Pesticides; tolerances in food, animal feeds, and raw agricultural commodities: Flumioxazin,

[Federal Register: April 18, 2001 (Volume 66, Number 75)]

[Rules and Regulations]

[Page 19870-19879]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr18ap01-13]

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-301116; FRL-6778-5]

RIN 2070-AB78

Flumioxazin; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

SUMMARY: This regulation establishes a tolerances for residues of flumioxazin in or on soybean seed and peanuts. Valent U.S.A. Corporation requested this tolerance under the Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality Protection Act of 1996.

DATES: This regulation is effective April 18, 2001. Objections and requests for hearings, identified by docket control number OPP-301116, must be received by EPA on or before June 18, 2001.

ADDRESSES: Written objections and hearing requests may be submitted by mail, in person, or by courier. Please

[[Page 19871]]

follow the detailed instructions for each method as provided in Unit VI.. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, your objections and hearing requests must identify docket control number OPP-301116 in the subject line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By mail: Joanne I. Miller, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,Washington, DC 20460; telephone number: (703) 305-6224; and e-mail address: miller.joanne@epa.gov.

SUPPLEMENTARY INFORMATION:

1. General Information

   1. Does this Action Apply to Me?

      You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to:

      Examples of Categories

      NAICS codes

      potentially affected entities

      Industry

      111

      Crop production 112

      Animal production 311

      Food manufacturing 32532

      Pesticide manufacturing

      This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.

   2. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?

      1. Electronically.You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http://www.epa.gov/. To access this document, on the Home Page select ``Laws and Regulations,'' ``Regulations and Proposed Rules,'' and then look up the entry for this document under the ``Federal Register--Environmental Documents.'' You can also go directly to the Federal Register listings at http://www.epa.gov/fedrgstr/. To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gov/opptsfrs/home/guidelin.htm. A frequently updated electronic version of 40 CFR part 180 is available at http:// www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180._00.html, a beta site currently under development.

      2. In person. The Agency has established an official record for this action under docket control number OPP-301116. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305-5805.

2. Background and Statutory Findings

   In the Federal Register of February 14, 2001 (66 FR 10292) (FRL- 6765-8), EPA issued a notice pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food Quality Protection Act of 1996 (FQPA) (Public Law 104-170) announcing the filing of pesticide petitions (PP 7F4841 and OF6171) for tolerances by Valent U.S.A. Corporation, 1333 North California, Boulevard, Suite 600, Walnut Creek, CA 94596-8025. This notice included a summary of the petition prepared by Valent U.S.A. Corporation, the registrant. There were no comments received in response to the notice of filing.

   The petition requested that 40 CFR part 180 be amended by establishing tolerances for residues of the herbicide flumioxazin, 2-

   [7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl] - 4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, in or on soybean seed and peanuts at 0.01part per million (ppm). Valent U.S.A. Corporation subsequently amended the petition to request tolerances in or on soybean seed and peanut nutmeat at 0.02 ppm.

   Section 408(b)(2)(A)(i) of the 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) 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) 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 * * *.''

   EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. For further discussion of the regulatory requirements of section 408 and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997) (FRL--5754-7).

3. Aggregate Risk Assessment and Determination of Safety

   Consistent with 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, consistent with section 408(b)(2), for a tolerances for residues of flumioxazin on soybean seed and peanut nutmeat at 0.02 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance follows.

   1. 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. The nature of the toxic effects caused by flumioxazin are discussed in the following Table 1 as well as the no observed adverse effect level (NOAEL) and the lowest observed

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      adverse effect level (LOAEL) from the toxicity studies reviewed.

      Table 1.-- Subchronic, Chronic, and Other Toxicity

      Guideline No.

      Study type

      Results

      870.1000

      Acute Oral - rat

      LD50>5,000 mg/kg (M and F); no clinical signs

      870.1100

      Acute Dermal - rat

      LD50>2,000 mg/kg; no clinical signs

      870.1200

      Acute Inhalation - rat LC50= 3.93 mg/L

      870.2400

      Primary Eye Irritation - No corneal irritation; mild irritation of rabbit

      iris cleared by 24 hours; mild irritation of conjunctival cleared by 48 hours

      870.2500

      Primary Skin Irritation - No erythema or edema rabbit

      870.2600

      Dermal sensitization - Not a dermal sensitizer guinea pig

      870.3100

      90-Day oral toxicity - rat NOAEL = mg/kg/day: 69.7 (M), 71.5 (F)

      LOAEL = mg/kg/day: 243.5 (M), 229.6 (F) based on a decrease in MCV both sexes; increase in platelets F only

      870.3100

      90-Day oral toxicity - rat NOAEL = mg/kg/day: 65.0 (M), 72.9 (F)

      LOAEL = mg/kg/day: 196.7 (M), 218.4 (F) based on hematology changes

      870.3150

      90-Day capsule - dog

      NOAEL = mg/kg/day: 10 (M and F) LOAEL = mg/ kg/day: 100 (M and F) based on dose dependent increase in total cholesterol, phospholipid and alkaline phosphatase

      870.3100

      90-Day oral toxicity - NOAEL = mg/kg/day: 429 (M and F) LOAEL = mg/ mouse

      kg/day: 1429 (M and F) based on increased liver weight in males

      870.3100

      4-Week oral toxicity - NOAEL = mg/kg/day: 151.5 (M), 164.5 (F) mouse

      LOAEL = mg/kg/day: 419.9 (M), 481.6 (F) based on increased absolute and/or relative liver weights in M and F

      870.3200

      21-Day dermal toxicity - NOAEL = mg/kg/day: 1,000 (LIMIT DOSE) LOAEL rat

      = mg/kg/day: 1,000 based on no effects

      870.3700a

      Prenatal developmental - Maternal NOAEL = 30 mg/kg/day (HDT) LOAEL = rat (oral)

      >30 mg/kg/day (HDT) Developmental NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects)

      870.3700a

      Prenatal developmental - Maternal NOAEL = 300 mg/kg/day (HDT) LOAEL rat (dermal)

      = >300 mg/kg/day (HDT) Developmental NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects)

      870.3700b

      Prenatal developmental - Maternal NOAEL = 1,000 mg/kg/day LOAEL = rabbit (oral)

      3,000 mg/kg/day (HDT) based on decrease in body weight and food consumption during dosing Developmental NOAEL = 3000 mg/kg/ day (HDT) LOAEL = >3,000 mg/kg/day

      870.3800

      Reproduction and fertility Parental/Systemic NOAEL = mg/kg/day: males effects - rat

      = 12.7, females = 15.1 LOAEL = mg/kg/day: males = 18.9, females = 22.7 based on increase in clinical signs (red substance in vagina) and increased female mortality as well as decreased body weight, body weight gain and food consumption Reproductive NOAEL = mg/kg/day: males = 18.9 (HDT), females = 22.7 (HDT) LOAEL = mg/kg/day: males = >18.9 (HDT), females = >22.7 (HDT) Offspring NOAEL = mg/kg/day: males = 6.3, females = 7.6 LOAEL = mg/kg/ day: males = 12.7, females = 15.1 based on a decrease in the number of liveborn and a decrease in pup body weight

      870.4100

      12-Month capsule - dog NOAEL = 100 mg/kg/day (M and F) LOAEL = 1,000 mg/kg/day (M and F), (LIMIT DOSE) based on the following for males and females: increased absolute and relative liver weights; 300% increase in alkaline phosphatase values

      870.4200

      Carcinogenicity - mouse NOAEL = mg/kg/day: males = 754.1, females = 859.1 (LIMIT DOSE) LOAEL = no systemic effects at LIMIT DOSE in males or females

      No evidence of carcinogenicity

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      870.4300

      Combined chronic

      NOAEL = mg/kg/day: males = 1.8, females = carcinogenicity - rat 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC)

      No evidence of carcinogenicity

      870.5100

      Gene mutation in S.

      Neither cytotoxic nor mutagenic up to 2,000 typhimurium and E. coli g/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. Results considered to be equivocal.

      870.5375

      Gene mutation in chinese Precipitation at 200 M. hamster ovary cells

      Cytotoxicity at 500 M. Positive +S9 100 M and negative at 30-500 M -S9. Aberrations were chromatid breaks and exchanges.

      870.5395

      In vivo rat bone marrow Negative in male (up to 5,000 mg/kg) and female rats (up to 4,400 mg/kg) when tested orally.

      870.5550

      UDS assay

      Negative up to 5,000 mg/kg.

      870.7485

      Metabolism and

      Gastrointestinal tract absorption >90% at 1 pharmacokinetics - rat mg/kg and up to 50% at 100 mg/kg. At least (oral)

      97% recovery in feces and urine 7 days after dosing. Highest levels of residues (36-49 ppb) in blood cells at low dose and 2800-3000 ppg at high dose (RBC levels > plasma). In addition to untransformed parent, 7 metabolites identified in urine and feces (38-46% for low dose and about 71% at high dose).

      870.7600

      Dermal penetration - rat Males dosed with suspension of 50 WDG formulation in water at 0.02, 0.20 or 1.0 mg/rat (0.002, 0.020 or 0.100 cm2. At 0.02 mg/rat, absorption ranged from 0.48% at 0.5 hours to 5.46% at 24 hours. At 0.2 mg/ rat, absorption ranged from 0.007% at 0.5 hours to 0.74% at 24 hours. At 1.0 mg/rat, absorption ranged from 0.004% at 0.5 hours to 10.47% at 24 hours.

      870.7600

      Dermal penetration - rat Females dosed with 200 or 800 mg/kg b.w. Dermal absorption for 200 and 800 mg/kg was 3.9 and 8.0% by 48 hours after initiation of treatment for 6 hours. Blood levels at 6-24 hours after dermal dosing with 200 mg/kg were similar to those obtained at 2-6 hours after oral dosing with 1 mg/kg. Blood levels at 6-24 hours after dermal dosing with 800 mg/kg were similar to those obtained at 2-6 hours after oral dosing with 30 mg/kg.

      Special Study - Rat

      Pregnant females were administered 400 mg/ Developmental: Critical kg by gavage on gestation day 11 or 12 or Time for Defects

      13 or 14 or 15. Day 12 administration showed: largest incidence of embryonic death, lowest fetal body weights and greatest incidence of ventricular spetal defects.

   2. Toxicological Endpoints

      The dose at which no adverse effects are observed (the NOAEL) from the toxicology study identified as appropriate for use in risk assessment is used to estimate the toxicological level of concern (LOC). However, the lowest dose at which adverse effects of concern are identified (the LOAEL) is sometimes used for risk assessment if no NOAEL was achieved in the toxicology study selected. An uncertainty factor (UF) is applied to reflect uncertainties inherent in the extrapolation from laboratory animal data to humans and in the variations in sensitivity among members of the human population as well as other unknowns. An UF of 100 is routinely used, 10x to account for interspecies differences and 10x for intra species differences.

      For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (acute RfD or chronic RfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factor is retained due to concerns unique to the FQPA, this additional factor is applied to the RfD by dividing the RfD by such additional factor. The acute or chronic Population Adjusted Dose (aPAD or cPAD) is a modification of the RfD to accommodate this type of FQPA Safety Factor.

      For non-dietary risk assessments (other than cancer) the UF is used to determine the LOC. For example, when 100 is the appropriate UF (10x to account for interspecies differences and 10x for intraspecies differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and compared to the LOC.

      The linear default risk methodology (Q*) is the primary method currently used by the Agency to quantify carcinogenic risk. The Q* approach assumes that any amount of exposure will lead to some degree of cancer risk. A Q* is calculated and used to estimate risk which represents a probability of occurrence of additional cancer cases (e.g., risk is expressed as 1 x 10-6or one in a million). Under certain specific circumstances, MOE calculations will be used for the carcinogenic risk assessment. In this non-linear approach, a ``point of departure'' is identified below which carcinogenic effects are not expected. The point of departure is typically a NOAEL based on an endpoint related to cancer effects though it may be a different value derived from the dose response curve. To estimate risk, a ratio of the point of departure to exposure (MOE cancer= point of departure/exposures) is calculated. A summary of the toxicological endpoints for flumioxazin used for human risk assessment is shown in the following Table 2:

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      Table 2.--Summary of Toxicological Dose and Endpoints for Flumioxazin for Use in Human Risk Assessment

      FQPA SF* and level of Exposure scenario

      Dose used in risk

      concern for risk Study and toxicological assessment, UF

      assessment

      effects

      Acute Dietary Females 13-50

      NOAEL = 3 mg/kg/day FQPA SF = 10 aPAD = Oral developmental and Acute RfD = 0.03 mg/kg/ acute RfD FQPA SF = supplemental prenatal day

      0.003 mg/kg/day

      studies in the rat LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects in fetuses)

      Acute Dietary General Population

      An endpoint attributable to a single dose (exposure) was not identified from the available studies, including the developmental toxicity studies in rats and rabbits.

      Chronic Dietary all populations

      NOAEL = 2 mg/kg/day UF FQPA SF = 10 cPAD = 2-Year Chronic/ = 100 Chronic RfD = chronic RfD FQPA SF = Carcinogenicity Study 0.02 mg/kg/day

      0.002 mg/kg/day

      in the rat LOAEL = 18 mg/kg/day based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC)

      Incidental Oral (short and

      NOAEL = 65 mg/kg/day Target MOE = 1,000 90-Day Toxicity Studies intermediate term)

      (Residential)

      in the rat LOAEL = 196.7 mg/kg/day based on hematology changes (decrease in MCV and increase in female platelets)

      Dermal (all durations)

      NOAEL = 30 mg/kg/day Target MOE = 1,000 Dermal Developmental (Residential)

      Study in the rat LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects in fetuses)

      Short-term Inhalation

      NOAEL = 3 mg/kg/day Target MOE = 1,000 Oral Developmental (Residential)

      Study in the rat LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects in fetuses)

      Intermediate- and Long-term

      NOAEL = 2 mg/kg/day Target MOE = 1,000 2-Year Chronic/ Inhalation

      (Residential)

      Carcinogenicity Study in the rat LOAEL = 18 mg/kg/day based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC)

      Cancer (oral, dermal, inhalation)

      Not likely to be a carcinogen for humans based on the lack of carcinogenicity in a 2-year rat study, an 18-month mouse study and a battery of mutagenic studies.

      *The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique to the FQPA.

   3. Exposure Assessment

      1. Dietary exposure from food and feed uses. No previous tolerances have been established for the residues of flumioxazin. Risk assessments were conducted by EPA to assess dietary exposures from flumioxazin in food as follows:

         i. Acute exposure. Acute dietary 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 one day or single exposure. The Dietary Exposure Evaluation Model (DEEM) analysis evaluated the individual food consumption as reported by respondents in the USDA 1989-1992 nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity. The following assumptions were made for the acute exposure assessments: For this acute analysis the assumption was made that 100% of the crops with flumioxazin tolerances are treated with flumioxazin. In addition, the assumption was made that all commodities contain tolerance level residues when consumed, with the exception of those with default processing factors. Default processing factors were used for peanuts-butter (1.89x) and for soybeans-sprouted seeds (0.33x). As the exposure and risk estimates were low, no further refinements were made to this analysis.

         ii. Chronic exposure. In conducting this chronic dietary risk assessment the DEEM analysis evaluated the individual food consumption as reported by respondents in the USDA 1989-1992 nationwide CSFII and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: For this chronic analysis the assumption was made that 100% of the crops with flumioxazin tolerances are treated with flumioxazin. In addition, the assumption was made that all commodities contain tolerance level residues when consumed, with the exception of those with default processing factors. Default processing factors were used for peanuts- butter (1.89x) and for soybeans-sprouted seeds (0.33x). As the exposure and risk estimates were low, no further refinements were made to this analysis.

      2. Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for flumioxazin in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of flumioxazin.

         The Agency uses the Generic Estimated Environmental Concentration (GENEEC) or the Pesticide Root Zone/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and Screening Concentrations in Ground

         [[Page 19875]]

         Water (SCI-GROW), which predicts pesticide concentrations in groundwater. In general, EPA will use GENEEC (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a screening-level assessment for surface water. The GENEEC model is a subset of the PRZM/EXAMS model that uses a specific high-end runoff scenario for pesticides. GENEEC incorporates a farm pond scenario, while PRZM/EXAMS incorporate an index reservoir environment in place of the previous pond scenario. The PRZM/EXAMS model includes a percent crop area factor as an adjustment to account for the maximum percent crop coverage within a watershed or drainage basin.

         None of these models include consideration of the impact processing (mixing, dilution, or treatment) of raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models by the Agency at this stage is to provide a coarse screen for sorting out pesticides for which it is highly unlikely that drinking water concentrations would ever exceed human health levels of concern.

         Since the models used are considered to be screening tools in the risk assessment process, the Agency does not use estimated environmental concentrations (EECs) from these models to quantify drinking water exposure and risk as a %RfD or %PAD. Instead drinking water levels of comparison (DWLOCs) are calculated and used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, and from residential uses. Since DWLOCs address total aggregate exposure to flumioxazin they are further discussed in the aggregate risk sections below.

         The hydrolysis study for flumioxazin indicates that flumioxazin forms the metabolite 482-HA, which can further hydrolyze to metabolites APF and THPA. The rates of the two hydrolytic reactions are very pH dependent, but the parent is not very stable at any likely environmental pH. Additional data indicated that THPA and APF are likely to be very mobile. Although THPA can comprise a major portion of the total residue in water, it does not possess the phenyl ring and is thus considered significantly less toxic than parent, APF, and 482-HA, thus THPA needs not be included in the residue of concern for drinking water. Therefore, parent flumioxazin and the metabolites 482-HA and APF are the residues of concern in drinking water.

         Based on the GENEEC and SCI-GROW models the estimated environmental concentrations (EECs) of flumioxazin and its metabolites of concern in water for acute exposures are estimated to be 2.4 parts per billion (ppb) for surface water and 6.3 ppb for ground water. The EECs for chronic exposures are estimated to be 0.67 ppb for surface water and 6.3 ppb for ground 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).

         Flumioxazin is not registered for use on any sites that would result in residential exposure.

      4. Cumulative exposure to substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''

         EPA does not have, at this time, available data to determine whether flumioxazin has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, flumioxazin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flumioxazin has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the final rule for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997).

   4. Safety Factor for Infants and Children

      1. In general. FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk assessments either directly through use of a margin of exposure (MOE) analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans.

      2. Prenatal and postnatal sensitivity. The data for flumioxazin indicate that there is both quantitative and qualitative evidence of increased susceptibility to flumioxazin from prenatal or postnatal exposures. Quantitative susceptibility is observed when the young respond more than the adults at a given dose, and qualitative susceptibility is observed when there is a unique biological target, such as the developing brain, that predisposes the individual.

         The quantitative and qualitative evidence of increased susceptibility is observed with the rat fetuses to in utero exposure to flumioxazin in the oral and dermal developmental studies. In both studies, there was an increased incidence in fetal cardiovascular anomalies (especially ventricular septal defects). In the oral study, no maternal effects were seen at the highest dose tested (HDT) (30 milligrams/kilograms (mg/kg/day)); whereas, the effects in the fetuses were observed at 10 mg/kg/day. In the dermal study, no maternal effects were noted at the HDT (300 mg/kg/day); whereas, the effects in the fetuses were observed at 100 mg/kg/day. Regarding the 2-generation rat reproduction study, parental effects (red substance in vagina and increased mortality in females as well as decreases in male and female body weights, body weight gains, and food consumption) were noted at 18.9 mg/kg/day in males HDT and 22.7 mg/kg/day in females HDT. Based on the results of the study, no apparent reproduction effects were attributed to test article administration. The effects observed regarding the offspring were a decrease in both the number of liveborn and pup body weights at 12.7 mg/kg/day for males and 15.1 mg/kg/day for females. Therefore, it was considered that there was both a quantitative and qualitative increase in susceptibility.

      3. Conclusion. There is a complete toxicity data base for flumioxazin and exposure data are complete or are estimated based on data that reasonably accounts for potential exposures. The FQPA safety factor (as required by the Food Quality Protection Act of August 3, 1996) has been retained at 10x for all population subgroups for all exposure durations (acute and chronic) in assessing the risk posed by this chemical. The reasons for retaining the 10x safety factor are as follows. First, there is evidence of increased susceptibility of the rat fetuses to in utero exposure to flumioxazin by the

         [[Page 19876]]

         oral and dermal route in the prenatal developmental toxicity studies in rats. In addition, there is evidence of increased susceptibility of young animals exposed to flumioxazin in the 2-generation reproduction toxicity study in rats. Finally, there is concern for the severity of the effects observed in fetuses and young animals when compared to those observed in the maternal and parental animals (dose- and treatment-related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, in the developmental studies; and decreases in the number of live born pups and pup body weights in the absence of parental toxicity in the reproduction study).

   5. Aggregate Risks and Determination of Safety

      To estimate total aggregate exposure to a pesticide from food, drinking water, and residential uses, the Agency calculates DWLOCs which are used as a point of comparison against the model estimates of a pesticide's concentration in water (EECs). DWLOC values are not regulatory standards for drinking water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food and residential uses. In calculating a DWLOC, the Agency determines how much of the acceptable exposure (i.e., the PAD) is available for exposure through drinking water e.g., allowable chronic water exposure (mg/kg/day) = cPAD - (average food + residential exposure). This allowable exposure through drinking water is used to calculate a DWLOC.

      A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weights. Default body weights and consumption values as used by the USEPA Office of Water are used to calculate DWLOCs: 2L/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg (child). Default body weights and drinking water consumption values vary on an individual basis. This variation will be taken into account in more refined screening-level and quantitative drinking water exposure assessments. Different populations will have different DWLOCs. Generally, a DWLOC is calculated for each type of risk assessment used: Acute, short-term, intermediate-term, chronic, and cancer.

      When EECs for surface water and groundwater are less than the calculated DWLOCs, OPP concludes with reasonable certainty that exposures to the pesticide in drinking water (when considered along with other sources of exposure for which OPP has reliable data) would not result in unacceptable levels of aggregate human health risk at this time. Because OPP considers the aggregate risk resulting from multiple exposure pathways associated with a pesticide's uses, levels of comparison in drinking water may vary as those uses change. If new uses are added in the future, OPP will reassess the potential impacts of residues of the pesticide in drinking water as a part of the aggregate risk assessment process.

      1. Acute risk. Using the exposure assumptions discussed in this unit for acute exposure to the subgroup of concern, the acute dietary exposure from food to flumioxazin will occupy 0.72% of the aPAD for females 13 years and older. In addition, there is potential for acute dietary exposure to flumioxazin in drinking water. After calculating DWLOCs and comparing them to the EECs for surface and ground water, EPA does not expect the aggregate exposure to exceed 100% of the aPAD, as shown in the following Table 3:

         Table 3.--Aggregate Risk Assessment for Acute Exposure to Flumioxazin

         Surface Ground Population subgroup

         aPAD (mg/ % aPAD water EEC water EEC Acute DWLOC kg)

         (food) (ppb)

         (ppb)

         (ppb)

         Females (13+ years)

         0.003

         0.72

         2.4

         6.3

         90

      2. Chronic risk. Using the exposure assumptions described inthis unit for chronic exposure, EPA has concluded that exposure to flumioxazin from food will utilize 0.5% of the cPAD for the U.S. population, 2.3% of the cPAD for all infants (01-9597Filed4-17-01; 8:45 am] BILLING CODE 6560-50-S