         FQPA Supplemental Information Document for Zeta-Cypermethrin


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

IR-4 Project, Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, Princeton, NJ 08540

PP #0E7717

	EPA has received a pesticide petition (PP #0E7717) 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 commodity pistachio at 0.05  parts per million (ppm), artichoke, globe at 0.80  parts per million (ppm), barley, grain at 1.7  parts per million (ppm), barley, hay at 5.0  parts per million (ppm), barley, straw at 19.0  parts per million (ppm), buckwheat, grain at 1.7  parts per million (ppm), buckwheat, hay at 5.0  parts per million (ppm), buckwheat, straw at 19.0  parts per million (ppm), oat, grain at 1.7  parts per million (ppm), oat, hay at 5.0  parts per million (ppm), oat, straw at 19.0  parts per million (ppm), rye, grain at 1.7  parts per million (ppm), rye, hay at 5.0  parts per million (ppm), and rye, straw at 19.0  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 tree nuts, globe artichoke, barley, buckwheat, oat and rye show that the proposed zeta-cypermethrin tolerances in or on the raw agricultural commodity pistachio at 0.05  parts per million (ppm), artichoke, globe at 0.80  parts per million (ppm), barley, grain at 1.7  parts per million (ppm), barley, hay at 5.0  parts per million (ppm), barley, straw at 19.0  parts per million (ppm), buckwheat, grain at 1.7  parts per million (ppm), buckwheat, hay at 5.0  parts per million (ppm), buckwheat, straw at 19.0  parts per million (ppm), oat, grain at 1.7  parts per million (ppm), oat, hay at 5.0  parts per million (ppm), oat, straw at 19.0  parts per million (ppm), rye, grain at 1.7  parts per million (ppm), rye, hay at 5.0  parts per million (ppm), and rye, straw at 19.0  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, FMC has used the NOEL of 10.0 mg/kg/day from the zeta-cypermethrin acute neurotoxicity study in rats. 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/HGPTT 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.


	4. Subchronic toxicity. Short- and intermediate-term toxicity (incidental oral exposure). The NOEL of 10.0 mg/kg/day based on clinical signs at the LEL of 50.0 mg/kg/day in the zeta-cypermethrin acute neurotoxicity study in rats would also be used for short-term %aPAD and MOE calculations (as well as acute, discussed in (1) above), and the NOEL of 5.0 mg/kg/day based on decreased motor activity in the
zeta-cypermethrin subchronic neurotoxicity study in rats, would be used for intermediate-term MOE calculations.
	5. Chronic toxicity. a. The chronic reference dose (RfD) 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 effect of concern 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 upon limited evidence for carcinogenicity in female mice; assignment of a Q* has not been recommended.
	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 were 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.

C. Aggregate Exposure

	1. Dietary exposure 	
      i. Food. Permanent tolerances, in support of registrations, currently exist for residues of zeta-cypermethrin on: alfalfa hay, alfalfa forage, alfalfa seed, aspirated grain fractions, sugar beets (roots and tops), head, stem and leafy Brassica vegetables, cabbage, field corn grain, pop corn grain, field corn forage, field corn stover, pop corn stover, sweet corn (K+CWHR), sweet corn forage, sweet corn stover, cotton undelinted seed, Citrus fruits (and dried pulp and oil), dried shelled peas and beans, edible podded legume vegetables, fruiting vegetables (except Cucurbits), leafy vegetables, head lettuce, bulb and green onions, pecans, rice grain, rice hulls, rice straw, sorghum forage, sorghum grain, sorghum stover, soybean seed, succulent shelled peas and beans, sugarcane, wheat forage, wheat grain, wheat hay, wheat straw, almond hulls, nongrass animal feed forage and hay, berries, cilantro leaves, pome fruit, stone fruit, grape, grass forage, fodder and hay group (forage and hay), tree nuts, peanut, rapeseed (canola), sunflower, sunflower refined oil, safflower seed, flax seed, oilseeds (seed and refined oil), turnip greens, cucurbit vegetables, root and tuber vegetables, okra, rice grain (wild), meat, fat and meat byproducts of cattle, goats, hogs, horses, sheep and poultry, eggs, milk and milk fat. For the purposes of assessing the potential dietary exposure for these existing and the subject proposed tolerances, FMC has utilized available information on anticipated residues, monitoring data and percent crop treated as follows:
Acute exposure and risk. Acute dietary exposure 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 one day or single exposure. For the purposes of assessing acute dietary risk for zeta-cypermethrin, FMC has used the NOEL 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). The LEL 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.  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. These assessments show that the percent acute Population Adjusted Dose (%aPAD) all fall below the EPA's level of concern (>= 100%). The 95th percentile of exposure for the overall U. S. population was estimated to be 0.002259 mg/kg/day (%aRfD of 2.26); 99[th] percentile 0.006990 mg/kg/day (%aRfD of 6.99); and 99.9th percentile 0.024661 mg/kg/day (%aRfD of 24.66). The 95th percentile of exposure for all infants (<1 year) was estimated to be 0.004860 mg/kg/day (%aRfD of 4.86); 99th percentile 0.012677 mg/kg/day (%aRfD of 12.68); and 99.9th percentile 0.035462 mg/kg/day (%aRfD of 35.46). The 95th percentile of exposure for children 1 to 2 years old and children 3 to 5 years old was estimated to be, respectively, 0.006431 mg/kg/day (%aRfD of 6.43) and 0.004420 mg/kg/day (%aRfD of 4.42); 99th percentile 0.015624 mg/kg/day (%aRfD of 15.62) and 0.011144 (%aRfD of 11.14); and 99.9th percentile 0.053514 mg/kg/day (%aRfD of 53.51) and 0.047157 (%aRfD of 47.16). The 95th percentile of exposure for females (13-49 years) was estimated to be 0.001929 mg/kg/day (%aRfD of 1.93); 99th percentile 0.005332 mg/kg/day (%aRfD of 5.33); and 99.9th percentile 0.020416 mg/kg/day (%aRfD of 20.42). Therefore, FMC concludes that the acute dietary risk of zeta-cypermethrin, as estimated by the dietary risk assessment, does not appear to be of concern.
Chronic exposure and risk. 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 effect of concern was based on clinical signs. A chronic dietary exposure/risk assessment has been performed for zeta-cypermethrin using the above cRfD.   Available information on anticipated residues, monitoring data and percent crop treated was incorporated into the analysis to estimate the anticipated residue contribution (ARC). The ARC is generally considered a more realistic estimate than an estimate based on tolerance level residues. The ARC are estimated to be 0.000691 mg/kg body weight (bwt)/day and utilize 1.2 percent of the cRfD for the overall U. S. population. The ARC for all infants (<1 year) are estimated to be 0.001234 mg/kg (bwt)/day and utilizes 2.1 percent of the cRfD. The ARC for children 1 to 2 years old and children 3 to 5 years old are estimated to be 0.0025071 mg/kg (bwt)/day and 0.001781 mg/kg (bwt)/day and utilizes 4.2 percent and 3.0 percent of the cRfD, respectively. The ARC for females (13-49 years) is estimated to be 0.000483 mg/kg (bwt)/day and utilizes 0.8 percent of the RfD. Generally speaking, the EPA has no cause for concern if the total dietary exposure from residues for uses for which there are published and proposed tolerances is less than 100 percent of the cRfD. Therefore, FMC concludes that the chronic dietary risk of zeta-cypermethrin, as estimated by the dietary risk assessment, does not appear to be of concern.

	ii. Drinking water. Laboratory and field data have demonstrated that cypermethrin is immobile in soil and will not leach into groundwater. Other data show that cypermethrin is virtually insoluble in water and extremely lipophilic. As a result, FMC concludes that residues reaching surface waters from field runoff will quickly adsorb to sediment particles and be partitioned from the water column. Drinking water estimated concentrations (DWEC) and the corresponding drinking water level of comparison (DWLOC) values were calculated for chronic and acute exposures. The results show that all DWLOC values exceed the DWEC values. Thus, exposure to zeta-cypermethrin and cypermethrin residues in drinking water is not of concern. US EPA's draft SOP for Incorporating Estimates of Drinking Water Exposure Into Aggregate Risk Assessments was used to perform a drinking water analysis. This SOP utilizes a variety of tools to conduct drinking water assessment. These tools include water models such as FQPA Index Reservoir
Screening Tool (FIRST), PRZM/EXAMS, SCIGROW and monitoring data. If monitoring data are not available then the models are used to predict potential residues in drinking water. The technique recommended in the drinking water SOP compares a calculated Drinking Water Level of Comparison (DWLOC) value to the Drinking Water Estimated Concentration (DWEC) value. The DWEC value results
from either the monitoring data residues or modeled water residues. If the DWLOC value exceeds the DWEC value then there is reasonable certainty that no harm will result from the acute or chronic aggregate exposure. In the case of cypermethrin and zeta-cypermethrin, monitoring data do not exist. Therefore, the FIRST model was used to estimate a surface water residue. The risk assessment for drinking water compares two values: the DWLOC and the DWEC. The DWLOC is the drinking water level of comparison. This is the maximum allowable drinking water concentration (in ppb). The DWEC is the drinking water environmental concentration, which is derived either from monitoring studies or from modeling. If the DWLOC is greater than the DWEC, then the overall exposure from water, food, and residential is considered to be acceptable. The calculated DWLOC values for acute and chronic exposures for all adults, adult females and children exceed the modeled DWEC surface water residues. Therefore, there is reasonable certainty that no harm will result from cumulative and aggregate (food and water) exposure to cypermethrin and zeta-cypermethrin residues.

	2. Non-dietary exposure. Occupational and residential risk were recently assessed for cypermethrin and zeta-cypermethrin under the re-registraion process for cypermethrin.  For occupational 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 handlers are below the Agency's level of concern (i.e., MOE >100) at baseline (long sleeved shirt, long pants, shoes and socks).  Occupational 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.  There are no residential handler scenarios for zeta-cypermethrin. All registered uses of zeta-cypermethrin are for occupational use only.  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	In consideration of potential cumulative effects of zeta-cypermethrin and other substances that may have a common mechanism of toxicity, to our knowledge there are currently no available data or other reliable information indicating that any toxic effects produced by zeta-cypermethrin would be cumulative with those of other chemical compounds; thus only the potential risks of zeta-cypermethrin have been considered in this assessment of its aggregate exposure. FMC intends to submit information for the EPA to consider concerning potential cumulative effects of zeta-cypermethrin consistent with the schedule established by EPA at 62 Federal Register 42020 (August 4, 1997) and other EPA publications pursuant to the Food Quality Protection Act.


E. Safety Determination

	1. U.S. population.  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 effect of concern was based on clinical signs. A chronic dietary exposure/risk assessment has been performed for zeta-cypermethrin using the above cRfD. Available information on anticipated residues, monitoring data and percent crop treated was incorporated into the analysis to estimate the anticipated residue contribution (ARC). The ARC is generally considered a more realistic estimate than an estimate based on tolerance level residues. The ARC are estimated to be 0.000691 mg/kg body weight (bwt)/day and utilize 1.2 percent of the cRfD for the overall U. S. population. The ARC for all infants (<1 year) are estimated to be 0.001234 mg/kg (bwt)/day and utilizes 2.1 percent of the cRfD. The ARC for children 1 to 2 years old and children 3 to 5 years old are estimated to be 0.0025071 mg/kg (bwt)/day and 0.001781 mg/kg (bwt)/day and utilizes 4.2 percent and 3.0 percent of the cRfD, respectively. The ARC for females (13-49 years) is estimated to be 0.000483 mg/kg (bwt)/day and utilizes 0.8 percent of the RfD.  Generally speaking, the EPA has no cause for concern if the total dietary exposure from residues for uses for which there are published and proposed tolerances is less than 100 percent of the cRfD. Therefore, FMC concludes that the chronic dietary risk of zeta-cypermethrin, as estimated by the dietary risk assessment, does not appear to be of concern.
Acute dietary exposure 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 one day or single exposure. For the purposes of assessing acute dietary risk for zeta-cypermethrin, FMC has used the NOEL 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). The LEL 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. 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. These assessments show that the percent acute Population Adjusted Dose (%aPAD) all fall below the EPA's level of concern (>=100%).   The 95th percentile of exposure for the overall U. S. population was estimated to be 0.002259 mg/kg/day (%aRfD of 2.26); 99[th] percentile 0.006990 mg/kg/day (%aRfD of 6.99); and 99.9th percentile 0.024661 mg/kg/day (%aRfD of 24.66). The 95th percentile of exposure for all infants (<1 year) was estimated to be 0.004860 mg/kg/day (%aRfD of 4.86); 99th percentile 0.012677 mg/kg/day (%aRfD of 12.68); and 99.9th percentile 0.035462 mg/kg/day (%aRfD of 35.46). The 95th percentile of exposure for children 1 to 2 years old and children 3 to 5 years old was estimated to be, respectively, 0.006431 mg/kg/day (%aRfD of 6.43) and 0.004420 mg/kg/day (%aRfD of 4.42); 99th percentile 0.015624 mg/kg/day (%aRfD of 15.62) and 0.011144 (%aRfD of 11.14); and 99.9th percentile 0.053514 mg/kg/day (%aRfD of 53.51) and 0.047157 (%aRfD of 47.16). The 95th percentile of exposure for females (13-49 years) was estimated to be 0.001929 mg/kg/day (%aRfD of 1.93); 99th percentile 0.005332 mg/kg/day (%aRfD of 5.33); and 99.9th percentile 0.020416 mg/kg/day (%aRfD of 20.42). Therefore, FMC concludes that the acute dietary risk of zeta-cypermethrin, as estimated by the dietary risk assessment, does not appear to be of concern.

	2. Infants and children.  
a. General. In assessing the potential for additional sensitivity of infants and children to residues of zeta-cypermethrin, FMC considered data from developmental toxicity studies in the rat and rabbit, and a two-generation reproductive study in the rat. The data demonstrated no indication of increased sensitivity of rats to zeta-cypermethrin or rabbits to cypermethrin in utero and/or postnatal exposure to zeta-cypermethrin or cypermethrin. The developmental toxicity studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during prenatal development to one or both parents. Reproduction studies provide information relating to effects from exposure to the pesticide on the reproductive capability of mating animals and data on systemic toxicity. 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.
b. Developmental toxicity studies. In the prenatal developmental toxicity studies in rats and rabbits, there was no evidence of developmental toxicity at the highest doses tested (35.0 mg/kg/day in rats and 700 mg/kg/day in rabbits). Decreased body weight gain was observed at the maternal LOEL in each study; the maternal NOEL was established at 12.5 mg/kg/day in rats and 100 mg/kg/day in rabbits.
c. Reproductive toxicity study. In the two-generation reproduction study in rats, offspring toxicity (body weight) and parental toxicity (body weight, organ weight, and clinical signs) was observed at 27.0 mg/kg/day and greater. The parental systemic NOEL was 7.0 mg/kg/day and the parental systemic LOEL was 27.0 mg/kg/day. There were no developmental (pup) or reproductive effects up to 45.0 mg/kg/day, highest dose tested.
d. Pre- and post-natal sensitivity.
i. Pre-natal. There was no evidence of developmental toxicity in the studies at the highest doses tested in the rat (70.0 mg/kg/day) or in the rabbit (700 mg/kg/day).  Therefore, there is no evidence of a special dietary risk (either acute or chronic) for infants and children which would require an additional safety factor.
ii. Post-natal. Based on the absence of pup toxicity up to dose levels which produced toxicity in the parental animals, there is no evidence of special post-natal sensitivity to infants and children in the rat reproduction study.
e. Conclusion. Based on the above, FMC concludes that reliable data support use of the standard 100-fold uncertainty factor, and that an additional uncertainty factor is not needed to protect the safety of infants and children. As stated above, aggregate exposure assessments utilized significantly less than 1 percent of the RfD for either the entire U. S. population or any of the 26 population subgroups including infants and children. Therefore, it may be concluded that there is reasonable certainty that no harm will result to infants and children from aggregate exposure to zeta-cypermethrin residues.


F. International Tolerances	There are no Canadian, or Mexican residue limits for residues of cypermethrin or zeta-cypermethrin in or on representative commodities for pistachio, globe artichoke or barley, buckwheat, oat and rye (grain, hay and straw).  The Codex MRLs for cypermethrin are for barley at 0.50 ppm.

