[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:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
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.
------------------------------------------------------------------------


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