Document ID: EPA-HQ-OPP-2014-0889-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-01-28T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Autumn Metzger (703) 305-5314

FMC Corporation

4F8290

	EPA has received a pesticide petition 4F8290 from FMC Corporation, 1735 Market Street, Philadelphia, PA 19103, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend the tolerances in 40 CFR part 180.418 for residues of zeta-cypermethrin in or on the raw agricultural commodities Corn, field, forage from 0.2 parts per million (ppm) to 9.0 ppm; Corn, field, stover from 3.0 ppm to 30.0 ppm; and Corn, pop, stover from 3.0 ppm to 30.0 ppm.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition.  Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism.  The metabolism of cypermethrin and zeta-cypermethrin in plants is adequately understood.  Studies have been conducted to delineate the metabolism of radiolabeled cypermethrin in various crops all showing similar results.  The residue of concern is the parent compound only.

	2. Analytical method.  There is a practical analytical method for detecting and measuring levels of cypermethrin and zeta-cypermethrin in or on food with a limit of detection that allows monitoring of food with residues at or above the levels set in these tolerances (Gas Chromatography with Electron Capture Detection (GC/ECD).

	3. Magnitude of residues.  Crop field trial residue data from studies conducted at the maximum label rates for representative commodities for field corn show that the proposed zeta-cypermethrin tolerances in or on the raw agricultural commodities corn, field, forage at 9.0 parts per million (ppm); corn, field, stover at 30.0 ppm; and corn, pop, stover at 30.0 ppm will not be exceeded when zeta-cypermethrin products labeled for these uses are applied as directed.

B. Toxicological Profile

	1. Acute toxicity.  For the purposes of assessing acute dietary risk, the BMDL1SD of 7.16 mg/kg/day based on neurotoxicity (motor activity) was used to determine the acute Population Adjusted Dose (aPAD) of 0.07 mg/kg/day.  The BMD of 11.20 mg/kg/day was based on clinical signs.  This acute dietary endpoint is used to determine acute dietary risks to all population subgroups.
	2. Genotoxicty.  The following genotoxicity tests were all negative: in vivo chromosomal aberration in rat bone marrow cells; in vitro cytogenic chromosome aberration; unscheduled DNA synthesis; CHO/HGPT mutagen assay; weakly mutagenic: gene mutation (Ames).
	3. Reproductive and developmental toxicity.  No evidence of additional sensitivity to young rats was observed following pre- or postnatal exposure to zeta-cypermethrin.
      a. A two-generation reproductive toxicity study with zeta-cypermethrin in rats demonstrated a NOEL of 7.0 mg/kg/day and a LOEL of 27.0 mg/kg/day for parental/systemic toxicity based on body weight, organ weight, and clinical signs.  There were no adverse effects in reproductive performance.  The NOEL for reproductive toxicity was considered to be > 45.0 mg/kg/day (the highest dose tested).
      b. A developmental study with zeta-cypermethrin in rats demonstrated a maternal NOEL of 12.5 mg/kg/day and a LOEL of 25 mg/kg/day based on decreased maternal body weight gain, food consumption and clinical signs.  There were no signs of developmental toxicity at 35.0 mg/kg/day, the highest dose level tested.
      c. A developmental study with cypermethrin in rabbits demonstrated a maternal NOEL of 100 mg/kg/day and a LOEL of 450 mg/kg/day based on decreased body weight gain.  There were no signs of developmental toxicity at 700 mg/kg/day, the highest dose level tested.
      d. In a rat developmental neurotoxicity (DNT) study there were no maternal effects at the highest dose tested.  The offspring NOAEL and LOAEL were set at 7.4 and 17.3 mg/kg/day, respectively, based on reduced body weight and body weight gain in female pups.
	4. Subchronic toxicity.  The short- and intermediate-term incidental oral exposure risk assessment is based on a NOAEL of 7.4 mg/kg/day from the developmental neurotoxicity study in rats.  The endpoint of concern is the decreased body weight seen in the offspring at the LOAEL of 17.3 mg/kg/day.  The dose and endpoint are appropriate for the route (oral), population (infants and children) and duration (seen during lacation days 13 - 21) of concern.
	5. Chronic toxicity. a. A zeta-cypermethrin NOEL of 6.0 mg/kg/day is available from a cypermethrin chronic feeding study in dogs.  The endpoint was based on clinical signs.
b. Cypermethrin is classified as a Group C chemical (possible human carcinogen with limited evidence of carcinogenicity in animals) based on an increased incidence of lung adenomas and combined adenomas plus carcinomas in female mice.  The 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 evidence to warrant a quantitative estimation of human cancer risk.  The chronic reference dose has been considered protective for all chronic effects as well as any potential cancer effects.
      
	6. Animal metabolism.  The metabolism of cypermethrin in animals is adequately understood.  Cypermethrin has been shown to be rapidly absorbed, distributed, and excreted in rats when administered orally.  Cypermethrin is metabolized by hydrolysis and oxidation.
      7. Metabolite toxicology.  The Agency has previously determined that the metabolites of cypermethrin are not of toxicological concern and need not be included in the tolerance expression nor in the risk exposure assessments.
	8. Endocrine disruption. Cypermethrin has been tested in eight of the eleven assays that are part of the EDSP (Endocrine Disruptor Screening Program) Tier 1 testing scheme and other scientifically relevant information (OSRI) is available that satisfies the requirements of the other three Tier 1 assays based on prior USEPA evaluation and acceptance of published literature studies.  The weight of evidence derived from the EDSP Tier 1 battery studies, OSRI studies, and other FIFRA guideline studies support the conclusion that cypermethrin does not alter the estrogen, androgen or steroidogenesis pathways of test systems.  There is no evidence to support a conclusion that cypermethrin results in alteration of either the hypothalamic-pituitary-gonadal axis or the hypothalamic-pituitary-thyroidal axis.  The available database and weight of evidence evaluation indicate that cypermethrin does not interact with endocrine systems in the EDSP Tier 1 screening and does not cause toxicity to endocrine organs and systems in higher tier in vivo Guideline studies.

C. Aggregate Exposure
	1. Dietary exposure 	
      i. Food. For the purposes of assessing the potential dietary exposure to zeta-cypermethrin the established tolerances were used (40 CFR 180.418).  In addition, amended tolerances for corn, field, forage; corn, field, stover; and corn, pop, stover have been proposed in this petition.  As corn forage and stover are animal feed commodities and a previous dietary assessment was made using the currently established tolerance on animal feed, nongrass, at 40 ppm (IR-4 zeta-cypermethrin tolerance petition for tropical fruits (PP 0E7804, Fed Reg Vol. 76, No. 38, February 25, 2011) this petition to amend the tolerances on corn, field, forage to 9.0 ppm; corn, field, stover to 30.0 ppm; and corn, pop, stover to 30.0 ppm will not change the results of the dietary exposure risk assessment.  For the purposes of assessing the potential dietary exposure for the existing and the proposed amended tolerances, available information on anticipated residues, monitoring data and percent crop treated has been utilized as follows:
Acute exposure and risk.  The acute dietary exposure estimates for zeta-cypermethrin, as estimated by the dietary risk assessment, do not appear to be of concern.  The BMDL1SD of 7.16 mg/kg/day from the zeta-cypermethrin acute neurotoxicity study in rats with an uncertainty factor (UF) of 100 (acute RfD = 0.07 mg/kg/day) and an additional FQPA SF of 3x for children <6 years old was used to determine acute dietary risks to all population subgroups (DP Numbers: D403600 and D403615).  Available information on anticipated residues, monitoring data and percent crop treated was incorporated into a Tier 3 analysis, using Monte Carlo modeling for commodities that may be consumed in a single serving.  Drinking water was incorporated directly in the dietary assessment.  The acute drinking water concentration of 3.77 ppb was provided in EFED's February 22, 2011 assessment (DP Numbers: D378901 and D385246).  The most highly exposed subpopulation for the acute scenario is children 1-2 years old and infants <1 yr, which utilize 87% of the aPAD at the 99.9th percentile of exposure.  The acute risk estimate for the general population utilizes 18% of the aPAD at the 99.9th percentile of exposure.
The results of the analysis show that for all populations, the estimated exposures are below the Agency's level of concern (< 100% aPAD).
Chronic exposure and risk.  A chronic dietary exposure/risk assessment has been performed for zeta-cypermethrin using the acute reference dose (aRfD) of 0.023 mg/kg/day for zeta-cypermethrin paired with average dietary exposure estimates for cypermethrins (DP Numbers: D403600 and D403615).  Available information on anticipated residues, monitoring data and percent crop treated was incorporated into the analysis.  The chronic dietary risk estimates for food and drinking water are below the EPA level of concern.  The chronic exposure for the general U.S. population is 4% of the cPAD.  The most highly exposed subpopulation for the chronic scenario is children 1-2 years old, utilizing 15% of the cPAD.
 For the chronic analysis, anticipated residue levels are utilized for most crops.  These anticipated residues were derived from previous analyses for cypermethrin and zeta-cypermethrin.  Anticipated residues (average field trial values) were calculated for the proposed amended uses from the field trial data.  Exposure estimates are based on these anticipated residues, USDA PDP monitoring data, and processing factors.  Drinking water was incorporated directly in the dietary assessment.  The chronic drinking water concentration of 0.066 ppb was provided in EFED's Feb 22, 2011 review (DP Numbers: D378901 and D385246).
The results of the analysis show that for all populations, the exposures are far below a level of concern (< 100% cPAD).
	ii. Drinking water.  For cypermethrin /zeta-cypermethrin, comprehensive water monitoring data do not exist for use in a dietary exposure analysis and risk assessment in drinking water.  Therefore drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the environmental fate characteristics of cypermethrin/zeta-cypermethrin. 
Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-GROW) models, the estimated environmental concentrations (EECs) of cypermethrin/zeta-cypermethrin for acute exposures are estimated to be 3.77 parts per billion (ppb) for surface water and 0.0036 ppb for ground water.  The EECs for chronic exposures are estimated to be 0.047 ppb for surface water and < 0.0036 ppb for ground water.  These estimates are based on EFED's Feb 22, 2011 review (DP Numbers: D378901 and D385246).  Version 1.06 of the EFED model PRZM-GW was also used to estimate groundwater contribution to the dietary risk cup, but estimated residues in water were lower than those estimated from SCI-GROW.
Modeled estimates of drinking water concentrations were directly entered into the dietary exposure model.  For acute dietary risk assessment, the water concentration value of 3.77 ppb was used to assess the contribution to drinking water.  For chronic dietary risk assessment, the water concentration value 0.066 ppb was used to assess the contribution to drinking water.
	2. Non-dietary exposure.  Occupational and residential risks were assessed for cypermethrin and zeta-cypermethrin under the re-registration process for cypermethrin.  For occupational and residential handler risk, short- and intermediate-term dermal risks were not assessed for occupational handlers since no short- or intermediate-term dermal endpoints were identified.  When data were available to assess risks, short- and intermediate-term inhalation risks to occupational and residential handlers are below the Agency's level of concern (i.e., MOE >100) at baseline.  Occupational and residential post-application exposures and risks were not assessed for applications of cypermethrin and zeta-cypermethrin to residential and commercial lawns, and in and around industrial, commercial, and residential premises since no short- or intermediate-term dermal endpoints of concern were identified and long-term exposures are not expected for tasks involving any of the registered use patterns.  Post-application risks to toddlers from incidental oral ingestion were assessed using a short-term incidental oral endpoint (10 mg/kg/day) for zeta-cypermethrin.  For residential post-application risks, MOEs are not a concern for any of the oral non-dietary scenarios, because they are greater than 100 and do not exceed HED's level of concern (i.e., MOE < 100) for risk assessments in non-occupational settings.  When the post-application risks to toddlers from incidental oral ingestion following applications to lawns were combined, the results indicate that the combined risks are below EPA's level of concern.

D. Cumulative Effects	
Section 408(b)(2)(D)(v) of the 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.  
   Cypermethrin is a member of the pyrethroid class of pesticides.  EPA has developed a draft science policy document on the proposed common mechanism of toxicity for naturally-occurring pyrethrins and pyrethroids.  This document was supported by the FIFRA Scientific Advisory Panel.  In addition, there is ongoing research by the EPA's Office of Research and Development to make improvements to the SHEDS model as well as development of physiologically-based pharmacokinetic models.  When available, the Agency will consider this research and make a determination of a basis for assessing cumulative risk.  FMC will submit information for EPA to consider concerning potential cumulative effects of zeta-cypermethrin consistent with the schedule established by EPA at 62 Federal Register 42020 (Aug. 4, 1997) and other EPA publications pursuant to the Food Quality Protection Act.

E. Safety Determination
	1. U.S. population.  Based on the current risk assessments, there is a reasonable certainty that no harm will result to the general population from exposure to zeta-cypermethrin residues from the proposed amended uses.
	2. Infants and children.  In assessing the potential for additional sensitivity of infants and children to residues of zeta-cypermethrin, data from developmental toxicity studies in the rat and rabbit, and a two-generation reproductive study in the rat, and a developmental neurotoxicity study in the rat were considered.  The data demonstrated no indication of increased sensitivity from in utero and/or postnatal exposure to zeta-cypermethrin or cypermethrin.  FFDCA section 408 provides that EPA may apply an additional margin of safety for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the database.  For zeta-cypermethrin, the FQPA safety factor has been set at 3X based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics (D381210, E. Scollon and A. Lowit, 27-June-2011).
   Based on the current risk assessment, there is reasonable certainty that no harm to infants and children will result from aggregate acute or chronic dietary (food and drinking water) exposure to zeta-cypermethrin residues. 
   
F. International Tolerances	
Although a Codex MRL of 10 mg/Kg for cypermethrin (including alpha- and zeta-cypermethrin) was established in 2009 on straw and fodder (dry) of cereal grains there are no established Codex, Canadian or Mexican residue limits for residues of cypermethrin or zeta-cypermethrin in or on the specific commodities of field corn forage, field corn stover, and pop corn stover.