[Federal Register Volume 63, Number 189 (Wednesday, September 30, 1998)]
[Notices]
[Pages 52260-52265]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-25756]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-828; FRL-6023-7]
Notice of Filing of Pesticide Tolerance Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-828, must
be received on or before October 30, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources 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 (CBI) 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
CBI. CBI should not be submitted through e-mail. Information marked as
CBI will not be disclosed except in accordance with procedures set
forth in 40 CFR part 2. A copy of the comment that does not contain CBI
must be submitted for inclusion in the public record. Information not
marked confidential may be disclosed publicly by EPA without prior
notice. All written comments will be available for public inspection in
Rm. 119 at the address given above, from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Mark Dow...................... Rm. 214, CM #2, 703- 1921 Jefferson
305-5533; e-mail: Davis Hwy,
[email protected]. Arlington, VA
gov.
Ann Sibold.................... Rm. 212, CM #2, 703- Do.
305-6502; e-mail:
[email protected]
a.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various raw food commodities under
section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21
U.S.C. 346a. EPA has determined that these petitions contain data or
information regarding the elements set forth in section 408(d)(2) of
the (FFDCA) as amended by the Food Quality Protection Act (FQPA) of
1996 (Pub. L. 104-170); however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports grantinig of the petition. Additional data may be needed
before EPA rules on the petition.
The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-828 (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''.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-828) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: September 19, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. The
petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
[[Page 52261]]
1. American Cyanamid Company
PP 8F4980
EPA has received a pesticide petition (PP 8F4980) from American
Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400, proposing
pursuant to section 408(d) of the FFDCA 21 U.S.C. 346a(d), to amend 40
CFR part 180 by establishing a tolerance for residues of 4-bromo-2-(4-
chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1-pyrrole-3-
carbonitrile, (chlorfenapyr) in or on the raw agricultural commodity
milk, milk fat, meat, meat fat and meat byproducts at 0.01, 0.03, 0.01,
0.03, and 0.30 parts per million (ppm) respectively, derived from the
use of chlorfenapyr ear tags on beef and dairy cattle. 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. Although not relevant to this use pattern, the
Agency has reviewed data submitted in support of pesticide petitions
5F4456, 5G4507, 5G453, 5G4548, and 5G4574 on the metabolism of
chlorfenapyr in several plants and concluded that the nature of the
residues of chlorfenapyr in plants is adequately understood and that
the residue of concern consists of the parent molecule. The metabolic
pathway of chlorfenapyr in the laying hen and the lactating goat was
also similar to that in laboratory rats.
2. Analytical method. Section 408 (b)(3) of the amended FFDCA
requires EPA to determine that there is a practical method for
detecting and measuring levels of the pesticide chemical residue in or
on food and that the tolerance be set at a level at or above of the
limit of detection of the designated method. The gas chromatography
analytical methods, M2395.01 and M2398.01, which are proposed as the
enforcement method for the residues of chlorfenapyr in milk and muscle/
fat, respectively, each have an Limit of Quantification (LOQ) of 0.01
ppm and method M2405, which is proposed as the enforcement method for
the residues of chlorfenapyr in liver/kidney tissues has an LOQ of 0.05
ppm. All methods have been validated at the EPA laboratories in
Beltsville, MD.
3. Magnitude of residues. There is an extensive data base on
chlorfenapyr that has been reviewed and accepted by the Agency. A
residue depletion study was conducted to determine whether the
application of two ear tags containing 30% chlorfenapyr to lactating
dairy cattle would result in residues in milk, milk fat or edible
tissues (muscle, liver, kidney, and fat). The results of this study
indicate that the proposed tolerances for the residues of chlorfenapyr
in milk, milk fat, meat, meat fat and meat by-products are more than
adequate to cover any residues that may result from this use pattern.
B. Toxicological Profile
1. Acute toxicity. Based on the EPA's toxicity category criteria,
the acute toxicity category for chlorfenapyr technical and the 3SC
formulation is Category II or moderately toxic (signal word WARNING)
and the acute toxicity category for the 2SC formulation is Category III
or slightly toxic (signal word CAUTION). Males appear to be more
sensitive to the effects of chlorfenapyr than females. The acute
toxicity profile indicates that absorption by the oral route appears to
be greater than by the dermal route. The following are the results from
the acute toxicity tests conducted on the technical material:
Rat Oral LD50: 441/1,152 milogram/kilogram body
weight (mg/kg b.w.) Male/Female (M/F); Tox. Category II
Rabbit Dermal LD50: >2,000 mg/kg b.w.(M/F); Tox.
Category III
Acute Inhal. LC50: 0.83/>2.7 mg/L (M/F); Tox.
Category III
Eye Irritation: Moderately Irritating; Tox. Category III
Dermal Irritation: Non-Irritating; Tox. Category IV
Dermal Sensitization: Non-Sensitizer
Acute Neurotoxicity: No-Observed-Adverse-Effect-Level (NOAEL) 45
mg/kg b.w; Not An Acute Neurotoxicant
2. Genotoxicty. Chlorfenapyr technical (94.5% active ingredient
(a.i.)) was examined in a battery of in vitro and in vivo tests to
assess its genotoxicity and its potential for carcinogenicity. These
tests are summarized below.
Microbial/Microsome Mutagenicity Assay: Non-mutagenic
Mammalian Cell Chinese Hamster Ovary (CHO)/HGPRT Mutagenicity
Assay: Non-mutagenic
In Vivo Micronucleus Assay: Non-genotoxic
In Vitro Chromosome Aberration Assay in CHO: Non-clastogenic
In Vitro Chromosome Aberration Assay in CHLC: Non-clastogenic
Unscheduled DNA Synthesis (UDS) Assay: Non-genotoxic.
3. Reproductive and developmental toxicity. Chlorfenapyr is neither
a reproductive nor a developmental toxicant and is not a teratogenic
agent in the Sprague-Dawley rat or the New Zealand white rabbit. This
is demonstrated by the results of the following studies:
Rat Oral Teratology: NOAEL for maternal toxicity 25 mg/kg b.w./
day; NOAEL for fetal/develop. toxicity 225 mg/kg b.w./day
Rabbit Oral Teratology: NOAEL for maternal toxicity 5 mg/kg
b.w./day
NOAEL for fetal/develop. toxicity 30 mg/kg b.w./day
Rat Two-Generation: NOAEL for parental toxicity /growth and
Reproduction offspring development 60 ppm (5 mg/kg b.w./day); NOAEL
for reproductive performance 600 ppm (44 mg/kg b.w./day).
4. Subchronic toxicity. The following are the results of the
subchronic toxicity tests that have been conducted with chlorfenapyr:
28-Day Rabbit Dermal: NOAEL 100 mg/kg b.w./day
28-Day Rat Feeding: NOAEL <600 ppm (< 71.6 mg/kg b.w./day)
28-Day Mouse Feeding: NOAEL <160 ppm (<32 mg/kg b.w./day)
13-Week Rat Dietary: NOAEL 150 ppm (11.7 mg/kg b.w./day)
13-Week Mouse Dietary: NOAEL 40 ppm (8.2 mg/kg b.w./day)
13-Week Dog Dietary: NOAEL 120 ppm (4.2 mg/kg b.w./day).
5. Chronic toxicity. Chlorfenapyr is not oncogenic in either
Sprague Dawley rats or CD-1 mice and is not likely to be carcinogenic
in humans. The following are the results of the chronic toxicity tests
that have been conducted with chlorfenapyr:
1-Year Neurotoxicity in Rats: NOAEL 60 ppm (2.6/3.4 mg/kg b.w./
day M/F)
1-Year Dog Dietary: NOAEL 120 ppm (4.0/4.5 mg/kg b.w./day M/F)
24-Month Rat Dietary: NOAEL for Chronic Effects 60 ppm (2.9/3.6
mg/kg b.w./day M/F)
NOAEL for Oncogenic Effects 600 ppm (31/37 mg/kg b.w./day M/F)
18-Month Mouse Dietary: NOAEL for Chronic Effects 20 ppm (2.8/
3.7 mg/kg b.w./day M/F)
NOAEL for Oncogenic Effects 240 ppm (34.5/44.5 mg/kg b.w./day M/
F).
6. Animal metabolism. A metabolism study was conducted in Sprague-
Dawley rats at approximately 20 and 200 mg/kg b.w using radiolabeled
chlorfenapyr. Approximately 65% of the administered dose was eliminated
during the first 24 hours (62% in feces and 3% in urine) and by 48
hours following dosing, approximately 85% of the dose had been excreted
(80% in feces and 5% in urine). The absorbed chlorfenapyr-related
residues were distributed throughout the body and detected in tissues
and organs of all
[[Page 52262]]
treatment groups. The principal route of elimination was via feces,
mainly as unchanged parent plus minor N-dealkylated, debrominated and
hydroxylated oxidation products.
7. Metabolite toxicology. The parent molecule is the only moiety
of toxicological significance which needs regulation in plant and
animal commodities.
8. Endocrine disruption. Collective organ weights and
histopathological findings from the two-generation rat reproduction
study, as well as from the subchronic and chronic toxicity studies in
two or more animal species, demonstrate no apparent estrogenic effects
or effects on the endocrine system. There is no information available
which suggests that chlorfenapyr would be associated with endocrine
effects.
C. Aggregate Exposure
1. Food. For purposes of assessing the potential dietary exposure,
a Theoretical Maximum Residue Contribution (TMRC) has been calculated
from the proposed tolerance of chlorfenapyr in milk at 0.01 ppm, milk
fat at 0.03 ppm, meat at 0.01 ppm, meat fat at 0.03 ppm and meat by-
products at 0.30 ppm. As there are no other established U.S. permanent
tolerances for chlorfenapyr, the only dietary exposure to residues of
chlorfenapyr in or on food will be limited to residues in milk, milk
fat, meat, meat fat and meat byproducts derived from cattle. The
contribution of all these tolerances to the daily consumption will be
insignificant for the overall U.S. population (utilizing only 0.23% of
the reference dose (RfD) as well as all sensitive subpopulations
including children aged 1-6 (0.52% of RfD utilized) and non-nursing
infants (utilization of 0.47% of RfD).
2. Drinking water. There is no available information about
chlorfenapyr exposures via levels in drinking water. There is no
concern for exposure to residues of chlorfenapyr in drinking water
because of this use pattern on ear tags. Moreover, because of its
extremely low water solubility (120 parts per billion (ppb) at 25 deg.
C). Chlorfenapyr is also immobile in soil and does not leach because it
is strongly adsorbed to all common soil types. In addition, the label
explicitly prohibits applications near aquatic areas. There is a
reasonable certainty that no harm will result from dietary exposure to
chlorfenapyr, because dietary exposure to residues on food will use
only a small fraction of the Reference Dose (RfD) (including exposure
of sensitive subpopulations), and exposure through drinking water is
expected to be insignificant.
3. Non-dietary exposure. Chlorfenapyr is currently not registered
for use in residential indoor or outdoor uses. However, based on the
physico-chemical characteristics of the compound, the proposed use
pattern as an ear tag and available information concerning its
environmental fate, non-dietary exposure is expected to be negligible.
The vapor pressure of chlorfenapyr is 4.05 x 10-8 mm of
mercury; therefore, the potential for non-occupational exposure by
inhalation is insignificant. Moreover, the current proposed
registration is for outdoor, terrestrial uses which severely limit the
potential for non-occupational exposure.
D. Cumulative Effects
The pyrrole insecticides represent a new class of chemistry with a
unique mechanism of action. The parent molecule, AC 303,630 is a pro-
insecticide which is converted to the active form, CL 303,268, via
rapid metabolism by mixed function oxidases (MFOs). The active form
uncouples oxidative phosphorylation in the insect mitochondria by
disrupting the proton gradient across the mitochondrial membrane. The
production of Adenosine Triphosphate (ATP) is inhibited resulting in
the cessation of all cellular functions. Because of this unique
mechanism of action, it is highly unlikely that toxic effects produced
by chlorfenapyr would be cumulative with those of any other pesticide
chemical.
In mammals, there is a lower titer of MFOs, and chlorfenapyr is
metabolized by different pathways (including dehalogenation, oxidation,
and ring hydroxylation) to other polar metabolites without any
significant accumulation of the potent uncoupler, CL 303,268. In the
rat, appoximately 85% of the administered dose is excreted in the feces
within 48 hours, thereby reducing the levels of AC 303,630 and CL
303,268 that are capable of reaching the mitochondria. This
differential metabolism of AC 303,630 to CL 303,268 in insects versus
to other polar metabolites in mammals is responsible for the selective
insect toxicity of the pyrroles.
E. Safety Determination
1. U.S. population. The RfD of 0.03 mg/kg b.w./day for the
residues of chlorfenapyr in milk, milk fat, meat, meat fat, and meat
byproducts, is calculated by applying a 100-fold safety factor to the
overall NOAEL of 3 mg/kg b.w./day. This NOAEL is based on the results
of the chronic feeding studies in the rat and mouse and the 2-
generation reproduction study in the rat (see B. Toxicological
Profile). Therefore, the combined TMRC for the proposed chlorfenapyr
tolerances in milk, milk fat, meat, meat fat and meat byproducts
(0.0000681 mg/kg b.w./day) will utilize approximately 0.23% of the RfD
for the general US population.
2. Infants and children. The TMRC in milk, milk fat, meat, meat
fat and meat byproducts consumed by a non-nursing infant (<1 year of
age) is 0.000141 mg/kg b.w./day. This will use 0.47% of the RfD for
non-nursing infants. The TMRC for the proposed chlorfenapyr tolerances
in milk, milk fat, meat, meat fat and meat byproducts consumed by a
child 1-6 years of age is 0.000156 mg/kg b.w./day, which is less than
1% (actual 0.52%) of the RfD. Therefore, the results of the toxicology
and metabolism studies support both the safety of chlorfenapyr to
humans based on the intended use as cattle ear tag and the granting of
the requested tolerances in milk, milk fat, meat, meat fat and meat by-
products.
F. International Tolerances
Section 408 (b)(4) of the amended FFDCA requires EPA to determine
whether a maximum residue level has been established for the pesticide
chemical by the Codex Alimentarius Commission.
There is neither a Codex proposal, nor Canadian or Mexican
tolerances/limits for residues of chlorfenapyr in meat and meat
byproducts. Therefore, a compatibility issue is not relevant to the
proposed tolerance. (Ann Sibold)
2. Rohm and Haas Company
PP 7F4894
EPA has received a pesticide petition (PP 7F4894) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399,
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 triazamate; ethyl (3-tert-
butyl-1-dimethylcarbamoyl-1H-1,2,4-triazol-5-ylthio) acetate in or on
the raw agricultural commodity apples at 0.1 parts per million (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.
[[Page 52263]]
A. Residue Chemistry
1. Plant metabolism. The metabolism of triazamate in plants
(apples) is adequately understood for the purposes of this tolerance.
The metabolism of triazamate involves hydrolysis of the ester and
oxidative demethylation of the carbamoyl group. Parent compound is
rapidly metabolized and is either not found or found at trace levels in
pome fruit. The majority of the residue which may remain on the fruit
is present as non-cholinesterase inhibiting metabolites whose
structures do not contain the dimethylcarbamoyl moiety. The metabolism
of triazamate in goats proceeds along the same metabolic pathway as
observed in plants. Because apple pomace is not fed to poultry, there
is no reasonable expectation that measurable residues of triazamate or
any of its metabolites will occur in eggs, poultry meat or poultry meat
by-products. The transfer of residues into milk and meat was minimal in
the goat metabolism and the majority of the residue which was found in
the milk and tissues was non-cholinesterase metabolites. Because of
this low transfer rate and the low measurable residues present in apple
pomace, there is no reasonable expectation of finding measurable
residues of triazamate or any of its metabolites in milk, meat or meat
by-products.
2. Analytical method. An analytical method using chemical
derivitization followed by gas chromatography (GC) using Nitrogen-
Phosphorous detection has been developed and validated for residues of
triazamate and its cholinesterase-inhibiting metabolite (RH-0422) for
pome fruit and processed apple fractions. For all matrices, the methods
involve Soxhlet extraction of the residue from fruit samples with
solvents, purification of the extracts by liquid-liquid partitioning,
derivitization of the metabolite with diazomethane, and final
purification of the residues using solid phase extraction column
chromatography. The limit of quantitation (LOQ) of the methods is 0.01
ppm for pome fruit, apple juice, sauce and wet apple pomace.
3. Magnitude of residues. --i. Acute risk. An acute dietary risk
assessment (Dietary Exposure Evaluation Model, Novigen Sciences Inc.,
1997) was conducted for triazamate using two approaches: (1) a Tier 1
approach using a tolerance level residue of 0.10 ppm and (2) Monte
Carlo simulations using an entire distribution of field trial residues
for pome fruit and adjusted for percent crop treated (Tier 3). Using
the Tier 1 approach margins of exposure (MOEs) at the 95th and 99th
percentiles of exposure for the overall U.S. population were 572 and
199, respectively. Using the Tier 3 procedure in which residues were
adjusted for percent crop treated, the MOEs for the 95th and 99th
percentiles were 8,769 and 1,511, respectively. Acute exposure was also
estimated for non-nursing infants, the most sensitive sub-population.
For this population, MOEs at the 95th and 99th percentiles of exposure
were 113 and 83, respectively. Using the Tier 3 method, MOEs were 909
and 396, respectively. Acute dietary risk is considered acceptable if
the MOE is greater than 30, an appropriate safety factor when based on
a human clinical study. Even under the conservative assumptions
presented here, the more realistic estimates of dietary exposure (Tier
3 analyses) clearly demonstrate adequate MOEs up to the 99th percentile
of exposure for all population subgroups.
ii. Chronic risk. Chronic dietary risk assessments (Dietary
Exposure Evaluation Model, Novigen Sciences Inc., 1997) were conducted
for triazamate using two approaches: (1) using a tolerance level
residue of 0.10 ppm assuming 100% of crop is treated and (2) using a
tolerance level residue of 0.10 ppm adjusted for projected percent crop
treated. The Theoretical Maximum Residue Contribution (TMRC) from the
proposed pome fruit tolerance represents 0.91% of the RfD for the U.S.
population as a whole. The subgroup with the greatest chronic exposure
is non-nursing infants (less than 1 year old), for which the TMRC
estimate represents 6.3% of the RfD. The chronic dietary risks from
this use do not exceed EPA's level of concern.
B. Toxicological Profile
1. Acute toxicity. Triazamate is a moderately toxic cholinesterase
inhibitor belonging to the carbamoyl triazole class. Triazamate
Technical was moderately toxic to rats following a single oral dose
(LD50 = 50-200 mg/kg), and after a 4-hr inhalation exposure
(LC50 value 0f > 0.47 mg/L); and was minimally to slightly
toxic to rats following a single dermal dose (LD50 > 5,000
mg/kg). In a guideline acute neurotoxicity study with triazamate in the
rat, the No-Observed-Adverse-Effect-Level (NOAEL) for clinical signs
was 5 mg/kg based on the observation of cholinergic signs in 1 of 10
male rats at 25 mg/kg. Triazamate was practically non-irritating to the
skin, moderately irritating to eyes in rabbits and did not produce
delayed contact hypersensitivity in the guinea pig.
2. Genotoxicty. Triazamate is not mutagenic or genotoxic.
Triazamate Technical was negative (non-mutagenic) in an Ames assay with
and without hepatic enzyme activation. Triazamate Technical was
negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT)
gene mutation assay using Chinese hamster ovary (CHO) cells in culture
when tested with and without hepatic enzyme activation. In isolated rat
hepatocytes, triazamate did not induce unscheduled DNA synthesis (UDS)
or repair when tested up to the maximum soluble concentration in
culture medium. Triazamate did not produce chromosome aberrations in an
in vitro assay using Chinese hamster ovary cells (CHO) or an in vivo
mouse micronucleus assay.
3. Reproductive and developmental toxicity. Triazamate Technical is
not a developmental or reproductive toxicant:
i. In a developmental toxicity study in rats with Triazamate
Technical, the NOAEL for developmental toxicity was 64 mg/kg (highest
dose tested). The NOAEL for maternal toxicity was 16 mg/kg based on
clinical signs of cholinergic toxicity at 64 mg/kg.
ii. In a developmental toxicity study in rabbits with Triazamate
Technical, the NOAEL for developmental toxicity was 10 mg/kg (highest
dose tested). The NOAEL for maternal toxicity was 0.5 mg/kg based on
clinical signs and decreased body weight at 10 mg/kg.
iii. In a 2-generation reproduction study in rats with Triazamate
Technical, the NOAEL for reproductive effects was 1,500 ppm (101 and
132 mg/kg/day for males and females, respectively; highest dose
tested). The NOAEL for parental toxicity was 10 ppm (0.7 and 0.9 mg/kg/
day for males and females, respectively) based on decreased plasma and
RBC cholinesterase activities at 250 ppm (17 and 21 mg/kg/day for males
and females, respectively).
4. Subchronic toxicity. In subacute and subchronic dietary toxicity
studies, Triazamate Technical produced no evidence of adverse effects
other than those associated with cholinesterase inhibition:
i. In a 90-day dietary toxicity study with Triazamate Technical in
the rat, the NOAEL for blood cholinesterase inhibition was 50 ppm (3.2
and 3.9 mg/kg/day for males and females, respectively), based on
decreases in plasma and RBC cholinesterase activities at 500 ppm (32
and 39 mg/kg/day for males and females, respectively). The NOAEL for
brain cholinesterase inhibition and/or clinical signs was 500 ppm (32
and 39 mg/kg/day for males and females respectively) based on decreased
brain cholinesterase activity and decreased body weight gain and
[[Page 52264]]
feed consumption at 1,500 ppm (93 and 117 mg/kg/day for males and
females, respectively).
ii. In a guideline subchronic neurotoxicity study (90-day dietary
feeding) with Triazamate Technical in the rat, the NOAEL for blood
cholinesterase inhibition was 10 ppm (0.6 and 0.7 mg/kg/day for males
and females, respectively), based on reductions in plasma and RBC
cholinesterase activities at 250 ppm (14.3 and 17.1 mg/kg/day for males
and females, respectively). The NOAEL for brain cholinesterase
inhibition and/or clinical signs was 250 ppm (14.3 and 17.1 mg/kg/day
for males and females respectively) based on decreases in brain
cholinesterase activity and cholinergic signs at 1,500 ppm (87 and 104
mg/kg/day for males and females, respectively).
iii. In a 90-day dietary toxicity study with Triazamate Technical
in the mouse, the NOAEL for blood cholinesterase inhibition was 2 ppm
(0.4 and 0.5 mg/kg/day for males and females, respectively) based on
based on decreases in plasma cholinesterase activity at 25 ppm (4 and 6
mg/kg/day for males and females, respectively). The NOAEL for brain
cholinesterase and/or clinical signs was 250 ppm (46 and 67 mg/kg/day
for males and females, respectively) based on decreases in brain
cholinesterase and decreases in body weight and feed consumption at
1,000 ppm (164 and 222 mg/kg/day for males and females, respectively).
iv. In a 90-day dietary toxicity study with Triazamate Technical in
the dog, the NOAEL for blood cholinesterase inhibition was 1 ppm for
males only (0.03 mg/kg/day) based on decreases in plasma cholinesterase
at 10 ppm (0.3 mg/kg/day). The dose of 1 ppm was a Lowest-Observed-
Effect-Level (LOEL) for females based on the presence of decreased
plasma cholinesterase activity (24%). The NOAEL for clinical signs was
10 ppm (0.3 mg/kg/day for males and females) based on a few clinical
signs at 100 ppm (3.1 mg/kg/day for males and females).
v. In a 21-day dermal toxicity study with Triazamate Technical, the
NOAEL for blood and brain cholinesterase inhibition was 10 mg/kg based
on decreases in plasma, RBC and brain cholinesterase activities at 100
mg/kg.
5. Chronic toxicity. In chronic dietary toxicity studies,
Triazamate Technical produced no evidence of adverse effects other than
those associated with cholinesterase inhibition and was not oncogenic
in the rat and mouse.
i. In a combined chronic dietary toxicity/oncogenicity study (24
months) in rats with Triazamate Technical, no evidence of oncogenicity
was observed at doses up to 1,250 ppm (62.5 mg/kg/day for males and
females; highest dose tested). The NOAEL for blood cholinesterase
inhibition was 10 ppm (0.5 and 0.6 mg/kg/day for males and females
respectively) based on decreases in plasma and RBC cholinesterase
activity at 250 ppm (11.5 and 14.5 mg/kg/day in males and females,
respectively). The NOAEL for brain cholinesterase inhibition and/or
clinical signs was 250 ppm (11.5 and 14.5 mg/kg/day in males and
females, respectively) based on clinical signs and decreases in brain
cholinesterase inhibition at 1,250 ppm (62.5 mg/kg/day for males and
females).
ii. In a combined chronic dietary toxicity study (18 months) in
mice with Triazamate Technical, no evidence of oncogenicity was
observed at doses up to 1,000-1,500 ppm (130-195 mg/kg/day for males
and females; highest dose tested). The NOAEL for blood cholinesterase
inhibition was 1 ppm (0.1 and 0.2 mg/kg/day for males and females,
respectively) based on decreased plasma cholinesterase activity at 50
ppm (6.7 and 8.4 mg/kg/day for males and females, respectively). The
NOAEL for brain cholinesterase inhibition and/or clinical signs was 50
ppm (6.7 and 8.4 mg/kg/day for males and females, respectively) based
on decreased brain cholinesterase activity and other evidence of
systemic toxicity at 1,000-1,500 ppm (130-195 mg/kg/day for males and
females).
iii. In a chronic dietary toxicity study (12 months) in dogs with
Triazamate Technical, the NOAEL for blood cholinesterase inhibition was
0.9 ppm (0.023 and 0.025 mg/kg/day for males and females, respectively)
based on decreased plasma cholinesterase activity at 15.0 ppm (0.42 mg/
kg/day for both males and females). The NOAEL for brain cholinesterase
inhibition was 15.0 ppm (0.42 mg/kg/day for both males and females)
based on decreased brain cholinesterase activity at 150 ppm (4.4 and
4.7 mg/kg/day for males and females, respectively).
6. Animal metabolism. The adsorption, distribution, excretion and
metabolism of triazamate in rats, dogs and goats was investigated.
Triazamate is rapidly absorbed when given orally (capsule or gavage)
but slower following dietary intake. Peak blood levels following
dietary administration were 10-fold lower than after gavage
administration of an equivalent mg/kg/dose. Elimination is
predominately by urinary excretion and triazamate does not accumulate
in tissues. The metabolism of triazamate proceeds via ester hydrolysis
and then a rapid stepwise cleavage of the carbamoyl group. The free
acid metabolite (RH-0422) is the only toxicologically significant
metabolite, given that it contains the dimethylcarbamoyl group. Other
metabolites of triazamate, which are seen in other animal and plant
metabolism studies, do not contain the carbamoyl group and do not
produce cholinesterase inhibition.
7. Metabolite toxicology. Common metabolic pathways for triazamate
have been identified in both plants (apple) and animals (rat, goat).
The metabolic pathway common to both plants and animals involves
hydrolysis of the ester and oxidative demethylation of the carbamoyl
group. Extensive degradation and elimination of polar metabolites
occurs in animals such that residue are unlikely to accumulate in
humans or animals exposed to these residues through the diet.
8. Endocrine disruption. The toxicology profile of triazamate shows
no evidence of physiological effects characteristic of the disruption
of mammalian hormones. In developmental and reproductive studies there
was no evidence of developmental or reproductive toxicity. In addition,
the molecular structure of triazamate does not suggest that this
compound would disrupt the mammalian hormone system. Overall, the
weight of evidence provides no indication that triazamate has endocrine
activity in vertebrates.
C. Aggregate Exposure
1. Dietary exposure. Tolerances for residues of triazamate should
be expressed as the total residue from triazamate [acetic acid, [(1-
((dimethylamino) carbonyl)-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-yl)
thio]-, ethyl ester] and its cholinesterase inhibiting metabolite
acetic acid, [(1-((dimethylamino) carbonyl)-3-(1,1-dimethylethyl)-1H-
1,2,4-triazol-5-yl) thio]. No other tolerances currently exist for
residues of triazamate on food crops.
i. Acute risk. An acute dietary risk assessment (Dietary Exposure
Evaluation Model, Novigen Sciences Inc., 1997) was conducted for
triazamate using two approaches: (a) A Tier 1 approach using a
tolerance level residue of 0.10 ppm. (b) Monte Carlo simulations using
an entire distribution of field trial residues for pome fruit and
adjusted for percent crop treated (Tier 3).
Using the Tier 1 approach margins of exposure (MOEs) at the 95th
and 99th percentiles of exposure for the overall U.S. population were
572 and 199, respectively. Using the Tier 3 procedure in which residues
were adjusted for
[[Page 52265]]
percent crop treated, the MOEs for the 95th and 99th percentiles were
8,769 and 1,511, respectively. Acute exposure was also estimated for
non-nursing infants, the most sensitive sub-population. For this
population, MOEs at the 95th and 99th percentiles of exposure were 113
and 83, respectively. Using the Tier 3 method, MOEs were 909 and 396,
respectively. Acute dietary risk is considered acceptable if the MOE is
greater than 30, an appropriate safety factor when based on a human
clinical study. Even under the conservative assumptions presented here,
the more realistic estimates of dietary exposure (Tier 3 analyses)
clearly demonstrate adequate MOEs up to the 99th percentile of exposure
for all population subgroups.
ii. Chronic risk. Chronic dietary risk assessments (Dietary
Exposure Evaluation Model, Novigen Sciences Inc., 1997) were conducted
for triazamate using two approaches: (a) Using a tolerance level
residue of 0.10 ppm assuming 100% of crop is treated and (b) Using a
tolerance level residue of 0.10 ppm adjusted for projected percent crop
treated. The Theoretical Maximum Residue Contribution (TMRC) from the
proposed pome fruit tolerance represents 0.91% of the RfD for the U.S.
population as a whole. The subgroup with the greatest chronic exposure
is non-nursing infants (less than 1 year old), for which the TMRC
estimate represents 6.3% of the RfD. The chronic dietary risks from
this use do not exceed EPA's level of concern.
2. Drinking water. An additional potential source of dietary
exposure to residues of pesticides are residues in drinking water.
Pesticides may reach drinking water either by leaching to groundwater
or by runoff to surface water. Both triazamate and its cholinesterase-
inhibiting metabolite are degraded rapidly in soil. This rapid
degradation has been observed in both laboratory and field studies and
makes it highly unlikely that measurable residues of either compound
could be found in ground or surface water when triazamate is applied
according to label directions. The negligible potential for mobility
was confirmed in four outdoor field dissipation studies and two outdoor
lysimeter studies. There is no established Maximum Concentration Level
(MCL) for residues of triazamate in drinking water. No drinking water
health advisory levels have been established for triazamate.
Significant exposure from cholinesterase-inhibiting residues of
triazamate in drinking water is not anticipated.
3. Non-dietary exposure. Triazamate is not registered for either
indoor or outdoor residential use. Non-occupational exposure to the
general population is therefore not expected and not considered in
aggregate exposure estimates.
D. Cumulative Effects
The potential for cumulative effects of triazamate with other
substances that have a common mechanism of toxicity was considered. It
is recognized the triazamate appears to be structurally related to the
carbamate class of insecticides which produce a reversible' inhibition
of the enzyme cholinesterase. However, Rohm and Haas Company concludes
that consideration of a common mechanism of toxicity is not appropriate
at this time since there is no reliable data to indicate that the toxic
effects caused by triazamate would be cumulative with those of any
other compound, including carbamates. Based on these points, Rohm and
Haas Company has considered only the potential risks of triazamate in
it's exposure assessment.
E. Safety Determination
1. U.S. population. The acute and chronic dietary exposure to
triazamate and its metabolite from the proposed use on pome fruit were
evaluated. Exposure to triazamate and its toxicologically significant
metabolite on pome fruit does not pose an unreasonable health risk to
consumers including the sensitive subgroup non-nursing infants. In Tier
1 and Tier 3 acute analyses for the 95th percentile exposures, MOEs
were greater than 100 for both the general U.S. population and non-
nursing infants. Using the TMRC and assuming 100% of crop treated, the
most conservative chronic approach), chronic dietary exposures
represents 0.6% of the RfD for the U.S. population and 6.3% for non-
nursing infants under 1 year old. 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.
Using the two conservative exposure assessments described in C.
Aggregate Exposure and taking into account the completeness and
reliability of the toxicity data, Rohm and Haas Company concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to residues of triazamate and its toxicologically significant
metabolite to the U.S. population and non-nursing infants.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of triazamate, data
from developmental toxicity studies in the rat and rabbit and two two-
generation reproduction studies in the rat are considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals and data on systemic
toxicity.
Developmental toxicity was not observed in developmental studies
using rats and rabbits. The NOAEL for developmental effects in rats was
64 mg/kg/day and rabbits was 10 mg/kg/day. In the two-generation
reproductive toxicity study in the rat, the reproductive/ developmental
toxicity NOAEL was 101-132 mg/kg/day. These NOAELs are 10-fold or
higher than those observed for systemic toxicity, i.e., cholinesterase
inhibition. Rohm and Haas Company concludes that there is a reasonable
certainty that no harm will occur to infants and children from
aggregate exposure to residues of triazamate.
F. International Tolerances
There are no approved CODEX maximum residue levels (MRLs)
established for residues of triazamate. (Mark Dow)
[FR Doc. 98-25756 Filed 9-29-98; 8:45 am]
BILLING CODE 6560-50-F