扫描二维码 分享好友和朋友圈
Final Rule.
SUMMARY
This regulation establishes a tolerance for the combined residues of the insecticide metaflumizone in or on the raw agricultural commodities citrus (crop group 10-10) at 0.04 parts per million (ppm); pome fruit (crop group 11-10) at 0.04 ppm; stone fruit (crop group 12-12) at 0.04 ppm; and tree nut (crop group 14-12) at 0.04 ppm. BASF Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA).
TABLE OF CONTENTS
Back to Top
DATES:
ADDRESSES:
FOR FURTHER INFORMATION CONTACT:
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this action apply to me?
B. How can I get electronic access to other related information?
C. How can I file an objection or hearing request?
II. Background and Statutory Findings
III. Aggregate Risk Assessment and Determination of Safety
A. Toxicological Profile
B. Toxicological Endpoints of Departure/Levels of Concern
C. Exposure Assessment
D. Safety Factor for Infants and Children
E. Aggregate Risks and Determination of Safety
IV. Other Considerations
A. Analytical Enforcement Methodology
B. International Residue Limits
V. Conclusion
VI. Statutory and Executive Order Reviews
VII. Congressional Review Act
List of Subjects in 40 CFR Part 180
PART 180—[AMENDED]
DATES:
Back to Top
This regulation is effective October 30, 2015. Objections and requests for hearings must be received on or before December 29, 2015, and must be filed in accordance with the instructions provided in 40 CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION.
ADDRESSES:
Back to Top
The docket for this action, identified by docket identification (ID) number EPA-HQ-OPP-2014-0607, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory Public Docket (OPP Docket) in the Environmental Protection Agency Docket Center (EPA/DC), West William Jefferson Clinton Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744, and the telephone number for the OPP Docket is (703) 305-5805. Please review the visitor instructions and additional information about the docket available at http://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT:
Back to Top
Susan Lewis, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; main telephone number: (703) 305-7090; email address: RDFRNotices@epa.gov.
SUPPLEMENTARY INFORMATION:
Back to Top
I. General Information
Back to Top
A. Does this action apply to me?
You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. The following list of North American Industrial Classification System (NAICS) codes is not intended to be exhaustive, but rather provides a guide to help readers determine whether this document applies to them. Potentially affected entities may include:
Crop production (NAICS code 111), e.g., agricultural workers; greenhouse, nursery, and floriculture workers; farmers.
Animal production (NAICS code 112), e.g., cattle ranchers and farmers, dairy cattle farmers, livestock farmers.
Food manufacturing (NAICS code 311), e.g., agricultural workers; farmers; greenhouse, nursery, and floriculture workers; ranchers; pesticide applicators.
Pesticide manufacturing (NAICS code 32532), e.g., agricultural workers; commercial applicators; farmers; greenhouse, nursery, and floriculture workers; residential users.
B. How can I get electronic access to other related information?
You may access a frequently updated electronic version of 40 CFR part 180 through the Government Printing Office's e-CFR cite at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.
C. How can I file an objection or hearing request?
Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2014-0607 in the subject line on the first page of your submission. All requests must be in writing, and must be received by the Hearing Clerk on or before December 29, 2015. Addresses for mail and hand delivery of objections and hearing requests are provided in 40 CFR 178.25(b).
In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR part 178, please submit a copy of the filing (excluding any Confidential Business Information (CBI)) for inclusion in the public docket. Information not marked confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA without prior notice. Submit the non-CBI copy of your objection or hearing request, identified by docket ID number EPA-HQ-OPP-2014-0607, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the online instructions for submitting comments. Do not submit electronically any information you consider to be CBI or other information whose disclosure is restricted by statute.
Mail: OPP Docket, Environmental Protection Agency Docket Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001.
Hand Delivery: To make special arrangements for hand delivery or delivery of boxed information, please follow the instructions at http://www.epa.gov/dockets/contacts.html.
Additional instructions on commenting or visiting the docket, along with more information about dockets generally, is available at http://www.epa.gov/dockets.
II. Background and Statutory Findings
Back to Top
In the Federal Register of December 17, 2014 (79 FR 75107) (FRL-9918-90), EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP #4F8286) by BASF Corporation, P.O. Box 13528, Research Triangle Park, NC 27709. The petition requested that 40 CFR 180.657 be amended by establishing a tolerance for the combined residues of theinsecticide metaflumizone (2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(trifluoromethoxy)phenyl] hydrazinecarboxamide; E and Z isomers) and its metabolite 4-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}-benzonitrile, in or on the raw agricultural commodities citrus (crop group 10-10) at 0.04 ppm; pome fruit (crop group 11-10) at 0.04 ppm; stone fruit (crop group 12-12) at 0.04 ppm; and tree nut (crop group 14-12) at 0.04 ppm. In addition, that petition requested removal of the existing tolerances for metaflumizone in or on fruit, citrus group 10 at 0.04 ppm and nut, tree, group 14 at 0.04 ppm upon establishment of the petitioned-for tolerances. That document included a summary of the petition prepared by BASF Corporation, the registrant. There were no substantive comments received in response to the notice of filing.
III. Aggregate Risk Assessment and Determination of Safety
Back to Top
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is “safe.” Section 408(b)(2)(A)(ii) of FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.” This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .”
Consistent with FFDCA section 408(b)(2)(D), 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 FFDCA section 408(b)(2), for a tolerance for metaflumizone, including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with establishing the tolerance follows.
A. 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.
Hematotoxicity (toxicity of the blood) was the primary toxic effect of concern following subchronic or chronic oral exposures to metaflumizone. Splenic extramedullary hematopoiesis, increased hemosiderin, and anemia were the most common hematotoxic effects reported after repeated oral dosing with metaflumizone. Chronic oral (gavage) exposures to dogs resulted in slight decreases in mean corpuscular hemoglobin concentration and total hemoglobin, leading to increased plasma bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver. In a chronic toxicity/carcinogenicity study in mice, anemia was observed in the form of increased hemosiderin in the spleen, increased mean absolute reticulocyte count, decreased mean corpuscular volume, and mean corpuscular hemoglobin.
The postulated pesticidal mode of action of metaflumizone involves inhibition of sodium channels in target insect species; however, in mammals (rats), there were only clinical signs of neurotoxicity (i.e., piloerection and body temperature variations) with no neuropathology in the presence of systemic toxicity (e.g., recumbency and poor general state) following acute or repeated exposures. Similarly, several immune system organs seem to be affected following metaflumizone administration via the oral, dermal, and inhalation routes (e.g., the presence of macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, and diffuse atrophy of the mandibular); however, there was no evidence of any functional deficits at the highest dose tested in a recently submitted and reviewed guideline immunotoxicity study. Therefore, the clinical neurotoxicity signs and the effects on the immune system organs following metaflumizone administration are likely to be secondary to the hematotoxic effects.
Metaflumizone induced an increased incidence of a missing subclavian artery at a relatively high dose that also caused severe maternal toxicity (e.g., late term abortions) in the developmental toxicity study in rabbits. There was no evidence (quantitative or qualitative) of increased susceptibility following in utero exposures to rats or rabbit and following pre- and post natal exposures. There was no evidence that metaflumizone is genotoxic and carcinogenicity studies with mice and rabbits were negative.
Specific information on the studies received and the nature of the adverse effects caused by metaflumizone as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov in the document entitled, “Metaflumizone: Human Health Risk Assessment in Support of Section 3 Registrations for Application of Metaflumizone to Pome Fruit (crop group (CG) 11-10) and Stone Fruit (CG 12-12); Updating the CG Designation for Citrus to 10-10 and Tree Nuts to 14-12; and Permitting Aerial Application to Citrus Fruits, Grapes, Tree Nuts, and Nurseries Containing Field-/Container-Grown Nonbearing Stone and Pome Fruit Trees” in docket ID number EPA-HQ-OPP-2014-0607.
B. Toxicological Endpoints of Departure/Levels of Concern
Once a pesticide's toxicological profile is determined, EPA identifies toxicological points of departure (POD) and levels of concern (LOCs) to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment. PODs are developed based on a careful analysis of the doses in each toxicological study to determine the dose at which the NOAEL and the LOAEL are identified. Uncertainty/safety factors are used in conjunction with the POD to calculate a safe exposure level—generally referred to as a population-adjusted dose (PAD) or a reference dose (RfD)—and a safe margin of exposure (MOE). For non-threshold risks, the Agency assumes that any amount of exposure will lead to some degree of risk. Thus, the Agency estimates risk in terms of the probability of an occurrence of the adverse effect expected in a lifetime. For more information on the general principles EPA uses in risk characterization and a complete description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
A summary of the toxicological endpoints for metaflumizone used for human risk assessment is provided below:
i. Acute Dietary Endpoint (General population including infants and children). An acute dietary endpoint was not established for this population group since an endpoint of concern (effect) attributable to a single dose was not identified in the database. Studies considered for this endpoint included the acute neurotoxicity study for which a LOAEL was not observed.
ii. Acute Dietary Endpoint (Females 13-49 years old). This endpoint was established based on a developmental effect observed in the rabbit developmental toxicity study that can be potentially due to a single dose of metaflumizone. This effect consisted of an increased incidence of an absent subclavian artery in the offspring at the LOAEL of 300 milligram/kilogram (mg/kg) body weight/day (bw/day) metaflumizone (NOAEL = 100 mg/kg bw/day). The rat developmental toxicity study was also considered for this endpoint; however, no developmental effects were observed in this study at the highest dose tested of 120 mg/kg bw/day metaflumizone. A combined uncertainty factor (UF) of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation. A Food Quality Protection Act (FQPA) safety factor (SF) of 3x was retained because the rabbit developmental toxicity study was performed via oral gavage dosing. In an absorption study submitted by the petitioner, dietary exposures (which are more relevant for human exposures) exhibited an approximately 2-fold greater absorption into the systemic circulation than oral gavage dosing and, thus, can potentially lead to toxicity at 2-fold lower levels of exposure. Thus, aPAD for females 13-49 years old is estimated to be 0.33 mg/kg bw/day.
iii. Chronic Dietary Endpoint. This endpoint was established based on results of a chronic toxicity study with dogs via capsule administration. The effects at the LOAEL of 30 mg/kg bw/day (NOAEL = 12 mg/kg bw/day), consisted of reduced general health condition, slight to severe ataxia, recumbency, and severe salivation, decreases in mean cell hemoglobin concentration (MCHC) and total hemoglobin (Hb) and increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation and an FQPA SF of 3x was retained for the higher absorption observed in dietary exposures to metaflumizone (see above). Thus, the chronic population adjusted dose (cPAD) is estimated to be 0.040 mg/kg bw/day.
iv. Incidental Oral (Short- and Intermediate-Term). This endpoint was selected on the basis of the maternal effects observed in the rat two-generation reproductive toxicity study at the LOAEL of 50 mg/kg bw/day metaflumizone (NOAEL = 20 mg/kg bw/day). Maternal toxicity consisted of poor general health and body weight deficits which were also associated with improper nursing behavior. Similar effects were also noted in a developmental neurotoxicity study (gavage, range finding) also considered for this endpoint. In this study, poor maternal health was also observed at the LOAEL of 120 mg/kg bw/day metaflumizone (NOAEL = 80 mg/kg bw/day). Both studies considered for this endpoint achieved a clear maternal NOAEL for the offspring effects, but the NOAEL of 20 mg/kg bw/day for the 2-generation reproductive toxicity study is considered more protective. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation, and an FQPA SF of 3x to account for the 2-fold greater absorption observed in dietary versus oral gavage exposures (see above). The LOC is 300.
v. Dermal (Short- and Intermediate-Term). This endpoint was based on a rat 90-day dermal toxicity study in which deficits in body weight, body-weight gain, and food consumption (in males and females); anogenital smearing; increased macrophages in the thymus; lymphocyte necrosis in the mesenteric lymph nodes; diffuse atrophy of the mandibular lymph node; and increased hemosiderin in the liver (females only) were observed at the LOAEL of 300 mg/kg bw/day (NOAEL = 100 mg/kg bw/day). The LOC, for both occupational and residential exposure is 100, based on a combined UF of 100 for interspecies (10x) and in intraspecies (10x) extrapolation. The FQPA SF is reduced to 1x for this exposure scenario because there is no residual uncertainty concerning potential effects on infants and children.
vi. Inhalation (Short- and Intermediate-Term). There is a 28-day inhalation study that is adequate for both exposure durations. There was no NOAEL identified for female rats. At the LOAEL of 0.10 milligrams per Liter (mg/L) metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, thymus, prostate, and adrenal cortex was observed in males. The LOAEL of 0.03 mg/L identified in females resulted in lymphocyte necrosis in the mesenteric lymph node.
The methods and dosimetry equations described in EPA's reference concentration (RfC) guidance (1994) are suited for calculating human-equivalent concentrations (HECs) based on the inhalation toxicity point of departure (NOAEL, LOAEL, or Benchmark Dose Lower Confidence Limit (BMDL)) for use in MOE calculations. The regional-deposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter (MMAD) and geometric standard deviation (σg) of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract. The RDDR accounts for interspecies differences in ventilation and respiratory-tract surface areas. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the subchronic inhalation toxicity study with metaflumizone, an RDDR was estimated at 2.81 based on systemic effects (lymphocyte necrosis in the mesenteric lymph node) in females at the LOAEL of 0.03 mg/L (no NOAEL established), and a MMAD of 1.7 micrometer (μm) and σg of 2.7.
For this action with metaflumizone, residential and occupational handler scenarios are being assessed. For residential handler scenarios, 2-hr/day inhalation exposures are assumed. Adjustment to shorter exposure scenarios relative to the animal toxicity study duration (e.g., 2 hr. residential exposures) should only be made if there is time-course information that would support a shorter time-frame. Since there is no such information available for metaflumizone, the unadjusted animal POD was used to assess the shorter duration residential handler exposures. Thus, the HEC equals the LOAEL from the study, and was calculated to be 0.084 mg/L. The FQPA SF of 10x is being retained for lack of a NOAEL for females in the study. The standard interspecies extrapolation UF can be reduced from 10x to 3x due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. The intraspecies UF remains at 10x. Therefore, the LOC for this scenario is 300, which includes the FQPA SF of 10x, interspecies (3x), and intraspecies (10x) extrapolation.
C. Exposure Assessment
1. Dietary Exposure from Food and Feed Uses. Tolerances have been established in (40 CFR 180.657) for the residues of metaflumizone, in or on a variety of raw agricultural commodities. Risk assessments were conducted by EPA to assess dietary exposures from metaflumizone in food as follows:
i. Acute Exposure. Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a 1-day or single exposure. Such effects were identified for metaflumizone. In estimating acute dietary exposure, EPA used food consumption information from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. As to residue levels in food, EPA assumed tolerance-level residues. It was further assumed that 100% of crops with the requested uses of metaflumizone were treated.
ii. Chronic Exposure. In conducting the chronic dietary exposure assessment, EPA used the food consumption data from the USDA NHANES/WWEIA. As to residue levels in food, EPA assumed tolerance-level residues. It was further assumed that 100% of crops with the requested uses of metaflumizone were treated.
iii. Cancer. EPA has concluded that metaflumizone does not pose a cancer risk to humans; therefore, a dietary exposure assessment for the purpose of assessing cancer risk is unnecessary.
iv. Anticipated Residue and Percent Crop Treated (PCT) Information. EPA did not use anticipated residue or PCT information in the dietary assessment for metaflumizone. Tolerance-level residues and 100 PCT were assumed for all food commodities.
2. Dietary Exposure from Drinking Water. The Agency used screening-level water exposure models in the dietary exposure analysis and risk assessment for metaflumizone in drinking water. These simulation models take into account data on the physical, chemical, and fate/transport characteristics of metaflumizone. Further information regarding EPA drinking water models used in pesticide exposure assessment can be found at http://www.epa.gov/oppefed1/models/water/index.htm.
Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-GROW) models, the estimated drinking water concentrations (EDWCs) of metaflumizone for acute exposures are estimated to be 1.03 parts per billion (ppb) for surface water and 1.09 x 10 ? [12] ppb for ground water. The EDWCs of metaflumizone for chronic exposures for non-cancer chronic assessments are estimated to be 0.487 ppb for surface water and 1.09 x 10 ? [12] ppb for ground water.
Modeled estimates of drinking water concentrations were directly entered into the dietary exposure model. For acute dietary risk assessment, the water concentration value of 1.03 ppb was used to assess the contribution of drinking water. For chronic dietary risk assessment, the water concentration value of 0.487 ppb was used to assess the contribution of drinking water.
3. From Non-Dietary Exposure. The term “residential exposure” is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Metaflumizone is currently registered for the following uses that could result in residential exposures: As a fire ant bait for application to lawns, landscapes, golf courses, and other non-cropland area; and as a fly bait for use around industrial buildings, commercial facilities, agricultural structures/premises, and recreational facilities/areas.
EPA assessed residential exposure using the following assumptions: Fire ant bait applications to home lawns are expected to result in short-term, residential handler exposure to adults. Fire ant bait applications to lawns and golf-courses are expected to result in short-term, post-application dermal exposure to adults, children 11 to <16 years old, and children 1 to <2 years old, and incident oral exposure for children 1 to <2 years old. For the fly bait product, residential handler exposure is not expected, because the product is applied by commercial handlers. The fly bait product is expected to result in short-term, post-application dermal exposure to adults, children 11 to <16 years old, and children 1 to <2 years old, and incident oral exposure for children 1 to <2 years old.
For residential handlers, dermal and inhalation exposures are combined since the endpoints are similar for these routes. For children (1- to <2-year-olds), post-application hand-to-mouth and dermal exposures are combined. Since the LOCs for the dermal, inhalation and incidental oral routes are not the same (dermal LOC = 100, inhalation LOC = 300, and incidental oral LOC = 300), these routes were combined using the aggregate risk index approach. Further information regarding EPA standard assumptions and generic inputs for residential exposures may be found at http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
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.”
Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to metaflumizone and any other substances and metaflumizone 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 metaflumizone 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 Office of Pesticide Programs 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.
D. Safety Factor for Infants and Children
1. In general. Section 408 of FFDCA provides that EPA shall apply an additional ten-fold 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 factor value based on the use of traditional uncertainty factors and/or special FQPA SFs, as appropriate.
2. Prenatal and Postnatal Sensitivity. There is no evidence for increased qualitative or quantitative sensitivity/susceptibility resulting from pre- and/or postnatal exposures. In the rat prenatal development toxicity study, there was no offspring toxicity reported at anydose tested whereas in the rabbit study a maltransformation based on an absent subclavian artery was noted to occur only in the presence of severe maternal toxicity. Similarly, offspring mortality in the 2-generation reproductive toxicity occurred only in the presence of a poor maternal health state. Thus, there is no evidence for increased susceptibility.
3. Conclusion. EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced from 10x to 3x for all oral exposure scenarios; retained at 10x for inhalation exposure scenarios; and reduced to 1x for dermal exposures. That decision is based on the following findings:
i. The toxicological database for metaflumizone is adequate for risk assessment and FQPA SF evaluation. Several studies are available for evaluating the safety of metaflumizone, although differences in dose administration and a missing NOAEL warrant retention of various FQPA safety factors in this instance.
Dietary exposures exhibited an approximately 2-fold greater absorption into the systemic circulation as compared to oral gavage and, thus, can potentially lead to toxicity at 2-fold lower levels of exposure. Applying an FQPA SF of 3x for all oral exposure scenarios is adequate to protect against any greater toxicity that might occur in dietary exposures (absorption was noted to be 2-fold greater in dietary versus oral gavage studies).
The FQPA SF of 10x is being retained for inhalation exposure scenarios for the use of a LOAEL instead of a NOAEL (no NOAEL achieved) for histopathological lesions consisting of lymphocyte necrosis in the mesenteric lymph node. The FQPA SF of 10x is adequate because the effect (lymphocyte necrosis) is considered minimal to slight and does not exhibit a strong dose dependence.
The FQPA SF for dermal exposure scenarios is being reduced from 10x to 1x since there is a route-specific study with a clear NOAEL.
ii. There is no indication that metaflumizone directly affects the nervous system. Clinical signs indicative of neurotoxicity were observed in several studies; however, these signs were generally observed in the presence of poor animal health (e.g., reduced general health condition, loss of body weight, or death). In addition, no neuropathology was observed in any study with metaflumizone. There is no need for a developmental neurotoxicity study or additional uncertainty factors to account for neurotoxicity.
iii. There are no residual concerns or uncertainties for increased sensitivity/susceptibility in developing animals resulting from pre- and/or postnatal exposure.
iv. There are no residual uncertainties identified in the exposure databases.
The dietary analyses assumed tolerance-level residues, 100 PCT, and modeled drinking water estimates. EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to metaflumizone in drinking water. EPA used similarly conservative assumptions to assess post-application exposure of children as well as incidental oral exposure of toddlers. These assessments will not underestimate the exposure and risks posed by metaflumizone.
E. Aggregate Risks and Determination of Safety
EPA determines whether acute and chronic dietary pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD. For linear cancer risks, EPA calculates the lifetime probability of acquiring cancer given the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the appropriate PODs to ensure that an adequate MOE exists. Based on the proposed/registered uses and since inhalation, dermal, and incidental oral exposures can be combined, aggregate acute (dietary), short-term (dietary, incidental oral, and/or dermal), and chronic (dietary) assessments were conducted.
1. Acute Risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute aggregate exposure assessment consists of exposure from only food and water. The acute dietary exposure assessment for females 13-49 years old was 1.6% of the aPAD and therefore, does not exceed EPA's LOC.
2. Chronic Risk. Since there are no registered/proposed uses that result in chronic residential exposure, the chronic aggregate exposure assessment consists of exposure from only food and water. The chronic dietary exposure estimate was ≤7.2% the cPAD and therefore, does not exceed EPA's LOC.
3. Short-Term Risk. Short-term aggregate exposure takes into account short-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Metaflumizone is currently registered for uses that could result in short-term residential exposure, and the Agency has determined that it is appropriate to aggregate chronic exposure through food and water with short-term residential exposures to metaflumizone. Since the LOC and toxicological points of departure for the short-term dermal and oral routes of exposure differ, the aggregate risk index method was used to determine aggregate risk (aggregate risk indices >1 are not a risk of concern).
Using the exposure assumptions described in this unit for short-term exposures, EPA has concluded the combined short-term food, water, and residential exposures result in aggregate risk indices of 42 for the general population, and 22 for children 1-2 years old. Because EPA's LOC for metaflumizone is an aggregate risk index less than 1, the aggregate risks are not of concern.
4. Intermediate-Term Risk. Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Metaflumizone is not currently registered for uses that could result in intermediate-term residential exposure; however, since the PODs for the short- and intermediate-term durations are the same for metaflumizone, the short-term aggregate assessment is protective of intermediate-term exposures.
5. Aggregate Cancer Risk for U.S. Population. As discussed in Unit III.A., EPA does not expect metaflumizone to pose a cancer risk to humans.
6. Determination of Safety. Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population, and to infants and children from aggregate exposure to metaflumizone residues.
IV. Other Considerations
Back to Top
A. Analytical Enforcement Methodology
EPA previously reviewed method validation and independent laboratory validation (ILV) studies for the BASF high-performance liquid chromatography (HPLC)/mass spectrometry (MS)/MS analytical method 531/0 and forwarded the method to FDA for tolerance enforcement (46264221.der; D308394, T. Bloem, 30-Nov-2005; D328915, T. Bloem, 17-May-2006). It is noted that following method validation, BASF incorporated several minor modifications to method 531/0 with this revised method specified as 531/1 (method 531/1 is the current enforcement method). Based on the similarities of the proposed crops to that currently registered and since the grape, citrus, and tree nut residue sampleswere analyzed using a method very similar to the current enforcement method and since adequate validation data were submitted, EPA concludes that the current enforcement method is suitable for enforcement of the tolerances recommended herein. The limit of quantitation (LOQ) is 0.01 ppm for metaflumizone (E and Z isomers) and 0.018 ppm for M320I04 (expressed in parent equivalents).
The method may be requested from: Chief, Analytical Chemistry Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350; telephone number: (410) 305-2905; email address: residuemethods@epa.gov.
B. International Residue Limits
In making its tolerance decisions, EPA seeks to harmonize U.S. tolerances with international standards whenever possible, consistent with U.S. food safety standards and agricultural practices. EPA considers the international maximum residue limits (MRLs) established by the Codex Alimentarius Commission (Codex), as required by FFDCA section 408(b)(4). The Codex Alimentarius is a joint United Nations Food and Agriculture Organization/World Health Organization food standards program, and it is recognized as an international food safety standards-setting organization in trade agreements to which the United States is a party. EPA may establish a tolerance that is different from a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain the reasons for departing from the Codex level.
Codex MRLs are not established in/on the relevant crops for metaflumizone; therefore, harmonization is not an issue for this petition.
V. Conclusion
Back to Top
Therefore, the tolerance is established for the combined residues of the insecticide metaflumizone (2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(trifluoromethoxy)phenyl] hydrazinecarboxamide; E and Z isomers), in or on the following raw agricultural commodities: Fruit, citrus, group 10-10 at 0.04 ppm; fruit, pome, group 11-10 at 0.04 ppm; fruit, stone, group 12-12 at 0.04 ppm; and nut, tree, group 14-12 at 0.04 ppm. The existing tolerances for fruit, citrus, group 10 at 0.04 ppm and for nut, tree, group 14 at 0.04 ppm are removed because they are superseded by the tolerances being established in this action.
地区：
