Document ID: EPA-HQ-OPP-2010-0102-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-19T04:00Z

Notice of Filing of a Pesticide Petition for the Establishment of
Tolerances for Residues of Triflusulfuron Methyl in or on Food
Commodities

ENVIRONMENTAL PROTECTION AGENCY

	EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4) 

Petition Number PP# 9E7669

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	EPA has received a pesticide petition, PP# 9E7669, from IR-4, 500
College Road East, Suite 201W, Princeton, New Jersey, 08540, proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing
tolerances for residues of triflusulfuron methyl, 2
[[[[[4-(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]amin
o]carbonyl]amino]sulfonyl]-3-methylbenzoate in or on the raw
agricultural commodity beet, garden, roots at 0.01 ppm and beet, garden,
tops at 0.02 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. Metabolism of triflusulfuron methyl in sugarbeets
was studied using triflusulfuron methyl labeled separately with
carbon-14 in the triazine ring and in the ester carbonyl group.
Triflusulfuron   methyl was extensively metabolized by sugar beets
treated at the 4-8-leaf growth stage with 100 grams active ingredient
per half acre (g ai/ha). Triflusulfuron methyl levels dropped rapidly
from 3 ppm in the sample taken on the day of the treatment to < 0.01 ppm
14 days after treatment. The initial step in the metabolic breakdown of
triflusulfuron methyl involves cleavage of the sulfonylurea bridge,
which is followed by further metabolism of the initial degradates. The
levels of principal radiolabeled metabolites found in plant samples (N-
desmethyl triazine amine, N,N-bis-desmethyl triazine amine, acid
sulfonamide, and its glucose conjugate) dropped to < 0.01 ppm at
maturity. No significant (> 0.01 ppm) residues of triflusulfuron methyl
or its radiolabeled metabolites were detected in mature roots or
foliage.

2. Analytical method.  A method for quantitation of Triflusulfuron
methyl in garden beets uses a high performance liquid chromatograph
(HPLC) with eluent and column-switching and ultra-violet (UV) detection
at 232 nm for the determination of triflusulfuron methyl residues in
garden beet foliage and roots. Sample clean-up is achieved through
reversed phase chromatography using eluent-switching. Column-switching
provides the resolution required for quantitation of triflusulfuron
methyl. The calculated LOQ values were 0.0069 ppm for roots and 0.0044
ppm on tops (leaves) respectively. Triflusulfuron methyl is detected at
levels as low as 0.005 ppm. Triflusulfuron methyl recoveries averaged
99% for foliage and 110% for roots.

3. Magnitude of residues

Residue trials were conducted on garden beets at 8 locations across the
U.S. and Canada.  The nature of triflusulfuron methyl residue in garden
beets is adequately understood through the sugar beet metabolism
studies.    These residue data were the basis for establishing
tolerances for garden beet tops and roots.

B. Toxicological Profile

1. Acute toxicity. 

Based on EPA criteria, technical triflusulfuron methyl is in acute
toxicity Category IV for oral and inhalation routes of exposure, and for
dermal irritation. Triflusulfuron methyl is in acute toxicity Category
III for dermal toxicity and for eye irritation.  Acute oral toxicity in
rats LD50 5,000 mg/kg; acute dermal toxicity in rabbits LD50 2,000
mg/kg; and acute inhalation toxicity in rats LC50 5.1 mg/L. Primary eye
irritation in rabbits, non-irritant primary dermal irritation in
rabbits, non- irritant dermal sensitization in guinea pigs, and
non-sensitizer acute neurotoxicity no observed adverse effect level
(NOAEL) = 2,000 mg/kg/day highest dose tested (HDT).

2. Genotoxicity. 

Mutagenicity data for technical triflusulfuron methyl include a reverse
mutation assay (Ames Test) which was negative at concentrations up to
1,000µ mg/plate, the HDT; a Salmonella typhimurium plate incorporation
assay which was negative at concentrations up to 3,000µ mg/plate, HDT;
and a Chinese hamster ovary/hypoxanthine-guanine (CHO/HPRT) assay which
was negative at concentrations up to 2,000 mg/kg/day, HDT. A chromosomal
aberration/ human lymphocyte assay was positive in the presence of
metabolic activation at concentrations greater than or equal to 1,500µ
mg/mL. A second chromosomal aberration/human lymphocyte assay was
positive in the presence of metabolic activation at concentrations of
2,000 µ mg/mL. Results in the absence of metabolic activation were
inconclusive for both chromosomal aberration studies. The mouse bone
marrow micronucleus test was negative at doses up to 5,000 mg/kg, HDT.
In three Salmonella typhimurium plate incorporation assays, metabolites
of triflusulfuron methyl were negative up to 5,000µ mg/plate, HDT.

3. Reproductive and developmental toxicity. 

In a 2-generation rat reproduction study, rats were fed dosages of 0,
0.588, 5.81, 44.0 and 89.5 mg/kg/day (males) and 0, 0.764, 7.75, 58.0,
and 115 mg/kg/days (females) with a reproductive toxicity NOAEL equal to
or greater than 89.5 and 115 mg/kg/day for males and females,
respectively, based on the absence of reproductive effects in rats at
the HDT. The NOAEL for systemic toxicity was 5.81 and 7.75 mg/kg/day for
males and females, respectively based on decreased body weight/body
weight gain (bwt/bwt gain) and food efficiency in males and females, and
decreased weights of offspring from the F0 generation on days 14 and 21
post-partum at 44.0 and 58.0 mg/kg/day in males and females,
respectively. 

Technical triflusulfuron methyl was evaluated for developmental toxicity
potential in rats and rabbits. Rats were fed dosages of 0, 30, 120, 
350, and 1,000 mg/kg/day with a developmental NOAEL equal to or greater 
than 1,000 mg/kg/day (HDT) and a maternal toxicity NOAEL of 120 mg/kg/
day with a lowest observed adverse effect level (LOAEL) of 350 mg/kg/
day based on reduced body weight gain in the 350 and 1,000 mg/kg/day 
animals, reduced food consumption in the 1,000 mg/kg/day animals and 
lower food efficiency in the 350 and 1,000 mg/kg/day. Rabbits were fed 
dosages of 0, 15, 90, 270, and 800 mg/kg/day with a NOAEL for 
developmental toxicity of 90 mg/kg/day with a LOAEL of 270 mg/kg/day 
based on the increase in abortions and a decrease in mean fetal body 
weight (bwt). The NOAEL for maternal toxicity is 90 mg/kg/day with a
LOAEL of 270 mg/kg/day based on the maternal death and abortions, and
increase in clinical signs noted in the mid-high and high dose groups,
decreased food efficiency and increased post mortem finding describing
gastrointestinal effects.

4. Subchronic toxicity. 

The subchronic toxicity of technical triflusulfuron methyl was evaluated
in rabbits, rats, and dogs. 

In a 21-day dermal toxicity study with rabbits fed dosages of 50, 300,
or 1,000 mg/kg/day, the systemic toxicity NOAEL was equal to or greater
than 1,000 mg/kg/day for males and females. The dermal toxicity NOAEL
was equal to or greater than 1,000 mg/kg/day for males and females.     

Two 90-day studies were conducted in the rat. In one study, rats were
fed dosages of 6.2, 127, 646, or 965 mg/kg/day (males) or 7.54, 150,
774, or 1,070 mg/kg/day (females). Triflusulfuron methyl exhibited 
subchronic toxicity at dietary concentrations of 2,000 ppm (127 and 150 
mg/kg/day for males and females) or greater in the form of decreased 
body weights, decreased body weight gains, decreased food efficiency, 
increased mean relative liver weights, and regenerative anemia. The
NOAEL was 6.2 mg/kg/day (males) and 7.54 mg/kg/day (females).     

In another study, rats were fed dosages of 6.56, 133, 658, or 1,036
mg/kg/day (males) or 7.71, 153, 783, or 1,124 mg/kg/day (females). 
Triflusulfuron methyl showed subchronic toxicity at dietary 
concentrations of 2,000 ppm (133 and 153 mg/kg/day for males and 
females) or greater in the form of decreased body weight, decreased 
body weight gain, decreased food efficiency, and increased mean liver 
weights. The NOAEL was 6.56 mg/kg/day (males) and 7.71 mg/kg/day
(females).

A subchronic neurotoxicity study with rats fed dosages of 0, 6.1,  46.1,
92.7, or 186.2 mg/kg/day (males) or 7.1, 51.6, 104.1, or 205.2 
mg/kg/day (females), resulted in a NOAEL of 92.7 (males) and 7.1 mg/kg/ 
day (females). This was based on decreased body weight/body weight gain
at the LOAEL of 186.2 mg/kg/day (males) and 51.6 mg/kg/day (females).   
 

In another 90-day subchronic study, dogs were fed dosages of 3.87,
146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day
(females). Triflusulfuron methyl was found to be hepatotoxic at 4,000
ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater
elevated hepatic enzyme levels and postmortem evidence, including
elevation in liver weights and microscopic evidence of bile stasis. 
Other microscopic findings considered to be treatment related were
testicular atrophy and decreased testicular weights and hypercellularity
of the sternal and femoral bone marrow, with a corresponding increase in
reticulocyte and leukocyte counts seen in the  high-dose males and
females. Based on the microscopic findings in the liver and testes of
the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day
(males) and 3.72 mg/kg/day (females).

5. Chronic toxicity. 

The chronic toxicity of technical triflusulfuron methyl was evaluated in
dogs, mice, and rats. In a 1- year oral toxicity study with dogs fed
dosages of 1.0, 26.9, 111.6 mg/  kg/day (males) and 1.2, 27.7, and 95.5
mg/kg/day (females), the NOAEL  for males was 26.9 mg/kg/day; this was
based on increases in alkaline  phosphatase, liver weight, and incidence
of minimal centrilobular  hypertrophy at the LOAEL of 111.6. For
females, the NOAEL was 27.7 mg/kg/day; this was based on increased liver
weight and increased incidence of minimal centrilobular hepatocellular
hypertrophy at the LOAEL of 95.5 mg/kg/day.

In an 18-month carcinogenicity study, mice were fed dosages of 1.37,
20.9, 349, and 1,024 mg/kg/day (males) and 1.86, 27.7, 488, and 1,360
mg/kg/day (females). Male mice had statistically significant positive
trends for hepatocellular adenomas and for combined adenoma/ carcinoma
(driven entirely by adenomas) at 349 and 1,024 mg/kg/day.  These
increases were not significant in pair-wise comparisons with control
groups and were determined not to be carcinogenic effects by the
Carcinogenicity Peer Review Committee (CPRC). The NOAEL was based on
body and organ weight effects and was 20.9 mg/kg/day (males) and 27.7
mg/kg/day (females). 

In the combined chronic toxicity/ carcinogenicity study, rats were fed
dosages of 0, 0.406, 4.06, 30.6, and 64.5 mg/kg/day (males) and 0,
0.546, 5.47, 41.5, and 87.7 mg/kg/day (females). Male rats have a
significant increasing trend and significant differences in pair-wise
comparisons of the 30.6 and 64.5 mg/kg/day dose groups with controls for
interstitial cell adenomas.  This effect was determined to be a
carcinogenic effect by the CPRC. No carcinogenic effects were noted in
females up to and including 87.7 mg/ kg/day HDT. The LOAEL for chronic
toxicity is 30.6 mg/kg/day (males) and 41.5 (females) based on decreased
body weight and body weight gain, alternations in the hematology
parameters (males predominately) and an increased incidence of
interstitial cell hyperplasia in males. The NOAEL for chronic toxicity
is 4.06 mg/kg/day (males) and 5.47 mg/kg/day (females). This value is
adjusted to the lowest concentration level of the chemical at this
dosage (60%), resulting in NOAELs of 2.44 mg/kg/ day (males) and 3.28
mg/kg/day (females).

6. Animal metabolism. 

For triflusulfuron methyl, in both the rat and the goat, a majority of
the administrated dose was excreted in feces and urine. The
biotransformation pathway for triflusulfuron methyl in the rat and the
goat was similar. The major pathway was demethylation of the
dimethylamino substituent on the triazine ring.  The intermediate
hydroxylated metabolite was also present. The secondary
biotransformation pathway was clevage of the sulfonylurea bridge to form
methyl saccharin, N-desmethyl triazine amine and N, N- bis-desmethyl
triazine amine. In the lactating goat, triflusulfuron methyl was not
excreted to any appreciable level in the milk. Levels of the ester
carbonyl-derived residues were generally below the limit of reliable
measurement (0.0006µ mg equivalent triflusulfuron methyl/mL) and
triazine-derived residues reached a daily level of about 0.001 ppm.
Therefore, the metabolic pathways in rats and lactating goats were very
similar. There were no significant plant metabolites of triflusulfuron
methyl that were not found in the rat or goat metabolism studies. In 
the unlikely event that triflusulfuron methyl were to enter the 
livestock diet, triflusulfuron methyl and its metabolites would be 
rapidly excreted and would not accumulate in meat, meat by-products, or 
milk.

7. Metabolite toxicology. 

The approximate lethal dose (ALD) of the degradation product,
N,N-bis-desmethyl triazine amine, in male rats was  450 mg/kg/day. Rats
were fed dose rates of 200, 300, 450, 670, 1,000, and 2,300 mg/kg of
triflusulfuron methyl. Deaths occurred up to test day 7 in rats dosed at
450 mg/kg body weight and above. Clinical signs of toxicity were
observed in lethally and nonlethally dosed rats. In an in vitro gene
mutation study, N,N,-bis-desmethyl triazine amine was not  mutagenic in
Salmonella typhimurium up to a dose of 5,000µ mg/ plate. For the
degradation product, triazine amine, the ALD in male rats was 670
mg/kg/day. The test substance dose was 200, 300, 450, 670, 1,000, or
2,300 mg/kg. Deaths occurred up to test day 4 in rats dosed at 670 mg/kg
and above. Clinical signs of toxicity were observed in lethally and
nonlethally dosed animals. In an in vitro gene mutation study, triazine
amine was not mutagenic in Salmonella typhimurium up to a dose of
5,000µ mg/plate.

8. Endocrine disruption. 

No special studies investigating potential estrogenic or other endocrine
effects of methyl have been conducted.  However, the standard battery of
required toxicology studies has been completed. These include an
evaluation of the potential effects on reproduction and development, and
an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure to doses that far exceed likely human
exposures. Based on these studies there is no evidence to suggest that
triflusulfuron methyl has an adverse effect on the endocrine system.

C. Aggregate Exposure

	

1. Dietary Exposure

The chronic reference dose (cRfD) of 0.024 mg/kg/day is based on the
NOEL of 2.44 mg/kg/day from a chronic rat feeding study and a 100X
safety factor.  

The residue of concern, as listed at 40 CFR 180.492, is parent
triflusulfuron methyl only.

2. Food

a. Chronic Dietary Exposure Assessment

Dietary exposure, resulting from the current and proposed uses of
triflusulfuron methyl on sugar beets, chicory, and garden beets, is well
within the acceptable limits for all sectors of the population, as
predicted by both the Chronic and Acute Modules of the Dietary Exposure
Evaluation Model with Food Commodity Intake Database (DEEM-FCIDTM,
Exponent, Inc., 2003 Version 2.14).  The percentage or proportion of a
crop that is treated can have a significant effect on the exposure
profile.  In this case, it was assumed for all crops that 100% was
treated with triflusulfuron methyl. 

The predicted chronic exposure for the U.S. population was 0.000015
mg/kg bw/day.  The population subgroup with the highest predicted level
of chronic exposure was the children 3-5 years subgroup with an exposure
of 0.000041 mg/kg bw/day.  Based on a chronic NOEL of 2.44 mg/kg bw/day
and a 100-fold safety factor, the cRfD would be 0.024 mg/kg bw/day.  For
both the U.S. population and the children 3-5 years subgroup, the
predicted exposure is equivalent to less than 1% of the cRfD.  Since the
predicted exposures, expressed as percentages of the cRfD, are well
below 100%, there is reasonable certainty that no chronic effects would
result from dietary exposure to triflusulfuron methyl.

b. Acute Dietary Exposure

There are no effects attributable to a single, oral dose of
triflusulfuron methyl. Therefore, an acute dietary risk assessment was
not conducted.

3. Drinking Water

Based on the PRZM/EXAMS and SCI-GROW models the EECs of triflusulfuron
methyl for chronic exposures are estimated to be 0.005 ppb for surface
water and 0.5 ug/L (micrograms/Liter) for ground water.  There was
little change from the food-only dietary risk assessments when the
higher ground water concentration was included in the chronic dietary
risk assessment; the predicted exposure for the general population was
0.000025 mg/kg/day, less than 1% of the cRfD, and the predicted exposure
for the most sensitive subpopulation, children 3-5 years, was 0.000056
mg/kg/day, less than 1% of the cRfD.  Thus, it can be concluded that the
chronic dietary exposure of triflusulfuron methyl, including the
contribution of drinking water, clearly meets the standard of reasonable
certainty of no harm.  

4. Non-Dietary Exposure

Triflusulfuron methyl is not registered for any use which could result
in non-occupational or non-dietary exposure to the general population.

D. Cumulative Effects

Triflusulfuron methyl belongs to the sulfonylurea class of crop
protection chemicals. Other structurally similar compounds in this class
are registered as herbicides. However, the herbicidal activity of
sulfonylureas is due to the inhibition of acetolactate synthase (ALS),
an enzyme found only in plants. This enzyme is part of the biosynthesis
pathway leading to the formation of branched chain amino acids. Animals
lack ALS and this biosynthetic pathway. This lack of ALS contributes to
the relatively low toxicity of sulfonylurea herbicides in animals. There
is no reliable information that would indicate or suggest that
triflusulfuron methyl has any toxic effects on mammals that would be
cumulative with those of any other chemical.

E. Safety Determination

Based on data and information submitted by DuPont, EPA previously
determined that the establishment of tolerances of triflusulfuron methyl
on the sugar beets and chicory raw agricultural commodities would
protect the public health, including the health of infants and children.

Establishment of new tolerances for triflusulfuron methyl on beet,
garden, roots at 0.01 ppm and beet, garden, tops at 0.02 ppm will also
not adversely impact public health.

 

1. U.S. Population

	

Based on the completeness and reliability of the toxicology database,
and using the conservative assumptions presented earlier, EPA has
established a cRfD of 0.024 mg/kg/day. This was based on the NOEL for
the chronic rat study, 2.44 mg/kg/day, and a 100-fold safety factor. It
has been concluded that the chronic dietary exposure was less than 1% of
the cRfD.  Generally, exposure below 100% of the cRfD are of no concern
because it represents the level at or below which daily dietary exposure
over a lifetime will not pose appreciable risk to human health. Thus,
there is reasonable certainty that no harm will result from chronic
exposures to triflusulfuron methyl residues.

2. Infants and Children

In assessing the potential for additional sensitivity of infants and
children to residues of triflusulfuron methyl, data from the previously
discussed developmental and multigeneration reproductive toxicity
studies were considered. 

Developmental studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure during pre-natal
development. Reproduction studies provide information relating to
reproductive and other effects on adults and offspring from pre-natal
and post-natal exposures to the pesticide. The studies with
triflusulfuron methyl demonstrated no evidence of developmental toxicity
at exposures below those causing maternal toxicity.  This indicates that
developing animals are not more sensitive to the effects of
triflusulfuron methyl administration than adults.  

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 toxicity and the completeness of the
database.  Based on current toxicological data requirements, the
database for triflusulfuron methyl relative to pre- and post-natal
effects for children is complete.  The sub-population with the highest
level of chronic exposure was Children 3-5 years, for whom exposure was
less than 1% of the cRfD. Based on these conservative analyses, there is
reasonable certainty that no harm will result to infants and children
from aggregate exposures to triflusulfuron methyl. 

F. International Tolerances

There is neither a Codex proposal, nor a Canadian or Mexican tolerance
for garden beets.

  Interregional Research Number 4 (IR-4)                                
               	Triflusulfuron Methyl

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