Fluxapyroxad; Pesticide Tolerances
Federal Register, Volume 79 Issue 38 (Wednesday, February 26, 2014)
Federal Register Volume 79, Number 38 (Wednesday, February 26, 2014)
Rules and Regulations
Pages 10670-10678
From the Federal Register Online via the Government Printing Office www.gpo.gov
FR Doc No: 2014-04164
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
EPA-HQ-OPP-2012-0638; FRL-9906-70
Fluxapyroxad; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: This regulation establishes tolerances for residues of fluxapyroxad in or on multiple commodities which are identified and discussed later in this document. BASF Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA).
DATES: This regulation is effective February 26, 2014. Objections and requests for hearings must be received on or before April 28, 2014, and must be filed in accordance with the instructions provided in 40 CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).
ADDRESSES: The docket for this action, identified by docket identification (ID) number EPA-HQ-OPP-2012-0638, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory Public Docket (OPP Docket) in the Environmental Protection Agency Docket Center (EPA/DC), EPA West Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744, and the telephone number for the OPP Docket is (703) 305-
5805. Please review the visitor instructions and additional information about the docket available at http://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Lois Rossi, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone number: (703) 305-7090; email address: RDFRNotices@epa.gov.
SUPPLEMENTARY INFORMATION:
-
General Information
-
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
Page 10671
provides a guide to help readers determine whether this document applies to them. Potentially affected entities may include:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
-
How can I get electronic access to other related information?
You may access a frequently updated electronic version of EPA's tolerance regulations at 40 CFR part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl. If OCSPP test guidelines are cited, insert the following: To access the OCSPP test guidelines referenced in this document electronically, please go to http://www.epa.gov/ocspp and select ``Test Methods and Guidelines.''
-
How can I file an objection or hearing request?
Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2012-0638 in the subject line on the first page of your submission. All objections and requests for a hearing must be in writing, and must be received by the Hearing Clerk on or before April 28, 2014. Addresses for mail and hand delivery of objections and hearing requests are provided in 40 CFR 178.25(b).
In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR part 178, please submit a copy of the filing (excluding any Confidential Business Information (CBI)) for inclusion in the public docket. Information not marked confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA without prior notice. Submit the non-CBI copy of your objection or hearing request, identified by docket ID number EPA-HQ-OPP-2012-0638, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the online instructions for submitting comments. Do not submit electronically any information you consider to be CBI or other information whose disclosure is restricted by statute.
Mail: OPP Docket, Environmental Protection Agency Docket Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001.
Hand Delivery: To make special arrangements for hand delivery or delivery of boxed information, please follow the instructions at http://www.epa.gov/dockets/contacts.htm.
Additional instructions on commenting or visiting the docket, along with more information about dockets generally, is available at http://www.epa.gov/dockets.
-
-
Summary of Petitioned-For Tolerance
In the Federal Register of December 19, 2012 (77 FR 75082) (FRL-
9372-6), January 16, 2013 (78 FR 3377) (FRL-9375-4), and July 19, 2013 (78 FR 43115) (FRL-9392-9), EPA issued notices pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petitions (PP 2F8053, PP 2F8058 and PP 3F8161 by BASF Corporation, 26 Davis Drive, Research Triangle Park, NC 27709. The petitions requested that 40 CFR 180.666 be amended by establishing tolerances for residues of the fungicide fluxapyroxad, 3-
(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro1,1'-biphenyl-2-yl)-
1H-pyrazole-4-carboxamide, in or on almond at 0.05 parts per million (ppm); almond, hulls at 4.0 ppm; berry, low growing, subgroup 13-07G at 4.0 ppm; bushberry, subgroup 13-07B at 6.0 ppm; caneberry, subgroup 13-
07A at 6.0 ppm; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 2.0 ppm; grapes at 2.0 ppm; grapes, raisin at 5.7 ppm; pecans at 0.05 ppm; rice, bran at 8.5 ppm; rice, grain at 5.0 ppm; rice, hulls strawberry at 4.0 ppm; sugarcane, cane at 3.0 ppm; vegetable, brassica leafy, group 5 at 3.0 ppm; vegetable, bulb, group 3-07 at 0.8 ppm; vegetable, cucurbit, group 9 at 0.4 ppm; vegetable, leafy, except brassica, group 4 at 15.0 ppm; vegetable, root, except sugar beet, subgroup 1B at 0.7 ppm (PP 2F8053); nongrass animal feeds, group 18 at 0.5 ppm; mint at 0.05 ppm (PP 2F8058); and by amending the tolerance for fruit, stone, group 12 from 2.0 ppm to 3.0 ppm (PP 3F8161). The documents referenced summaries of the petitions prepared by BASF Corporation, the registrant, which are available in dockets EPA-HQ-OPP-2012-0638 (PP 2F8053), EPA-HQ-OPP-2012-0924 (PP 2F8058), and EPA-HQ-OPP-2013-0477 (PP 3F8161), http://www.regulations.gov.
Based on EPA's review of the data supporting the petitions, BASF Corporation revised their petition PP 2F8053 by proposing tolerances for fish-freshwater finfish; fish-shelfish, crustacean; and hog, meat byproducts; and by decreasing, increasing, or deleting previously proposed tolerances for various commodities, as follows: Almond at 0.02 parts per million (ppm); almond, hulls at 4.0 ppm; berry, low growing, subgroup 13-07G at 4.0 ppm; bushberry, subgroup 13-07B at 7.0 ppm; caneberry, subgroup 13-07A at 5.0 ppm; fish-freshwater finfish at 0.01 ppm; fish-shellfish, crustacean at 0.01 ppm; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 2.0 ppm; grape, raisin at 5.7 ppm; hog, meat byproducts at 0.01 ppm; pecan at 0.06 ppm; rice, bran at 8.5 ppm; rice, grain at 5.0 ppm; rice, hulls at 15.0 ppm; sugarcane, cane at 3.0 ppm; vegetable, brassica leafy, group 5 at 4.0 ppm; vegetable, bulb, group 3-07 at 1.5 ppm; vegetable, cucurbit, group 9 at 0.5 ppm; vegetable, leafy, except brassica, group 4 at 30.0 ppm; vegetable, root, except sugarbeet, subgroup 1B at 0.9 ppm. EPA issued a notice announcing the filing of the revised petition in the Federal Register of November 27, 2013 (78 FR 70906) (FRL-9902-87). That document referenced a summary of the revised petition prepared by BASF, which is available in docket EPA-HQ-OPP-2012-0638.
Three comments were received on the notices of filing. EPA's response to the comments is discussed in Unit IV.C.
-
Aggregate Risk Assessment and Determination of Safety
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .''
Consistent with FFDCA section 408(b)(2)(D), and the factors specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available scientific data
Page 10672
and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure for fluxapyroxad including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with fluxapyroxad follows.
-
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.
Fluxapyroxad is of low acute toxicity by the oral, dermal and inhalation routes, is not irritating to the eyes and skin, and is not a dermal sensitizer. The primary target organ for fluxapyroxad exposure via the oral route is the liver with secondary toxicity in the thyroid for rats only. Liver toxicity was observed in rats, mice, and dogs, with rats as the most sensitive species for all durations of exposure. In rats, adaptive effects of hepatocellular hypertrophy and increased liver weights and changes in liver enzyme activities were first observed. As the dose or duration of exposure to fluxapyroxad increased, clinical chemistry changes related to liver function also occurred, followed by hepatocellular necrosis, neoplastic changes in the liver, and tumors. Thyroid effects were observed only in rats. These effects were secondary to changes in liver enzyme regulation, which increased metabolism of thyroid hormone, resulting in changes in thyroid hormones, thyroid follicular hypertrophy and hyperplasia, and thyroid tumor formation. Tumors were not observed in species other than rats or in organs other than the liver and thyroid.
Fluxapyroxad is classified as ``Not likely to be Carcinogenic to Humans'' based on convincing evidence that carcinogenic effects are not likely below a defined dose range. There is no mutagenicity concern from in vivo or in vitro assays. The hypothesized mode of action (i.e., a non-genotoxic) for treatment related tumors (i.e., the liver and thyroid) was supported by a full panel of in vitro and in vivo studies that showed no evidence of genotoxicity, together with mechanistic studies in the liver and thyroid of rats that satisfied stringent criteria for establishing tumorgenic modes of action. The studies clearly identified the sequence of key events, dose-response concordance and temporal relationship to the tumor types. The Agency has determined that the chronic population adjusted dose (PAD) will adequately account for all chronic effects, including carcinogenicity that could result from exposure to fluxapyroxad because the points of departure (POD) for the chronic population adjusted dose (cPAD) is based on the most sensitive endpoint, liver effects. Effects in the liver preceded liver tumors and the effects observed in the thyroid (in rats only) were believed to be secondary to the liver effects.
No evidence of neurotoxicity was observed in response to repeated administration of fluxapyroxad. An acute neurotoxicity study showed decreased rearing and motor activity. This occurred on the day of dosing only and in the absence of histopathological effects or alterations in brain weights. This indicated that any neurotoxic effects of fluxapyroxad are likely to be transient and reversible due to alterations in neuropharmacology and not from neuronal damage. There were no neurotoxic effects observed in the subchronic dietary toxicity study. No evidence of reproductive toxicity was observed. Developmental effects observed in both rats and mice (thyroid follicular hypertrophy and hyperplasia in rats and decreased defecation, food consumption, body weight/body weight gain, and increased litter loss in rabbits) occurred at the same doses as those that caused adverse effects in maternal animals, indicating no quantitative susceptibility. Since the maternal toxicities of thyroid hormone perturbation in rats and systemic toxicity in rabbits likely contributed to the observed developmental effects there is low concern for qualitative susceptibility. An immunotoxicity study in mice showed no evidence of immunotoxic effects from fluxapyroxad.
Subchronic oral toxicity studies in rats, developmental toxicity studies in rabbits, and in vitro and in vivo genotoxicity studies were performed for fluxapyroxad metabolites F700F001, M700F002, and M700F048. Like fluxapyroxad, no genotoxic effects were observed for any of these metabolites. All three metabolites displayed lower subchronic toxicity via the oral route than fluxapyroxad, with evidence of non-
specific toxicity (decreased body weight) observed only for M700F0048 at the limit dose. Only M700F0048 exhibited developmental toxicity at doses similar to those that caused developmental effects in rabbits with fluxapyroxad treatment. However, these effects (abortions and resorptions) were of a different nature than for fluxapyroxad (paw hyperflexion) and are considered secondary to maternal toxicity. The Agency considers these studies sufficient for hazard identification and characterization and concludes that these metabolites do not have hazards that exceed those of fluxapyroxad in nature, severity, or potency.
Specific information on the studies received and the nature of the adverse effects caused by fluxapyroxad as well as the no-observed-
adverse-effect-level (NOAEL) and the lowest-observed-adverse-effect-
level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov in document, ``Human Health Risk Assessment for Use of Fluxapyroxad on Numerous Crops'' at pp. 52 in docket ID number EPA-
HQ-OPP-2012-0638.
-
Toxicological Points of Departure/Levels of Concern
Once a pesticide's toxicological profile is determined, EPA identifies toxicological POD and levels of concern to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment. PODs are developed based on a careful analysis of the doses in each toxicological study to determine the dose at which 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 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 fluxapyroxad used for human risk assessment is shown in Table 1 of this unit.
Page 10673
Table 1--Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Human Health Risk Assessment
----------------------------------------------------------------------------------------------------------------
Point of departure and
Exposure/Scenario uncertainty/safety RfD, PAD, LOC for risk Study and
factors assessment toxicological effects
----------------------------------------------------------------------------------------------------------------
Acute dietary (General population NOAEL = 125 mg/kg/day.. Acute RfD = 1.25 mg/kg/ Acute neurotoxicity
including infants and children, and UFA = 10x.............. day.. study in rats.
females 13-49 years of age). UFH = 10x.............. aPAD = 1.25 mg/kg/day.. LOAEL = 500 mg/kg/day
FQPA SF = 1x........... based on decreased
motor activity and
decreased rearing.
Chronic dietary (All populations).... NOAEL = 2.1 mg/kg/day.. Chronic RfD = 0.021 mg/ Chronic toxicity/
UFA = 10x.............. kg/day.. carcinogenicity study
UFH = 10x.............. cPAD = 0.021 mg/kg/day. in rats.
FQPA SF = 1x........... LOAEL = 11 mg/kg/day
based on non-
neoplastic changes in
the liver (foci,
masses).
Incidental oral short-term (1 to 30 NOAEL = 9 mg/kg/day.... LOC for MOE = 100...... 28-day oral toxicity
days). UFA = 10x.............. study in rats.
UFH = 10x.............. LOAEL = 176 mg/kg/day
FQPA SF = 1x........... based on changes in
thyroid hormones and
thyroid follicular
hypertrophy/
hyperplasia.
--------------------------------------------------
Dermal short- and intermediate-term No hazard identified 28-day dermal toxicity
(1 day to 6 months). study in rats.
LOAEL = Not observed.
--------------------------------------------------
Inhalation short-term (1 to 30 days). NOAEL= 9 mg/kg/day..... LOC for MOE = 100...... 28-day oral toxicity
UFA = 10x.............. study in rats.
UFH = 10x.............. LOAEL = 176 mg/kg/day
FQPA SF = 1x........... based on changes in
thyroid hormones and
thyroid follicular
hypertrophy/
hyperplasia.
--------------------------------------------------------------------------
Inhalation intermediate-term (1 to 6 Inhalation (or oral) LOC for MOE = 100...... 90-day dietary study in
months). study NOAEL = 7.3 mg/ rats.
kg/day. LOAEL = 35.1 mg/kg/day
UFA = 10x.............. based on thyroid
UFH = 10x.............. follicular hypertrophy/
FQPA SF = 1x........... hyperplasia.
--------------------------------------------------------------------------
Cancer (Oral, dermal, inhalation).... Classification: Not likely to be carcinogenic to humans at doses
sufficient to induce liver and/or thyroid tumors. Quantification of risk
using a non-linear approach (i.e., RfD) will adequately account for all
chronic toxicity, including carcinogenicity.
----------------------------------------------------------------------------------------------------------------
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. LOC = level
of concern. mg/kg/day = milligram/kilogram/day. MOE = margin of exposure. NOAEL = no-observed-adverse-effect-
level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor.
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among
members of the human population (intraspecies).
-
Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to fluxapyroxad, EPA considered exposure under the petitioned-
for tolerances as well as all existing fluxapyroxad tolerances in 40 CFR 180.666. EPA assessed dietary exposures from fluxapyroxad 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 fluxapyroxad. In estimating acute dietary exposure, EPA used food consumption information from the United States Department of Agriculture (USDA) 2003-2008 National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). As to residue levels in food, EPA used tolerance level residues adjusted upward to account for metabolites of concern not included in the tolerance expression, 100 percent crop treated (PCT) assumptions, and dietary exposure evaluation model (DEEM) default and empirical processing factors.
ii. Chronic exposure. In conducting the chronic dietary exposure assessment, EPA used the food consumption data from the USDA 2003-2008 NHANES/WWEIA. As to residue levels in food, a moderately refined chronic dietary exposure analysis was performed. An assumption of 100 PCT and DEEM default and empirical processing factors were used for the chronic dietary analysis. Combined average field trial residues for parent and highest average field trial residues for metabolites of concern were used for all plant commodities. For livestock commodities tolerance level residues adjusted upward to account for metabolites of concern not included in the tolerance expression were used.
iii. Cancer. Based on the data summarized in Unit III.A., EPA has concluded that a nonlinear RfD approach is appropriate for assessing cancer risk to fluxapyroxad. Cancer risk was assessed using the same exposure estimates as discussed in Unit III.C.1.ii., chronic exposure.
iv. Anticipated residue and percent crop treated (PCT) information. Section 408(b)(2)(E) of FFDCA authorizes EPA to use available data and information on
Page 10674
the anticipated residue levels of pesticide residues in food and the actual levels of pesticide residues that have been measured in food. If EPA relies on such information, EPA must require pursuant to FFDCA section 408(f)(1) 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. For the present action, EPA will issue such data call-ins as are required by FFDCA section 408(b)(2)(E) and authorized under FFDCA section 408(f)(1). Data will be required to be submitted no later than 5 years from the date of issuance of these tolerances.
2. Dietary exposure from drinking water. The Agency used screening level water exposure models in the dietary exposure analysis and risk assessment for fluxapyroxad in drinking water. These simulation models take into account data on the physical, chemical, and fate/transport characteristics of fluxapyroxad. 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 Tier 1 Rice Model and the Pesticide Root Zone Model Ground Water (PRZM GW), the estimated drinking water concentrations (EDWCs) of fluxapyroxad for acute exposures are estimated to be 127 parts per billion (ppb) for surface water and 203 ppb for ground water. The EDWCs for chronic exposures for non-cancer assessments are estimated to be 127 ppb for surface water and 184 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 203 ppb was used to assess the contribution to drinking water. For chronic dietary risk assessment, the water concentration of value 184 ppb was used to assess the contribution to drinking water.
3. From non-dietary exposure. The term ``residential exposure'' is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Fluxapyroxad is registered for the following uses that could result in residential exposures: residential turf. EPA assessed residential exposure using the following assumptions: Residential handler exposures are expected to be short-term (1 to 30 days) via either the dermal or inhalation routes of exposures. Intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners. Since no dermal hazard was identified for fluxapyroxad, MOEs were calculated for the inhalation route of exposure only.
Both adults and children may be exposed to fluxapyroxad residues from contact with treated lawns. Adult postapplication exposures were not quantitatively assessed since no dermal hazard was identified for fluxapyroxad and inhalation exposures are typically negligible in outdoor settings. The exposure assessment for children included incidental oral exposure resulting from transfer of residues from the hands or objects to the mouth, and from incidental ingestion of soil. Post application hand-to-mouth and object-to-mouth exposures are expected to be short-term (1 to 30 days) in duration due to the intermittent nature of applications in residential environments. 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.''
EPA has not found fluxapyroxad to share a common mechanism of toxicity with any other substances, and fluxapyroxad does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that fluxapyroxad does not have 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 EPA's Web site at http://www.epa.gov/pesticides/cumulative.
-
Safety Factor for Infants and Children
1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA shall apply an additional tenfold (10x) 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 based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor (SF). In applying this provision, EPA either retains the default value of 10x, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor.
2. Prenatal and postnatal sensitivity. No evidence of quantitative susceptibility was observed in a reproductive and developmental toxicity study in rats or in developmental toxicity studies in rats and rabbits. Developmental toxicity data in rats showed decreased body weight and body weight gain in the offspring at the same dose levels that caused thyroid follicular hypertrophy/hyperplasia in parental animals. Effects in rabbits were limited to paw hyperflexion, a malformation that is not considered to result from a single exposure and that usually reverses as the animal matures. Developmental effects observed in both rats and rabbits occurred at the same doses as those that caused adverse effects in maternal animals, indicating no quantitative susceptibility. The Agency has low concern for developmental toxicity because the observed effects were of low severity, were likely secondary to maternal toxicity, and demonstrated clear NOAELs. Further, the NOAELs for these effects were at dose levels higher than the points of departure selected for risk assessment for repeat-exposure scenarios. Therefore, based on the available data and the selection of risk assessment endpoints that are protective of developmental effects, there are no residual uncertainties with regard to pre- and/or postnatal toxicity.
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 to 1x. That decision is based on the following findings:
i. The toxicity database for fluxapyroxad is complete. Although no subchronic inhalation data is available EPA has waived that data requirement based on, among other things, its conclusion that even if an additional 10x safety factor was applied, inhalation exposure would not raise a risk of concern.
ii. There is no indication that fluxapyroxad is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity. Neither the acute or the subchronic neurotoxicity studies indicated specific neurotoxicity responses to fluxapyroxad. Because fluxapyroxad can disrupt thyroid
Page 10675
hormone levels, the Agency considered the potential for fluxapyroxad to cause developmental neurotoxicity as a result of thyroid hormone disruption, which is more sensitive endpoint than the endpoints used in a developmental neurotoxicity study. Based on its evaluation of thyroid hormone data submitted for fluxapyroxad and the ontogeny of thyroid hormone metabolism, the Agency has determined that adverse thyroid hormone disruptions in the young are unlikely to occur at dose levels as low as the points of departure chosen for risk assessment. The Agency has low concern for neurotoxic effects of fluxapyroxad at any life stage.
iii. Based on the developmental and reproductive toxicity studies discussed in Unit III.D.2., there are no residual uncertainties with regard to prenatal and/or postnatal toxicity.
iv. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessments were performed based on 100 PCT and tolerance-level residues or field trial residue data. The dietary risk assessment is based on reliable data, is conservative and will not underestimate dietary exposure to fluxapyroxad. EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to fluxapyroxad in drinking water. EPA used similarly conservative assumptions to assess postapplication exposure of children as well as incidental oral exposure of toddlers. These assessments will not underestimate the exposure and risks posed by fluxapyroxad.
-
Aggregate Risks and Determination of Safety
EPA determines whether acute and chronic dietary pesticide exposures are safe by comparing aggregate exposure estimates to the acute PAD (aPAD) and cPAD. For linear cancer risks, EPA calculates the lifetime probability of acquiring cancer given the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the appropriate PODs to ensure that an adequate MOE exists.
1. Acute risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food and water to fluxapyroxad will occupy 12% of the aPAD for children 3-5 years old, the population group receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic exposure to fluxapyroxad from food and water will utilize 64% of the cPAD for infants (
-
