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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR
PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kathryn Montague, 703

- 305

- 1243

BASF

5F8421

EPA has received a pesticide pet ition ( 5F8421 ) from BASF Corporation

, 26 Davis Drive, P.O. Box 13528, Research Triangle Park, NC 27709 request ing, 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

1. By establis hing a tolerance for residues of

3

- (4,5

- Dihydro

- isoxazol

- 3

- yl)

- 4

- methanesulfonyl

- 2

- methylphenyl]

- (5

- hydroxyl

1

- methyl

- 1H

- pyrazol

- 4

- yl)methanone in or on the raw agricultural commodity sugarcane ,

cane at 0.0 1 parts per million (ppm). EPA has determined t hat the petition contains data

or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. A dditional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of Topramezone was determined in corn forage, stover and grain using 14C labeled materials applied to young corn plants at an

exagger ated application rate of 0.134 lb ai/acre. Topramezone and one significant metabolite, M670H05, were found in low levels in the plant matrices with the majority of the radioactive residues incorporated into natural products. M670H05 resulted from
oxidation of the carbonyl bridge to a carboxylic acid with concomitant loss and breakdown of the pyrazole ring. The significant metabolite M670H05 was found in the rat metabolism study.

2. Analytical method. Suitable independently validated analytical methods (fo r animal matrices) are submitted for detecting and measuring Topramezone levels in or on food with a limit of detection that is satisfactory for enforcing the requested tolerances. Residues are first extracted from the matrices by aqueous solvent then clea ned up by acid partitioning into organic solvent, then base partitioned, and quantified with application to high performance liquid chromatography with dual mass selective detectors (LC/MS/MS).2

3. Magnitude of residues. A total of eight (8) sugarcane res idue trials were conducted in NAFTA growing regions 3, 4, 6 and 13. Topramezone in the form of Armezon herbicide (2.8 pounds topramezone per gallon) was applied late postemergence to sugarcane, just prior to canopy closure. A single application was made at a targeted rate of 4.0 fluid ounces per acre (0.0875 pounds topramezone per acre).

All samples were analyzed for residues of topramezone (BAS 670 H), and its metabolite, M670H05, using BASF Method D1302, which quantifies residues by LC

- MS/MS. Mean

reco veries for all analytes were within the acceptable range of 70

- 120%. Fortification levels for each analyte were adequate to bracket residue levels found in treated samples. The method limit of detection (LOD) and limit of quantitation (LOQ) for both analyt es were 0.002 and 0.01 ppm, respectively.

No residues above the LOD of topramezone and its metabolite were found in any of the control samples (n=8) analyzed. After one broadcast application of topramezone, totaling 0.087 lb ai/A to 0.094 lb ai/A per seas on for sugarcane, maximum residues were <LOD ppm for topramezone and M670H05 in/on all sugarcane samples (n=16) harvested at crop maturity (97 to 255 DALA). Mean residues were 0.002 ppm for topramezone and M670H05 in/on all treated sugarcane samples (n=16) harvested at crop maturity (97 to 255 DALA).

B. Toxicological Profile

1. Acute toxicity. a. Oral (rat): LD50 = >2000 mg/kg b.w. (male/female) = Category III b. Dermal (rat): LD50 = >2000 mg/kg b.w. (male/female) = Category III c. Inhalation (rat): LC 50 = >5.8 mg/L (male/female) = Category IV d. Primary eye irritation (rabbit): slightly irritating = Category III e. Primary dermal irritation (rabbit): slightly irritating = Category III f. Dermal sensitization (guinea pig): not a sensitizer g. Oral neuro toxicity (rat): NOAEL = 2000mg/kg b.w.(male/female)

2. Genotoxicty. Topramezone was tested for its genotoxic potential in a battery of five in vitro or in vivo studies covering all required end

- points (gene mutations,
chromosomal and chromosome aberrati ons, and DNA damage and repair) several batches
of Topramezone have been tested over the time, from early laboratory produced material to current manufacturing process material. Topramezone did not demonstrate any genotoxic effects in vivo. In vitro, eithe r batches tested for chromosomal aberrations caused a slight, significant clastogenic effect in the presence of S

- 9 mix, but the in vivo test for the equivalent end

- point was negative. Three of the four batches tested in the
bacterial reverse mutation ass ay were not mutagenic, but the batch with the least purity displayed a weak mutagenic effect at the highest dose in Salmonella typhimurium TA98
in the absence of S

- 9 mix, most likely caused by impurities, which are not present in the current production bat ch. Overall, the weight of the evidence is that Topramezone is not genotoxic.3

3. Reproductive and developmental toxicity. The reproductive and developmental toxicity of Topramezone was investigated in a 2

- generation rat reproduction study as well
as in r at, mouse and several rabbit teratology studies (with different batches of Topramezone ) and a rat developmental neurotoxicity study. There were no adverse effects on fertility of both genders and no effect on the reproductive performance of
males in the t wo

- generation study at any dose tested. There was, however, a high litter loss in F0 and F1 associated with insufficient maternal care at higher dose levels with clear maternal toxicity. General parental toxicity included eye

- and kidney effects, caused by elevated tyrosine levels due to HPPD (hydroxyphenylpyruvate dioxygenase) inhibition. The same organs were affected in subchronic and chronic feeding studies with rats. Pup effects were observed in the F1 and F2 generation including perinatal pup mortality and impaired body weight gain, the lower body weight effects were considered to lead to brain and spleen weight changes and delays in preputial separation. As observed in the parental animals, effects on eyes and kidneys were observed in the pups. Renal p elvis dilation was observed at lower doses, although there was no overt maternal toxicity, significantly elevated tyrosine levels were observed in the dams and pups. The NOAEL for fertility (F0 and F1, both genders) was 4,000 ppm (about 450 mg/kg b.w./day) ; the NOAEL for reproductive performance was 40 ppm (about 4 mg/kg body weight/day) for the F1 females. The NOAEL for general toxicity was 4 ppm (about 0.4 mg/kg b.w./day). The NOAEL for developmental toxicity (growth and development of the offspring) was 4 ppm (about 0.4 mg/kg body weight/day) for the F1 pups, but was lower than 4 ppm for the F2 pups due to renal pelvis dilations at all dose levels. Developmental neurotoxicity was not observed at any dose in the developmental neurotoxicity study. At all do se levels, eye effects due to elevated tyrosine levels were found in dams and pups. Additionally there were decreased body weights in the dams at the high and mid dose, but there were no indications of adverse effects on reproductive performance of the par ental females. In pups of both genders, decreased pre and post weaning body weight gains and body weights were observed at the low dose level and above. This is an indicator of a retardation of the general physical development, which is
considered to be re sponsible for a slight delay of maturation. The NOAEL for developmental neurotoxicity was 800 mg/kg b.w./day (highest dose tested). There is no NOAEL for the eye lesions and reduced body weight gain of the pups. NOAELs for these
effects were determined in prenatal development studies in rats, rabbits and mice. No developmental toxicity was noted in the mouse prenatal development study. In the prenatal development study in rats no teratogenic effect was observed, but there was maternal toxicity together with skeletal variations in the pups. The same skeletal variation (i.e. supernumerary ribs) was also found in rabbit prenatal development studies. This effect is associated with the family of HPPD inhibiting substances. In addition, several rabbits had pups wi th a soft tissue malformation: unilateral kidney agenesis. The NOAEL for the skeletal variations and the kidney agenesis was 0.5 mg/kg b.w./day, the NOAEL for overt maternal toxicity was 50 mg/kg b.w./day. The developmental effects in rabbits
occurred at d ose

- levels below overt maternal toxicity, however measured tyrosine blood levels in the dams were substantially elevated at these dose levels. Elevated tyrosine levels are known to cause kidney toxicity.

4. Subchronic toxicity. The subchronic toxicity of Topramezone was investigated
in 90

- day feeding studies in rats, mice and dogs, and in a 28

- day dermal administration4

study in rats. Several supplemental short

- term mechanistic studies in rats and mice were performed to elucidate the mode of action. Genera lly, very mild toxicity was observed in mice and dogs at high doses. In a combined neurotoxicity 90

- day feeding study in rats, no signs of neurotoxicity were observed. Effects were seen in the pancreas, eye, kidney, liver and thyroid gland. The target orga ns are identical with those in the chronic feeding
studies with rats. Two modes of action have been elucidated for Topramezone by short

term mechanistic studies, one leading to effects on eyes, kidney and liver, and a second leading to effects at the thyro id: Topramezone causes elevated tyrosine levels by HPPD inhibition accounting for effects on eye, liver and kidney. The mouse is the accepted model for this tyrosine level elevations, and a NOAEL of 1.2 mg/kg b.w./day was established for tyrosine elevation in mice. Other mechanistic studies demonstrated an impairment of pituitary

- thyroid hormone levels by enhancing the hepatic clearance of thyroid hormones. The NOAEL for interference with thyroid hormones was 0.4 mg/kg b.w./day. The NOAEL for effects on the exocrine pancreas in rats was 1.1 mg/kg b.w./day. Similar effects were seen in the 28

- day dermal study with rats; the NOAEL was 100 mg/kg b.w./day.

5. Chronic toxicity. The chronic toxicity and oncogenicity studies with Topramezone include two 12

- month feeding studies with dogs, an 18

- month mouse feeding study, a 12

- month rat chronic feeding study and a 24

- month rat oncogenicity study. In the chronic dog study mild reductions of the body weight were observed at high doses. The NOAEL was 100 ppm (2.9 and 3.1 mg/kg b.w./day in males and females respectively).
In the 18

- month chronic feeding study in mice increased liver weights were seen at high doses. The NOAEL was 80 ppm (19 and 26 mg/kg b.w./day in males and females respectively). Topramezone was not car cinogenic to mice. In the chronic feeding studies in rats the main target organs were eye, liver, kidney, thyroid gland and pancreas. The same organs were affected in the subchronic studies. Short

- term mechanistic studies
demonstrated that Topramezone caus es elevated tyrosine levels by HPPD inhibition accounting for effects on eye, liver and kidney. The mouse is the accepted model for this tyrosine level elevation, and a NOAEL of 1.2 mg/kg b.w./day was established for tyrosine elevation in mice. The NOAEL f or effects on the exocrine pancreas in rats 6 ppm in both genders (0.4 and 0.5 mg/kg b.w./day in males and females respectively). At
the end of the 24

- month oncogenicity study, there was a slight but significant increase in benign thyroid adenomas in both genders. The thyroid was the only organ affected and the increase of the adenomas was significant only at the highest dose tested, while considerable general toxicity was already seen at 20

- times lower doses. The mechanism of thyroid tumor formation by Top ramezone was thoroughly investigated in short

- term mechanistic studies. An enhanced hepatic clearance of thyroid hormones impairs pituitary

- thyroid hormone levels leading to hypertrophy , hyperplasia and ultimately neoplasia. There is general agreement that this mechanism is well

- understood in rodents and is of minor relevance to humans. A clear NOAEL of 0.4 mg/kg b.w./day was demonstrated for effects on thyroid hormone levels. A threshold (non

- linear) cancer assessment is proposed and a cancer classificatio n as “not likely to be a human carcinogen”

.

6. Animal metabolism. In the rat metabolism studies the majority of the residue5

was excreted within 48 hours from both males and females. In all matrices investigated unchanged parent is the main component. Deg radation starts with hydroxylation of the oxazole ring. The identified metabolites from both pyrazole ring label and phenyl ring label studies are reported. Goat and hen metabolism studies were conducted with feeding levels of about 10 ppm. In the goat, th e majority of the applied dose was excreted. Non

metabolized BAS 670H was the major radioactive residue, and M670H02, formed from hydroxylation at the 4

- position of the isoxazole ring, was the only significant metabolite formed. In poultry BAS 670 F was al so rapidly excreted. Residues in liver consisted mainly of BAS 670H and the only significant metabolite in poultry was again M670H02. The significant metabolite M670H02 was found in the rat metabolism study

.

7. Metabolite toxicology

. Toxicity of the meta bolites of Topramezone with potential exposure to humans was concurrently evaluated during toxicity testing of the parent, because both plant and animal metabolites are formed during the course of toxicity testing. Both plant and animal metabolites are con sidered not of toxicological concern. Some testing was conducted on the anaerobic aquatic metabolite, 670M10. The results as given below show no toxicological concern:

Bacterial reverse mutation test (Ames): no effect = negative Mammalian somatic cell gen e mutation test (MNT): no effect = negative Cytogenetic study in vivo (mouse

– HPRT): no effect = negative 28 day feeding study (rat): NOAEL 1197 mg/kg b.w./da and 1304 mg/kg b.w./day (male and female, respectively)

.

8. Endocrine disruption

. Topramezone has been shown to alter thyroid hormone
levels in rats as also observed with other 4

- hydroxyphenylpyruvate dioxygenase (HPPD) enzyme inhibitor active ingredients. However, there have been no effects noted on
sexual or other hormones in numerous subchronic and chronic toxicity studies with multiple species.

C. Aggregate Exposure

1. Dietary exposure. Exposure assessments were conducted to evaluate the potential risk due to acute and chronic dietary exposure of the U.S. population to residues of Topramezon e. The current tolerance values are listed in the U.S. 40 CFR § 180.612. This analysis includes all commodities with established tolerances values a nd proposed new tolerances for sugarcane, cane = 0.01 ppm.

i. Food.

Acute Dietary Exposure Assessment
The US EPA has determined that an acute dietary assessment is required for all sub

populations.

An a cute dietary exposure estimate (food and drinking water) w as conducted for all populations u sing the currently established tolerances for topramezone (40 CFR 1 80.612) and currently proposed tolerances for sugarcane, cane . The assessment was conducted6

using tolerance values, default process factors, and 100% crop treatment factors. The consumption data was from the USDA Continuing Survey of Food Intake by Indivi duals (CSFII 1994

- 1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM

- FCID) software. The
water concentration used in the acute dietary assessment was 40 ppb based on the aquatic

ap plication rate.

The resulting exposure estimates were compared against the topramezone acute Population Adjusted Dose (aPAD) of 0.00 8 mg/kg b.w/day for all populations except females 13

- 49 years of age. The topramezone acute Population Adjusted Dose (a PAD)
for females 13

– 49 years of age is 0.005 mg/kg b.w/day. Th e endpoint of 0.008 mg/kg bw/day is based on the NOAEL of 8.0 mg/kg/day with the standard inter

- and intra

species uncertainty factors of 100X and an FQPA safety factor of 1 0

. The endpoint of 0.005 mg/kg bw/day is based on the NOAEL of 0.5 mg/kg/day with the standard inter

and intra

- species uncertainty factors of 100X and an FQPA safety factor of 1. T he most highly exposed population subgroup was all infants (< 1 year) which utilized 93.9 % of
the aPAD.

The results of the analysis show that the estimated exposure is below the Agency's level of concern (< 100% aPAD). Additional refinements in the dietary risk assessment (i.e. utilizing anticipated residue values, percent crop treated values ) would further reduce the estimated exposure value.

Chronic Dietary Exposure Assessment Chronic dietary exposure (food and drinking water) were conducted using the currently established tolerances for topramezone (40 CFR 180.612) and currently proposed

t olerances for sugarcane, cane . The assessment was conducted using tolerance values, default process factors, and 100% crop treatment factors. The consumption data was from the USDA Continuing Survey of Food Intake by Individuals (CSFII 1994

- 1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM

- FCID) software. The water concentration used in the chronic dietary assessment was 40 ppb based on the aquatic application rate and not taking into account degradation in water body

.

The chronic Population Adjusted Dose (cPAD) used for U.S. population and all sub

populations is 0.004 mg/kg bw/day. This endpoint is based on the NOAEL value of 0.4 using the standard inter

- and intra

- species un certainty factors of 100X and with a FQPA safety factor of 1. The most highly ex posed population sub

- group was infants (<1year old) which utilized 76.8 % cPAD. The results of the chronic dietary assessment are presented in Table 1

.

Table 1. Results for Topramezone Chronic Dietary Exposure Analysis Considering

all Current and Proposed Tolerances using DEEM

- FCID, food and drinking water.

Population Exposure Estimate %cPAD Subgroups (mg/kg b.w./day)7

U.S. Population 0.000859 21.48 All Infants (< 1 ye ar old) 0.003073 76.83 Children (1

- 2 years old) 0.001230 30.75 Children (3

- 5 years old) 0.001016 25.40 Children (6

- 12 years old) 0.000753 18.83 Youth (13

- 19 years old) 0.000616 15.40 Adults (20

- 49 years old) 0.000847 21.18 Adults (50+ years old) 0.00 0820 20.50 Females (13

- 49 years old) 0.000828 20.70

The results of the analysis show that for all populations, the exposures are below the US

EPA level of concern (< 100% cPAD). Additional refinements in the chronic dietary risk assessment (i.e. utili zing anticipated residue values and percent crop treated values) would further reduce the estimated exposure values

.

Acute Aggregate Exposure and Risk (food and water) The aggregate acute risk includes exposure of topramezone from food and water. The

resu lts demonstrate that there are no risk concerns for any subpopulation based on the proposed uses and the results meet the FQPA standard of reasonable certainty of no
harm.

Short

- and Intermediate

- Term Aggregate Exposure and Risk (food, water, and
resid ential)

Short

- and intermediate

- term aggregate risk assessments include exposure from food, water, and residential uses. T opramezone is registered for use on turfgrass and golf courses. The US EPA has conducted a risk assessment for this use of Topramezo ne (Topramezone: Human Health Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential Turfgrass). For this assessment, the US EPA used a dermal absorption value of 13%, the correct value for dermal absorption is 2.6% and it is noted in the document. But, the calculations for exposure were done with 13%. The residential exposure calculations were repeated using a dermal absorption value of .6%. The short

term aggregate MOE was determined for the General population and Children 1

- 2 y ears of age. The aggregate MOE for the General population is 321 and the aggregate MOE
for children 1

- 2 years of age is 220. The aggregate MOE limit of concern for both of these populations is 100. So an MOE greater than 100 indicates that there is no r isk concern from the aggregate exposures for Topramezone.

Chronic Aggregate Exposure and Risk (food and water) The aggregate chronic risk includes exposure of Topramezone from food and water (Table 1). The results demonstrate there are no risk concerns for any subpopulation based on the proposed uses and the results meet the FQPA standard of reasonable certainty of
no harm.8

ii. Drinking water

. The concentration of topramezone in water is based on the aquatic use pattern with an application rate of 40 ppb. The acute surface water concentration used in the dietary assessment was 40 ppb based on the application
rate. The chronic surface water concentration used in the assessment was also 40 ppb, which assumes no degradation in the water body. This is a ve ry conservative
water value and over

- estimates the actual chronic drinking water exposure.

2. Non

- dietary exposure

. Topramezone is registered for use on turfgrass and golf courses. The US EPA has conducted a risk assessment for this use of Topramezone (Topramezone: Human Health Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential Turfgrass). For this assessment, the US EPA used a dermal absorption value of 13%, the correct value for dermal absorption is 2.6% and it is noted

in the document. But, the calculations for exposure were done with 13%. The
calculations were repeated using a dermal absorption value of 2.6%. For adults, the exposure includes handler and dermal exposure from turf. The MOE for adults was
1033. For child ren 1

- 2 years of age, the exposure includes dermal exposure from turf and exposure from hand

- to

- mouth activities. The MOE for children 1

- 2 years of age is 678.
The MOE values are greater the limit of concern of 100. The MOE values greater than
100 ind icates that there is no risk concern from the non

- dietary uses of topramezone.

D. Cumulative Effects

At this time, there is no available information to indicate that Topramezone or its metabolites have a common mechanism of toxicity with other substanc es. Therefore, there is no reason to include this pesticide or its metabolites in a cumulative risk assessment. For the purposes of this tolerance action EPA has not assumed that Topramezone and its metabolites have a common mechanism of toxicity with othe r substances.

E. Safety Determination

1. U.S. population. Based on the current risk assessments, the US EPA can conclude that there is a reasonable certainty that no harm will result to the general population from aggregate exposure to tompramezone resi dues from the proposed uses.

2. Infants and children

. Based on the current risk assessments, the US EPA can conclude that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to topramezone residues fro m the proposed uses

.

F. International Tolerances

No maximum residue levels (MRLs) have been established for Topramezone by the Codex Alimentarius Commission (CODEX) or in Mexico.