Pesticides; tolerances in food, animal feeds, and raw agricultural commodities: Tepraloxydim,
[Federal Register: August 2, 2001 (Volume 66, Number 149)]
[Rules and Regulations]
[Page 40141-40151]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02au01-11]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-301148; FRL-6791-7]
RIN 2070-AB78
Tepraloxydim; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: This regulation establishes a tolerance for combined residues of tepraloxydim (2-[1-[[[(2E)-3-chloro-2-propenyl]oxy]imino]propyl]-3- hydroxy-5-(tetrahydro-2H-pyran-4-yl)-cyclohexene-1-one) and its metabolites convertible to GP (3- (tetrahydropyran-4-yl)pentane-1,5- dioic acid) and OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5- dioic acid), calculated as tepraloxydim, in or on canola, seed;
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cotton, undelinted seed; cotton, gin byproducts; soybean, seed; soybean, hulls; and soybean, aspirated grain fractions; and the combined residues of tepraloxydim and its metabolites convertible to GP, OH-GP, and GL (3-(2-oxotetrahydropyran-4-yl)pentane-1,5-dioic acid), calculated as tepraloxydim, in or on milk; meat of cattle, goats, hogs, horses, and sheep; meat byproduct (except kidney) of cattle, goats, hogs, horses, and sheep; kidney of cattle, goats, hogs, horses, and sheep; fat of cattle, goats, hogs, horses, and sheep; poultry, meat; poultry, meat byproducts (except liver), poultry, fat; poultry, liver, and eggs. Nippon Soda Company, Ltd 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 August 2, 2001. Objections and requests for hearings, identified by docket control number OPP-301148, must be received by EPA on or before October 1, 2001.
ADDRESSES: Written objections and hearing requests may be submitted by mail, in person, or by courier. Please 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-301148 in the subject line on the first page of your response.
FOR FURTHER INFORMATION CONTACT: By mail: Jim Tompkins, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,Washington, DC 20460; telephone number: (703) 305-5697 ; and e-mail address: tompkins.jim@epa.gov.
SUPPLEMENTARY INFORMATION:
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General Information
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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 Potentially Categories
NAICS 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.
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How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?
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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_180/Title_40/40cfr180_00.html, a beta site currently under development.
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In person. The Agency has established an official record for this action under docket control number OPP-301148. 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.
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Background and Statutory Findings
In the Federal Register of December 22, 1999 64 FR 71774) (FRL- 6398-6), 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 a pesticide petition (PP 8F4945) for tolerance by BASF Corporation, acting as agent for Nippon Soda Company, Ltd., P.O. Box 13528, Research Triangle Park, NC 27709-3528. This notice included a summary of the petition prepared by Nippon Soda, 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 a tolerance for combined residues of the herbicide tepraloxydim, (2-[1-[[[(2E)-3-chloro-2-propenyl]oxy]imino]propyl]-3- hydroxy-5-(tetrahydro-2H-pyran-4-yl)-cyclohexene-1-one) and its metabolites convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5- dioic acid) and OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5- dioic acid) (calculated as the herbicide) in or on the raw agricultural commodities cotton, seed at 0.2 part per million (ppm); cotton meal at 0.2 ppm, cotton gin trash at 3.0 ppm; soybean seed at 5.0 ppm; soybean hulls, poultry meat and fat at 0.5 ppm; and poultry, liver at 1.0 ppm; and eggs at 0.2 ppm.
During the course of the review, the Agency determined that the available data support the following tolerances: tepraloxydim (2-[1-
[[[(2E)-3-chloro-2-propenyl] oxy]imino]propyl]-3-hydroxy-5-(tetrahydro- 2H-pyran-4-yl)-cyclohexene-1-one) and its metabolites convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and OH-GP (3-hydroxy- 3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid), calculated as tepraloxydim, in or on cotton, undelinted seed at 0.2 ppm; cotton, gin byproducts at 3.0 ppm; soybean, seed at 6.0 ppm; soybean, hulls at 8.0 ppm; and soybean, aspirated grain fractions at 1200 ppm; and the combined residues of tepraloxydim and its metabolites convertible to GP, OH-GP, and GL (3-(2-oxotetrahydropyran-4-yl)pentane-1,5-dioic acid), calculated as tepraloxydim, in or on milk at 0.1 ppm; meat of cattle, goats, hogs, horses, and sheep at 0.2 ppm; meat byproduct (except kidney) of cattle, goats, hogs, horses, and sheep at 0.2 ppm; kidney of cattle, goats, hogs, horses, and sheep at 0.5 ppm; fat of cattle, goats, hogs, horses, and sheep at 0.15 ppm; poultry, meat at 0.2 ppm; poultry, meat byproducts (except liver)
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at 0.2 ppm; poultry, fat at 0.3 ppm; poultry, liver at 1.0 ppm; and eggs at 0.20 ppm. The available data also support the establishment of a tolerance with regional registration, as defined in Sec. 180.1(n) for the combined residues of tepraloxydim and its metabolites convertible to GP and OH-GP, calculated as tepraloxydim in or on the raw agricultural commodity canola, seed at 0.5 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).
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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 tolerance[s] for the combined residues of tepraloxydim (2-[1-[[[(2E)-3-chloro-2- propenyl]oxy]imino]propyl]-3-hydroxy-5- (tetrahydro-2H-pyran-4-yl)-cyclohexene-1-one) and its metabolites convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid), calculated as tepraloxydim, in or on cotton, undelinted seed at 0.2 ppm; cotton, gin byproducts at 3.0 ppm; soybean, seed at 6.0 ppm; soybean, hulls at 8.0 ppm; soybean, aspirated grain fractions at 1200 ppm; and the combined residues of tepraloxydim and its metabolites convertible to GP, OH-GP, and GL (3-(2-oxotetrahydropyran-4-yl)pentane- 1,5- dioic acid), calculated as tepraloxydim, in or on milk at 0.1 ppm; meat of cattle, goats, hogs, horses, and sheep at 0.2 ppm; meat byproduct (except kidney) of cattle, goats, hogs, horses, and sheep at 0.2 ppm; kidney of cattle, goats, hogs, horses, and sheep at 0.5 ppm; fat of cattle, goats, hogs, horses, and sheep at 0.15 ppm; poultry, meat at 0.2 ppm; poultry, meat byproducts (except liver) at 0.2 ppm; poultry, fat at 0.3 ppm; poultry, liver at 1.0 ppm; and eggs at 0.20 ppm; and a tolerance with regional registration, as defined in Sec. 180.1(n) for the combined residues of tepraloxydim and its metabolites convertible to GP and OH-GP, calculated as tepraloxydim, in or on the raw agricultural commodity canola, seed at 0.5 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance 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. The nature of the toxic effects caused by tepraloxydim are discussed in the following Table 1 as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed.
Table 1.-- Subchronic, Chronic, and Other Toxicity
Guideline No.
Study Type
Results
870.3100
90-Day oral toxicity in NOAEL = M=22, F=26 mg/kg/day rats LOAEL = M=223, F=257 mg/kg/day based on decreased body weight/body weight gain, changes in kidney proximal tubule, and changes in clinical chemistry parameters indicative of liver and kidney impairment.
870.3150
90-Day oral toxicity in NOAEL = M=12.9, F=14.3 mg/kg/day dogs LOAEL = M=63.3, F=68.0 mg/kg/day based on increased liver and thyroid weights and histopathology of spleen.
870.3200
28-Day dermal toxicity in NOAEL = 1,000 mg/kg/day (limit dose) rats LOAEL = Not determined.
870.3700a
Prenatal developmental in Maternal NOAEL = 120 mg/kg/day rats LOAEL = 360 mg/kg/day based on decreased body weight and food consumption. Developmental NOAEL = 40 mg/kg/day LOAEL = 120 mg/kg/day based on decreased fetal body weight, retarded ossification, and hydroureter.
870.3700b
Prenatal developmental in Maternal NOAEL = 60 mg/kg/day; LOAEL = 180 rabbits
mg/kg/day based on decreased body weight and food consumption. Developmental NOAEL = 180 mg/kg/day (HTD) LOAEL = >180 mg/kg/day based on no developmental effects at the HTD.
870.3800
Reproduction and fertility Parental/Systemic NOAEL = M=50.6, F=55.0 mg/ effects in rats
kg/day
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LOAEL = M= 260.0, F= 276.0 mg/kg/day based on decreased body weight/ weight gain and food consumption. Reproductive NOAEL = 260 mg/kg/day LOAEL = > 260 mg/kg/day based on no reproductive effects. Offspring NOAEL = M=50.6, F=55.0 mg/kg/day LOAEL = M= 260.0, F= 276.0 mg/kg/day based on reduced pup body weight gain and lower pup body weight during lactation.
870.4100b
Chronic toxicity in dogs NOAEL = M=11.5, F=12.5 mg/kg/day LOAEL = M=56.0, F=60.6 mg/kg/day based on reduced epididymal and prostate activities, transitional epithelial hyperplasia of the urinary bladder, and abnormal liver function and liver foci.
870.4200
Carcinogenicity in rats NOAEL = M=5, F=38 mg/kg/day LOAEL = M=30, F=272 mg/kg/day based on hepatic lesions in both sexes, increased incidences of hepatocellular adenoma/ carcinoma in females, adrenal medullary tumors in females, and uterine schwannoma in females. Some evidence of carcinogenicity in females
870.4300
Carcinogenicity in mice NOAEL = M=37, F=52 mg/kg/day LOAEL = M=332, F=490 mg/kg/day based on decreased body weight/gain, increased relative liver weight in males, and uterine sclerosis. Female mice developed liver tumors at an excessively toxic dose.
870.5100
Gene Mutation
Ames test: Negative at all doses; cytotoxic at HTD of 5,000 g/ml. Mammalian (CHO/HPRT): Negative; HTD = 3,000 g/ml (limit of solubility = 1000 g/ml).
870.5395 and 870.5375
Cytogenetics
In vivo (mouse bone marrow): Negative; HTD = 500 mg/kg. In vitro (chromosomal aberration in CHO cells): Negative; HTD = 1,000 g/ ml (limit of solubility).
870.5550
Other Effects
UDS in primary male rat hepatocytes: Negative; HTD = 500 g/ml; cytotoxic at 100 g/ml.
870.6200a
Acute neurotoxicity
NOAEL = max(one hour post dosing), the plasma, liver, and kidney almost exclusively contained the parent compound. The results indicate that the distribution, metabolism, and excretion of tepraloxydim is independent from dose levels, sex, route of administration (oral vs. i.v.), or site of label (pyran vs. cyclohexanone).
870.7600
Dermal penetration
The available rat dermal absorption study (unacceptable)
is considered unacceptable. A dermal absorption rate of 36% was derived based on the results of a 28-day dermal toxicity study in rats and developmental toxicity study in rats.
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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
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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-\6\ or 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 (MOEcancer= point of departure/exposures) is calculated. A summary of the toxicological endpoints for tepraloxydim used for human risk assessment is shown in the following Table 2:
Table 2.-- Summary of Toxicological Dose and Endpoints for tepraloxydim for Use in Human Risk Assessment
Dose (mg/kg/day),
Population (if Study and Toxicological Exposure Scenario
Uncertainty Factor (UF) applicable); Endpoint
Effects
Acute Dietary
NOAEL = 40; UF = 100; Females 13-50: Reduced Developmental Toxicity- FQPA* = 3X; Females 13- fetal body weight, Rat 50 ONLY.
reduced ossification indicative of delayed maturation, and the occurrence of hydroureter at 120 mg/ kg/day (LOAEL). General Population: This risk assessment is not required. No appropriate single dose end-point. Acute RfD = 0.4 mg/kg Acute PAD = 0.13 mg/kg/ day (Females 13-50 ONLY)
Chronic Dietary
NOAEL = 5 UF = 100; NOAEL = 100 ppm (5 mg/ Carcinogenicity-Rat FQPA = 1X
kg/day) based on male liver microscopic lesions (eosinophilic foci) at 600 ppm (30 mg/kg/day). Chronic RfD = 0.05 mg/ kg/day
Incidental Oral, Short-Term
NOAEL = 120; FQPA = 1X Reduced maternal body Developmental Toxicity- weight gain and food Rat consumption at 360 mg/ kg/day (LOAEL).
Incidental Oral, Intermediate-Term NOAEL = 22; FQPA = 1X NOAEL = 300 ppm (males Subchronic Oral 22, females 26 mg/kg/ Toxicity-Rat day) based on reduced body weight/body weight gain, proximal tubule kidney changes in males, and clinical chemistry changes indicative of hepatic and kidney impairment in both sexes at 3000 ppm (223 and 257 mg/kg/ day.
Dermal, Short- and Intermediate-Term NOAEL = 40
Reduced fetal body Developmental Toxicity- weight, reduced
Rat ossification indicative of delayed maturation, and the occurrence of hydroureter at 120 mg/ kg/day (LOAEL). The dermal absorption factor of 36% should be used for route-to- route extrapolation.
Dermal, Long-Term
NOAEL= N/A
This risk assessment N/A is not required due to the seasonal use of the chemical.
Inhalation, Short-and Intermediate- NOAEL= 40
Reduced fetal body Developmental Toxicity- Term
weight, reduced
Rat ossification indicative of delayed maturation, and the occurrence of hydroureter at 120 mg/ kg/day (LOAEL). Use route-to-route extrapolation and a 100% absorption rate (default value).
Inhalation, Long-Term
NOAEL = N/A
This risk assessment N/A is not required due to the seasonal use of the chemical.
\*\ The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique to the FQPA.
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Exposure Assessment
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Dietary exposure from food and feed uses. Tolerances have been not established (40 CFR part 180) for the combined residues of tepraloxydim and its metabolites, in or on a variety of raw agricultural commodities. Risk assessments were conducted by EPA to assess dietary exposures from tepraloxydim 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 1 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 acute risk assessments, a food consumption distribution is calculated for each population subgroup of interest based on 1 day consumption data. The only population subgroup of concern for this risk assessment is females (13-50 years old). The consumption distribution can be multiplied by a residue point estimate for a deterministic (Tier I/II type) exposure/risk assessment, or used with a residue distribution in a probabilistic (Monte Carlo) type risk assessment. Exposure estimates are expressed in mg/kg bw/day and as a percent of the aPAD.
In conducting this acute dietary risk assessment, the Agency has made highly conservative assumptions. Default concentration factors were used for the processed commodities. One hundred percent of the proposed crops are assumed to be treated with tepraloxydim and residues were assumed to be at tolerance levels. This is expected to result in an overestimate of dietary exposure. Therefore, this acute dietary (food only) risk assessment should be viewed as a highly conservative risk estimate. The percent aPAD that would be above EPA`s level of concern would be 100%. Percent crop treated (PCT) and/or anticipated residues were not used. A DEEM acute analysis was performed using proposed and recommended tolerance levels for the combined residues of tepraloxydim and its metabolites for females (13-50 years old). Based on the results of this analysis, exposure to tepraloxydim from food will utilize 4.4% of aPAD for females (13-50 years old), the only population subgroup of concern.
ii. Chronic exposure. In conducting this chronic dietary risk assessment the DEEManalysis 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 chronic dietary risk assessment, residue estimates for foods (e.g. apples) or food-forms (e.g. apple juice) of interest are multiplied by the averaged consumption estimate of each food/food-form of each population subgroup. Exposure estimates are expressed in mg/kg/day and as a percent of the cPAD.
In conducting this chronic dietary risk assessment, the Agency has made highly conservative assumptions which result in an overestimate of human dietary exposure. A DEEM chronic exposure analysis was performed using the proposed tolerance level residues and 100% of the crop treated to estimate the exposure for the general population and subgroups of interest. This is expected to result in an overestimate of dietary risk. Therefore, this chronic dietary (food only) risk assessment should be viewed as a highly conservative risk estimate. Thus, in making a safety determination for these tolerances, EPA takes into account this highly conservative exposure assessment. The Agency is generally concerned with chronic exposures that exceed 100% of the cPAD or chronic RfD. Percent crop and/or anticipated residues were not used. Based on this analysis the exposure to tepraloxydim from food will utilize 6.8% cPAD for the general population, 31% cPAD for all infants (>1 year old), 15% cPAD for children (1-6 old), 10% cPAD for children (7-12 old), 7.4% cPAD for males (13-19 old), and 5.0% for females (13-50 old) and males (20+ years old).
iii. Cancer. Tepraloxydim has been reviewed by the Agency for carcinogenicity classification. In accordance with the EPA Draft Guidelines for Carcinogenic Risk Assessment (July, 1999), the Agency has classified tepraloxydim as data are inadequate for an assessment of human carcinogenic potential because some evidence is suggestive of carcinogenic effects, but other equally pertinent evidence does not confirm a concern. The Agency concluded that quantification of human cancer risk is not required because although there was some evidence of carcinogenicity in female rats based on an increased incidence of liver tumors at the high dose, this finding was not supported by the results of the chronic study. The Agency also concluded that female mice developed liver tumors at an excessively toxic dose, and although male mice had non-neoplastic liver changes similar to or exceeding those seen in female mice at the same dose, there was no increase in liver tumor incidence in males. Further more tepraloxydim was not mutagenic in a battery of assays. Therefore a cancer risk assessment was not performed.
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Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for tepraloxydim 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 tepraloxydim.
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 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
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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 tepraloxydim they are further discussed in the aggregate risk sections below.
Based on the GENEEC and SCI-GROW models the EECs of tepraloxydim for acute exposures are estimated to be 17.6 g/L for surface water and 0.0015 g/L parts per billion (ppb) for groundwater. EECs for chronic exposures are estimated to be 10.3 g/L ppb for surface water and 0.0015 g/L ppb for ground water.
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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).
Tepraloxydim is not registered for use on any sites that would result in residential exposure.
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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 tepraloxydim 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, tepraloxydim 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 tepraloxydim 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).
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Safety Factor for Infants and Children
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Safety factor for infants and children--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 database 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.
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Prenatal and postnatal sensitivity. Based on the available data, both quantitative and qualitative evidence of increased susceptibility was observed following in utero tepraloxydim exposure to rats. In the prenatal rat developmental toxicity study, the developmental toxicity NOAEL/LOAEL is below the maternal toxicity NOAEL/LOAEL. Additionally, the developmental effects observed (reduced fetal body weights, retarded ossification indicative of delayed maturation, and the occurrence of hydroureter) were considered to be more severe than those observed in maternal animals (decreased body weight gain and food consumption). No evidence of increased susceptibility was seen following pre/post natal exposure in the 2-generation reproduction study.
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Conclusion. The toxicology database for tepraloxydim is complete except for a developmental neurotoxicity study which is required due to evidence of neurotoxicity (effects on motor activity and grip strength) observed in acute and subchronic neurotoxicity studies with adult animals and a 28-day inhalation toxicity study is required because there is no inhalation toxicity available for risk assessment. The exposure data are complete or are estimated based on data that reasonably accounts for potential exposures. EPA determined that the 10X safety factor to protect infants and children should be reduced to 3x for tepraloxydim. The Agency concluded that a safety factor is required for tepraloxydim since there is evidence of increased susceptibility of the young demonstrated in the prenatal developmental study in rats. The Committee recommended that the FQPA safety factor be reduced to 3x because: the toxicology database is complete; the requirement of a developmental neurotoxicity study is not based on criteria reflecting special concern for the developing fetuses or young which are generally used for requiring a DNT study - and a safety factor (e.g.: neuropathy in adult animals; CNS malformations following prenatal exposure; brain weight or sexual maturation changes in offspring; and/or functional changes in offspring) - and therefore does not warrant an FQPA safety factor\1\; the dietary (food and drinking water) exposure assessments will not underestimate the potential exposures for infants and children; and there are currently no residential uses.
\1\ This is an interim step towards accordance with the proposed OPP Policy on Determination of the Appropriate FQPA Safety Factor(s) for Use in the Tolerance-Setting Process' which was presented to the FIFRA SAP meeting in May, 1999 and placed in the Docket for Public Comment (64 FR 37001, July 8, 1999; Docket No. 37001).
The FQPA safety factor for tepraloxydim is applicable to only Females 13-50 years population subgroup for acute dietary risk assessment (there are currently no residential exposure scenarios), since there is concern for increased susceptibility of the young demonstrated in the prenatal developmental study in rats. The developmental effects are presumed to occur following a single exposure of females of child-bearing age and, therefore, are appropriate for risk assessment for females aged 13-50 years old.
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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
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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, the Office of Pesticide Programs 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.
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Acute risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food to tepraloxydim will occupy 4.4% of the aPAD for females 13 years and older. In addition, there is potential for acute dietary exposure to tepraloxydim 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 Tepraloxydim
Surface Ground Water aPAD (mg/ % aPAD Water EEC EEC (g/ m>g/L)3 (g/ L)3
L)3
Females (13-50 years)
0.13
4.4
17.6
0.0015
3,700
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Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that exposure to teparloxydim from food will utilize 6.8% of the cPAD for the U.S. population, 31% of the cPAD for all infants (g/ m>g/L) (g/ L)
L)
U.S. Population
0.05
6.8
10.3
0.0015
1,600 Females (13-50 years old)
0.05
5.0
10.3
0.0015
1,400 All Infants (01-19325Filed8-1-01; 8:45 a.m.] BILLING CODE 6560-50-S
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