[Federal Register Volume 63, Number 165 (Wednesday, August 26, 1998)]
[Notices]
[Pages 45497-45503]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-22428]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-825; FRL-6023-4]


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-825, must 
be received on or before September 25, 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

[[Page 45498]]

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.                                   
Mary L. Waller................  Rm. 247, CM #2, 703     Do.             
                                 308-9354; e-mail:                      
                                 [email protected]
pa.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); 
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-825 (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-825) 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: August 10, 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.

1. Novartis Crop Protection, Inc.

PP 7E4919 and 8F4978

    EPA has received two pesticide petitions (7E4919 and 8F4978 from 
Novartis Crop Protection, Inc., 410 Swing Road, 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 by 
establishing tolerances for residues of fludioxonil (4-(2,2-difluoro-
1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile) in or on the raw 
agricultural commodities: grapes at 1.00 parts per million (ppm) 
(7E4919); canola, peanuts, sunflowers, leafy vegetables except brassica 
(Crop Group 4); brassica leafy vegetables (Crop Group 5); legume 
vegetables (Crop Group 6); foliage of legume vegetables (Crop Group 7); 
fruiting vegetables (Crop Group 8); cucurbit vegetables (Crop Group 9); 
forage, fodder, and straw of cereal grains (Crop Group 16); grass , 
forage, fodder, and hay (Crop Group 17); and non-grass animal feeds 
(Crop Group 18) at 0.01 ppm; root and tuber vegetables (Crop Group 1); 
leaves of root and tuber vegetables (Crop Group 2); bulb vegetables 
(Crop Group 3); cereal grains (Crop Group 15); and herbs and spices 
(Crop Group 19) at 0.02 ppm; and cotton at 0.05 ppm (8F4978). 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 fludioxonil is adequately 
understood for the purpose of the proposed tolerances. The residues of 
regulatory concern is the parent compound only. Metabolism in grapes 
involves oxidation of the pyrrole ring, primarily at the 2 and 5 
positions. Subsequent opening of the oxidized pyrrole ring yields a 
metabolite with an amide plus a carboxylic acid group. This open-ring 
metabolite undergoes further oxidation at the bridgehead carbon 
followed by decarboxylation.
    2. Analytical method. Novartis has developed and validated 
analytical methodology for enforcement purposes as part of the original 
corn, sorghum, and potato registrations. This method (Novartis Crop 
Protection Method AG-597B) has passed an Agency petition method 
validation (PMV) and is currently the enforcement method for potatoes. 
As part of this petition, Novartis has validated the method on the 
crops, fractions, and crop representatives of each crop grouping 
associated with this submittal. The method validation study (ABR-97060) 
contains recovery data on over eighty individual substrates. In most 
cases, a limit of quantitation of 0.01 ppm of fludioxonil was achieved. 
For several very difficult substrates, a limit of quantitation of 0.02 
ppm and for cotton substrates a limit of 0.05 ppm were achieved.

[[Page 45499]]

    For the analysis of grapes, grape juice, and wine the analytical 
Method AG-579B14 is proposed as the regulatory enforcement method. It 
has been validated by the Agency as an enforcement method for 
fludioxonil as AG-57912. In Method AG-579B14, whole fruit or wine 
samples are extracted with acetonitrile/water (90/10). Red and white 
grapes, as well as red and white wine samples were analyzed by this 
method. Recoveries (from 0.02 ppm to 1.0 ppm) ranged from 73% to 114% 
with a mean of 92% (n=15).
    3. Magnitude of residues. Residue trials were conducted on cotton, 
wheat, radishes, lettuce, cucumbers and peas in the major crop growing 
areas of the U.S. in addition to residue trials previously on corn, 
sorghum, potatoes and grapes. Several trials were conducted on each 
crop. Rates were 0.5 x , 1.0 x , 2.5 x  and 5.0 x  of the proposed use 
rate on all crops except cotton where 1.0 x  and 3.0 x  were used.
    From 6 cotton trials, field trash, gin trash, un-delinted seed and 
cottonseed fractions (hulls, meal, refined oil) were analyzed for 
fludioxonil at a method limit of determination of 0.05 ppm. At this 
level, no quantifiable residues of fludioxonil were found in any RAC or 
fraction at the proposed or the exaggerated (3 x ) rate.
    Seven trials were completed on wheat. At a method limit of 
quantification of 0.02 ppm, no quantifiable residues of fludioxonil 
were observed in any RAC at the proposed treatment rate or at rates up 
to 5 x  the proposed treatment rate.
    Five trials were completed on radishes which represents the 
absolute worst case for potential uptake of residues because of its 
very rapid growth and short growing season (27-55 days in these 
studies). Both root and top samples from all rates in all 5 trials were 
analyzed at a method limit of determination of 0.01 ppm. No fludioxonil 
residue (<0.01 ppm) was found in any root or top sample at the proposed 
use rate or at rates up to 5 x  the proposed use rate.
    Mature lettuce leaves from all treatment rates of the 6 trials were 
analyzed for fludioxonil at a method limit of determination of 0.01 
ppm. No fludioxonil residue was found in any lettuce sample at the 
proposed use rate or up to 5 x  the proposed use rate.
    Cucumbers from all treatment rates in all 6 trials were analyzed at 
a method limit of determination of 0.01 ppm. No fludioxonil residue was 
found in any cucumber sample at the proposed use rate or up to 5 x  the 
proposed use rate.
    Peas with pods from 5 trials were analyzed at a method limit of 
determination of 0.01 ppm. No fludioxonil residue was found in any pea 
sample at the proposed use rate or at rates up to 5 x  the proposed use 
rate.
    Thirty (30) field trials were conducted under maximum label rates 
on ten varieties of grapes in the major grape-growing regions of 
France, Switzerland, and Chile. Grape residue data were generated from 
fifty (50) samples treated at the maximum use rate. Data on transfer to 
grape juice were generated from sixteen (16) samples and data 
concerning transfer to wine were based on twenty-six (26) samples. 
Raisin data were produced from sixteen (16) samples.
    Supplemental data (including fifteen (15) decline curves) were 
generated using exaggerated rates (due to multiple applications) on 89 
additional samples of whole fruit. Supplemental data were also provided 
on eight additional juice samples and on twelve additional wine 
samples. Raisin data on eight samples were also provided. These data 
demonstrate dose response, provide additional decline information, 
provide additional information on transfer to juice and wine, and show 
that residue data obtained from other grape-growing countries (Italy 
and South Africa) fully support the results obtained from France, 
Switzerland, and Chile. The raisin data also demonstrate no significant 
concentration of residues.
    Analysis of mature grapes at harvest following a single foliar 
application of fludioxonil at 500 grams a.i./ha at flowering, up to the 
beginning of bunch closing, resulted in maximum whole fruit residues of 
0.77 ppm. Similarly, analysis of grapes at harvest following two foliar 
applications of fludioxonil at 250 grams a.i./ha/application at 
flowering and again at stages up to fruit softening resulted in maximum 
whole fruit residues of 0.33 ppm. These results suggest that the 
application at flowering does not contribute to the residue in fruit. 
The data fully support an import tolerance of 1 ppm on grapes imported 
into the U.S..
    The data support a 60-day pre-harvest interval (PHI) as listed on 
the GEOXE label for France. The data also support Chilean, Slovenian, 
and Bosnian PHIs of 15-days, 7-days (berries) to 21-days (applications 
to the vine), and 21-days, respectively for the combination product, 
Switch . There is no PHI on the Swiss Switch label, but the second 
application is limited by the label to mid-August, which results in a 
PHI greater than 21 days.
    No significant concentration of residues was observed in grape 
juice, wine, or raisins. Thus, tolerances are not required for these 
processing fractions.

B. Toxicological Profile

    1. Acute toxicity. Fludioxonil and end use formulations have very 
low toxicity to the mammalian species by the oral, dermal, or 
inhalation route. The dose needed to kill 50% of animals was calculated 
to be greater than 5,000 mg/kg (oral), 2,000 mg/kg (dermal), and 2.6 
mg/L (inhalation) in these studies. The eye and skin irritations seen 
in animals upon acute exposure indicate that no more than transient and 
slight irritation. No sensitizing potential was noted with either the 
technical material or the formulated product.
    2. Genotoxicity. Mutagenicity potential of fludioxonil was tested 
in several studies. In the Chinese hamster ovary cell assay, some 
clastogenic and polyploidogenic effects were seen at or near the 
precipitating concentration of the test substance. However, results 
were negative in the Ames assay, Chinese hamster V79 cell assay, 
hepatocyte DNA repair assay, rat hepatocyte micronucleus test, mouse 
bone marrow test, and Chinese hamster bone marrow test. A dominant 
lethal test conducted in the mouse was also negative.
    3. Reproductive and developmental toxicity. Fludioxonil is not a 
teratogen and does not affect reproduction or fertility. No fetal 
toxicity was observed even at the highest dose tested in both the 
rabbit (300 mg/kg) and the rat (1,000 mg/kg) teratogenicity studies. In 
a two-generation rat reproduction study, a reduction of pup body weight 
was seen at the highest feeding level of 3,000 ppm in the presence of 
maternal toxicity. The NOEL was 300 ppm for both maternal and fetal 
toxicity in this study.
    4. Subchronic toxicity. In a 90-day dietary toxicity study the 
kidney and liver have been identified as target organs. In a subchronic 
study in rats, the NOEL was 10 ppm based on liver toxicity. In a 
subchronic study in mice, the NOEL was 100 ppm based on blue urine (a 
metabolite); the maximum tolerated dose was 7,000 ppm. In a subchronic 
study in dogs, the NOEL was 200 ppm based on clinical observations; the 
maximum tolerated dose was 8,000 ppm.
    5. Chronic toxicity. In an 1-year chronic toxicity study in dogs, 
the NOEL was 100 ppm based on body weight effects; the maximum 
tolerated dose was 8,000 ppm.
    Two 18-month dietary oncogenicity studies were performed in mice. 
While a NOEL of 1,000 ppm was clearly established in the first study, 
its highest feeding level (3,000 ppm) did not meet the criteria for a 
maximum tolerated dose. In the second 18-month study, the

[[Page 45500]]

maximum tolerated dose was determined to be 5,000 ppm based on kidney 
effects. There were no treatment-related increases in neoplasia at any 
dose level tested in either study.In a combined chronic toxicity/
oncogenicity study in rats, the incidence of liver tumors in top-dose 
females (3,000 ppm) was marginally higher than the concurrent controls 
but within historical control range. The NOEL for chronic toxicity was 
1,000 ppm in both sexes.
    6. Animal metabolism. The metabolism of fludioxonil in rats is 
adequately understood. The compound is rapidly absorbed and excreted. 
In rats, excretion in the feces is greater than excretion via the 
urine. Metabolism involves primarily oxidation at the 2 position of the 
pyrrole ring, with minor amounts of oxidation at the 5 position of the 
pyrrole ring and the 4 position of the phenyl ring. All of these 
oxidized metabolites are conjugated with glucuronic acid and sulfuric 
acid and then rapidly eliminated.
    7. Metabolite toxicology. The residues of concern for tolerance 
setting purposes is the parent compound. Consequently, there is no 
additional concern for toxicity of metabolites. In grapes, fludioxonil 
is metabolized only to a limited extent. The metabolites thus formed 
have also been found in the rat. The major metabolites are those that 
result from the oxidation of the pyrrole ring and they are rapidly 
excreted upon conjugation. Consequently, there is no additional concern 
for toxicity of any metabolites in grapes.
    8. Endocrine disruption. Fludioxonil does not belong to a class of 
chemicals known for having adverse effects on the endocrine system. No 
estrogenic effects have been observed in the various short and long 
term studies conducted with various mammalian species.

C. Aggregate Exposure

    1. Dietary exposure --i. Food. For purposes of assessing the 
potential dietary exposure under the proposed tolerance, Novartis has 
estimated aggregate exposure based on the theoretical maximum residue 
concentration (TMRC) from the tolerance level of 1.0 ppm in or on 
grapes and from the established or proposed tolerance levels. The TMRC 
is a worse case estimate of dietary exposure since it is assumed that 
100% of all crops for which tolerances are proposed or established are 
treated and that pesticide residues are present at the tolerance 
levels.
    Fludioxonil's current registered use for seed treatment on corn and 
sorghum seeds does not contribute to dietary exposure because there are 
no detectable residues. EPA has ruled that these uses are food uses not 
requiring tolerances. For potato seed treatment, a tolerance of 0.02 
ppm has been set. In conducting this exposure assessment, very 
conservative assumptions have been used (i.e., 100% of potatoes and 
grapes will contain fludioxonil residues at tolerance levels), 
resulting in an overestimate of human exposure.
    ii. Drinking water. Exposure of the general population to residues 
of fludioxonil from drinking water is considered unlikely for two 
reasons: (1) the import tolerance for grapes would not lead to the 
exposure of the general population to residues of pesticides in 
drinking water; and (2) the movement of fludioxonil into groundwater is 
highly unlikely due to its chemistry. In addition, the EPA has not 
established a Maximum Contaminant Level for residues of fludioxonil in 
drinking water.
    2. Non-dietary exposure. Non-occupational exposure for fludioxonil 
has not been calculated since the current registration for fludioxonil 
is limited to commercial crop production. Since the chemical is not 
used in or around the home, Novartis considers the potential for non-
occupational exposure to the general population to be non-existent.

D. Cumulative Effects

    Consideration of a common mechanism of toxicity is not appropriate 
at this time since Novartis is unaware of any reliable information that 
indicates that toxic effects produced by fludioxonil would be 
cumulative with those of any other chemical compounds. Consequently, 
Novartis is considering the potential risks of only fludioxonil in its 
aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based on the available chronic toxicity data, 
EPA has set the Reference Dose (RfD) for fludioxonil at 0.03 mg/kg/day. 
This RfD is based on a 1-year feeding study in dogs with a No Observed 
Effect-Level (NOEL) of 3.3 mg/kg/day (100 ppm) and an uncertainty 
factor of 100. No additional uncertainty factor was judged to be 
necessary as body weight was the most sensitive indicator of toxicity 
in that study.
    2. Infants and children. Using GENEEC water and aggregate exposures 
(water plus diet) 5.65% and 5.75% of the RfD were obtained for the most 
sensitive sub-populations, non-nursing infants and children (1-6 
years), respectively. Aggregate exposure (water plus diet) utilizing 
the summed SCI-GROW estimated water concentrations (turf and seed 
treatment uses) resulted in an overall exposure of 1.72% of the RfD for 
the U.S. population. Aggregated exposure (water plus dietary) to non-
nursing infants and children (1-6 years) was 3.49% and 4.69% of the 
RfD, respectively, using the combined turf and seed treatment water 
estimates. It should be noted that the aggregate exposure assessment 
greatly overestimates exposure since both GENEEC and SCI-GROW models 
generate extremely conservative and unrealistic water concentrations. 
In addition, all non-detected residues were assumed to be at the limit 
of quantitation and no market share adjustment was made. Therefore, a 
more than reasonable certainty exists that no harm will result from 
exposure to fludioxonil residues through food and water consumption if 
the proposed uses are registered.

F. International Tolerances

    There are no Codex maximum residue levels established for residues 
of fludioxonil.      (Mary L. Waller)

2. Rohm and Haas Company

PP 8F4994

    EPA has received a pesticide petition (PP 8F4994) 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 (Acetic acid, [[1-
[(dimethylamino)carbonyl]-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-yl]-
,ethyl ester) in or on the raw agricultural commodity leafy green 
vegetables (crop subgroup 4A) at 2.5 parts per million (ppm); leaf 
petioles (crop subgroup 4B) at 0.6 ppm; head and stem Brassica (crop 
subgroup 5A) at 12.5 ppm and leafy Brassica (crop subgrop 5B) at 5.75 
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 triazamate in plants 
(apples, potatoes, sugar beets) is adequately understood for the 
purpose of these tolerances. None of these crops are fed to animals and 
livestock metabolism studies are

[[Page 45501]]

not required. The metabolism of triazamate involves oxidative 
demethylation of the carbamoyl group. Parent compound is rapidly 
metabolized and is either not found or found at trace levels in plants. 
The majority of the total dosage is present as other non-cholinesterase 
inhibiting metabolites whose structures do not contain the 
dimethylcarbamoyl moiety. Tolerances for residues of triazamate should 
be expressed as the total residue from triazamate and its only 
cholinesterase-inhibiting metabolite RH-0422.
    2. Analytical method. An analytical method employing liquid 
chromatography followed by two-stage mass spectroscopy detection has 
been developed and validated for residues of triazamate and RH-0422 in 
leafy and cole crop vegetables. The method involves extraction by 
blending with solvents and purification of the extracts by solid phase 
extraction chromatography. The limit of quantitation of the method is 
0.01 ppm for both analytes.
    3. Magnitude of residues. A total of 58 field residue trials in 
geographically representative regions of the U.S. was conducted with a 
50% wettable powder formulation in the representative crops for the 
leafy and cole crop vegetable crop groups. Three or four applications 
were made at 0.25 lb. a.i./acre. Samples were harvested at 7 days after 
the last application. The highest detected value (sum of the residues 
of triazamate and RH-0422) in an individual sample was 0.63 ppm in head 
lettuce, 1.62 ppm in leaf lettuce, 2.23 ppm in spinach, 0.54 ppm in 
celery, 11.5 ppm in broccoli, 4.86 in cabbage and 5.54 ppm in mustard 
greens.

B. Toxicological Profile

    1. Acute toxicity. Triazamate is a moderately toxic cholinesterase 
inhibitor belonging to the carbamate 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 of > 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 
NOEL 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. In a developmental 
toxicity study in rats with Triazamate Technical, the no-observed-
effect-level (NOEL) for developmental toxicity was 64 mg/kg (highest 
dose tested) (HDT). The NOEL for maternal toxicity was 16 mg/kg based 
on clinical signs of cholinergic toxicity at 64 mg/kg.
    In a developmental toxicity study in rabbits with Triazamate 
Technical, the NOEL for developmental toxicity was 10 mg/kg (HDT). The 
NOEL for maternal toxicity was 0.5 mg/kg based on clinical signs and 
decreased body weight at 10 mg/kg.
    In a two-generation reproduction study in rats with Triazamate 
Technical, the NOEL for reproductive effects was 1,500 ppm (101 and 132 
milligrams/kilograms/day (mg/kg/day) for males and females, 
respectively; HDT). The NOEL 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).
    The acceptable developmental studies (prenatal developmental 
toxicity studies in rats and rabbits and two-generation reproduction 
study in rats) provided no indication of increased sensitivity of rats 
or rabbits to in utero and or post-natal exposure to triazamate. 
Triazamate Technical is not a developmental or reproductive toxicant.
    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 NOEL 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 NOEL 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 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 NOEL 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 NOEL 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 NOEL for blood cholinesterase inhibition was 2 ppm 
(0.4 and 0.5 mg/kg/day for males and females, respectively) based on 
decreases in plasma cholinesterase activity at 25 ppm (4 and 6 mg/kg/
day for males and females, respectively). The NOEL 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 NOEL 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 NOEL 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 
NOEL blood and brain cholinesterase inhibition was 10 mg/kg based on 
decreases in plasma, RBC and brain cholinesterase activities at 100 mg/
kg.

[[Page 45502]]

    5. Chronic toxicity -- i. Rat, mouse and dog studies. 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.
    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; HDT). The NOEL 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 NOEL 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).
    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; 
HDT). The NOEL 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 NOEL 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).
    In a chronic dietary toxicity study (12 months) in dogs with 
Triazamate Technical, the NOEL 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 NOEL 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).
    ii. Human Studies. A randomized double-blind, ascending dose study 
was conducted in human male volunteers to determine the safety and 
tolerability of Triazamate Technical and to establish a NOEL for 
adverse clinical toxicity. Single doses of Triazamate Technical, when 
administered orally by capsule to healthy male subjects, were tolerated 
up to and including a dose of 1.0 mg/kg. The 3.0 mg/kg dose of 
triazamate was not clinically tolerated well. Clinically, the NOEL was 
0.3 mg/kg of triazamate based on minimal clinical signs at 1.0 mg/kg 
that were considered possibly related to treatment. Transient decreases 
in plasma and RBC cholinesterase occurred at doses lower than the dose 
that elicited adverse clinical signs.
    Using its Guidelines for Carcinogen Risk Assessment published 
September 24, 1986 (51 FR 33992), Rohm and Haas Company considers 
triazamate to be classified as a Group ``E,'' not a likely human 
carcinogen.
    A Reference dose (RfD) of 0.01 mg/kg/day is proposed for humans, 
based on the clinical NOEL in the human study (0.3 mg/kg) and applying 
an Uncertainty Factor (UF) of 30. The dose of 0.3 mg/kg was the highest 
dose in humans that did not produce toxicologically significant adverse 
effects (i.e., signs of cholinergic toxicity) and is 10 times lower 
than a dose that produced unequivocal signs of cholinergic toxicity in 
man. In addition, the clinical NOEL in humans is comparable to the no-
observable-adverse-effect level (NOAEL) of 0.42 mg/kg/day following 
chronic dosing in the dog, the most sensitive laboratory animal 
species. An Uncertainty Factor of 10 is applied to the clinical NOEL in 
humans to account for potential variability within humans with respect 
to sensitivity towards triazamate. An additional Uncertainty Factor of 
3 is included, since at 0.03 mg/kg (i.e., 1/10th the dose that was a 
clinical NOEL) there was a transient but measurable depression in 
plasma cholinesterase in humans. Although a change in the plasma 
pseudo-cholinesterase (i.e., butyl-cholinesterase) is not 
toxicologically significant since this enzyme is not molecularly 
similar to acetyl-cholinesterase, the additional uncertainty factor of 
3 establishes a reference dose at a level where a measurable response 
of any kind, irrespective of the toxicological significance of the 
finding, will not plausibly occur.
    6. Animal metabolism. The absorption, 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, (RH-0422) is the only toxicologically significant metabolite, 
given that it contains the carbamoyl 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, potato, sugar beet) and 
animals (rat, goat, hen). The metabolic pathway common to both plants 
and animals involves oxidative demethylation of the carbamoyl group. 
Extensive degradation and elimination of polar metabolites occurs in 
animals such that residues 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. A RfD of 0.01 mg/kg/day is proposed for 
humans, based on the clinical NOEL in the human study (0.3 mg/kg) and 
applying an Uncertainty Factor of 30.
    2. Food -- i. Acute risk. An acute dietary risk assessment (Dietary 
Exposure Evaluation Model , Novigen Sciences Inc., 1997) was conducted 
for triazamate using a Tier 3 Monte Carlo simulations approach using 
the distribution of residues for apples, pears, head and leaf lettuce, 
spinach, celery, broccoli, cabbage and mustard greens, the entire 
distribution of daily food consumption data for pome fruit and leafy 
and cole crop vegetables and adjustments for percent crop treated. The 
Margins of Exposure (MOEs) for the 95th percentile exposures were 270 
for the U.S. population and 388 for the most sensitive sub-population, 
Children 1-6 years old. This indicates that acute dietary risk is 
acceptable because the MOE is greater than 30, and 30 is the 
appropriate Uncertainty Factor when

[[Page 45503]]

the assessment is based on a human clinical study.
    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 levels and 
assuming 100% of crop is treated, and (2) using anticipated residue 
concentration levels adjusted for projected market share or percentage 
of crop treated. The Theoretical Maximum Residue Contribution (TMRC) 
and Anticipated Residue Contribution (ARC) from these two scenarios 
represents 35.0% and 3.6%, respectively, of the RfD for the U.S. 
populution as a whole. The subgroup with the greatest chronic exposure 
is Children 1-6 years old for which the TMRC and ARC estimates 
represents 59.4% and 7.0%, respectively, of the RfD. The chronic 
dietary risks from these uses do not exceed EPA's level of concern.
    3. Drinking water. Both triazamate and its cholinesterase-
inhibiting metabolite RH-0422 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 
would be found in ground or surface water when triazamate is applied 
according to the proposed label use directions.
    4. Non-dietary exposure. Triazamate is not registered for either 
indoor or outdoor residential uses. 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, although structurally a pseudo-carbamate, 
exhibits toxicity similar to the carbamate class of insecticides, and 
that these compounds 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 EPA does not have the methodology to resolve this 
complex scientific issue concerning common mechanisms of toxicity. 
Based on these points, Rohm and Haas Company has considered only the 
potential risks of triazamate and RH-0422 in its cumulative exposure 
assessment.

E. Safety Determination

    1. U.S. population. The acute and chronic dietary exposures to 
triazamate and its metabolite from the proposed use on leafy and cole 
crop vegetables were evaluated. Exposure to triazamate and its 
toxicologically significant metabolite in or on pome fruit or leafy and 
cole crop vegetables does not pose an unreasonable health risk to 
consumers including the sensitive subgroup non-nursing infants. In Tier 
3 acute analyses for the 95th percentile exposures, MOEs were 270 for 
the general U.S. population. Using the TMRC and assuming 100% of crop 
treated, the most conservative chronic approach, chronic dietary 
exposures represents 35.0% of the RfD for the U.S. population. EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health.
    Using the two conservative exposure assessments described above 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.
    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.
    FFDCA section 408 provides that EPA may apply an additional 
Uncertainty Factor for infants and children in the case of threshold 
effects to account for pre-and post- natal effects and the completeness 
of the toxicity database. Based on current toxicological data 
requirements, the toxicology database for triazamate relative to pre- 
and post- natal effects is complete. For triazamate, developmental 
toxicity was not observed in developmental studies using rats and 
rabbits. The NOEL 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 NOEL 
was 101-132 mg/kg/day. These NOELs are 10-fold or higher than those 
observed for systemic toxicity, i.e., cholinesterase inhibition.
    In Tier 3 acute dietary analyses for the 95th percentile exposures, 
MOEs were 388 for Children 1-6 years old. Using the TMRC and assuming 
100% of crop treated, the most conservative chronic approach, chronic 
dietary exposures represents 59.4% of the RfD for Children 1-6 years 
old. Using the ARC and adjusted for an anticipated market share or 
percentage of crop treated, the chronic dietary exposure to this 
subgroup represents 7.0% of the RfD. Therefore 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 infants and children.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs) 
established for residues of triazamate. MRLs have been established for 
vegetables at 0.05 ppm in Italy, for sugar beets at 0.05 ppm in the 
Czech Republic and 0.15 ppm in the U.K., for potatoes at 0.02 ppm in 
France, for cabbage at 0.1 ppm in Hungary, and for peas at 0.05 ppm in 
the Czech Republic and 0.02 ppm in Hungary and for green peas at 0.05 
ppm in Hungary.      (Mark Dow)

[FR Doc. 98-22428 Filed 8-25-98; 8:45 am]
BILLING CODE 6560-50-F