/day in
males and 58.7 mg/kg/day in females. The reproductive LOEL was greater
than 223.2 mg/kg/day in males and 261.4 mg/kg/day in females; the
reproductive NOEL was equal to or greater than 223.2 mg/kg/day in males
and 261.4 mg/kg/day in females.
4. Subchronic toxicity. A 21-day dermal toxicity study in rats
resulted in a NOEL of 100 mg/kg/day in males and greater than 1,000 mg/
kg/day in females. The only treatment-related effect was a decrease in
body weight gain of the 1,000 mg/kg/day group in males.
5. Chronic toxicity. A 1-year chronic oral study in dogs resulted
in a LOEL of 40 mg/kg/day based on decreased weight gain and a NOEL of
10 mg/kg/day for systemic toxicity. A 78-week carcinogenicity study was
performed on mice. Males in the 971.6 mg/kg/day group had decreased
body weight gains and an increased incidence of microconcretion/
mineralization in the testis and epididymis. No treatment-related
effects were noted in females. Based on these results, a LOEL of 971.9
mg/kg/day was established in males and NOELs of 410 mg/kg/day in males
and 1,214.6 mg/kg/day in females were established. The study showed no
evidence of carcinogenicity. A combined chronic toxicity/
carcinogenicity study in rats resulted in a LOEL of 225.2 mg/kg/day in
males and 138.6 mg/kg/day in females based on decreased body weight
gains, and a NOEL of 108.3 mg/kg/day in males and 56.3 mg/kg/day in
females. The study showed no evidence of carcinogenicity.
6. Animal metabolism. EPA stated that the nature of the residue in
ruminants was determined to be adequately understood. In the tissues
and milk of goats, the major extractable residue was the unmetabolized
parent compound. Based on the low residues of the parent compound in
corn grain and the low transfer of residues in the metabolism study,
tolerances on poultry products were not required. In the rat metabolism
study, parent compound was absorbed rapidly but incompletely. Excretion
was relatively rapid at all doses tested with majority of radioactivity
eliminated in the urine and feces by 72 hours. Fecal elimination of
parent was apparently the result of unabsorbed parent.
7. Metabolite toxicology. The toxicology studies listed below were
conducted with the 3-CSA metabolite. Based on the toxicological data of
the 3-CSA metabolite, EPA concluded that it has lower toxicity compared
to the parent compound and that it should not be included in the
tolerance expression. The residue of concern is the parent compound
only.
i. A 90-day rat feeding study resulted in a LOEL in males of
>20,000 ppm and a NOEL of 20,000 ppm (1,400 mg/kg/day). In females, the
LEL is 10,000 ppm (772.8 mg/kg/day) based on decreased body weight
gains and a NOEL of 1,000 ppm (75.8 mg/kg/day).
ii. A developmental toxicity resulted in a LOEL for maternal
toxicity of >1,000 mg/kg/day based on the absence of systemic toxicity,
a NOEL of 1,000 mg/kg/day. The developmental LOEL is >1,000 mg/kg/day
and the NOEL is 1,000 mg/kg/day.
iii. The microbial reverse gene mutation did not produce any
mutagenic effect while the mammalian cell gene mutation/chinese hamster
ovary cells did not show a clear evidence of mutagenic effect in the
Chinese hamster ovary cells.
iv. The mouse micronucleus assay did not show any clastogenic or
aneugenic effect.
8. Endocrine disruption. No specific tests have been conducted with
halosulfuron-methyl to determine whether the chemical may have an
effect in humans that is similar to an effect produced by a naturally
occurring estrogen or other endocrine effects. However, there were no
significant findings in other relevant toxicity tests, i.e., teratology
and multi-generation reproduction studies, which would suggest that
halosulfuron-methyl produces effects characteristic of the disruption
of the estrogenic hormone.
C. Aggregate Exposure
1. Dietary exposure-- i. Food. For purposes of assessing the
potential dietary exposure from food under existing tolerances,
aggregate exposure based on the Theoretical Maximum Residue
Contribution (TMRC) which is an estimate of the level of residues
consumed daily if each food item contained pesticide residues equal to
the tolerance. The calculated TMRC value was 0.0005 mg/kg body weight/
day for the general US population which will utilize only 0.51% of the
Reference Dose (RfD) for established tolerances for halosulfuron-methyl
and its metabolites in/on raw agricultural commodities of field corn,
grain sorghum (milo) and secondary tolerances in meat and meat
byproducts (cattle, goats, hogs, horses, and sheep). TMRC is obtained
by multiplying the tolerance levels for each commodity by the average
daily consumption of the food forms of that commodity eaten by the U.S.
population and various population subgroups. In conducting this
exposure assessment, conservative assumptions were made, e.g., 100% of
all commodities will contain halosulfuron-methyl residues and those
residues would be at the level of their respective tolerances. This
results in a large overestimate of human exposure. Monsanto conducted
another dietary exposure analysis to include food from crops in
subsequent petitions including this petition. This analysis added
dietary exposure from the following raw agricultural commodities using
the proposed tolerance levels of each commodity, viz.; sweet corn
(kernel + cobs with husks removed at 0.05 ppm, forage at 0.2 ppm,
fodder/stover at 0.8 ppm), pop corn (grain at 0.05 ppm, fodder/stover
at 0.8 ppm), sugarcane (cane at 0.05 ppm), tree nut crop grouping (nut
meat at 0.05 ppm, hulls at 0.2 ppm), pistachio nuts (nutmeat at 0.05
ppm, hulls at 0.2 ppm), cotton (undelinted seed at 0.05 ppm, gin
byproduct at 0.2 ppm) and rice (grain at 0.05 ppm and straw at 0.2
ppm). Food consumption data from the USDA Nationwide Food consumption
survey for 1989-1992 and the EXPOSURE-1 software by TAS, Inc. were used
in the calculation. Even with the same conservative assumptions, the
potential dietary exposure to halosulfuron-methyl from consumption of
products for which it is currently labeled and proposed resulted in a
TMRC of 0.00064 mg/kg body weight/day and represents only 0.6% of the
RfD for the general U.S. population. Field corn and sorghum forage and
fodder are fed to animals, thus exposure of humans to residues from
these commodities might result if such residues are transferred to
meat, milk, poultry or eggs. However, based on the results of animal
metabolism and the amount of halosulfuron-methyl expected in animal
feeds, Monsanto concludes that there is no reasonable expectation that
residues of halosulfuron-methyl will exceed existing tolerances in
meat. The regulation of animal commodities and poultry products are not
required.
ii. Drinking water. There is no Maximum Contaminant Level (MCL)
established for residues of halosulfuron-methyl. It is not listed for
MCL development or drinking water monitoring under the Safe Drinking
Water Act nor is it a target of EPA's National Survey of Wells for
Pesticides.
[[Page 29404]]
Monsanto is not aware of any halosulfuron-methyl detections in any
wells, ponds, lakes or streams resulting from its use in the United
States. A Lifetime Health Advisory Level (HAL), calculated using EPA
procedures, may be used as a preliminary acceptable level in drinking
water. The calculated level is 700 ppb which assumes a 20% relative
contribution from water and which is sufficient to provide ample
margins of safety. In addition, EPA has concluded that potential levels
of halosulfuron-methyl or metabolites in soil and water do not appear
to have significant toxicological effects on humans or animals and
presents a negligible risk.
The EPA has expressed concern regarding potential groundwater
contamination by the sulfonylurea (SU) class of chemistry in general
and has required generic label warnings for halosulfuron-methyl;
however, results of the field dissipation and lysimeter studies and a
recently completed aquatic sediment study with halosulfuron-methyl
should mitigate the concern for this chemical in particular.
Based on the very low level of mammalian toxicity, lack of other
toxicological concerns and low use rates, Monsanto believes that there
is reasonable certainty that no harm will result from exposure to
halosulfuron-methyl via drinking water sources.
iii. Non-dietary exposure. Halosulfuron-methyl is labeled for use
on commercial and residential turf and other non-crop sites which could
have minimal opportunity for exposure. The agricultural uses including
the proposed uses in tree nut crop group, pistachio nuts, cotton and
rice will not increase the non-occupational exposure appreciably, if at
all. Any exposure to halosulfuron-methyl resulting from turf use will
result from dermal exposure during application and will be limited
because of low use rates. In the 21-day dermal study, no treatment
related adverse effects were observed and the NOAEL was determined to
be greater than the highest dose tested, >1,000 mg/kg. Halosulfuron-
methyl is non-volatile with a vapor pressure of <1 x="">-7 mm
Hg, hence, inhalation exposure during and after application will not
add significantly to aggregate exposure. Based on the physical and
chemical characteristics, low use rates, low acute toxicity and lack of
other toxicological concerns, Monsanto believes that the risk posed by
non-occupational exposure to halosulfuron-methyl is minimal.
D. Cumulative Effects
Halosulfuron-methyl belongs to the sulfonyl urea class of
chemistry. The mode of action of halosulfuron-methyl is the inhibition
of the plant enzyme aceto lactase synthetase (ALS), which is essential
for the production of required amino acid in plants. Although other
registered sulfonyl ureas may have similar herbicidal mode of action,
there is no information available to suggest that these compounds
exhibit a similar toxicity profile in the mammalian system that would
be cumulative with halosulfuron-methyl. Thus, consideration of a common
mechanism of toxicity is not appropriate at this time. Monsanto is
considering only the potential risks of halosulfuron-methyl in its
aggregate exposure assessment.
E. Safety Determination
1. U.S. population--Chronic dietary exposure. As stated above, the
EPA's calculated aggregate chronic exposure to halosulfuron-methyl from
the established tolerances for field corn and grain sorghum raw
agricultural commodities utilizes only 0.51% of the RfD using very
conservative assumptions. Monsanto's subsequent calculation to include
the proposed tolerances on sweet corn, pop corn, sugarcane, tree nut
crop grouping, pistachio nuts, rice and cotton estimates that it will
utilize only 0.6% of the RfD for the entire 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. Toxicology data indicating low potential for mammalian toxicity
and lack of other toxicity concerns plus the conservative assumptions
used in this calculation support the conclusion that there is a
``reasonable certainty of no harm'' to the U.S. population in general
from aggregate exposure to halosulfuron-methyl residues from all
anticipated dietary exposures and all other non-occupational exposures.
2. Acute dietary exposure. The detailed DRES acute exposure
analysis evaluates individual food consumption and estimates the
distribution of single day exposures through the diet for the US
population and certain subgroups. Since the toxicological effect to
which high end exposure is compared is developmental toxicity, EPA
determined that the DRES subgroup of concern is females (13+ years)
which approximates women of child-bearing age. The appropriate NOEL to
use to assess safety in acute exposure is 50 mg/kg body weight/day from
a developmental toxicity study in rabbits.
For shorter term risk, the Margin of Exposure (MOE), a measure of
how closely the high end exposure comes to the NOEL and is calculated
as a ratio of the NOEL to the exposure (NOEL/exposure = MOE). For
toxicological endpoints established based upon animal studies ,the
agency is generally not concerned unless the MOE is below 100. In this
analysis, tolerance levels were used to calculate the exposure of the
highest exposed individual (females, 13+ year subgroup). High end
exposure for this subgroup resulted in an MOE in excess of 30,000.
Therefore, the acute dietary exposure to halosulfuron-methyl does not
represent a risk concern. Monsanto has calculated the MOE for all
tolerances (established and proposed) which resulted in an MOE of
31,623 for the entire U.S. population. Monsanto's calculation used the
individual food consumption data from the 1989-1992 USDA Food
Consumption Surveys and the EXPOSURE-4 software by TAS, Inc. Therefore,
Monsanto concludes that there is a reasonable certainty that no harm
will result from acute aggregate exposure to halosulfuron-methyl
residues.
3. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of halosulfuron-methyl,
Monsanto considered data from developmental toxicity studies in the rat
and rabbit and a 2-generation reproduction study in the rat. The
developmental toxicity studies are designed to evaluate the potential
for adverse effects on the developing organism resulting from exposure
during prenatal development to the female parent. Reproduction studies
provide information relating to effects from exposure to the chemical
on the reproductive capability of both (mating) parents and on off
spring from pre-natal and post-natal exposure to the pesticide as well
as systemic toxicity.
In a developmental toxicity study in the rat, the NOEL for both
maternal and developmental toxicity was considered to be 250 mg/kg/day.
In a developmental toxicity study in rabbits, a NOEL for both
developmental and maternal toxicity was considered to be 50 mg/kg/day.
A dietary 2-generation reproduction study in rats resulted in parental
toxicity at 223.2 mg/kg/day in males and 261.4 mg/kg/day in females in
the form of decreased body weights, decreased body weight gains, and
reduced food consumption during the premating period. Very slight
effects were noted in body weight of the offspring at this dose. This
effect was
[[Page 29405]]
considered to be developmental toxicity (developmental delay) rather
than a reproductive effect. No effects were noted on reproductive or
other developmental toxicity parameters. The systemic/developmental
toxicity NOEL was 50.4 mg/kg/day in males and 58.7 mg/kg/day in
females. The reproductive NOEL was equal to or greater than 223.2 mg/
kg/day in males and 261.4 mg/kg/day in females. In all cases, the
reproductive and developmental NOELs were greater than the NOEL on
which the RfD was based, thus allowing for an additional margin of
safety and indicating that halosulfuron-methyl does not pose any
increased risk to infants or children.
4. Chronic analysis. Using the conservative dietary exposure
assumptions described above, the TMRC for the most exposed subgroups is
0.00117 mg/kg body weight/day for nonnursing infants (less than 1-year
old) and 0.001008 mg/kg body weight/day for children (1 to 6 years
old), and that this aggregate exposure to residues of halosulfuron-
methyl utilizes only 1.170 and 1.008% of the RfD, respectively when
existing tolerances are considered. Monsanto's subsequent analysis
included contribution from the proposed tolerances in sugarcane, sweet
corn/popcorn, tree nut crop grouping, pistachio nuts, rice and cotton.
The TMRC utilized only 1.7 and 1.3% of the RfD, respectively.
FFDCA section 408 provides that EPA may apply an additional safety
factor (up to 10) in the case of threshold effects for infants and
children to account for pre- and post-natal toxicity and the
completeness of the data base. Based on current toxicological data
requirements, the data base relative to pre- and post-natal effects in
children is complete. Further, the NOEL of 10 mg/kg/day from the 1-year
feeding study in dogs, which was used to calculate the RfD (discussed
above), is already lower than the NOELs from the reproductive and
developmental studies with halosulfuron-methyl by a factor of at least
25- and 5-fold, respectively. An additional safety factor is not
warranted and the RfD of 0.1 mg/kg/day is appropriate for assessing
aggregate risk to infants and children.
Therefore, based on complete and reliable toxicity data and the
conservative exposure assessment, Monsanto concludes that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to halosulfuron-methyl residues.
F. International Tolerances
Maximum residue levels have not been established for residues of
halosulfuron-methyl on corn, sorghum, sugarcane, sweet corn, pop corn,
tree nuts, pistachio nuts, rice or cotton or any other food or feed
crop by the Codex Alimentarius Commission.
2. Norvartis Crop Protection Inc.
PP 3F4225
EPA has received a pesticide petition (PP 3F4225) from Norvartis
Crop Protection INC., P.O. Box 18300, Greensboro, NC 27419, 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 extending time limited
tolerances for residues of Triasulfuron in or on the raw agricultural
commodity grass, forage at 7.0 ppm, grass, hay at 2.0 ppm and kidney of
cattle, goats, hogs, horses, and sheep at 0.5 ppm. EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition. Additional data may be
needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue in plants is
understood. The metabolism of triasulfuron in wheat proceeds by
hydroxylation of the phenyl ring and hydrolytic cleavage of the urea
bridge. The residue of regulatory concern is parent triasulfuron.
Because the metabolism work in wheat can be translated to grasses,
parent compound is the residue of regulatory concern for grasses.
2. Analytical method. Triasulfuron in grass was analyzed by
Analytical Method AG-500B which the validated tolerance enforcement
method. According to Method AG-500B, triasulfuron is extracted with a
mixture of methanol and phosphoric acid. The extract is diluted with
water. Triasulfuron residues are partitioned into dichloromethane and
cleaned up on a BondElut CN solid phase extraction column. Residues are
determined by column-switching HPLC utilizing a Lichrosorb CN column
followed by a Zorbax ODS column, with UV detection at 232 nm.
3. Magnitude of residues. A total of 16 field trials have been
conducted in 16 States. Seven sites tested bromegrass or fescue, 5 used
bluegrass, and 4 used bermudagrass. A total of 69.6% of U.S.
pastureland was represented by these trials. Two post broadcast spray
applications were made 60-days apart at a rate of 12 grams active
ingredient/A/application. Time-limited tolerances were previously
established at 7 ppm in grass, forage and 2 ppm in grass, hay pending
the submission of additional residue trials. These additional field
trials which are included in the numbers above did not show residues
exceeding the current tolerances in either grass, forage (0-day PHI) or
grass, hay (30-days PHI). The feeding of either substrate to beef or
dairy cattle will not result in existing tolerances in animal
commodities being exceeded.
B. Toxicological Profile
1. Acute toxicity. Triasulfuron has a low order of acute toxicity.
The rat oral LD50 is > 5,000 milligrams/kilogram (mg/kg),
the acute rabbit dermal LD50 is > 2,000 mg/kg and the rat
inhalation LC50 is > 5.2 mg/L. Triasulfuron is slightly
irritating to the eye but not irritating to skin. It is not a skin
sensitizer in guinea pigs. The commercial formulation of triasulfuron
(75WP) has a similar acute toxicity profile. Both the technical
material and the 75WP formulation require a Category III CAUTION Signal
Word on the label.
2. Genotoxicty. Assays for genotoxicity were comprised of tests
evaluating the potential of triasulfuron to induce point mutations
(Salmonella typhimurium, Saccharomyces cerevisiae and mouse lymphoma
L5178Y/TK/+/- cells), chromosome aberrations (micronucleus test in
Chinese hamsters) and the ability to induce either unscheduled DNA
synthesis in rat hepatocytes and human fibroblasts. The results
indicate that triasulfuron is not mutagenic or clastogenic and does not
induce unscheduled DNA synthesis.
3. Reproductive and developmental toxicity. The developmental and
teratogenic potential of triasulfuron was investigated in rats and
rabbits. The results indicate that triasulfuron was maternally toxic in
the rat at doses of > 300 mg/kg/day. Developmental toxicity in the form
of delayed skeletal maturation was observed only at the highest dose
tested (HDT) of 900 mg/kg/day. The corresponding maternal and
developmental NOELs were established at doses of 100 and 300 mg/kg/day,
respectively in the rat. In the rabbit, maternal toxicity was observed
at the HDT of 240 mg/kg/day; no evidence of developmental toxicity was
present at 240 mg/kg/day. The maternal developmental NOELs were 120 and
240 mg/kg/day, respectively. No evidence of teratogenicity was observed
at the HDT in either the rat or rabbit.
[[Page 29406]]
There was no effect of triasulfuron on reproductive performance in a 2
generation rat reproduction study conducted at doses of 1, 50 and 250
mg/kg/day. Maternal and fetal toxicity as indicated by decreased body
weight gain was noted at the HDT of 250 mg/kg/day. The maternal and
developmental NOEL was 50 mg/kg/day.
4. Subchronic toxicity. The subchronic toxicity of triasulfuron was
evaluated in the rat and dog at high doses. Triasulfuron was poorly
tolerated in the rat at doses of > 516 mg/kg/day as indicated by
increased mortality, decreased body weight gain and kidney damage due
to the presence of triasulfuron-containing calculi present in the
urogenital tract. The NOEL in the rat was 10 mg/kg/day. Triasulfuron
was not well tolerated by the dog at doses of 10,000 ppm (250 mg/kg/
day) as indicated by body weight reduction, anemia, and effects on the
spleen, liver and kidney. The NOEL was 1,000 ppm (33 mg/kg/day).
5. Chronic toxicity. The chronic toxicity of triasulfuron was
investigated in long term studies in the rat, mouse and dog. Target
organs included the liver, kidney and blood. NOELs were established at
dose levels of 32.1, 1.2, and 129 mg/kg/day, respectively. The mouse is
the most sensitive species with a NOEL = 1.2 mg/kg/day. The
carcinogenicity studies on triasulfuron showed no evidence of an
oncogenic response in either mouse or rat. The chemical is classified
in category E.
6. Animal metabolism. The metabolism of triasulfuron has been well
characterized in standard FIFRA rat, goat and poultry metabolism
studies. Parent triasulfuron accounts for the majority of the excreted
dose in these species. Cleavage of the sulfonylurea bridge occurs at a
low rate but it is more prevalent in goats and hens than in rats.
Hydroxylation of the phenyl ring, which constitutes the major metabolic
pathway elucidated in wheat, also was found in the rat. None of the
metabolites identified in these studies are considered to be
toxicologically different than parent.
7. Metabolite toxicology. The metabolism of triasulfuron has been
well characterized in rat, goat and poultry metabolism studies. None of
the metabolites identified in these studies are considered to be
toxicologically different than parent.
8. Endocrine disruption. Triasulfuron does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. There was no effect of triasulfuron on reproductive performance
in a 2-generation rat reproduction study conducted at doses of 1, 50
and 250 mg/kg/day. Although residues of triasulfuron have been found in
raw agricultural commodities, there is no evidence that triasulfuron
bioaccumulates in the environment.
C. Aggregate Exposure
1. Food. Novartis has estimated the aggregate exposure to
triasulfuron based on the established and time-limited tolerances for
triasulfuron (40 CFR 180.459). The theoretical maximum residue
contribution to diet is obtained by multiplying the tolerance level
residue for all these raw agricultural commodities by the consumption
data which estimates the amount of these products consumed by various
population subgroups. Because some of these raw agricultural
commodities (e.g. wheat and barley forage and fodder, grass forage and
hay) are fed to animals, the transfer of residues to animal commodities
has been calculated based on a conservatively constructed cattle diet.
In addition, Novartis has conservatively assumed that 100% of the raw
agricultural commodities contain residues of triasulfuron at tolerance
levels.
2. Drinking water. Another potential source of exposure of the
general population to residues of pesticides are residues in drinking
water. The potential for triasulfuron to enter surface or groundwater
sources of drinking water is limited because of the low use rate. The
Maximum Contaminant Level Guideline (MCLG) calculated for triasulfuron
according to EPA's procedures is 84 ppb, a value that is substantially
greater than levels that are likely to be found in the environment
under proposed conditions of use.
3. Non-dietary exposure. Novartis has evaluated the estimated non-
occupational exposure to triasulfuron and concludes that the potential
for non-occupational exposure to the general population is unlikely
since triasulfuron is not planned to be used in or around the home,
including home lawns.
D. Cumulative Effects
Novartis also has considered the potential for cumulative effects
of triasulfuron and other chemicals belonging to this class that may
have a common mechanism of toxicity. Novartis concluded that
consideration of a common mechanism of toxicity is not appropriate at
this time since there is no data to establish whether a common
mechanism exists.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above, based on the completeness and reliability of the
toxicity data, Novartis has concluded that aggregate exposure to
triasulfuron will utilize a maximum of 4.63% of the RfD 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. Therefore,
Novartis concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to triasulfuron or residues of
triasulfuron that may appear in raw agricultural commodities.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of triasulfuron,
Novartis has considered data from developmental toxicity studies in the
rat and rabbit and a 2-generation reproduction study in the rat on
triasulfuron. The developmental toxicity studies are designed to
evaluate adverse effects on the developing organism resulting from
chemical exposure during prenatal development to one or both parents.
Reproduction studies provide information relating to effects from
exposure to a chemical on the reproductive capability of mating animals
and data on systemic toxicity.
Developmental toxicity in the form of delayed skeletal maturation
was observed in the rat only at the HDT of 900 mg/kg/day. The
corresponding maternal and developmental NOELs were established at
doses of 100 and 300 mg/kg/day, respectively in the rat. In the rabbit,
maternal toxicity was observed at the HDT of 240 mg/kg/day; no evidence
of developmental toxicity was present at 240 mg/kg/day.
There was no effect of triasulfuron on reproductive performance in
a 2 generation rat reproduction study conducted at doses of 1, 50 and
250 mg/kg/day. Maternal and fetal toxicity as indicated by decreased
body weight gain was noted at the HDT 250 mg/kg/day. The maternal and
developmental NOELs were 50 mg/kg/day.
Section 408 of the FFDCA provides that EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, for triasulfuron,
[[Page 29407]]
the NOEL of 1.2 mg/kg/day from the mouse oncogenicity study, which was
used to calculate the RfD of 0.01 mg/kg/day, was approximately 50 times
lower than the developmental NOEL level from the rat multigeneration
reproduction study. There is no evidence to suggest that developing
organisms are more sensitive to the effects of triasulfuron than are
adults.
Using the conservative exposure assumptions described above and the
chronic toxicity NOEL of 1.2 mg/kg/day (RfD of 0.01 mg/kg/day),
Novartis has determined that the % of the RfD that will be utilized by
aggregate exposure to residues of triasulfuron is 3.98% for nursing
infants less than 1-year old, 15.43% for non-nursing infants, 10.91%
for children 1 to 6-years old and 7.34% for children 7 to 12-years old.
Therefore, based on the completeness and reliability of the toxicity
data 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 triasulfuron residues.
F. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue
levels (MRL's) established for residues of triasulfuron in or on raw
agricultural commodities.
3. Zeneca Ag Products
PP 8F4954
EPA has received a pesticide petition (PP 8F4954) from Zeneca Ag
Products, 1800 Concord Pike, Wilmington, DE 19850-5458 proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
for residues of the herbicide, 2-[4-(methylsulfonyl)-2-nitrobenzoyl]-
1,3-cyclohexanedione, in or on the raw agricultural commodities field
corn, field corn fodder and field corn forage at 0.01 ppm. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue of 2-[4-
(methylsulfonyl)-2-nitrobenzoyl]-1,3-cyclohexanedione, (hereafter
referred to by the trade name ZA1296) in plants is adequately
understood. ZA1296 is rapidly and completely metabolized in corn. No
single extract or component accounted for greater than 0.01 ppm in
grain. Numerous components were characterised in forage and fodder,
including the metabolite 2-amino-4-methylsulfonyl benzoic acid (AMBA)
and its conjugates and 4-methylsulfonyl-2-nitrobenzoic acid (MNBA). In
addition to ZA1296, MNBA was included in crop residue analysis.
2. Analytical method. The proposed analytical method involves
extraction, partition, clean-up and separation of ZA1296 and MNBA,
oxidation of ZA1296, reduction, clean-up and detection of residues by
reversed-phase HPLC using fluorescence detection. The limit of
quantitation for ZA1296 and the metabolite MNBA is 0.01 ppm.
3. Magnitude of residues. Twenty residue trials were conducted in
the US (EPA regions I, II, V and VI). The proposed use of ZA1296 does
not result in residues (LOQ of 0.01 ppm) of ZA1296 or the metabolite
MNBA in field corn grain, forage or fodder.
B. Toxicological Profile
1. Acute toxicity. A battery of acute toxicity tests were conducted
which place ZA1296 in acute oral toxicity category IV, acute dermal
toxicity category III, acute inhalation toxicity category IV, primary
eye irritation category III, and primary dermal irritation category IV.
ZA1296 is not a skin sensitizer. ZA1296 is not a neurotoxin in males
and females at 2,000 mg/kg (limit test).
2. Genotoxicty. ZA296 was found to be negative for mutagenicity in
a battery of mutagenicity tests (in vitro) Ames Testing, Mouse
Lymphoma, Human Lymphocytes and in vivo Mouse Micronucleus).
3. Reproductive and developmental toxicity--i. Developmental
toxicity (rabbit). New Zealand white rabbits were dosed orally by
gavage with 0, 100, 250 or 500 mg/kg/day ZA1296 on days 8-20 of
gestation. The top dose level in this study was set on the basis of
significant maternal toxicity seen at higher dose levels in a
preliminary study. At dose levels of 250 and 500 mg/kg/day there was a
low incidence of whole litter losses. ZA1296 was not associated with
significant maternal toxicity or evidence of teratogenicity. Dose
levels of 100 mg/kg/day or more were associated with changes in the
ossification of the fetal skeleton but not with structural
malformation. The changes in ossification are transient in nature and
considered not to be of toxicological significance in terms of post
natal development. A developmental NOAEL of 100 mg/kg/day was
established in this study.
ii. Developmental toxicity (rat). Rats were dosed orally by gavage
with 0, 100, 300 or 1,000 mg/kg/day ZA1296 on days 7-16 of gestation.
Maternal toxicity, as evidenced by reductions in body weight and food
consumption, was seen at dose levels of 100, 300 or 1,000 mg/kg/day
ZA1296. Administration of ZA1296 at dose levels of up to 1,000 mg/kg/
day produced no evidence of teratogenicity. An increased incidence of
minor skeletal defects and skeletal variants and increases in mean
manus and pes scores were seen at all dose levels and were indicative
of reduced ossification or a disturbance in the normal pattern of
ossification. The changes in ossification are transient in nature and
are considered not to be of toxicological significance in terms of
post-natal development. Fetal weight was reduced at 1,000 mg/kg/day. A
developmental NOAEL of 300 mg/kg/day was established in this study.
iii. Reproductive toxicity (rat). In a 3-generation study rats were
fed diets containing 0, 2.5, 10 or 2500 ppm ZA1296. Dietary
administration of ZA1296 had no effect on mating performance but was
found to result in reduced pup survival at a dose of 2,500 ppm in all
3-generations and at 100 ppm in the second generation only. These
findings were not present in recovery subgroups removed from treated
diet in the third generation. There was also a reduction in the number
of pups per litter, and effects on body weights and in the eye and
kidney. In the third generation, there were no effects in the eyes or
kidneys of offspring from animals which were returned to control diet 4
weeks prior to mating and effects on litter size were less marked than
in the continuous treatment group. A NOEL of 2.5 ppm ZA1296 (0.3 mg/kg/
day) was established in this study. In light of the mechanism of
toxicity, investigations into the effects seen in this study in pups
are considered not to be relevant to human risk assessment.
iv. Reproductive toxicity (mouse). In a 2-generation study mice
were fed diets containing 0, 10, 50, 350, 1,500 or 7.000 ppm ZA1296.
There were no adverse effect of ZA1296 on the reproductive performance
of the mouse, on fertility and fecundity of the F0 and F1 adult animals
or on survival of their offspring. The body weights of the offspring
were reduced at 1,500 and 7,000 ppm ZA1296. A NOEL of 350 ppm ZA1296
(71 mg/kg/day) was established in this study.
4. Subchronic toxicity--i. 21-day dermal (rabbits). Rabbits were
repeatedly dosed with ZA1296 at 0, 10,
[[Page 29408]]
500 or 1,000 mg/kg/day for 21 days. The NOEL for sub-acute dermal
toxicity was >1,000 mg/kg/day (limit dose).
ii. 90-day rodent (rat). In a first study male and female rats were
dosed with 0, 1, 125, 1,250 or 12,500 ppm ZA1296 in the diet for 90-
days. The NOEL was determined to be 1ppm for males and females (0.09
and 0.1 mg/kg/day, respectively) based on reduced bodyweight and
increased liver weight in males and females at 125 ppm and increased
kidney weight and ocular keratitis in males at 125 ppm. 125 ppm (13 mg/
kg/day) was a NOEL for the ocular keratitis in females. In a second
study in male rats dosed with ZA1296 at 0, 10, 20 or 150 ppm ZA1296 in
the diet for 90-days, a NOEL of 20 ppm (1.7 mg/kg/day) was determined
for reduced bodyweight. At the 10 ppm dose level ocular keratitis and
increased liver and kidney weights were observed. In a third study in
male and female rats dosed with ZA1296 at 0, 2.5, 5.0, 7.5 or 150 ppm
in the diet for 90-days, NOELs of 5 ppm (0.41 mg/kg/day) for ocular
keratitis and increased kidney weight and 7.5 ppm (0.63 mg/kg/day) for
reduced bodyweight were determined in males. NOELs of 7.5 ppm (0.71 mg/
kg/day) for reduced bodyweight and increased liver weight and 150 ppm
(14 mg/kg/day) for increased kidney weight were determined in females.
At 2.5 ppm in males increased liver weight was observed. In light of
investigations into the mechanism of toxicity, these changes are all
considered not to be relevant to human risk assessment.
iii. 90-day rodent (mouse). Mice were dosed 0, 50, 350 or 7,000 ppm
in the diet for 90-days. In females no clear toxic effects were
observed at 7,000 ppm (1,500 mg/kg/day). In males 7,000 ppm (1,200 mg/
kg/day) was associated with a reduced growth rate and food utilization.
In males and females 350 ppm (62 and 80 mg/kg/day, respectively)
produced no effects which were considered to be toxicologically
significant.
iv. 90-day non-rodent (dog). Beagle dogs were dosed with ZA1296 at
0, 100, 600 or 1,000 mg/kg/day as a daily oral dose by capsule, for a
period of 90-days. The NOEL in the dog over 90-days was 100 mg/kg/day.
Minimal toxicity was observed at 600 and 1,000 mg/kg/day, evident as
reduced bodyweights in males and a microcytic polycythemia in both
sexes. Mesothelial proliferation of the atrium of the heart was evident
in 2 male dogs at 1,000 mg/kg/day.
v. 90-day neurotoxicity (rat). Rats were dosed with ZA1296 at 0,
2.5, 100 or 5,000 ppm in the diet for 90-days. The NOAEL for subchronic
neurotoxicity was determined to be 5,000 ppm (400 and 460 mg/kg/day for
males and females, respectively) based on the absence of changes
indicative of neurotoxicity.
5. Chronic toxicity--i. 1-year non-rodent (dog). Beagle dogs were
dosed with ZA1296 at 0, 10, 100 or 600 mg/kg/day as a daily oral dose
by capsule, for a period of 1-year. The NOEL in this study was 100 mg/
kg/day. At 600 mg/kg/day males showed a significant reduction in
bodyweight and both sexes showed a slight microcytic polycythemia,
indicating that a maximum tolerated dose had been achieved. Minimal
ocular keratitis was observed in 1 male and 1 female at 600 mg/kg/day.
ii. 1-year rodent (mouse). Mice were dosed with ZA1296 at 0, 10,
50, 350 or 7,000 ppm in the diet for 1 year. The NOEL in males and
females was 350 ppm (56 and 72 mg/kg/day, respectively). At 7,000 ppm
(limit dose) bodyweight was reduced in males, and there was an
increased incidence of eosinophilic change in the gall bladder of
females.
iii. Combined rodent chronic toxicity/oncogenicity (rat). Rats were
dosed with ZA1296 at 0, 7.5, 100 or 2,500 ppm in the diet for up to 2
years. In addition rats were fed diet containing 1 or 2.5 ppm ZA1296
for up to 2-years to determine the chronic ocular toxicity. Oral
administration of 7.5, 100 or 2,500 ppm ZA1296 for at least 2-years
caused ocular keratitis, reduced bodyweights, increased liver and
kidney weights, and an increased incidence of common spontaneous
lesions in the Alderley Park rat. In light of investigations into the
mechanism of toxicity, these changes are all considered not to be
related to human risk assessment. Satellite groups of rats fed 1 and
2.5 ppm ZA1296 showed that dietary levels of 2.5 ppm in males and 7.5
ppm in females were without ocular effect. ZA1296 was considered not to
be carcinogenic in the rat in this study. A NOEL of 7.5 ppm ZA1296 was
established for females.
iv. Oncogenicity in the rodent (mouse). Mice were fed diets
containing 0, 10, 350 or 7,000 ppm ZA1296 for up to 80-weeks. Oral
administration of 7,000 ppm (900-1,100 mg/kg/day) ZA1296 (limit dose)
for at least 80-weeks produced no evidence of carcinogenicity in male
or female mice.
6. Animal metabolism. The absorption, distribution, metabolism and
excretion of ZA1296 has been thoroughly investigated in rats and
studied in mice. In both species ZA1296 is well absorbed following an
oral dose. Elimination of ZA1296 is rapid in both species, with most of
the ZA1296 eliminated, in the urine, unchanged with only minor amounts
of the urinary and fecal metabolites, including MNBA and AMBA,
detected. In poultry ZA1296 is excreted generally unchanged. In
ruminants ZA1296 is extensively metabolised and excreted. AMBA dosed to
ruminants is readily absorbed and excreted, generally unchanged. AMBA
is not accumulated in edible tissues or milk.
7. Metabolite toxicology. In acute oral toxicity studies in male
and female rats both MNBA and AMBA had an oral LD50 of
>5,000 mg/kg. In the Ames assay, both MNBA and AMBA were found to be
negative for mutagenicity in the absence and presence of metabolic
activation.
8. Endocrine disruption. EPA is required to develop a screening
program to determine whether certain substances (including all
pesticides and inerts) ``may have an effect in humans that is similar
to an effect produced by a naturally occurring estrogen, or such other
endocrine effect.'' EPA is currently working with interested
shareholders, including other government agencies, public interest
groups, industry, and research scientists, to develop a screening and
testing program and a priority setting scheme to implement this
program. Congress has allowed 3-years from the passage of FQPA (August
3, 1999) to implement this program. When this program is implemented,
EPA may require further testing of ZA1296 and end-use product
formulations for endocrine disrupter effects.
9. Reference dose. As required by the Food Quality and Protection
Act of 1996, the mechanism of toxicity of ZA1296 has been thoroughly
investigated in studies (FQPA) in the rat, mouse and man. These data
clearly demonstrate that the response to ZA1296 administration in man
is very similar to that seen in the mouse which should therefore, be
used in preference to the rat when assessing the safety of ZA1296 to
humans. The proposed reference dose (RfD) for use in the assessment of
risk from chronic exposure is 0.56 mg/kg/day and is derived from the 1
year chronic toxicity study in the mouse with a NOEL of 56 mg/kg/day
and a 100-fold uncertainty factor.
C. Aggregate Exposure
1. Dietary exposure. The potential dietary exposure to ZA1296 was
estimated from tolerance levels and 100% crop treated. No tolerances
are proposed for meat, milk and eggs. The total dietary exposure for
the U.S. population and the most highly exposed
[[Page 29409]]
subgroup in the population, non-nursing infants, is 0.000011 mg/kg/day
and 0.000027 mg/kg/day, respectively.
2. Drinking water. Drinking water estimated concentrations (DWEC)
were calculated using EPA models for groundwater and surface water -
SCI-GROW, GENEEC and PRZM/EXAMS. Chronic Drinking Water Levels of
Concern (DWLOC) were calculated according to the EPA SOP and compared
to the DWEC. Estimated average contributions of ZA1296 in surface and
groundwater are less than the levels of concern for ZA1296 in drinking
water as a contribution to chronic aggregate exposure.
3. Non-dietary exposure. Zeneca has not estimated non-occupational
exposure for ZA1296 since the only pending registration for ZA1296 is
limited to commercial crop production use. ZA1296 products are not
labelled for any residential uses therefore, eliminating the potential
for residential exposure. The potential for non-occupational exposure
to the general population is considered to be insignificant.
D. Cumulative Effects
Zeneca also considered the potential for cumulative effects of
ZA1296 and other substances that have a common mechanism of toxicity.
Zeneca has concluded that consideration of a common mechanism of
toxicity is not appropriate at this time since there is no indication
that toxic effects produced by ZA1296 would be cumulative with those of
any other chemical compounds. Triketone chemistry is new and ZA1296 has
a novel mode of action compared to currently registered active
ingredients.
E. Safety Determination
1. U.S. population. Dietary and occupational exposure will be the
major routes of exposure to the U.S. population and ample margins of
safety have been demonstrated for both situations. The total dietary
exposure for the U.S. population is 0.000011 mg/kg/day. This utilizes
only 0.002% of the RfD. The MOE for occupational exposure is >5,500.
Based on the completeness and reliability of the toxicity data and the
conservative exposure assessments, there is reasonable certainty that
no harm will result from the aggregate exposure of residues of ZA1296
including all anticipated dietary exposure.
2. Infants and children. The total dietary exposure for the most
highly exposed subgroup in the population, non-nursing infants, is
0.000027 mg/kg/day. This utilizes only 0.0048% of the RfD. There are no
residential uses of ZA1296 and the estimated average contributions of
ZA1296 in surface and groundwater are less than the levels of concern
for ZA1296 in drinking water as a contribution to chronic aggregate
exposure. Based on the completeness and reliability of the toxicity
data and the conservative exposure assessments, there is reasonable
certainty that no harm will result from the aggregate exposure of
residues of ZA1296 including all anticipated dietary exposure.
F. International Tolerances
A maximum residue level has not been established for ZA1296 by the
Codex Alimentarius Commission.
[FR Doc. 98-14160 Filed 5-28-98; 8:45 am]
BILLING CODE 6560-50-F
