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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 petition (5F8421) from BASF Corporation, 26 Davis 

Drive, P.O. Box 13528, Research Triangle Park, NC 27709 requesting, 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 establishing a tolerance for residues of

3-(4,5-Dihydro-isoxazol-3-yl)-4-methanesulfonyl-2-methylphenyl]-(5-hydroxyl1-methyl-1H-pyrazol-4-yl)methanone in or on the raw agricultural commodity sugarcane, 

cane at 0.01 parts per million (ppm). EPA has determined that the petition contains data 

or information regarding the elements set forth in section 408 (d)(2) of 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. Additional 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 

exaggerated 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 (for 

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 cleaned 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).
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3. Magnitude of residues. A total of eight (8) sugarcane residue 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 

recoveries 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 analytes 

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 season 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): LC50 = >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 neurotoxicity (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 aberrations, 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, either 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 assay 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 batch. Overall, the weight of the evidence is that Topramezone is not 

genotoxic.
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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 rat, 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 two-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 pelvis 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 dose 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 parental 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 responsible 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 with 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 dose-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 administration 
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study in rats. Several supplemental short-term mechanistic studies in rats and mice were 

performed to elucidate the mode of action. Generally, 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 organs are identical with those in the chronic feeding 

studies with rats. Two modes of action have been elucidated for Topramezone by shortterm mechanistic studies, one leading to effects on eyes, kidney and liver, and a second 

leading to effects at the thyroid: 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 carcinogenic 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 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 elevation, and a NOAEL of 1.2 mg/kg b.w./day was established for 

tyrosine elevation in mice. The NOAEL for 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 Topramezone 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 classification as “not likely to be a human 

carcinogen”.

6. Animal metabolism. In the rat metabolism studies the majority of the residue 
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was excreted within 48 hours from both males and females. In all matrices investigated 

unchanged parent is the main component. Degradation 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, the majority of the applied dose was excreted. Nonmetabolized 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 also 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 metabolites 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 considered 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 gene 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 Topramezone. The current tolerance values are listed in the U.S. 40 CFR § 180.612. 

This analysis includes all commodities with established tolerances values and 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 subpopulations. 

An acute dietary exposure estimate (food and drinking water) was conducted for all 

populations using the currently established tolerances for topramezone (40 CFR 180.612) 

and currently proposed tolerances for sugarcane, cane. The assessment was conducted 
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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 acute dietary assessment was 40 ppb based on the aquatic 

application rate. 

The resulting exposure estimates were compared against the topramezone acute 

Population Adjusted Dose (aPAD) of 0.008 mg/kg b.w/day for all populations except 

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

for females 13 – 49 years of age is 0.005 mg/kg b.w/day. The endpoint of 0.008 mg/kg 

bw/day is based on the NOAEL of 8.0 mg/kg/day with the standard inter- and intraspecies uncertainty factors of 100X and an FQPA safety factor of 10. The endpoint of

0.005 mg/kg bw/day is based on the NOAEL of 0.5 mg/kg/day with the standard interand intra-species uncertainty factors of 100X and an FQPA safety factor of 1. The 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 

tolerances 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 subpopulations 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 uncertainty factors of 100X and with a FQPA 

safety factor of 1. The most highly exposed 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)
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U.S. Population 0.000859 21.48

All Infants (< 1 year 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) 0.000820 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. utilizing 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 

results 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 

residential)

Short- and intermediate-term aggregate risk assessments include exposure from food, 

water, and residential uses. 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 residential 

exposure calculations were repeated using a dermal absorption value of .6%. The shortterm aggregate MOE was determined for the General population and Children 1-2 years 

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 risk 

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.
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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 very 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 children 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 indicates 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 substances. 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 other 

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 residues 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 from 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.