Alpha-Cypermethrin; Pesticide Tolerances
Federal Register, Volume 78 Issue 22 (Friday, February 1, 2013)
Federal Register Volume 78, Number 22 (Friday, February 1, 2013)
Rules and Regulations
Pages 7266-7275
From the Federal Register Online via the Government Printing Office www.gpo.gov
FR Doc No: 2013-02206
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ENVIRONMENTAL PROTECTION AGENCY
EPA-HQ-OPP-2010-0234; FRL-9376-1
Alpha-Cypermethrin; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of alpha-
cypermethrin, 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 1, 2013. Objections and requests for hearings must be received on or before April 2, 2013, 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-2010-0234, 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: BeWanda Alexander, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-
0001; telephone number: (703) 305-7460; email address: alexander.bewanda@epa.gov.
SUPPLEMENTARY INFORMATION:
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General Information
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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).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
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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://ecfr.gpoaccess.gov/cgi/t/text/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.
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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-2010-0234 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 2, 2013. 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-2010-0234, 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.
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Summary of Petition-For Tolerance
In the Federal Register of May 19, 2010 (75 FR 28009) (FRL-8823-2), 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 0F7690) by BASF Corporation, 26 Davis Drive, P.O. Box 13528, Research Triangle Park, NC 27709-3528. The petition requested that 40 CFR 180.418 be amended by
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establishing tolerances for residues of the insecticide alpha-
cypermethrin in or on tree nuts, Group 14; dried shelled pea and bean, except soybean, subgroup 6C; corn, grain; pop corn; sweet corn; soybeans; and sugar beet, roots at 0.05 parts per million (ppm); succulent shelled pea and bean, subgroup 6B; and root and tuber vegetables, Group 1 at 0.1 ppm; cucurbit vegetables, Group 9; fruiting vegetables, Group 8; sugar beet, tops; and wheat, grain at 0.2 ppm; citrus fruit, Group 10 at 0.35 ppm; cottonseed; edible podded legume vegetable, subgroup 6A; and sorghum, grain at 0.5 ppm; and rice, grain at 1.5 ppm; citrus, dried pulp at 1.8 ppm; head and stem Brassica, subgroup 5A at 2.0 ppm; citrus, oil at 4.0 ppm; leafy vegetable, except Brassica, Group 4 at 10 ppm; and alfalfa, hay at 15 ppm. There were no comments received in response to the notice of filing.
Based upon review of the data supporting the petition, EPA has established tolerances for alpha-cypermethrin ((R)-cyano(3-
phenoxyphenyl)methyl (1S,3S)-rel-3-(2,2-dichloroethenyl)-2,2-
dimethylcyclopropane carboxylate) as explained in Unit IV.D.
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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 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 alpha-cypermethrin including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with alpha-
cypermethrin follows.
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Toxicological Profile
EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.
Alpha-cypermethrin, cypermethrin, and zeta-cypermethrin are all pyrethroid insecticides and are isomer mixtures of the same chemical. The cypermethrins have been evaluated for a variety of toxic effects in experimental toxicity studies. Behavioral changes commonly seen with type II pyrethroids were consistently noted in the toxicology database for the cypermethrins. These behavioral changes included tremors, gait abnormalities, limb conditions, ataxia and hypersensitivity. Additionally, body weight changes were routinely observed and mortality was seen in a few studies in rats and dogs. Clinical signs were also noted in all acute neurotoxicity studies. Decreased activity, gait abnormalities, tremors, limb conditions, and hypersensitivity were observed at the mid and high doses. Additionally, slight nerve degeneration was seen in the acute neurotoxicity study with alpha-
cypermethrin at the high dose. In the subchronic neurotoxicity studies with cypermethrin and zeta-cypermethrin, similar behavioral effects were seen along with decreased food consumption, body weight, and body weight gain.
Acute toxicology studies conducted with cypermethrins indicate moderate acute toxicity via the oral route and low toxicity via the acute dermal or inhalation routes. Additionally, mild irritation was seen in primary eye and skin irritation studies but no dermal sensitization was observed.
Dermal toxicity studies are available for zeta-cypermethrin (rat) and cypermethrin (rabbit), in which local irritation was observed in rats and rabbits at the highest doses tested. No systemic effects were observed in the 21-day dermal study in the rat conducted with zeta-
cypermethrin at dose levels up to 1,000 milligrams/kilogram/day (mg/kg/
day). In the dermal toxicity study in rabbits with cypermethrin, systemic effects were observed (focal necrosis of the liver, decreased testicular weights, and decreased body weight in females). However, these observations in the rabbit were not used for risk assessment because the testing method (i.e., abraded skin) does not simulate actual exposure and results in compromised test conditions. Additionally, there would be physiological differences between abraded and non-abraded animals, further undermining the relevance of these results for risk assessment.
Developmental toxicity and reproduction studies are available for the cypermethrins. In the developmental toxicity studies in rats with cypermethrin and zeta-cypermethrin, there was no evidence of developmental toxicity up to the highest doses tested. Maternal toxicity included decreased body weight gain and food consumption in both chemicals. Splayed limbs, spasms and hypersensitivity to noise and convulsions were seen with cypermethrin, and ataxia, urine-stained abdominal fur, and fecal-stained fur were seen with zeta-cypermethrin. In the developmental toxicity study in rats with alpha-cypermethrin, offspring effects were limited to decreased fetal body weight. Maternal effects observations in the study were unsteady gait, piloerection, limb splay, and hypersensitivity to sound and touch at the same dose. In the developmental toxicity studies in rabbits with the cypermethrins, there was no evidence of developmental toxicity up to the highest dose tested. Maternal effects seen with cypermethrin included decreased body weight gain, anorexia, abdomino-genital staining, decreased feces, and red or pink material in the pan. With alpha-cypermethrin, maternal effects were body weight loss and decreased food consumption. Multi-generation reproduction studies in rats are available for cypermethrin and zeta-cypermethrin. In the reproduction study with cypermethrin, decreased body weight gain was observed in adult animals and decreased body weight gain was seen in offspring animals at the highest dose tested. In the reproduction study using zeta-cypermethrin, decreased body weight gain and mortality were observed in offspring animals in the presence of mortality, increased brain weights, decreased body weights, and neurotoxicity in maternal animals.
No effects were observed in an immunotoxicity study in rats with alpha-cypermethrin up to the limit dose.
Alpha-cypermethrin is classified as a Group C ``Possible human carcinogen,'' based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in females in a mouse carcinogenicity study. The
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presence of common benign tumors (lung adenomas), in one species (mice) and one sex (female), with no increase in the proportion of malignant tumors or decrease in the time-to-tumor occurrence, together with the lack of mutagenic activity, was not considered strong enough to warrant a quantitative estimation of human risk. Quantification of risk using a non-linear approach (i.e., acute population-adjusted dose (aPAD), acute reference dose (aRfD)) adequately accounts for all chronic toxicity, including carcinogenicity that could result from exposure to alpha-
cypermethrin. While the Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective because increasing toxicity with increasing duration of exposure is not demonstrated for the cypermethrins. The no-
observed-adverse-effect-level (NOAEL) observed in the mouse cancer study in which tumors were observed is 14 mg/kg/day, 2-fold higher than the point of departure (POD) used for acute risk assessment. The lowest-observed-adverse-effect-level (LOAEL) in the mouse cancer study is 57 mg/kg/day based on liver effects, not tumor formation. The tumors were seen at 229 mg/kg/day. The acute POD of 7.16 mg/kg/day selected for risk assessment is 32-fold lower than the dose that induced lung tumors in mice. Only the mouse study with cypermethrin resulted in tumor formation, no evidence of carcinogenicity was observed in cancer studies in rats with cypermethrin or mice with alpha-cypermethrin.
Specific information on the studies received and the nature of the adverse effects caused by chemical name as well as the NOAEL and the LOAEL from the toxicity studies can be found at http://www.regulations.gov in document Human Health Risk Assessment for New Active Ingredient--Alpha-cypermethrin at pg. 23 in docket ID number EPA-HQ-OPP-2012-0185-0005.
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Toxicological Points of Departure and Levels of Concern
Once a pesticide's toxicological profile is determined, EPA identifies toxicological POD and levels of concern (LOC) 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 no adverse effects are observed and the lowest dose at which adverse effects of concern 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, EPA 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 alpha-cypermethrin used for human risk assessment is shown in Table 1 of this unit.
Table 1--Summary of Toxicological Doses and Endpoints for Alpha-Cypermethrin for Use in Human Health Risk
Assessment
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POD and uncertainty/ RfD, PAD, LOC for
Exposure/Scenario safety factors risk assessment Study and toxicological effects
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Acute dietary (children >=6 years Wolansky MDL1SD = aRfD = 0.07 mg/kg/ Wolansky BMD = 11.20 mg/kg/day
old and adults). 7.16 mg/kg/day. day. based on motor activity.
UFA = 10x........... aPAD = 0.07 mg/kg/
UFH = 10x........... day.
FQPA SF = 1x........
Acute dietary (children =6 years old NOAEL = 0.01 mg/L. rat--LOAEL = 0.05 mg/L based on
and adults) (1 to 6 months). HEC = 0.008 mg/L.... increased salvation.
HED = 1.15 mg//kg/
day.
UFA = 3x............
UFH = 10x...........
FQPA SF = 1x........
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Cancer (Oral, dermal, inhalation) Alpha cypermethrin has been classified as a Group C ``Possible human
carcinogen based on lung adenomas in female mice. Because of the rapid
reversibility of the most sensitive neurotoxicity endpoint used for
quantifying risks, there is no increase in hazard with increasing dosing
duration. Therefore, the acute dietary endpoint is protective of the
endpoints from repeat dosing studies, including cancer dietary exposures.
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Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. BMD = benchmark dose. BMDL = benchmark dose (lower confidence limit). UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration. HED = human equivalent dose. Mg/kg/day = milligrams/kilogram/day. Mg/L = milligrams/liter.
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Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to alpha-cypermethrin, EPA considered exposure under the petitioned-for tolerances as well as all existing cypermethrin and zeta-cypermethrin tolerances in 40 CFR 180.418. EPA assessed dietary exposures from alpha-cypermethrin 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 alpha-cypermethrin.
In assessing aggregate risk to alpha-cypermethrin, EPA considered not only the exposure associated with the proposed food uses for alpha-
cypermethrin, but also the potential dietary and drinking water contribution and residential exposure from existing uses of cypermethrin and zeta-cypermethrin. In estimating acute dietary exposure, EPA used food consumption information from the U.S. Department of Agriculture (USDA) 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII). As to residue levels in food, EPA used a partially refined (probabilistic) dietary exposure assessment to determine the exposure and risk estimates which result from the use of cypermethrins on the crops listed under 40 CFR 180.418 and the proposed new uses. Anticipated residues from USDA Pesticide Data Program (PDP) monitoring data, field trial data, and empirical processing factors, and percent crop treated (PCT) estimates for some commodities were used where appropriate.
ii. Chronic exposure. Based on the data summarized in Unit III.A., there is no increase in hazard from repeated exposures to alpha-
cypermethrin; the acute dietary exposure assessment is higher than for chronic dietary exposures because the acute exposure levels are greater than the chronic exposure levels, therefore, a chronic dietary risk assessment was not conducted.
iii. Cancer. As noted in Unit III.A., the Agency has determined that quantification of risk using a non-linear approach (i.e., aPAD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to alpha-cypermethrin. Additionally, because an assessment of cancer risk would estimate exposure based on average residue levels and the acute assessment used high-end residue levels, the acute dietary assessment will be protective of any cancer effects resulting from consumption of alpha-
cypermethrin residues in foods.
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 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 demonstrating that the levels in food are not above the levels anticipated.
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:
Condition a: 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 the pesticide residue.
Condition b: The exposure estimate does not underestimate exposure for any significant subpopulation group.
Condition c: 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.
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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 FFDCA section 408(b)(2)(F), EPA may require registrants to submit data on PCT. The following maximum PCT estimates were used in the acute dietary risk assessment, which was relied on in assessing chronic risk, for the following crops that are currently registered for the cypermethrins: Almonds, 2.5%; apples, 2.5%; broccoli, 30%; cabbage, 30%; carrot, 10%; cauliflower, 25%; celery, 60%; cherries, 5%; grapefruit, 50%; green beans, 20%; green peas, 15%; lemon, 2.5%; lettuce, 65%; orange, 45%; peach, 5%; peppers, 30%; potato, 5%; sweet corn, 20%; spinach, 45%; tomato, 10%; and watermelon, 10%.
The following average PCT estimates were used to calculate average dietary exposures in order to assess short-term aggregate risk to the cypermethrins: Almonds, 1%; apples, 1%; broccoli, 20%; cabbage, 15%; carrot, 2.5%; cauliflower, 15%; celery, 35%; cherries, 5%; grapefruit, 35%; green beans, 15%; green peas, 10%; lemon, 1%; lettuce, 55%; orange, 35%; peach, 2.5%; peppers, 15%; potato, 1%; sweet corn, 15%; spinach, 30%; tomato, 5%; and watermelon, 2.5%. The zeta-cypermethrin PCT data was used as a surrogate for future PCT of alpha-cypermethrin.
In most cases, EPA uses available data from the U.S. Department of Agriculture/National Agricultural Statistics Service (USDA/NASS), proprietary market surveys, and the National Pesticide Use Database for the chemical/crop combination for the most recent 6-7 years. EPA uses an average PCT for chronic dietary risk analysis. The average PCT figure for each existing use is derived by combining available public and private market survey data for that use, averaging across all observations, and rounding to the nearest 5%, except for those situations in which the average PCT is less than 1. In those cases, 1% is used as the average PCT and 2.5% is used as the maximum PCT. EPA uses a maximum PCT for acute dietary risk analysis. The maximum PCT figure is the highest observed maximum value reported within the recent 6 years of available public and private market survey data for the existing use and rounded up to the nearest multiple of 5%.
The Agency believes that the three conditions discussed in Unit III.C.1.iv. have been met. With respect to Condition a, PCT estimates are derived from Federal and private market survey data, which are reliable and have a valid basis. The Agency is reasonably certain that the percentage of the food treated is not likely to be an underestimation. As to Conditions b and c, 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 reliable information on the regional consumption of food to which alpha-cypermethrin may be applied in a particular area.
2. Dietary exposure from drinking water. The Agency used screening level water exposure models in the dietary exposure analysis and risk assessment for alpha-cypermethrin in drinking water. These simulation models take into account data on the physical, chemical, and fate/
transport characteristics of alpha-cypermethrin. 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 First Index Reservoir Screening Tool (FIRST) and Screening Concentration in Ground Water (SCI-GROW) models the estimated drinking water concentrations (EDWCs) of alpha-cypermethrin were 3.77 parts per billion (ppb) for surface water and 0.0036 ppb for ground water. In the dietary risk assessment conducted to support the proposed uses, EPA incorporated the surface water EDWCs directly into the dietary model, since surface water estimates were higher than those provided 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). Alpha-cypermethrin is not registered for any specific use patterns that would result in residential exposure. There are no proposed residential uses associated with alpha-cypermethrin; however, there are registered residential uses for cypermethrin and zeta-cypermethrin that have been reassessed to reflect updates to the Agency's 2012 Residential standard operating procedures (SOPs) along with policy changes for body weight assumptions and inhalation rates. These revised residential exposures have been incorporated into the human health aggregate risk assessment for alpha-
cypermethrin, which must consider all potential exposures to the cypermethrins. The Agency has determined that short-term exposures are likely to occur in a residential setting for the cypermethrins; however, they do not increase in potency with repeated dosing. EPA assessed residential exposure using the following assumptions. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:
Mixer/loader/applicator using hose-end sprayer on turf;
Mixer/loader/applicator using backpack on turf and gardens;
Mixer/loader/applicator using manually pressurized handwand for indoor surfaces;
Application via aerosol can for indoor surfaces and space.
Since a dermal endpoint was not identified, only a quantitative inhalation handler exposure assessment was performed. Residential handler inhalation exposure estimates were calculated based on a human equivalent concentration and human equivalent dose which reflect 24 hours of exposure. Since handler exposure is expected to be significantly less than 24 hours, the inhalation exposure estimates are sufficiently protective of all scenarios (turf, gardens, and indoor surface space). Although there is potential inhalation exposure resulting from the application of dog tags and spot-on products for pets, inhalation exposure is considered negligible for these scenarios and therefore a quantitative assessment was not performed for these uses.
There is the potential for post-application exposure for individuals as a result of being in an environment that has been previously treated with cypermethrin or zeta-cypermethrin. However, the combination of low vapor pressure for chemicals typically used as active ingredients in outdoor residential pesticide products and dilution in outdoor air is likely to result in minimal inhalation exposure. Therefore, a quantitative post-application inhalation exposure assessment for cypermethrin turf uses was not conducted. Since a dermal endpoint was not identified, and indoor post-application inhalation exposure resulting from aerosol space sprays, foggers, and pet (i.e., dog tag, spot-on) uses is negligible, the only
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potential post-application exposure pathways of concern are incidental oral for children, and post-application inhalation exposure for adults and children resulting from indoor crack and crevice applications made with a manually pressurized handwand. The quantitative exposure/risk assessment for residential post-application exposures is based on the following scenarios:
Incidental oral (hand-to-mouth, object-to-mouth, and soil ingestion) exposure from turf for children.
Incidental oral (hand-to-mouth and object-to-mouth) exposure from indoor foggers for children.
Incidental oral (hand-to-mouth and object-to-mouth) exposure from pets for children.
Inhalation exposure for adults and children resulting from crack and crevice application to an indoor surface.
Incidental oral (hand-to-mouth and object-to-mouth) exposure for children from indoor surface applications.
Risk estimates resulting from different exposure routes may be combined when it is likely that they can occur simultaneously based on the use pattern and when the toxicological effects across different routes of exposure are the same. Although, in the case of children, inhalation and incidental oral exposure routes share a common toxicological endpoint, risk estimates were not combined for those routes for turf, indoor fogger, and pet since post-application inhalation exposure is considered negligible. However, inhalation and incidental oral exposures were combined for post-application risk assessment associated with the indoor crack and crevice use. Inhalation and incidental oral routes have different LOCs. Therefore, in order to combine exposure from the various routes, the aggregate risk index (ARI) approach is used to estimate exposure and risk. When this approach is used, aggregate risks are not of concern provided the calculated ARI is greater than 1.
The incidental oral scenarios from indoor exposure following crack and crevice applications and outdoor exposure from turf were not combined, not only because they are not likely to co-occur, but also because combining these scenarios would be overly-conservative due to the conservative nature of each of the individual assessments.
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.''
The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins, including the cypermethrins, share a common mechanism of toxicity. The members of this group share the ability to interact with voltage-gated sodium channels, ultimately leading to neurotoxicity. The cumulative risk assessment for the pyrethroids and pyrethrins was published in the Federal Register on November 9, 2011 (76 FR 69726) (FRL-8888-9), and is available at http://www.regulations.gov in the public docket, EPA-HQ-
OPP-2011-0746. Further information about the determination that pyrethroids and pyrethrins share a common mechanism of toxicity may be found in document ID: EPA-HQ-OPP-2008-0489-0006.
The cypermethrins were included in a recent cumulative risk assessment for pyrethrins and pyrethroids. The proposed new uses of alpha-cypermethrin will not significantly impact the cumulative assessment because, in the cumulative assessment, residential exposure was the greatest contributor to the total exposure. There are no new residential uses for the cypermethrins, and the proposed new uses will have no impact on the residential component of the cumulative risk estimates.
Dietary exposures make a minor contribution to total pyrethroid exposure. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chemical. The dietary exposure assessment for the single chemical included conservative assumptions, using field trial data for many commodities, including the proposed new uses, with the assumption of 100 PCT, and the most sensitive apical endpoint in the cypermethrins hazard database was selected to derive the POD. Additionally, the POD selected for alpha-cypermethrin is specific to the cypermethrins, whereas the POD selected for the cumulative assessment was based on-
common-mechanism-of-action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.
For information regarding EPA's efforts to evaluate the risk of exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.
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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 Food Quality Protection Act (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. In guideline developmental and reproduction studies with the cypermethrins, there was no evidence of increased qualitative or quantitative susceptibility in rats or rabbits.
In a guideline developmental neurotoxicity (DNT) study with zeta-
cypermethrin, there was increased sensitivity in the offspring based on body weight changes in pups (5%-10%) in the absence of treatment-
related effects in maternal animals. Although, there was a 5%-8% decrease in maternal body weight in this study, a body weight decrease of 50 studies (studies assessing what dose results in lethality to 50% of the tested population) in the scientific literature indicate that pyrethroids can result in increased quantitative sensitivity in the young, typically in the form of neurotoxicity. Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to pyrethroid age-dependent pharmacokinetics--the activity of enzymes associated with the metabolism of pyrethroids. With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic models indicate that the differential adult-juvenile pharmacokinetics will result in a 3X greater dose at the target organ in juveniles compared to adults. No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to inter-species differences between rats and humans and to differences between juveniles and adults. Specifically, there are in vitro pharmacodynamic data and in vivo data indicating similar responses between adult and juvenile rats at low doses and data indicating that the rat is a conservative model compared to the human based on species-specific pharmacodynamics of homologous sodium channel isoforms in rats and humans.
3. Conclusion. The FQPA SF was reduced to 1X for the general population, women of child bearing age and children > 6 years. For exposures from birth to Based on an evaluation of over 70 guideline toxicity studies for 24 pyrethroids submitted to the Agency, including prenatal developmental toxicity studies in rats and rabbits, and prenatal and postnatal multi-generation reproduction toxicity studies and DNTs in rats in support of pyrethroid registrations, there is no evidence that pyrethroids directly impact developing fetuses. None of the studies show any indications of fetal toxicity at doses that do not cause maternal toxicity.
Increased susceptibility was seen in offspring animals in the DNT study with zeta-cypermethrin (decreased pup body weights) and DNT and reproduction studies with beta-cyfluthrin (decreased body weights and tremors). However, the reductions in body weight and the other non-specific effects occur at higher doses than neurotoxicity, the effect of concern for pyrethroids. The available developmental and reproduction guideline studies in rats with zeta-cypermethrin did not show increased sensitivity in the young to neurotoxic effects. Overall, findings of increased sensitivity in juvenile animals in pyrethroid studies are rare. Therefore, the residual concern for the postnatal effects is reduced.
High-dose LD50 studies (studies assessing what dose results in lethality to 50% of the tested population) in the scientific literature indicate that pyrethroids can result in increased quantitative sensitivity to juvenile animals. Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to pyrethroid age-dependent pharmacokinetics--the activity of enzymes associated with the metabolism of pyrethroids. Furthermore, a rat PBPK model predicts a three-fold increase of pyrethroid concentration in juvenile brain compared to adults at high doses.
In vitro pharmacodynamic data and in vivo data indicate that adult and juvenile rats have similar responses to pyrethroids at low doses and therefore juvenile sensitivity is not expected at relevant environmental exposures. Further, data also show that the rat is a conservative model compared to the human based on species-specific pharmacodynamics of homologous sodium channel isoforms.
iii. There are no residual uncertainties with regard to dietary and residential exposure. The dietary exposure assessments are based on high-end health protective residue levels (that account for parent and metabolites of concern), processing factors, and PCT assumptions. Furthermore, conservative, upper-bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been underestimated.
Taking all of this information into account, EPA has reduced the FQPA SF for women of child-bearing age and children over 6 years to 1X since after evaluation of over 70 guideline toxicity studies submitted to the Agency, including prenatal developmental toxicity studies in rats and rabbits, and multi-generation reproduction toxicity studies and DNTs in rats, there is no evidence that pyrethroids directly impact developing fetuses. Additionally, none of the studies show any indications of fetal/offspring toxicity at doses that do not cause maternal toxicity. However, since there remains some uncertainty as to juvenile sensitivity due to the findings in the high-dose LD50 studies, EPA is retaining a FQPA SF for infants and children less than 6 years of age. This age group is a close approximation to the most sensitive human population, children from birth to 50 studies. The high doses that produced juvenile sensitivity in the literature studies are well above normal dietary or residential exposure levels of pyrethroids to juveniles and lower levels of exposure anticipated from dietary and residential uses are not expected to overwhelm the juvenile's ability to metabolize pyrethroids, as occurred with the high doses used in the literature studies. The lack of increased neurotoxic sensitivity of the young in the overwhelming majority (69 of 70) of the prenatal and postnatal guideline studies for pyrethroids supports this conclusion, despite the relatively high doses used in those studies. Second, limited in vitro and in vivo data indicate similar pharmacodynamic response to pyrethroids between juvenile and adult rats. The portion of the uncertainty factor that accounts for potential pharmacodynamic differences between animals and humans (i.e., the inter-species extrapolation factor) is likely to overstate the risk of the cypermethrins given the data showing similarities in pharmacodynamics between animals and humans. For the inter-species factor, the pharmacodynamic portion of the factor is generally considered to be 3X. However, for pyrethroids the actual difference is likely to be lower than 3X. In addition, there are data that show that there are no lifestage pharmacodynamic differences between young and adult rats. Standard uncertainty factors, such as those used in the cypermethrin risk assessment, assume that there will be such differences. Finally, as indicated, pharmacokinetic modeling only predicts a 3X difference between juveniles and adults. Thus, even if there is increased juvenile neurotoxic sensitivity and even if the existing interspecies and intraspecies factors do not provide extra protection due to the conservative nature of their pharmacodynamic components for pyrethroids, the 3X additional factor will protect the young. Therefore, the FQPA factor of 3X is protective of potential juvenile sensitivity.
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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.
1. Acute risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food and water to alpha-cypermethrin will occupy 87% of the aPAD for all infants (=6 years old = 100; children
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