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

[Federal Register: September 24, 2004 (Volume 69, Number 185)]

[Rules and Regulations]

[Page 57207-57216]

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

[DOCID:fr24se04-13]

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-2004-0293; FRL-7680-2]

Lactofen; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

SUMMARY: This regulation establishes tolerances for residues of lactofen in or on cotton undelinted seed, cotton gin byproducts, and peanut. Valent U.S.A. Corporation requested this tolerance under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA).

DATES: This regulation is effective September 24, 2004. Objections and requests for hearings must be received on or before November 23, 2004.

ADDRESSES: To submit a written objection or hearing request follow the detailed instructions as provided in Unit VI. of the SUPPLEMENTARY INFORMATION. EPA has established a docket for this action under Docket identification (ID) number OPP-2004-0293. All documents in the docket are listed in the EDOCKET index at http://www.epa.gov/edocket/.

Although listed in the index, some information is not publicly available, i.e., CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material,

[[Page 57208]]

is not placed on the Internet and will be publicly available only in hard copy form. Publicly available docket materials are available either electronically in EDOCKET or in hard copy at the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The docket telephone number is (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: Joanne I. Miller, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460- 0001; telephone number: (703) 305-6224; e-mail address: miller.joanne@epa.gov.

SUPPLEMENTARY INFORMATION:

1. General Information

   1. 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. Potentially affected entities may include, but are not limited to:

      Crop production (NAICS 111), e.g., agricultural workers; greenhouse, nursery, and floriculture workers; farmers.

      Animal production (NAICS 112), e.g., cattle ranchers and farmers, dairy cattle farmers, livestock farmers.

      Food manufacturing (NAICS 311), e.g., agricultural workers; farmers; greenhouse, nursery, and floriculture workers; ranchers; pesticide applicators.

      Pesticide manufacturing (NAICS 32532), e.g., agricultural workers; commercial applicators; farmers; greenhouse, nursery, and floriculture workers; residential users.

      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 this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entities. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.

   2. How Can I Access Electronic Copies of this Document and Other Related Information?

      In addition to using EDOCKET (http://www.epa.gov/edocket/), you may

      access this Federal Register document electronically through the EPA Internet under the ``Federal Register'' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of 40 CFR part 180

      is available on E-CFR Beta Site Two at http://www.gpoaccess.gov/ecfr/.

      To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gpo/opptsfrs/home/guidelin.htm/ .

2. Background and Statutory Findings

   In the Federal Register of January 29, 2003 (68 FR 4475) (FRL-7287- 6), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of pesticide petitions (PP 8F3591 and 9F3798) by Valent U.S.A. Corporation, 1333 North California Blvd., Suite 600, Walnut Creek, CA 94596-8025. The petitions requested that 40 CFR 180.432 be amended by establishing tolerances for residues of the herbicide lactofen, 1-(carboethoxy)ethyl 5-[2-chloro-4- (trifluoromethyl)phenoxy]-2-nitrobenzoate, in or on cottonseed at 0.01 part per million (ppm), cotton gin byproducts at 0.02 ppm (PP 9F3798), and peanut nutmeats at 0.01 ppm (PP 8F3591). That notice included a summary of the petitions prepared by Valent U.S.A. Corporation, the registrant. There were no comments received in response to the notice of filing.

   The proposed and established tolerances are corrected to conform to the Food and Feed Commodity Vocabulary Database (http://www.epa.gov/pesticides/foodfeed/ ) and to lower the established tolerances for snap

   bean and soybean to 0.01 ppm as required by the Lactofen Tolerance Reassessment (http://www.epa.gov/pesticides/reregistration/lactofen/)

   to read as follows: Tolerances for residues of the herbicide lactofen, 1-(carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2- nitrobenzoate, in or on beans, snap, succulent (excluding limas) at 0.01 ppm; cotton, undelinted seed at 0.01 ppm; cotton, gin byproducts at 0.02 ppm; peanut at 0.01 ppm; and soybean, seed at 0.01 ppm.

   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....''

   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 of FFDCA 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) of FFDCA, 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) of FFDCA, for tolerances for residues of lactofen on cotton, undelinted seed at 0.01 ppm; cotton, gin byproducts at 0.02 ppm; and peanut at 0.01 ppm ppm. EPA's assessment of exposures and risks associated with establishing the tolerances 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 lactofen are discussed in Table 1 of this unit as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed.

      [[Page 57209]]

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

      Guideline No.

      Study Type

      Results

      870.3100

      13-Week oral toxicity-- NOAEL = 14.1 milligrams/kilogram/day (mg/kg/ rodents (rat)

      day). LOAEL = 73.7 mg/kg/day based on decreased body weight, increased incidence of anemia, increased levels of serum enzymes and bilirubin, decreased levels of glucose, increased liver weights, and increased incidence of microscopic liver lesions.

      870.3100

      90-Day oral toxicity-- NOAEL = not established. rodents (mouse)

      LOAEL = 28.6 mg/kg/day based on changes clinical chemistry parameters, increases in organ weight, and histopathological findings.

      870.3700

      Prenatal developmental-- Maternal NOAEL = 50 mg/kg/day. rodents (rat)

      Maternal LOAEL = 150 mg/kg/day based on signs of toxicity (excessive salivation, lethargy, dried red material around the nares and inguinal regions) and statistically significant decreases in body weight gain. Developmental NOAEL = 50 mg/kg/day. Developmental LOAEL = 150 mg/kg/day based on decreased fetal weight and skeletal abnormalities (increased incidence of bent ribs and/or limb bones) and reduced ossification of vertebral arches.

      870.3700

      Prenatal developmental-- Maternal NOAEL >= 20 mg/kg/day. nonrodents (rabbit)

      Maternal LOAEL > 20 mg/kg/day Highest Dose Tested (HDT). Developmental NOAEL >= 20 mg/kg/day. Developmental LOAEL > 20 mg/kg/day HDT.

      870.3800

      Reproduction and fertility Parental/Systemic NOAEL = 2.6 mg/kg/day. effects

      Parental/Systemic LOAEL = 26.2 mg/kg/day based on mortality and decreased male fertility. Reproductive NOAEL = 2.6 mg/kg/day. Reproductive LOAEL = 26.2 mg/kg/day based on decreased male fertility. Offspring NOAEL = 2.6 mg/kg/day. Offspring LOAEL = 26.2 mg/kg/day based on reduced pup body weigh and decreases in the absolute and relative spleen weight.

      870.4100

      Chronic toxicity--dogs NOAEL = 0.79 mg/kg/day. LOAEL = 3.96 mg/kg/day based on increased incidence of proteinaceous casts in the kidneys, and statistically significant increases in the absolute weights of the thyroid and adrenal glands in males.

      870.4300

      Combined Chronic toxicity NOAEL = 2 mg/kg/day. Carcinogenicity--rats LOAEL = 19 mg/kg/day based on statistically significant increases in the incidence of mottled or discolored livers and changes in clinical chemistry. No evidence of carcinogenicity.

      870.4300

      Carcinogenicity--mice NOAEL = not established. LOAEL = 1.4 mg/kg/day Lowest Dose Tested (LDT) based on hepatocytomegaly, increased liver weight, and increased sinusoidal cell pigmentation. Likely to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological effects (peroxisome proliferation) in the livers of rodents but unlikely to be carcinogenic at doses below those causing these changes.

      870.5100

      Gene mutation in S.

      No cytotoxicity evident at 50 [mu]g (gram)/ typhimurium/

      plate in the absence or presence of mammalianmicrosome

      metabolic activation. PPG-844 induced a mutagenicity assay.

      dose-relatedincrease in revertant colonies of strain TA1538 in the absence of S9 activation; however, no effect seen in strain TA98 (derived from TA1538).

      870.5100

      Gene mutation in S.

      Cytotoxicity was not evident for any strain typhimurium/mammalian up to the limit dose (5,000Fg/plate). No microsome mutagenicity evidence of PPG-844 induced mutagenic assay

      effect.

      870.5375

      In vitro cytogenetic assay No evidence of clastogenic effect in the with Chinese Hamster

      presence or absence of S9 activation. Ovary (CHO) cells

      870.5375

      Mammalian cells in culture No evidence of cytotoxicity at any dose gene mutation in CHO

      tested. No clear indication of mutagenic cells

      effect in the presence or absence of S9 activation.

      870.5550

      Unscheduled DNA Synthesis No unscheduled DNA synthesis.

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      In vivo DNA covalent

      A covalent binding index of 1.4 0.6 was determined for lactofen. This suggests a low binding to mouse hepatic DNA may occur. This finding could not be attributed solely to DNA binding since some protein-binding of the parent compound and/or metabolite could be occurring.

      Analysis of biochemical Aryl CoA oxidase, catalase, and carnitine and microscopic

      acetlytransferase activities not affected parameters in Chimpanzee by treatment. No nuclear enlargement, liver

      cytoplasmic eosinophilia, or hepertrophy observed in liver biopsies after 0, 1, and 3 months of treatment. Slight + response for peroxisomal staining (brown stippling).

      Results of the analysis of Catalase and CN-insensitive palmiloyl CoA biochemical parameters in oxidase increased. Rats (2,000 ppm) and mouse and rat liver

      mice (50 ppm) showed increased nuclear Following Exposure to PPG- enlargement, cytoplasmic eosinophilia, 844.

      hypertrophy, and peroxisomes in number of peroxisomes. The NOAEL for this study was established at 0.3 mg/kg/day, based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 1.5 mg/kg/day.

      Measurement of peroxisome Concentration-dependent increase in CN- proliferation in primary insensitive palmitoyl CoA oxidase rat hepatocytes induced activities with each of the metabolites. by PPG-844 and five of EM: Lactofen (0.01 millimole (mM)) its metabolites

      increased number of peroxisomes and glycogen aggregates. Other metabolites showed occasional peroxisomes.

   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 intraspecies differences.

      Three other types of safety or uncertainty factors may be used: ``Traditional uncertainty factors;'' the ``special FQPA safety factor;'' and the ``default FQPA safety factor.'' By the term ``traditional uncertainty factor,'' EPA is referring to those additional uncertainty factors used prior to FQPA passage to account for database deficiencies. These traditional uncertainty factors have been incorporated by the FQPA into the additional safety factor for the protection of infants and children. The term ``special FQPA safety factor'' refers to those safety factors that are deemed necessary for the protection of infants and children primarily as a result of the FQPA. The ``default FQPA safety factor'' is the additional 10X safety factor that is mandated by the statute unless it is decided that there are reliable data to choose a different additional factor (potentially a traditional uncertainty factor or a special FQPA safety factor).

      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 an UF of 100 to account for interspecies and intraspecies differences and any traditional uncertainty factors deemed appropriate (RfD = NOAEL/UF). Where a special FQPA safety factor or the default FQPA safety factor is used, 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 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). An example of how such a probability risk is expressed would be to describe the risk as one in one hundred thousand (1 X 10-\5\), one in a million (1 X 10-\6\), or one in ten million (1 X 10-\7\). 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 lactofen used for human risk assessment is shown in Table 2 of this unit:

      [[Page 57211]]

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

      Dose Used in Risk Assessment,

      Special FQPA SF and Exposure Scenario

      Interspecies and Level of Concern for Study and Toxicological Intraspecies and any Risk Assessment

      Effects Traditional UF

      Acute Dietary

      NOAEL = 50 mg/kg/day UF Special FQPA SF = 3 Rat Developmental (Females 13-50 years of age)......... = 100 Acute RfD = 0.5 aPAD = acute RfD/

      Toxicity Study mg/kg/day

      Special FQPA SF = 0.17 LOAEL = 150 mg/kg/day mg/kg/day

      based on decreased fetal weight and skeletal abnormalities.

      Acute Dietary

      An endpoint attributable to a single dose (exposure) was not identified (General population including infants from the available studies, including the developmental toxicity studies and children).

      in rats and rabbits.

      Chronic Dietary

      NOAEL = 0.79 mg/kg/day Special FQPA SF = 1 Dog chronic toxicity (All populations).................... UF = 100 Chronic RfD = cPAD = chronic RfD/ LOAEL = 3.96 mg/kg/day 0.008 mg/kg/day

      Special FQPA SF =

      based on increased 0.008 mg/kg/day

      incidence of proteinaceous casts in the kidneys, and statistically significant increases in the absolute weights of the thyroid and adrenal glands in males.

      Cancer

      Lactofen acts via a peroxisome proliferation mechanism of action. Likely (Oral, dermal, inhalation)........... to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological effects (peroxisome proliferation) in the livers of rodents but unlikely to be carcinogenic at doses below those causing these changes. Lactofen is considered to be a threshold carcinogen. NOAEL = 0.3 mg/kg/day based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 1.5 mg/kg/day.

   3. Exposure Assessment

      1. Dietary exposure from food and feed uses. Tolerances have been established (40 CFR 180.432) for the residues of lactofen in or on succulent snap bean and soybeans. Risk assessments were conducted by EPA to assess dietary exposures from lactofen 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\TM\) 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: The acute dietary analysis uses average food residue values from field trial studies and percent crop treated (PCT) information.

         ii. Chronic exposure. In conducting this chronic dietary risk assessment, the DEEM\TM\ analysis evaluated the individual food consumption as reported by respondents in the USDA 1989-1992 CSFII and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: The chronic dietary analysis utilized average residue values based on field trial studies, concentration factors from processing studies, and PCT information.

         iii. Cancer. In conducting this cancer dietary risk assessment, the DEEM\TM\ analysis evaluated the individual food consumption as reported by respondents in the USDA 1989-1992 CSFII and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: The chronic dietary analysis utilized the average consumption values for food and average residue values for those foods over a 70-year lifetime.

         iv. Anticipated residue and PCT information. Section 408(b)(2)(E) of FFDCA authorizes EPA to use available data and information on the anticipated residue levels of pesticide residues in food and the actual levels of pesticide chemicals that have been measured in food. If EPA relies on such information, EPA must require that data be provided 5 years after the tolerance is established, modified, or left in effect, demonstrating that the levels in food are not above the levels anticipated. Following the initial data submission, EPA is authorized to require similar data on a time frame it deems appropriate. As required by section 408(b)(2)(E) of FFDCA, EPA will issue a data call- in for information relating to anticipated residues to be submitted no later than 5 years from the date of issuance of this tolerance.

         Section 408(b)(2)(F) of FFDCA states that the Agency may use data on the actual percent of food treated for assessing chronic dietary risk only if the Agency can make the following findings:

         Condition 1, that the data used are reliable and provide a valid basis to show what percentage of the food derived from such crop is likely to contain such pesticide residue.

         Condition 2, that the exposure estimate does not underestimate exposure for any significant subpopulation group

         Condition 3, if data are available on pesticide use and food consumption in a particular area, the exposure estimate does not understate exposure for the population in such area. In addition, the Agency must provide for periodic evaluation of any estimates used. To provide for the periodic evaluation of the estimate of PCT as required by section 408(b)(2)(F) of FFDCA, EPA may require registrants to submit data on PCT.

         The Agency used PCT information as follows:

         Table 3.--PCT for Registered Lactofen Uses

         Crop

         PCT

         Cotton

         5 Succulent snap beans

         5 Soybeans

         5

         The Agency believes that the three conditions listed in this unit have been met. With respect to Condition 1, PCT estimates are derived from Federal and private market survey data, which are

         [[Page 57212]]

         reliable and have a valid basis. EPA uses a weighted average PCT for chronic dietary exposure estimates. This weighted average PCT figure is derived by averaging State-level data for a period of up to 10 years, and weighting for the more robust and recent data. A weighted average of the PCT reasonably represents a person's dietary exposure over a lifetime, and is unlikely to underestimate exposure to an individual because of the fact that pesticide use patterns (both regionally and nationally) tend to change continuously over time, such that an individual is unlikely to be exposed to more than the average PCT over a lifetime. For acute dietary exposure estimates, EPA uses an estimated maximum PCT. The exposure estimates resulting from this approach reasonably represent the highest levels to which an individual could be exposed, and are unlikely to underestimate an individual's acute dietary exposure. The Agency is reasonably certain that the percentage of the food treated is not likely to be an underestimation. As to Conditions 2 and 3, regional consumption information and consumption information for significant subpopulations is taken into account through EPA's computer-based model for evaluating the exposure of significant subpopulations including several regional groups. Use of this consumption information in EPA's risk assessment process ensures that EPA's exposure estimate does not understate exposure for any significant subpopulation group and allows the Agency to be reasonably certain that no regional population is exposed to residue levels higher than those estimated by the Agency. Other than the data available through national food consumption surveys, EPA does not have available information on the regional consumption of food to which lactofen may be applied in a particular area.

      2. Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for lactofen 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 lactofen.

         The Agency uses the Generic Estimated Environmental Concentration (GENEEC) or the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and Screening Concentration in Ground Water (SCI-GROW), which predicts pesticide concentrations in ground water. 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 screen for sorting out pesticides for which it is unlikely that drinking water concentrations would 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), which are the model estimates of a pesticide's concentration in water. EECs derived from these models are used 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 lactofen they are further discussed in the aggregate risk sections in Unit III.E.

         Based on the PRZM/EXAMS and SCI-GROW models, the EECs of lactofen for acute exposures are estimated to be 0.39 parts per billion (ppb) for surface water and 0.006 ppb for ground water. The EECs for chronic exposures are estimated to be 0.008 ppb for surface water and 0.006 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).

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

      4. Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA 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.''

         Lactofen is a member of the diphenyl ether group of herbicides, which includes acifluorfen (lactofen's major metabolite), nitrofen, oxyfluorfen, and fomefasen. In addition, lactofen degrades to acifluorfen in the environment. The Agency has evidence that these compounds induce similar toxic effects but has not yet determined whether these compounds exhibit a common mechanism of toxicity. The Agency defers the cumulative risk assessment of lactofen and the other diphenyl ethers to a later date. For the purposes of this tolerance action, therefore, EPA has not assumed that lactofen 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 policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's web site at http://www.epa.gov/pesticides/cumulative/ .

   4. Safety Factor for Infants and Children

      1. In general. Section 408 of FFDCA 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 based on reliable data 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 MOE analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans. In applying this provision, EPA either retains the default value of 10X when reliable data do not support the choice of a different factor, or, if reliable data are available, EPA uses a different additional safety

         [[Page 57213]]

         factor value based on the use of traditional uncertainty factors and/or special FQPA safety factors, as appropriate.

      2. Prenatal and postnatal sensitivity. The toxicology database for lactofen is complete for FQPA purposes except for a developmental toxicity study in rabbits. Based on the quality of the exposure data, EPA determined that the 10X SF to protect infants and children should be reduced to 3X and still be protective for any possible toxicity to infants and children which might be observed in the missing rabbit developmental study. The FQPA factor was reduced based on the following:

         i. The available data provide no indication of quantitative or qualitative increased susceptibility from in utero and/or postnatal exposure to lactofen in rats.

         ii. The available rabbit developmental toxicity study was considered unacceptable because dosing was not done at a high enough level to observe significant toxicity. However, the study provides sufficient information to indicate that the NOAEL for both maternal and developmental effects will be 20 mg/kg/day (the HDT that elicited no significant toxicity) or higher. The acute dietary risk assessment for which the missing rabbit developmental study could potentially be used currently uses a NOAEL = 50 mg/kg/day from the rat developmental study. Risk estimates using a new developmental rabbit study could increase at most by a factor of 2.5X (50/20 mg/kg/day); therefore, a 3X UF is protective for any toxicity which might be observed in the outstanding rabbit developmental study.

         iii. Endpoints for other risk assessments (chronic and cancer) utilize NOAELs significantly lower than 20mg/kg/day; therefore the developmental rabbit study will not affect these assessments. Based on mechanistic studies with transgenic mice, lactofen has been classified as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Lactofen is currently classified as likely to be carcinogenic to humans at high enough doses to cause the biochemical and histopathological changes in the liver of rodents, but unlikely to be carcinogenic to humans below those doses causing these changes. A non-linear methodology (MOE) was applied for the estimation of human cancer risk using a NOAEL of 0.3 mg/kg/day. Generally, for threshold cancer effects where the mode of action is well understood, the general margin of exposure that indicates a reasonable certainty of no harm would be 100 (10X for intraspecies extrapolation and 10X for interspecies variation). Given that the % cPAD (Food) is