Notice of Filing of Pesticide Petitions

EPA has received pesticide petitions as follows proposing the establishment and/or amendment of regulations for residues of certain pesticide chemicals in or on various raw agricultural commodities under section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions contain data or information regarding the elements set forth in section 408(d)(2); 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. The official record for this notice, as well as the public version, has been established for this notice of filing under docket control number PF-811 (including comments and data submitted electronically as described below). A public version of this record, including printed, paper versions of electronic comments, which does not include any information claimed as CBI, is available for inspection from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The official record is located at the address in ``ADDRESSES'' at the beginning of this document. Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

Electronic comments must be submitted as an ASCII file avoiding the use of special characters and any form of encryption. Comment and data will also be accepted on disks in Wordperfect 5.1/6.1 file format or ASCII file format. All comments and data in electronic form must be identified by the docket control number PF-811 and appropriate petition number. Electronic comments on this notice may be filed online at many Federal Depository Libraries.

Authority: 21 U.S.C. 346a.

List of Subjects

Environmental protection, Agricultural commodities, Food additives, Feed additives, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: August 10, 1998.

James Jones, Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

Below summaries of the pesticide petitions are printed. The summaries of the petitions were prepared by the petitioners. The petition summary announces the availability of a description of the analytical methods available to EPA for the detection and measurement of the pesticide chemical residues or an explanation of why no such method is needed.

AgrEvo USA Company

PP 7F4923

EPA has received a pesticide petition (PP 7F4923) from AgrEvo USA Company, Little Falls Centre One, 2711 Centerville Road, Wilmington, DE 19808, proposing pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of buprofezin in or on the raw agricultural commodities head lettuce at 5 parts per million (ppm), leaf lettuce at 13 ppm, and the cucurbits crop group at 0.5 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; 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 metabolic profile of buprofezin has been elucidated in a wide range of crops, including tomatoes, lettuce, and cotton, and citrus. The nature of the residue in all plant species is well defined and comparable from crop to crop. Buprofezin was the only significant residue in tomatoes, lettuce and cotton. Trace levels (1-6%) of two metabolites were also identified. These metabolites correspond to the oxidative loss of N-t- butyl (BF9), followed by opening of the heterocyclic ring with concomitant loss of CH2-S-C=O (BF12). No other single metabolite exceeded 7.5% of the total residue. Some of the minor components were, however, shown to be polar conjugates of BF4 (buprofezin hydroxylated in the t-butyl group) based on work in citrus. In the tomato study, which was run prior to the citrus, cotton and lettuce metabolism studies, these metabolites were not specifically looked for due to the high percentage of the residue accounted for by the parent. 2. Analytical method. Background Metabolism studies on lettuce and tomatoes have shown that the only significant residue in these crops is buprofezin. Development of the analytical method took place in parallel with the metabolism studies and the method was designed to quantify two metabolites (BF9 and BF12) in addition to the parent compound. This method was used for analysis of samples from the field trials on lettuce and cucurbits, but for tolerance enforcement only the parent compound is considered. i. Data collection method. Samples are extracted with acetone. The extracts are filtered and the acetone removed by rotary evaporation. The remaining aqueous extract is acidified with hydrochloric acid and partitioned with hexane. The hexane is applied to a Florisil column and the residues are then eluted from the column with ether/

hexane (50/50). The acidic aqueous phase is adjusted to pH 7 and partitioned into ethyl acetate/hexane (50/50). This organic extract is combined with the eluate from the Florisil column, evaporated to dryness, taken up in toluene and analyzed by GC with NP detection. The limit of quantitation of this method is 0.01ppm in the sample. ii. Tolerance enforcement method. The metabolism work and the field sample analyses showed that the only significant residue in treated crops was buprofezin. Accordingly, the method proposed for tolerance enforcement quantifies only buprofezin. The method is identical to the data collection method except the acid partition step was omitted. The method was validated by an independent laboratory using lettuce, tomato and cucumber as the test matrices. iii. Multiresidue methods. Buprofezin was tested through protocols D and F using tomatoes (a representative non-fatty food) and cottonseed (a representative fatty food). Recoveries were satisfactory such that the multiresidue methods could be used for tolerance enforcement or as confirmatory methods. 3. Magnitude of residues. --i. Residues in lettuce. Head and leaf lettuce were treated with buprofezin in a 40SC formulation at sixteen locations throughout the USA in 1994. APPLAUD 40 SC was applied at the maximum application rate, minimum application interval and minimum preharvest interval. The residues detected in lettuce consisted entirely of buprofezin with no observed residues of metabolites greater than the limit of quantitation. Residues on leaf lettuce ranged between 1.29 ppm and 12.60 ppm. Residues on head lettuce were lower than those detected on leaf lettuce (removal of wrapper leaves on head lettuce resulted in a further reduction in observed residues). With the wrapper leaves in place, residues were between 0.29 ppm and 4.79 ppm. (With wrapper leaves removed, the residues ranged from 0.03 ppm to 1.44 ppm.) Tolerances are therefore proposed for residues of buprofezin in or on head lettuce at 5 ppm, and leaf lettuce at 13 ppm. ii. Residues in representative cucurbits crops. APPLAUD 40 SC Insect Growth Regulator was applied to cucumbers, melons, and summer squash at various geographic locations throughout the United States. The product was applied four times at the maximum application rate, minimum application interval, and minimum preharvest interval. The residue consisted entirely of buprofezin with only a few traces of metabolites, all below the limit of quantitation (LOQ). Residues on cucumbers ranged between 50 for buprofezin was 1,635 mg/kg in males and 2,015 mg/kg in females. The acute rat dermal LD50 was 5,000 mg/kg in both sexes. The 4-hour rat inhalation LC50 was > 4.57 mg/L. Buprofezin was slightly irritating to rabbit eyes and skin and did not induce dermal sensitization in guinea pigs. 2. Genotoxicty. No evidence of genotoxicity was noted in a battery of in vitro and in vivo studies. Studies included Ames Salmonella and mouse lymphoma gene mutation assays, a mouse micronucleus assay, an in vitro human lymphocyte cytogenetics assay and an in vitro rat hepatocyte UDS assay. 3. Reproductive and developmental toxicity. A developmental toxicity study was conducted in rats at dose levels of 0, 50, 200 or 800 mg/kg/day. The (systemic) maternal NOEL for this study was 200 mg/ kg/day based on weight loss, decreased food consumption, clinical signs, increased resorption rate, increased loss of entire litters and one maternal death at 800 mg/kg/day. The developmental (fetal) NOEL was also 200 mg/kg/day based on reduced fetal body weights and increased incidence of delayed ossification at 800 mg/kg/day. Slightly reduced ossification was also noted at 200 mg/kg/day but this was within historical control range and thus not considered to be significant. A developmental toxicity study was conducted in rabbits at dose levels of 0, 10, 50 or 250 mg/kg/day. The maternal (systemic) NOEL was 50 mg/kg/day based on decreased weight gain, decreased food consumption and the complete resorption of 2 litters at 250 mg/kg/day. No evidence of developmental toxicity was noted; therefore the developmental (fetal) NOEL was 250 mg/kg/day, the highest dose tested (HDT). Two rat reproduction studies have been conducted at dietary concentrations of 0, 10, 100 or 1,000 ppm. One was a two-generation study that included a teratological evaluation. The other was a one- generation reproduction study conducted to further evaluate some possible changes noted in the first study. Based on the results from both studies, the parental NOEL was 1,000 ppm (HDT). There were no effects on any reproductive parameters but pup weights were decreased at 1,000 ppm. Thus, the reproductive NOEL was 100 ppm. 4. Subchronic toxicity. A 90-day feeding study was conducted in rats at dietary concentrations of 0, 40, 200, 1,000 or 5,000 ppm. Effects noted at 1,000 and/or 5,000 ppm included decreased weight gain, clinical pathology changes, increased liver and thyroid weights, and gross and/or microscopic evidence of liver, thyroid and kidney lesions. Only marginal effects, consisting of slightly reduced feed intake and slightly decreased glucose levels, were noted at 200 ppm. Although the report conservatively concluded the NOEL to be 40 ppm, the NOEL was considered by the EPA to be 200 ppm (15 mg/kg/day). A 90-day study was conducted in which beagle dogs were administered buprofezin via capsule at dose levels of 0, 2, 10, 50 or 300 mg/kg/day. Effects noted at 50 and/or 300 mg/kg/day included various clinical signs of toxicity, substantially decreased weight gain, clinical pathology changes, increased liver, kidney and thyroid weights, and microscopic liver lesions. The NOEL was 10 mg/kg/day. 5. Chronic toxicity. A 2-year study was conducted in which beagle dogs were administered buprofezin via capsule at dose levels of 0, 2, 20 or 200 mg/kg/day. Effects noted at 20 and/or 200 mg/kg/day included decreased

weight gain, clinical pathology changes, increased liver and thyroid weights, decreased liver function (measured by BSP clearance) and microscopic liver lesions. Although the report concluded that the NOEL for this study was 2 mg/kg/day, marginal effects in females at 2 mg/kg/ day were considered to be a possible effect by the EPA reviewer pending receipt of additional historical control data. These data were submitted with this petition and will establish that the dose of 2 mg/ kg/day is a NOEL for this study. A 2-year rat feeding study was conducted at dietary concentrations of 0, 5, 20, 200 or 2,000 ppm. No evidence of oncogenicity was noted at any dose level. Effects noted at 2,000 ppm included decreased weight gain, increased liver and thyroid weights, and an increased incidence of non-neoplastic liver and thyroid lesions. A possible increase in thyroid lesions was also noted at 200 ppm. According to the EPA reviewer, the NOEL for this study was 200 ppm (10 mg/kg/day). However, the conclusions of the original report and a subsequent histopathological reevaluation, not yet reviewed by the Agency, indicate that the NOEL should be considered to be 20 ppm (1 mg/kg/day). A 2-year mouse feeding study was conducted at dietary concentrations of 0, 20, 200, 2,000 and 5,000 ppm. Effects observed at 2,000 and/or 5,000 ppm included decreased weight gain, minor clinical pathology changes, increased liver weights and an increased incidence of non-neoplastic liver lesions. Increased liver weights were also noted at 200 ppm. Thus, the NOEL was considered to be 20 ppm (1.8 mg/ kg/day). There were slightly increased incidences of liver tumors in females at 5,000 ppm and of lung tumors in males at 200 and 5,000 ppm. The increased incidences of these common tumors were not considered to be treatment-related by either the study director or EPA reviewer but the study was referred to the EPA Carcinogenicity Peer Review Group for further evaluation. 6. Animal metabolism. The metabolism and pharmacokinetics of buprofezin have been evaluated in rats following single oral doses of 10 and 100 mg/kg. These studies indicate that buprofezin is rapidly absorbed and excreted following oral administration, with >90% excreted within 48 hours. Metabolism occurred primarily via hydroxylation of the phenyl ring followed by conjugation and oxidation of the sulfur and cleavage of the thiadiazinone ring. 7. Endocrine disruption. No special studies have been conducted to investigate the potential of buprofezin to induce estrogenic or other endocrine effects. The standard battery of required toxicity studies has been completed. These studies include an evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure. These studies are generally considered to be sufficient to detect any endocrine effects. The only effect noted on endocrine organs was an increased incidence of follicular cell hypertrophy and C-cell hyperplasia of the thyroid gland in rats administered buprofezin at dietary concentrations of 2,000 ppm for 24 months. Buprofezin also caused mild to moderate hepatotoxic effects at this dietary concentration. AgrEvo believes that the effect on the thyroid most likely resulted from increased turnover of T3/T4 in the liver with a resultant rise in TSH secretion (due to the hepatotoxicity). The rat is known to be much more susceptible than humans to these effects due to the very rapid turnover of thyroxine in the blood in rats (12 hours vs. about 5 - 9 days in humans). Therefore, the thyroid pathological changes, which have been noted following administration of high doses of buprofezin, are considered to be of minimal relevance to human risk assessment, particularly considering the low levels of buprofezin to which humans are likely to be exposed.

C. Aggregate Exposure

1. Dietary exposure. Buprofezin is an insect growth regulator which is approved for use under a section 18 emergency exemption for control of whitefly on cotton in Arizona and California and red scale on citrus in California. Non-crop uses of buprofezin are limited to an Experimental Use Permit for use on ornamentals in greenhouses, thus only dietary exposures are being considered. 2. Food. Potential dietary exposures from food commodities under the proposed food tolerances for buprofezin and the approved section 18 temporary tolerances were estimated using the Exposure I software system (TAS, Inc.) and the 1977-78 USDA consumption data. Two scenarios were evaluated. In the first, worst-case scenario, it was assumed that all lettuce and cucurbits contained residues at the proposed tolerance levels of: leaf lettuce (13 ppm), head lettuce (5 ppm) and the cucurbit crop group (0.5 ppm). In addition, since temporary tolerances have been granted under a section 18 emergency exemption for citrus fruit (2.0 ppm), dried citrus pulp (10.0 ppm), cotton seed (1.0 ppm), cotton gin by- products (20 ppm), milk (0.03 ppm), and cattle, sheep, hogs, goats, and horse meat (0.02 ppm), fat (0.02 ppm), and meat by-products (0.5 ppm), these products were also included in the analysis. The section 18 provides for use on cotton in Arizona and California and on citrus in California. Even though the use is restricted to Arizona and California in these section 18s, the worst-case scenario assumed 100% of the crop treated. A slightly more realistic assessment was also conducted using estimates of percent crop treated. But again, the unrealistic assumption was made that all residues would be at the tolerance level in all of the crops that were treated. In addition, the section 18 temporary tolerances are somewhat high, especially those for juice and milk; permanent tolerances based upon new processing and feeding studies will be proposed in the near future when application is made for full registration on cotton and citrus. 3. Drinking water. Exposure to buprofezin from drinking water is expected to be negligible. The potential for buprofezin to leach into groundwater was assessed in various laboratory studies as well as terrestrial field dissipation studies conducted in two locations and in varying soil types. The degradation of buprofezin occurs rapidly with half-lives in soil ranging from 22 to 59 days. No evidence of leaching of parent or degradation products was observed in aged leaching or terrestrial field dissipation studies. The major routes of degradation result in mineralization to carbon dioxide and the formation of ``bound'' residues. Buprofezin tends to bind to the top layers of soil with low mobility. The Koc for most soils fell in the range 2,100- 4,800. The solubility in water is low which will result in minimal field runoff and a low potential for contamination of surface water. Therefore, the contribution of any such residues to the total dietary intake of buprofezin will be negligible. 4. Non-dietary exposure. There is a current Experimental Use Permit (EUP) for the use of buprofezin on ornamentals in greenhouses. Exposure to the general population would be minimal in this use and thus was not considered.

D. Cumulative Effects

At the present time, there are insufficient data available to allow AgrEvo to properly evaluate the potential for cumulative effects with other pesticides to which an individual may be exposed. For the purposes of this assessment, therefore, AgrEvo has assumed that buprofezin does not have

a common mechanism of toxicity with any other registered pesticides. Therefore, only exposure from buprofezin is being addressed at this time.

E. Safety Determination

The toxicity and residue databases for buprofezin are considered to be valid, reliable and essentially complete. The standard margin of safety approach is considered appropriate to assess the risk of adverse effects from exposure to buprofezin for both acute and chronic effects. EPA has adopted a temporary RfD for buprofezin at 0.002 mg/kg/day. This RfD was based on the systemic lowest effect level (LEL) of 2.0 mg/kg/ day (LDT) from a 2-year dog study and using a 1,000-fold uncertainty factor. An extra factor of 10 was added to the standard 100-fold safety factor since the RfD was based on a LEL (rather than a NOEL) and the database lacked an acceptable reproductive study. Additional data have been submitted to upgrade the reproduction study and to support the lowest dose in the 2-year dog study as a NOAEL. With the upgrading of these studies, the critical study for the establishment of a permanent RfD would be the rat chronic/oncogenicity study. The NOEL for this study is 1 mg/kg/day. Applying a standard safety factor of 100 for this study, to account for interspecies extrapolation and intraspecies variation, would result in a RfD of 0.01 mg/kg/day. It is this proposed RfD which was used to assess risk to the public. 1. U.S. population. --i. Acute risk. EPA has previously selected, in their approval of the section 18 emergency exemption use, a developmental NOEL of 200 mg/kg/day from a rat developmental study for the acute dietary endpoint. However, it appears that this is an inappropriate acute endpoint since the clinical effects noted at the higher dose (800 mg/kg/day) occurred only after at least 5 days of dosing and the fetal effects (reduced fetal body weight and delayed ossification) are not likely to be due to an acute (1 day) exposure. Based on this assessment, AgrEvo has not evaluated the risk from acute exposure to any subgroup of the population. Previously, EPA has assessed the acute risk from use of buprofezin on citrus and cotton to the population subgroup of females 13+ years of age. Using the developmental NOEL of 200 mg/kg/day, the Margin of Exposure (MOE), according to EPA calculations, was 5,000 for this subgroup. ii. Chronic risk. Chronic dietary exposures for the US population as a whole utilize 65% of the buprofezin RfD in the worst case scenario of 100% of crop treated and all residues at the proposed tolerance level (lettuce, cucurbits) and temporary tolerance level (cotton, citrus, meat/milk commodities from the section 18s). In the more realistic scenario, adjusting for the percent crop treated, the U.S. population chronic dietary exposure utilizes only 1.75% of the RfD. There is generally no concern for exposures below 100% of the RfD since it represents the level at or below which noappreciable risks to human health is posed. Therefore, there is reasonable certainty that no harm would result to the U.S. population from exposure to buprofezin. 2. Infants and children. Data from rat and rabbit developmental toxicity studies and rat multigeneration reproduction studies are generally used to assess the potential for increased sensitivity to infants and children. The developmental toxicity studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during prenatal development. Reproduction studies provide information relating to reproductive and other effects on adults and offspring from prenatal and postnatal exposure to the pesticide. No indication of increased sensitivity to infants and children was noted in either of the developmental studies. However, in the reproduction studies, the NOEL for pups (100 ppm) was lower than for adults (1,000 ppm). Based on the intake of buprofezin in pups up to 8 weeks of age, the RfD for children, using a 1,000 fold safety factor, would be 0.01 mg/kg/day. This is the same RfD that is calculated for chronic exposure utilizing the rat chronic/oncogenicity study. Evaluation of the dietary exposure to infants and children was conducted utilizing the same assumptions as for the U.S. population as a whole. Adjustment for the percent crop treated resulted in dietary exposures that were 2.5% and 3.4% of the RfD for non-nursing infants less than 1 year old and children (1-6 years), respectively. This scenario still assumes that all residues in the crops that are treated are at the tolerance level. There is generally no concern for exposures below 100% of the RfD since it represents the level at or below which no appreciable risks to human health is posed. Thus, there is a reasonable certainty that no harm will result to the most highly exposed population subgroups, non- nursing infants, less than 1 year old, and children between 1 and 6 years of age, from exposure to buprofezin.

F. International Tolerances

Buprofezin was reviewed by the Joint Meeting of the Food and Agriculture Organization Panel of Experts on Pesticide Residues in Food and the Environment and the World Health Organization Expert Group on Pesticide Residues (JMPR) to establish Codex MRLs in 1991, 1995 and 1997. Permanent MRLs were granted for cucumbers and tomatoes, and a temporary MRL was granted for oranges, as described below. Additional residue trial data on oranges will be available for the 1999 JMPR meeting to determine if this MRL should also be made permanent.

------------------------------------------------------------------------ Commodity MRL ------------------------------------------------------------------------ Cucumber 0.3 ppm Tomato 0.5 ppm Oranges, Sweet, Sour 0.3 ppm (temporary). ------------------------------------------------------------------------

[FR Doc. 98-22429 Filed 8-25-98; 8:45 am] BILLING CODE 6560-50-F