Topramezone; Pesticide Tolerances
Federal Register, Volume 78 Issue 152 (Wednesday, August 7, 2013)
Federal Register Volume 78, Number 152 (Wednesday, August 7, 2013)
Rules and Regulations
Pages 48068-48075
From the Federal Register Online via the Government Printing Office www.gpo.gov
FR Doc No: 2013-18975
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
EPA-HQ-OPP-2012-0262; FRL-9388-9
Topramezone; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of topramezone in or on multiple commodities which are identified and discussed later in this document. BASF Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA).
DATES: This regulation is effective August 7, 2013. Objections and requests for hearings must be received on or before October 7, 2013, and must be filed in accordance with the instructions provided in 40 CFR Part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).
ADDRESSES: The docket for this action, identified by docket identification (ID) number EPA-HQ-OPP-2012-0262, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory Public Docket (OPP Docket) in the Environmental Protection Agency Docket Center (EPA/DC), EPA West Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744, and the telephone number for the OPP Docket is (703) 305-
5805. Please review the visitor instructions and additional information about the docket available at http://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Lois Rossi, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone number: (703) 305-7090; email address: RDFRNotices@epa.gov.
SUPPLEMENTARY INFORMATION:
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General Information
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Does this action apply to me?
You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. The following list of North American Industrial Classification System (NAICS) codes is not intended to be exhaustive, but rather provides a guide to help readers
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determine whether this document applies to them. Potentially affected entities may include:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
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How can I get electronic access to other related information?
You may access a frequently updated electronic version of EPA's tolerance regulations at 40 CFR Part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.
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How can I file an objection or hearing request?
Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR Part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2012-0262 in the subject line on the first page of your submission. All objections and requests for a hearing must be in writing, and must be received by the Hearing Clerk on or before October 7, 2013. Addresses for mail and hand delivery of objections and hearing requests are provided in 40 CFR 178.25(b).
In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR Part 178, please submit a copy of the filing (excluding any Confidential Business Information (CBI)) for inclusion in the public docket. Information not marked confidential pursuant to 40 CFR Part 2 may be disclosed publicly by EPA without prior notice. Submit the non-CBI copy of your objection or hearing request, identified by docket ID number EPA-HQ-OPP-2012-0262, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the online instructions for submitting comments. Do not submit electronically any information you consider to be CBI or other information whose disclosure is restricted by statute.
Mail: OPP Docket, Environmental Protection Agency Docket Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001.
Hand Delivery: To make special arrangements for hand delivery or delivery of boxed information, please follow the instructions at http://www.epa.gov/dockets/contacts.htm.
Additional instructions on commenting or visiting the docket, along with more information about dockets generally, is available at http://www.epa.gov/dockets.
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Summary of Petitioned-For Tolerance
In the Federal Register of May 23, 2012 (77 FR 30481) (FRL-9347-8), EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 2F7997) by BASF Corporation, 26 Davis Drive, P.O. Box 13528, Research Triangle Park, NC 27709. The petition requested that 40 CFR 180.612 be amended by establishing tolerances for residues of the herbicide topramezone (3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)phenyl(5-
hydroxy-1-methyl-1H-pyrazol-4-yl)methanone), in or on fish and shellfish at 0.05 parts per million (ppm). That document referenced a summary of the petition prepared by BASF Corporation, the registrant, which is available in the docket, http://www.regulations.gov. There were no comments received in response to the notice of filing.
Based upon review of the data supporting the petition, EPA has revised the proposed commodity definitions and established tolerances for livestock meat by-products, which are needed as a result of the increased livestock dietary burden associated with the proposed use for topramezone. The reasons for these changes are explained in Unit IV.C.
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Aggregate Risk Assessment and Determination of Safety
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .''
Consistent with FFDCA section 408(b)(2)(D), and the factors specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure for topramezone including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with topramezone follows.
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Toxicological Profile
EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. Topramezone is a member of the class of herbicides known as HPPD inhibitors. Inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) results in decreased carotenoid synthesis and ultimately bleaching of target plants. In mammals, HPPD is involved in the catabolism of the amino acid tyrosine, and its inhibition causes blood levels of tyrosine to rise; a condition known as tyrosinemia. Some of the toxicities resulting from tyrosinemia in laboratory animals include ocular, developmental, liver, and kidney effects. Topramezone exhibits a mammalian toxicity profile that is consistent with HPPD inhibition.
The primary target organs affected following oral administration of topramezone in animal toxicity studies were the eyes, thyroid, pancreas, and liver. The most sensitive species was the rat, and in rats and dogs, males were more sensitive than females. The effects on the eyes in chronic toxicity studies consisted of pannus (vascularization) and keratitis (cloudiness) of the cornea in both sexes. Hypertrophy and hyperplasia of the thyroid, hypertrophy and focal necrosis in the liver, and degeneration of the pancreas were among the histopathology findings reported across different subchronic and chronic studies in rats and dogs. Results of chronic toxicity studies in dogs, mice, and rats also suggest decrements in body weights, body-weight gains, and food utilization (dogs only).
There was evidence for increased susceptibility following in utero exposure to topramezone in rats and rabbits. In rabbits, fetal abnormalities
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including supernumerary thoracic vertebrae and supernumerary 13th rib were observed in the presence of maternal toxicity in six of eight developmental toxicity studies conducted in two different strains. In rats, developmental effects consisting of skeletal variations occurred in the presence of maternal toxicity. Increased maternal serum levels of tyrosine were reported in several developmental toxicity studies (several in rabbits and one in mice), consistent with the proposed mode of action for topramezone involving HPPD inhibition. In the rat 2-
generation reproductive toxicity study, there was no evidence of increased pre- or post-natal susceptibility; offspring effects occurred in the presence of maternal effects. The offspring effects consisted of decreased pup body weight/body-weight gain in F2 (both sexes) and increased time to preputial separation (F1 males). Maternal effects were consistent with HPPD inhibition (decreased body weights, decreased body-weight gains, increased thyroid and kidney weights, and microscopic findings in the eyes, kidneys, and thyroid). No reproductive effects were reported.
Topramezone did not show any evidence of neurotoxicity in the acute (ACN) or subchronic (SCN) neurotoxicity studies, but in a rat developmental neurotoxicity (DNT) study, where dosing with topramezone took place during the prenatal as well as postnatal time periods, there was evidence for increased qualitative susceptibility. In the maternal animals, toxicity was limited to corneal opacity, whereas effects in the offspring included neurobehavioral and neuropathological changes. Offspring neurobehavioral effects consisted of a decreased auditory startle reflex at postnatal day 24 in both sexes (20-30%) and at postnatal day 60 for males (55%). There were also mild decreases in offspring absolute brain weights and neuropathological effects involving decreased brain morphometric measurements (e.g., hippocampus, and parietal cortex).
Topramezone is classified as ``not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.'' EPA has determined that the thyroid tumors arise through a non-linear mode of action, and the chronic reference dose (cRfD) is expected to be protective of alterations in hormone homeostasis that may result in thyroid tumor formation. Mutagenicity studies conducted on technical topramezone and its major metabolites did not demonstrate any mutagenic potential.
Specific information on the studies received and the nature of the adverse effects caused by topramezone as well as the no-observed-
adverse-effect-level (NOAEL) and the lowest-observed-adverse-effect-
level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov in document ``Topramezone: Human-Health Risk Assessment for (1) New Uses in Non-Crop Aquatic Sites and (2) Increased Maximum Application Rate for Currently Registered Terrestrial Uses in the Maintenance of Bare Grounds (Roadsides, Utility and Railroad Rights-of-Ways, Industrial Sites, and Tank Farms),'' pages 36-39 in docket ID number EPA-HQ-OPP-2012-0262.
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Toxicological Points of Departure/Levels of Concern
Once a pesticide's toxicological profile is determined, EPA identifies toxicological points of departure (POD) and levels of concern to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment. PODs are developed based on a careful analysis of the doses in each toxicological study to determine the dose at which no adverse effects are observed (the NOAEL) and the lowest dose at which adverse effects of concern are identified (the LOAEL). Uncertainty/safety factors are used in conjunction with the POD to calculate a safe exposure level--generally referred to as a population-adjusted dose (PAD) or a reference dose (RfD)--and a safe margin of exposure (MOE). For non-threshold risks, the Agency assumes that any amount of exposure will lead to some degree of risk. Thus, the Agency estimates risk in terms of the probability of an occurrence of the adverse effect expected in a lifetime. For more information on the general principles EPA uses in risk characterization and a complete description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
A summary of the toxicological endpoints for topramezone used for human risk assessment is shown in the Table of this unit.
Summary of Toxicological Doses and Endpoints for Topramezone for Use in Human Health Risk Assessment
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Point of departure
Exposure/scenario and uncertainty/ RfD, PAD, LOC for Study and toxicological effects
safety factors risk assessment
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Acute Dietary (General population LOAEL = 8 mg/kg bw.. UF = 100X (for Developmental Neurotoxicity Study
including infants and children). inter- and intra- in Rats.
species Offspring LOAEL = 8 mg/kg bw based
extrapolation). on decreased maximum auditory
FQPA SF = 10X...... startle reflex response,
aRfD = 0.008 mg/kg decreased brain weights, and
bw. changes in brain morphology.
aPAD = 0.008 mg/kg
bw.
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Acute Dietary (Females 13-49 NOAEL = 0.5 mg/kg/ UF = 100X (for Developmental Toxicity Study in
years old). day. inter- and intra- Rabbits.
species Developmental LOAEL = 5 mg/kg/day
extrapolation). based on alterations in skeletal
FQPA SF = 1X....... ossification sites and increased
aRfD = 0.005 mg/kg/ number of pairs of ribs.
day.
aPAD = 0.005 mg/kg/
day.
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Chronic Dietary (All populations) NOAEL= 0.4 mg/kg/day UF = 100X (for Chronic toxicity/Carcinogenicity
inter- and intra- Study in Rats.
species LOAEL = 3.6 mg/kg/day based on
extrapolation). increased incidences of corneal
FQPA SF = 1X....... opacity, decreased body weight
cRfD = 0.004 mg/kg/ and body-weight gains in males
day. and histopathological evaluations
cPAD = 0.004 mg/kg/ in the eyes, thyroid and pancreas
day. of both sexes.
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Incidental Oral (Short- and NOAEL = 0.4 mg/kg/ Residential LOC for Two-Generation Reproduction Study
Intermediate-Term). day. MOE = 100. in Rats.
Offspring LOAEL = 4.2 mg/kg/day
based decreases in body weights
and body-weight gains in the F2
generation offspring and
increased time to preputial
separation in the F1 male
offspring.
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Short- and Intermediate-Term, Oral NOAEL = 0.4 mg/ Residential LOC for Two-Generation Reproduction Study
Dermal. kg/day. MOE = 100. in Rats.
(DAF = 2.6%)........ Parental LOAEL = 4.2 mg/kg/day
based on decreased body weight,
body-weight gain in males,
increased thyroid and kidney
weights of both sexes, and
microscopic findings in eyes,
kidney and thyroid of both sexes.
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Short- and Intermediate-Term Oral NOAEL= 0.4 mg/ Residential LOC for Two Generation Reproduction Study
Inhalation. kg/day (inhalation MOE = 100. in Rats.
absorption = 100%). Parental LOAEL = 4.2 mg/kg/day
based on decreased body weight,
body-weight gain in males,
increased thyroid and kidney
weights of both sexes, and
microscopic findings in eyes,
kidney and thyroid of both sexes.
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Cancer (Oral, dermal, inhalation) In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment,
topramezone was classified as ``not likely to be carcinogenic to humans at
doses that do not alter rat thyroid hormone homeostasis.'' EPA has
determined that the thyroid tumors arise through a non-linear mode of action
and that the NOAEL (0.4 mg/kg/day) for deriving the cRfD will be protective
of thyroid hormone alterations and thyroid tumor formation.
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FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. LOC = level
of concern. mg/kg/day = milligram/kilogram/day. MOE = margin of exposure. NOAEL = no-observed-adverse-effect-
level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor.
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Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to topramezone, EPA considered exposure under the petitioned-
for tolerances as well as all existing topramezone tolerances in 40 CFR 180.612. EPA assessed dietary exposures from topramezone in food as follows:
i. Acute exposure. Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide, if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a 1-day or single exposure. Such effects were identified for topramezone.
In estimating acute dietary exposure for both the general U.S. population (including infants and children) and for females 13-49 years of age, EPA used food consumption information from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). As to residue levels in food, EPA assumed 100 percent crop treated (PCT), Dietary Exposure Evaluation Model (DEEM) 7.81 default processing factors, and tolerance-level residues.
ii. Chronic exposure. In conducting the chronic dietary exposure assessment EPA used the same food consumption data and assumptions of tolerance-level residues, 100 PCT and DEEM 7.81 default processing factors.
iii. Cancer. Based on the data summarized in Unit III.A., EPA has concluded that topramezone does not pose a cancer risk to humans at levels that do not alter rat thyroid hormone homeostasis, and doses at or below the cRfD are not expected to alter thyroid homeostasis. Therefore, a dietary exposure assessment beyond the chronic assessment for the purpose of assessing cancer risk is unnecessary.
iv. Anticipated residue and PCT information. EPA did not use anticipated residue or PCT information in the dietary assessment for topramezone. Tolerance-level residues and 100 PCT were assumed for all food commodities.
2. Dietary exposure from drinking water. The highest drinking water concentrations are expected to result from the direct aquatic applications. Estimates of drinking water exposure levels were based on label instructions (i.e., proposed application rates, duration, and water concentration of direct aquatic applications at potable surface water intakes). For acute and chronic dietary risk assessment, the water concentration value of 45 parts per billion (ppb) was used to assess the contribution to drinking water.
3. From non-dietary exposure. The term ``residential exposure'' is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Topramezone is currently registered for turf and golf course uses that could result in residential exposures. Topramezone is also proposed for use in direct aquatic applications that could result in exposure during recreational swimming activities. EPA assessed
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residential exposure using the following assumptions: For adults, short-term aggregate assessment considered the post-application exposure resulting from the physical activities on turf. For children, short-term aggregate assessment considered combined dermal and incidental oral (hand-to-mouth) post-application exposures to children 1 2 male and female pups and increased time to preputial separation in the F1 males. These effects were observed in the presence of parental/systemic toxicity that included: Decreased body weight, decreased body-weight gain in males, increased thyroid and kidney weights of both sexes, and microscopic findings in the eyes, kidney, and thyroid of both sexes.
In the developmental neurotoxicity (DNT) study, there was evidence for qualitative susceptibility. In the maternal animals, toxicity was limited to corneal opacity whereas effects in the offspring manifested as: Neurobehavioral changes (decreased auditory startle reflex), decreases in absolute brain weight, and decreases in brain morphometric measurements (e.g., hippocampus, and parietal cortex).
3. Conclusion. While EPA is retaining the 10X FQPA safety factor for the acute dietary risk assessment for the U.S. general population including infants and children, EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced to 1X for the acute dietary risk assessment for females of child-bearing age (i.e., 13-49 years old), the chronic dietary risk assessment for the U.S. general population, and all non-
dietary exposure scenarios. That decision is based on the following findings:
i. The toxicity database for topramezone is complete, except for an immunotoxicity study. A database uncertainty factor (UFDB) is not required for the lack of an immunotoxicity study since the PODs used for overall risk assessments are based on effects seen in target organs (e.g., eyes, thyroid, and liver) consistent with the actions of this chemical as an HPPD inhibitor. An immunotoxicity study is not likely to
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yield a lower POD and the preliminary results of the retrospective analyses provide strong support for not retaining the UFDB as no immunotoxicity study available thus far has provided sensitive endpoints for use in deriving points of departure.
ii. There is some indication that topramezone is a neurotoxic chemical for developing animals. While there was no evidence of neurotoxicity or neuropathology to the adult nervous system following a single oral administration to rats at the limit dose in the ACN study or following repeated dietary administration to rats in the SCN study or in the maternal animals of the DNT study, there were neurobehavioral as well as neuropathological effects observed in the offspring of the DNT study as described above.
The LOAEL of 8 mg/kg/day of the DNT study is based on decreased auditory startle reflex, decreases in brain weight, and brain morphometric parameters at the lowest dose tested. A NOAEL was not established. Nevertheless, the LOAEL (8 mg/kg/day) was employed as the point of departure in assessing the risk for the general U.S. population, including infants and children, since the offspring were exposed to topramezone both in utero and during the lactation period. The 10X FQPA safety factor is retained as a UFL (i.e., use of a LOAEL to extrapolate a NOAEL.)
iii. As discussed in Unit III.D.2., there is evidence that topramezone results in increased susceptibility in the prenatal developmental studies in rats and rabbits. But the degree of concern for the effects seen in those studies is low because there were clear NOAELs for the offspring effects and EPA selected points of departure that are protective of those effects. As explained in Unit III.D.3.ii., EPA is retaining the 10X FQPA safety factor for the lack of a NOAEL in the DNT study and believes that doing so will be protective of infants and children.
iv. There are no residual uncertainties in the exposure database. The dietary and residential exposure analyses are conservative in nature. The dietary exposure assessment uses tolerance-level residues and assumes 100 PCT. EPA used similarly conservative assumptions to assess post-application exposure to children/adults. The residential exposure assessment uses chemical-specific turf transferable residue data and the 2012 Residential Standard Operating Procedures (SOPs) and is considered health-protective. These assessments will not underestimate the exposure and risks posed by topramezone.
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Aggregate Risks and Determination of Safety
EPA determines whether acute and chronic dietary pesticide exposures are safe by comparing aggregate exposure estimates to the acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer risks, EPA calculates the lifetime probability of acquiring cancer given the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the appropriate PODs to ensure that an adequate MOE exists.
1. Acute risk. Acute aggregate risk is made up only of dietary sources; therefore, the acute exposure estimates provided in the acute dietary exposure analysis represent acute aggregate exposures. EPA has concluded that acute exposure to topramezone from food and drinking water will utilize 98% of the aPAD for the most highly exposed population subgroup (all infants
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