Document ID: EPA-HQ-OPP-2010-0472-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-23T05:00Z

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

EPA Registration Division contact: Andrew Ertman (703) 308-9367

IR-4 Project

PP 0E7804

	EPA has received a pesticide petition (PP 0E7804) from IR-4 Project, Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, Princeton, NJ 08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.418 by establishing a tolerance for residues of zeta-cypermethrin in or on the raw agricultural commodities avocado, papaya, star apple, black sapote, mango, sapodilla, canistel, and mamey sapote at 0.45 parts per million (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 in plants is adequately understood. Studies have been conducted to delineate the metabolism of radiolabelled 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 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 avocado show that the proposed zeta-cypermethrin tolerances in or on the raw agricultural commodities avocado, papaya, star apple, black sapote, mango, sapodilla, canistel, and mamey sapote at 0.45 parts per million (ppm) will not be exceeded when the zeta-cypermethrin products labeled for these uses are used as directed.

B. Toxicological Profile

	1. Acute toxicity.  For the purposes of assessing acute dietary risk, the NOAEL of 10.0 mg/kg/day from the zeta-cypermethrin acute neurotoxicity study in rats was used to determine the acute Population Adjusted Dose (aPAD) of 0.1 mg/kg/day. The LOAEL of 50.0 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. The chronic reference dose (cRfD) of 0.06 mg/kg/day for zeta-cypermethrin is based on a NOEL of 6.0 mg/kg/day from a cypermethrin chronic feeding study in dogs and an uncertainty factor of 100. 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. No special studies investigating potential estrogenic or other endocrine effects of cypermethrin have been conducted. However, no evidence of such effects was reported in the standard battery of required toxicology studies which have been completed and found acceptable. Based on these studies, there is no evidence to suggest that cypermethrin has an adverse effect on the endocrine system.  An order has been issued for Tier I screening of cypermethrin as part of the Endocrine Disruptor Screening Program, and Other Scientifically Relevant Information has been submitted for review in response to the order.
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, tolerances for pistachio; globe artichoke; and barley, buckwheat, oat and rye (grain, hay and straw) have been proposed in addition to those included in this petition.  For the purposes of assessing the potential dietary exposure for these existing and the proposed 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 NOAEL of 10.0 mg/kg/day from the zeta-cypermethrin acute neurotoxicity study in rats with an uncertainty factor (UF) of 100 (acute RfD =0.10 mg/kg/day) was used to determine acute dietary risks to all population subgroups.  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 1.04 ppb was provided in EFED's Feb 8, 2007 review (J. Melendez; D334937). The most highly exposed subpopulation for the acute scenario is children 1-2 years old which utilizes 53% of the aPAD at the 99.9th percentile of exposure.  The acute risk estimate for the general population utilizes 24% of the aPAD at the 99.9th percentile of exposure.  The results of the acute dietary assessment are presented in Table 1.
Table 1.	Results for Zeta-Cypermethrin Acute Dietary (Food and Water) Exposure Analysis Using DEEM-FCID at the 99.9th Percentile
                                  Population
                               Exposure Estimate
                                     %aPAD
                                   Subgroups
                                (mg/kg bw/day)
                                       
                                U.S. Population
                                   0.024368
                                     24.37
                         All Infants (< 1 year old)
                                   0.035972
                                     35.97
                           Children (1-2 years old)
                                   0.053316
                                     53.32
                           Children (3-5 years old)
                                   0.047081
                                     47.08
                           Children (6-12 years old)
                                   0.018877
                                     18.88
                            Youth (13-19 years old)
                                   0.023538
                                     23.54
                           Adults (20-49 years old)
                                   0.019506
                                     19.51
                            Adults (50+ years old)
                                   0.024625
                                     24.62
                         Females (13  -  49 years old)
                                   0.019197
                                     19.20

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 chronic reference dose (cRfD) of 0.06 mg/kg/day for zeta-cypermethrin based on a NOEL of 6.0 mg/kg/day from a cypermethrin chronic feeding study in dogs and an uncertainty factor of 100. 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 1% of the cPAD.  The most highly exposed subpopulation for the chronic scenario is children 1-2 years old, utilizing 4% 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 new 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 0.013 ppb was provided in EFED's Feb 8, 2007 review (J. Melendez, D334937).  The results of the chronic dietary assessment are presented in Table 2. 

Table 2. Results for Zeta-Cypermethrin Chronic Dietary (Food and Water) Exposure Analysis Using DEEM-FCID
                                  Population
                               Exposure Estimate
                                     %cPAD
                                   Subgroups
                                (mg/kg bw/day)
                                       
                                U.S. Population
                                   0.000724
                                      1.2
                         All Infants (< 1 year old)
                                   0.001326
                                      2.2
                           Children (1-2 years old)
                                   0.002603
                                      4.3
                           Children (3-5 years old)
                                   0.001848
                                      3.1
                           Children (6-12 years old)
                                   0.001029
                                      1.7
                            Youth (13-19 years old)
                                   0.000604
                                      1.0
                           Adults (20-49 years old)
                                   0.000513
                                      0.9
                            Adults (50+ years old)
                                   0.000547
                                      0.9
                           Females (13-49 years old)
                                   0.000511
                                      0.9

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 1.04 parts per billion (ppb) for surface water and 0.0036 ppb for ground water. The EECs for chronic exposures are estimated to be 0.013 ppb for surface water and 0.0036 ppb for ground water.
Modeled estimates of drinking water concentrations were directly entered into the dietary exposure model. For acute dietary risk assessment, the water concentration value of 1.04 ppb was used to assess the contribution to drinking water. For chronic dietary risk assessment, the water concentration value 0.013 ppb was used to assess the contribution to drinking water.

	2. Non-dietary exposure. Occupational and residential risk 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-occuring 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 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 1X due to the completeness of the toxicology database, the lack of residual concerns regarding pre- and post-natal toxicity, and the reliance on exposure data that are unlikely to underestimate exposure.
   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	
There are no Codex, Canadian or Mexican residue limits for residues of cypermethrin or zeta-cypermethrin in or on representative commodities for avocado, papaya, star apple, black sapote, mango, sapodilla, canistel, and mamey sapote.