FLUORIDE ACTION NETWORK PESTICIDE PROJECT
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Fludioxonil (Novartis). August 26, 1998. Two Pesticide Tolerance Petitions. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/August/Day-26/p22428.htm
[Federal Register: August 26, 1998 (Volume 63, Number 165)]
[Notices]
[Page 45497-45503]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26au98-59]
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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:
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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,
Dow.mark@epamail.epa. Arlington, VA
gov.
Mary L. Waller................ Rm. 247, CM #2, 703 Do.
308-9354; e-mail:
waller.mary@epamail.e
pa.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);
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:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 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 (LD<INF>50</INF>
= 50-200 mg/kg), and after a 4-hr inhalation exposure (LC<INF>50</INF>
value of > 0.47 mg/L); and was minimally to slightly toxic to rats
following a single dermal dose (LD<INF>50</INF> >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