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Thiazopyr (Rohm & Haas). Nov 22, 1996, Pesticide Tolerance Petition. Federal Register.
[Federal Register: November 22, 1996 (Volume 61, Number 227)] [Notices] [Page 59440-59443] >From the Federal Register Online via GPO Access [wais.access.gpo.gov] ----------------------------------------------------------------------- ENVIRONMENTAL PROTECTION AGENCY [PF-673; FRL-5573-8] Pesticide Tolerance Petition; Notice of Filing AGENCY: Environmental Protection Agency (EPA). ACTION: Notice of filing. ----------------------------------------------------------------------- SUMMARY: This notice is a summary of a pesticide petition proposing the establishment of a regulation for residues of thiazopyr in or on orange and grapefruit. This summary was prepared by the petitioner. DATES: Comments, identified by the docket number [PF-673], must be received on or before, December 23, 1996. ADDRESSES: By mail, submit written comments to Public Response and Program Resources Branch, Field Operations Division (7506C), Office of Pesticide Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. In person, bring comments to Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA 22202. Comments and data may also be submitted electronically by sending electronic mail (e-mail) to: opp-docket@epamail.epa.gov. Electronic comments on this notice may be filed on-line at many Federal Depository Libraries. Additional information on electronic submissions can be found below in this document. Information submitted as a comments concerning this document may be claimed confidential by marking any part or all of that information as ``Confidential Business Information'' (CBI). CBI should not be submitted through e-mail. Information marked as CBI will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. A copy of the comment that does not contain CBI must be submitted for inclusion in the public record. Information not marked confidential may be disclosed publicly by EPA without prior notice. All written comments will be available for public inspection in Rm. 1132 at the address given above, from 8 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. FOR FURTHER INFORMATION CONTACT: Joanne Miller (PM-23) Rm. 237, CM #2, 1921 Jefferson Davis Highway, Arlington, VA (703) 305-6224. e-mail: miller.joanne@epamail.epa.gov. SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP) 3F4187 from Rohm and Haas Company, Philadelphia, PA, 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 the herbicide thiazopyr in or on the raw agricultural commodity orange (whole fruit) and grapefruit (whole fruit) at 0.05 ppm. The proposed analytical method is gas chromatography using mass selective detection. Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, Rohm and Haas Company has submitted the following summary of information, data and arguments in support of their pesticide petition. This summary was prepared by Rohm and Haas Company and EPA has not fully evaluated the merits of the petition. EPA edited the summary to clarify that the conclusions and arguments were the petitioners and not necessarily EPAs and to remove certain extraneous material. I. Rohm & Haas Petition Summary A. Residue Chemistry 1. Plant metabolism. Metabolism studies were conducted on peanuts, cotton and lemon. The metabolism of thiazopyr in all crops was extensive. Little thiazopyr was observed in crop tissues. About 10 metabolites were identified and quantified in each study. In peanuts, cotton, and lemon, any individual metabolite represented less than 13-, 9-, and 10-percent of the total dosage, respectively. The metabolic pathway for all three crops is the same. 2. Analytical method. A gas-liquid chromatographic analytical method using mass selective detection has been validated in citrus for enforcement purposes. This method converts thiazopyr and its metabolites to a common moiety which is quantified. The limit of quantitation of the method is 0.025 ppm for citrus whole fruit and processed fractions. 3. Magnitude of residues. The maximum application rate of 2 pounds of the active ingredient per acre was applied 3 months prior to harvest in 20 field trials. No detectable thiazopyr residue was found above the limit of quantitation of the residue method in whole fruit. After a single application of thiazopyr at 10 pounds per acre 3 months prior to harvest, processed commodities of citrus were produced and analyzed. No residue was found above the limit of quantitation of the method in the processed fractions. B. Toxicological Profile 1. Acute toxicity. Thiazopyr technical was practically non-toxic by ingestion of a single dose (LD<INF>50 > 5.0 g/kg) in rats and was practically non-toxic by dermal application (LD<INF>50 > 5.0 g/kg in rats). Thiazopyr technical was not significantly toxic to rats after a 4-hr inhalation exposure, with an LC<INF>50 value of > 1.2 mg/L (highest concentration attainable) for both sexes. Thiazopyr technical was classified as slightly irritating to the eye and no more than slightly irritating to the skin. Thiazopyr technical was not a dermal sensitizer. 2. Genotoxicity. Thiazopyr technical was negative (non-mutagenic) in the Ames microbial mutation assay with and without hepatic enzyme activation. Thiazopyr technical was negative in a hypoxanthine guanine phosphoribosyl [[Page 59441]] transferase (HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in culture when tested with and without hepatic enzyme activation. In isolated rat hepatocytes, thiazopyr technical did not induce unscheduled DNA synthesis (UDS) or repair when tested up the maximum soluble concentration in culture medium. In an in vivo bone marrow cytogenetic (micronucleus) assay no significant increases in micronuclei were seen in bone marrow cells. Thiazopyr did not produce chromosome effects in vivo. On the basis of the results of this battery of tests, it is concluded that thiazopyr is not mutagenic or genotoxic. 3. Reproductive and developmental toxicity. No observed effect levels (NOELs) for developmental toxicity were established at 100 mg/ kg/day in the rat and 175 mg/kg/day in the rabbit. In a 2-generation reproduction study in rats there were no treatment-related effects on any reproductive parameter in the adults or their offspring. The NOEL was considered to be 1,000 ppm for reproductive effects (73 - 91 mg/kg/ day for males and females, respectively) and 10 ppm for adult toxicity (0.72 - 0.94 mg/kg/day for males and females, respectively). Overall, thiazopyr was not associated with significant developmental or reproductive effects below maternally toxic doses. 4. Subchronic toxicity. The NOEL in a 90-day rat feeding study was 100 ppm (6.6 - 8.0 mg/kg/day in males and females, respectively), and the LOEL was 1,000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increases in absolute and relative liver weights, hepatic enlargement and discoloration, hepatocellular hypertrophy, and effects on parameters associated with altered liver function. In a 90-day dog feeding study the NOEL was 10 ppm (0.2 mg/kg/day for males; 0.3 mg/kg/day for females) and the lowest observed effect level (LOEL) 100 ppm based on hepatocellular hypertrophy/hyperplasia. In a 21-day dermal toxicity study in the rat, the NOEL was 100 mg/ kg/day. The LOEL was 500 mg/kg/day based on minimal hepatocellular vacuolation in females. 5. Chronic toxicity. In a 2-year combined chronic toxicity/ oncogenicity study in the rat the NOEL was 100 ppm (4.4 - 5.6 mg/kg/day for males and females, respectively), and the LOEL was 1,000 ppm (44.4 - 56.0 mg/kg/day) based on hematologic and clinical chemistry changes, increased organ weights and incidences of hepatocellular hypertrophy and vacuolation, nephropathy, and thyroid follicular hypertrophy and/or hyperplasia. An increased incidence of thyroid follicular tumors was observed in males at the two highest doses of 1,000 and 3,000 ppm. The thyroid tumors were determined in three special thyroid function studies to be secondary to a disturbance of thyroid/pituitary homeostasis and were attributed to a hormonally-mediated mechanism for thyroid tumor induction. The effects were dose-responsive and with the exception of thyroid weight, all effects were completely reversible when thiazopyr was removed from the diet. In an 18 month combined chronic toxicity/oncogenicity study in the mouse the NOEL was 10 ppm in males (1.6 mg/kg bw/day) and 100 ppm in females (26.8 mg/kg bw/day) and the LOEL 100 ppm in males (16.9 mg/kg bw/day) and 400 ppm in females (108.1 mg/kg bw /day) based on increased absolute and relative liver weights, serum chemistry changes, enlarged and/or discolored livers, hepatocellular hypertrophy, increased eosinophilia and vacuolization in livers of both sexes. No evidence of oncogenicity was observed at any dose level. In a 1-year dog feeding study the NOEL was 20 ppm (0.8 mg a.i./kg bw/day) and the LOEL 200 ppm (8.0 mg/kg/day) based on liver hypertrophy and changes in clinical chemistry parameters associated with liver function. 6. Animal metabolism. Thiazopyr technical administered by the oral or intravenous route in the rat was extensively absorbed and extensively degraded via oxidation of the thiazoline ring, oxidation of the isobutyl side chain of the pyridine ring and cleavage of the methyl ester. Thiazopyr was rapidly and extensively eliminated, with very low residues in the tissue and carcass. Glycine thioamide ester and unsaturated nitrile acid were the major metabolites in rat excreta. Thiazopyr was also rapidly eliminated from goats and chickens, and oxidation of the thiazoline ring and the isobutyl side chain were also the major route for metabolic degradation of thiazopyr in goat and chicken. 7. Metabolite toxicity. Common metabolic pathways for thiazopyr have been identified in animals (rat, hen, goat, bluegill sunfish) and crop plants (cotton, peanut, citrus). Pathways common to both types of metabolism include oxidative opening of the thiazoline ring, oxidation of the isobutyl side chain and methyl ester cleavage. Overall, the metabolism of thiazopyr is similar in plants and animals. Thiazopyr undergoes extensive degradation and elimination to polar metabolites that are unlikely to accumulate in humans or animals exposed to these residues in the diet. A 4-week dietary study was conducted to assess the subchronic toxicity of thiazopyr monoacid. The results of this study suggest that thiazopyr monoacid also perturbs thyroid/liver homeostasis by the same mechanism elucidated for the parent compound, thiazopyr. The NOEL for this study was 1,000 ppm (1,591 mg/kg/day for males, 1,740 mg/kg/day for females). In comparison to the NOEL of 100 ppm in the rat subchronic and chronic dietary studies, the NOEL of 1,000 ppm in this study suggests that thiazopyr monoacid is approximately 10-fold less toxic than the parent, thiazopyr. 8. Conclusions. Using its Guidelines for Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992), the EPA's Health Effects Division Carcinogenicity Peer Review Committee concluded that there was limited evidence for carcinogenicity and therefore classified thiazopyr as a Group C--possible human carcinogen. A Margin of Exposure (MOE) approach was recommended to evaluate potential consequences of human exposure. A NOEL of 4.4 mg/kg/day and a LOEL of 44.2 mg/kg/day were selected as the critical dose levels to be used in the MOE carcinogenicity risk assessment. The database for chronic toxicity assessment is complete. Based on chronic toxicity testing, the dog was the most sensitive species. The RfD Committee of the USEPA Health Effects Division established an Reference Dose (RfD) for thiazopyr of 0.008 mg/kg/day based on the NOEL of 0.8 mg a.i./kg/day and application of a 100-fold safety factor. C. Aggregate Exposure 1. Dietary exposure--(i) food. For purposes of assessing the potential dietary exposure under this tolerance, EPA estimates aggregate exposure using the tolerance on citrus whole fruit at 0.05 ppm. The potential exposure is obtained by multiplying the tolerance level residues by the consumption data which estimates the amount of citrus or citrus products eaten by various population subgroups. Citrus pulp is fed to animals, thus exposure of humans to residues in citrus pulp might result if such residues are transferred to meat, milk, poultry, or eggs. However, based on the results of animal metabolism studies and the amount of thiazopyr residues expected in animal feeds, EPA has concluded that there is no reasonable expectation that measurable residue of thiazopyr will occur in meat and milk. Citrus pulp is not a poultry [[Page 59442]] feed item, thus no residues are expected in poultry or eggs. There are no other established U.S. tolerances for thiazopyr, and there are no registered uses for thiazopyr on food or feed crops in the United States. Using a Dietary Risk Evaluation System analysis, Rohm and Haas calculates that the potential exposure to thiazopyr from consumption of orange and grapefruit products represents 1.47 percent of the thiazopyr RfD for the general population. The percentage of the RfD for the most highly exposed sub-group, non-nursing infants, is 3.14 percent. In conducting this exposure assessment, Rohm & Haas has made very conservative assumptions--that 100 percent of the oranges and grapefruit contain thiazopyr residues and that those residues would all be at the level of the tolerance. This clearly is an overestimation of the potential human exposure. (ii) Drinking water. Other potential dietary sources of exposure of the general population to residues of pesticides are residues in drinking water. A prospective ground water study conducted in a citrus grove, in an area considered vulnerable to leaching of pesticide residue to groundwater, demonstrated that thiazopyr does not leach. A degradate of thiazopyr, thiazopyr monoacid, was observed. Using consumption of 2 liters per day of drinking water (consistent with the National Primary Drinking Water Regulations--Synthetic Organic and Inorganic Chemicals, (56 FR 3526, January 30, 1991)), and the most conservative estimate of potential monoacid concentration, Rohm and Haas calculates that the monoacid uses 2.9 percent of the thiazopyr RfD. This value is substantially below the 20 percent of the RfD typically allocated for drinking water in 56 FR 3526. In conducting this exposure assessment, Rohm and Haas has made the very conservative assumption that all drinking water contains the maximum level of monoacid residues observed in a study designed to evaluate the worst case situation. In addition, the thiazopyr monoacid was considered for purposes of this assessment to be toxicologically equivalent to the parent compound, even though the monoacid metabolite is expected to be of lower overall toxicity than the parent compound. 2. Non-dietary exposure. Thiazopyr is not registered for any use which could result in non-occupational, non-dietary exposure to the general population. D. Cumulative Effects There is no reliable information to indicate that thiazopyr has a common mechanism of toxicity with any other chemical compound. Thiazopyr is based on a totally new class of chemistry, thus EPA should consider only the potential risks of thiazopyr in its exposure assessment. E. Safety Determination 1. U.S. population. Using the conservative exposure assumptions described above, and based on the completeness and reliability of the toxicity data, Rohm and Haas has concluded that aggregate exposure to thiazopyr will utilize 4.37 percent of the RfD for the U.S. population. EPA generally has no concern for exposures below 100 percent of the RfD because the RfD represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose appreciable risks to human health. Therefore, Rohm and Haas concludes that there is a reasonable certainty that no harm will result from aggregate exposure to thiazopyr residues. The complete toxicology profile of thiazopyr shows no evidence of physiological effects characteristic of the disruption of the hormone estrogen. Based on this observation thiazopyr does not meet the criteria for an estrogenic compound. 2. Infants and children. In assessing the potential for additional sensitivity of infants and children to residues of thiazopyr, EPA considers data from developmental toxicity studies in the rat and rabbit and a 2-generation reproduction study in the rat. 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, data on systemic toxicity, and the survival, growth and development of the offspring. Based on the current toxicological data requirements, the database relative to pre- and post-natal effects for children is complete. The NOEL at 0.8 mg/kg/day from the dog study, which was used to calculate the RfD (discussed above), is already lower than the NOEL's from the developmental studies in rats and rabbits by a factor of more than 100 fold. Therefore, Rohm and Haas concludes that an additional uncertainty factor is not warranted and that the RfD at 0.008 mg/kg/day is appropriate for assessing aggregate risk to infants and children. F. International Tolerances There are no Codex maximum residue levels [MRL] established for residues of thiazopyr. G. Other Considerations/Conclusions Thiazopyr will be a useful addition for weed control in citrus growing areas, particularly where annual grass pressures are high, because it provides control against aggressive grass weeds at significantly lower use rates than existing products. Thiazopyr has a new unique mode of action and offers benefits in integrated pest management programs to counter the potential for weed resistance. Thiazopyr is extremely safe around citrus trees, including young citrus trees. Therefore, permanent tolerances should be established for residues of thiazopyr in orange (whole fruit) at 0.05 ppm and grapefruit (whole fruit) at 0.05 ppm. II. Administrative Matters Interested persons are invited to submit comments on this notice of filing. Comments must bear a notation indicating the docket number, [PF-673]. All written comments filed in response to this petition will be available in the Public Response and Program Resources Branch, at the Virginia address given above from 8 a.m. to 4 p.m., Monday through Friday, except legal holidays. A record has been established for this notice under docket number [PF-673] 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 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The public record is located in Rm. 1132 of the Public Response and Program Resources Branch, Field Operations Division (7506C), Office of Pesticide Programs, Environmental Protection Agency, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202. 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. The official record for this notice of filing rulemaking, as well as the public version as described above, will be kept in paper form. Accordingly, EPA will transfer all comments received electronically into printed, paper form [[Page 59443]] as they are received and will place the paper copies in the official record which will also include all comments submitted directly in writing. The official rulemaking record is the paper record maintained at the address in ``ADDRESSES'' at the beginning of this document. List of Subjects Environmental Protection, Administrative Practice and Procedure, Agricultural Commodities, Pesticides and Pests, Reporting and Recordkeeping Requirements. Dated: November 14, 1996. Donald R. Stubbs, Acting Director, Registration Division, Office of Pesticide Programs. [FR Doc. 96-29930 Filed 11-21-96; 8:45 am] BILLING CODE 6560-50-F