7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. However, as bitertanol is an import tolerance only, there are no exposures via drinking water or residential sources. Therefore, an aggregate risk assessment has not been conducted. Page 42 of 58 8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to bitertanol and any other substances and bitertanol does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that bitertanol has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway Bitertanol has no registered uses in the United States; therefore, an occupational exposure assessment has not been conducted.

10.0 Data Needs and Label Requirements 10.1 Toxicology HED recommends that an acute neurotoxicity battery, and a 90 day neurotoxicity study with bitertanol be submitted. The requirement for a developmental neurotoxicity toxicity study is held in reserve, pending the submission and review of the acute and subchronic neurotoxicity studies.

10.2 Residue Chemistry The tolerance should be increased to 0.50 ppm to harmonize with Codex.

Storage stability data are required to determine the stability of residues in bananas during cold storage. No data were provided on how long the banana samples from submitted field trial studies were stored prior to analysis.

Field trial data for the suspension concentrate formulation are required ( these field trials are currently being conducted by the registrant and are planned for completion in 2006). a Additional data are required in order for the submitted field trials conducted in Costa Rica and Honduras to be acceptable: the number of trials, the location of the trials within the countries, and the formulation type used. Page 43 of 58 Page 44 of 58 REFERENCES:

Literature References:

1. AR Allen & RC MacPhail [ 1993] Bitertanol, a triazole fungicide, increases operant responding but not motor activity. Neurotoxicology and Teratology Vol 15 No. 4 pages 237 242. 2. KM Crofton [ 1996] A Structure activity relationship for neurotoxicity of triazole fungicides. Toxicology Letters 84 ( 3) 155 159 3. EPA/ OTS Doc # 88 920006908 [ Initial submission: ( 1,2,4 triazole 1) 3,3 dimethylbutan 2 ol studies of embryo & teratogenic effects in rats following oral administration with cover letter & attachments] 4. FAO and WHO working groups [ 1983] Bitertanol. FAO Plant production and protection paper Vol 61 pages 47 57. 5. FAO and WHO working groups [ 1987]. Bitertanol. FAO Plant production and protection paper. Vol 86/ 2 page 19 23. 6. FAO and WHO working groups [ 1998] Bitertanol. Pesticide residues in food. Toxicological evaluations page 39 61. 7. J Lewalter and U Korallus [ 1986] Erythrocyte protein conjugates as a principle of biological monitoring for pesticides. Toxicology Letters Vol 33 Nos 1/ 3 153 165. 8. P Mineau, DC Boersma and B Collins [ 1994] An analysis of avian reproduction studies submitted for pesticide registration. Ecotoxicology and Environmental Safety 29( 3) 304 329. 9. M Peterka, M Tucek and D Vesely [ 1996] Embryotoxicity of none mordants in chick embryo: The chest method. Acta Veterinaria Brno 65( 3) 213 217. 10. JL Schardien [ 1993] Pesticides. In Chemically Induced Birth Defects. Published 1993. International Standard book Number: 0 8247 8775 7. 2: 675 721 11. T Vergieva [ 1990] Triazoles teratogenicity in rats. Teratology Aug: 42 ( 2) 27A 28A 12. T Yamano and S Morita [ 1995] Effects of pesticides on isolated rat hepatocytes, mitocondria, and microsomes II. Archives of Environmental Contamination and Toxicology 28: ( 1) 1 7.

References to Toxicity Studies on Bitertanol:

MRID: 00025640 Mobay Chemical Corporation ( 1979) Synopsis of the Human Safety of Baycor ( Formerly Bay KWG 0599). Summary of studies 099184 B through 099184 Q. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; CDL: 099184 A)

MRID: 00025641 Thyssen, J.; Kimmerle, G.; Lorke, D. ( 1977) KWG 0599: Acute Toxicity Studies: Report No. 6546; Report No. 51413. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 B)

MRID: 00025645 Herbold, B.; Lorke, D. ( 1978) KWG 0599: Micronucleus Test on Mouse to Evaluate KWG 0599 for Potential Mutagenic Effects: Report No. 7860; Report No. 66652. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 F)

MRID: 00025646 Herbold, B.; Lorke, D. ( 1978) KWG 0599: Dominant Lethal Study on Page 45 of 58 Male Mouse To Test for Mutagenic Effects: Report No. 7964; Report No. 67067. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 G)

MRID: 00025647 F.; Bomhard, E.; Loser, E.; et al. ( 1978) KWG 0599: Subchronic Toxicity Study on Rats: Report No. 8002; Report No. 67074. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 H)

MRID: 00025648 Hoffman, K.; Schilde, B.; Lorke, D. ( 1979) KWG 0599: Subchronic Toxicity Study on Dogs: Report No. 8053; Report No. 67374. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 I)

MRID: 00025651 Herbold, B.; Lorke, D. ( 1979) KWG 0599: Salmonella/ Microsome Test for Detection of Point Mutagenic Effects: Report No. 8152; Re port No. 67959. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; prepared by Bayer, AG, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099184 L)

MRID: 00025733 Puhl, R. J.; Obrist, J. J.; Pither, K. M. ( 1979) The Excretion of Baycor( TM) phenyl UL 14C following Administration of a Single Oral Dose to Rats: Report No. 68307. ( Unpublished study received Dec 21, 1979 under 3125 EX 168; submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 099185 Q)

MRID: 00114277 Flucke, W.; Lorke, D. ( 1981) KWG 0599: Evaluation for Sensitization in Guinea Pigs ( Maximization Test after Magnusson and Kligman): Report No. 9934; 80324. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Bayer AG, W. Ger., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071090 C)

MRID: 00114279 Bomhard, E.; Loeser, E.; Lorke, D.; et al. ( 1981) KWG 0599: Chronic Toxicity Study on Rats ( 2 year Feeding Experiment): Bayer Report No. 10104; 69985. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Bayer AG, W. Ger., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071090 E)

MRID: 00114280 Bomhard, E.; Loeser, E.; Lorke, D.; et al. ( 1981) KWG 0599: ( Bitertanol, the Active Ingredient of Baycor) Chronic Toxicity Study on Mice ( 2 year Feeding Experiment): Bayer Report No. 10103; 69095. ( Unpublished study received Sep 15, 1958 under 2E2756; prepared by Bayer AG, W. Ger., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 A)

MRID: 00114281 Loser, E.; Eiben, R.; Lorke, D.; et al. ( 1981) KWG 0599: Multigeneration Reproduction Study on Rats: Report No. 10024; 69096. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Bayer AG, W. Ger., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 B) Page 46 of 58 MRID: 00114283 Nagumo, K.; Teraki, Y.; Chiba, T.; et al. ( 1981) Teratogenicity Test of KWG 0599 in Pregnant Rats: ( Submitter) 80571. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by St. Marianna Univ., First Dept. of Anatomy, Laboratory of Embryology, Japan, submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 D)

MRID: 00114284 Roetz, R.; Lorke, D. ( 1982) KWG 0599 ( Bitertanol, the Active Ingredient of Baycor): Study of Embryotoxic ( and Teratogenic) Effects on Rabbits after Oral Administration: Bayer Report No. 10979; 82239. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Bayer AG, W. Ger., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 E)

MRID: 00114285 Riach, C.; Harris, W. ( 1980) KWG 0599: Testing the Modification of Cellular DNA in Escherichia coli: Report No. 1896; 69099. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Inveresk Research International, Scot., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 F)

MRID: 00114286 Shirasu, Y.; Moriya, M.; Ohta, T. ( 1981) Bitertanol: Microbial Mutagenicity Study: ( Submitter) 80331. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Institute of Environmental Toxicology, Japan, submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 G)

MRID: 00114287 Bond, J.; McGregor, D.; McMillan, L.; et al. ( 1981) Bitertanol: Testing for Aneuploid Induction of HE 1004 in Sordaria brevicollis: IRI Project No. 416594; 80333. ( Unpublished study received Sep 15, 1982 under 2E2756; prepared by Inveresk Research International, Scot., submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071091 H)

MRID 00129560 Puhl, R.; Hurley, J. ( 1983). The Absorption, Excretion, and Metabolism of Baycor phenyl UL 14C by Rats: 85832. ( Unpublished study received August 1, 1983 under 2E2756; submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 071760 A.

MRID: 00149829 Heimann, K.; Vogel, O. ( 1984) Subacute Study of Dermal Toxicity To Rabbits: KWG 0599: Report No. 12571. Unpublished Mobay study No. 86863 prepared by Bayer AG, Institute of Toxicology. 67 p. MRID: 00149830 Schluter, G. ( 1983) Study to Determine Embryotoxic and Teratogenic Effects on Rabbits Following Oral Administration: KWG 0599: Re port No. 11548. Unpublished Mobay study No. 86432 prepared by Bayer AG, Institute of Toxicology. 21 p.

MRID: 00150149 Hixson, E. ( 1984) Dermal Absorption of [ Carbon 14] Baycor Applied As a 50% Wettable Powder: Study No. 83 723 01; 86638. Unpublished study prepared by Mobay Chemical Corp. 16 p.

MRID: 00154936 Machemer, L.; Lorke, D. ( 1977) Studies of Embryotoxic and Teratogenic Effects on Rats following Oral Administration: KWG 0599: Report No. 6697; 53072. Unpublished study prepared by Bayer AG. 61 p.

MRID: 00154937 Roetz, R. ( 1982) Examination for Embryotoxic Effects on Rabbits: Procedure ( S. O. P) No. 1360; 82 T 215. Unpublished study prepared by Reproduction Tox. Lab., Bayer AG. 11 p. Page 47 of 58 MRID: 00157465 Hoffmann, K.; Vogel, O. ( 1983) Second Chronic Toxicity Study with Dogs on Oral Administration: ( Feeding Study, 0 3 25 ppm 12 Months, 200 ppm 20 Months): KWG 0599 ( Bitertanol): Report No.: 12328. Unpublished study prepared by Bayer AG. 302 p.

MRID: 00157466 Hoffmann, K.; Groening, P. ( 1983) Chronic Oral Toxicity Study on Dogs: ( 2 Year Feeding Experiment): ( Common Name: Bitertanol): KWG 0599: Report No.: 12307: Mobay Agchem No.: 86304. Unpublished study prepared by Bayer Ag Institut fuer Toxikologie. 299 p.

MRID: 00157853 Yonemura, H.; Shimazaki, M.; Yamazaki, K.; et al. ( 1981) Subacute Toxicity Tests with Bitertanol ( KWG 0599) in Rats: Report No. 90891. Unpublished study prepared by Mobay Chemical Corp. 145 p.

MRID: 00163455 Mihail, F.; Luckhaus, G. ( 1986) Subacute Oral Toxicity Study with Special Attention to Effect on the Liver: [ September 9, 1986]: KWG 0599 ( c. n. Bitertanol): Report No. 13230. Unpublished Mobay Report No. 90496. 12 p.

MRID: 40163201 Hoffmann, K.; Groening, P. ( 1986) Chronic Oral Toxicity Study on Dogs ( 2 year Feeding Experiment): Supplemental Submission ...: ( Common Name: Bitertanol): Bayer Report No.: 12307: Mobay AgChem No.: 86304. Unpublished study prepared by Bayer Ag Institut Fuer Toxikologie. 12 p.

MRID: 40163202 Hoffmann, K.; Vogel, O. ( 1986) Second Chronic Toxicity Study with Dogs on Oral Administration: ( Feeding Study, 0 3 25 ppm 12 months, 200 ppm 20 months): Supplemental Submission ... Mobay Report No. 86298: KWG 0599 ( Bitertanol): Report No.: 12328. Unpublished study prepared by Bayer Ag Institute of Toxicology. 12 p.

MRID: 40163203 Hoffmann, K.; Vogel, O. ( 1987) Second Chronic Toxicity Study with Dogs on Oral Administration: ( Feeding Study, 0 3 25 ppm 12 months, 200 ppm 20 months): Supplemental Submission ... KWG 0599 ( Bitertanol): Report No.: 12328: 86298 3. Unpublished study prepared by Bayer Ag Institute of Toxicology. 19 p.

MRID: 40163205 Schluter, G. ( 1987) Study to Determine Embryotoxic and Teratogenic Effects on Rabbits following Oral Administration: Supplemental Submission ...: Mobay Report No. 86432: KWG 0599: Bericht Nr.: 11548. Unpublished study prepared by Bayer Ag Institut fur Tox ikologie. 18 p.

MRID: 40186401 Hoffmann, K.; Groening, P. ( 1987) Chronic Oral Toxicity Study on Dogs: ( 2 year Feeding Experiment): [ Using Baycor]: Bayer Report No. 12307. Unpublished Mobay AgChem Report No. 86304 prepared by Bayer AG Institut Fuer Toxikologie. 19 p.

MRID: 40490801 Becker, H.; Mueller, E.; Vogel, W.; et al. ( 1987) Embryotoxicity Page 48 of 58 ( Including Teratogenicity) Study with KWG 0599 in Rabbits: Project 065283; 94704. Unpublished study prepared by Research and Consulting Co., AG. 281 p.

MRID: 40829401 Machemer, L. ( 1987) Embryotoxicity ( including Teratogenicity) Study with KWG 0599 in the Rabbit: Project No. 065283, Report No. 94704, 94704 1. Unpublished study prepared by Research & Consulting Co. AG. 10 p. Page 49 of 58 APPENDICES A C APPENDIX A: TOXICOLOGY DATA REQUIREMENTS The requirements ( 40 CFR 158.340) for food use for { Bitertanol} are in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used.

Table 1: Toxicity data requirements for Bitertanol ( PC 117801).

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . . . . yes yes No yes yes yes yes yes yes a yes yes yes 870.3100 Oral Subchronic ( rodent) . . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( nonrodent) . . . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3465 90 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes no no yes yes yes no no 870.3700a Developmental Toxicity ( rodent) . . . . . . . . . . . . . . . 870.3700b Developmental Toxicity ( nonrodent) . . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes 870.4100a Chronic Toxicity ( rodent) . . . . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( nonrodent) . . . . . . . . . . . . . . . . . 870.4200a Oncogenicity ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( mouse) . . . . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes b yes yes b yes yes b 870.5100 Mutagenicity  Gene Mutation  bacterial . . . . . . . . 870.5300 Mutagenicity  Gene Mutation  mammalian . . . . . . 870.5450 Mutagenicity  Structural Chromosomal Aberrations NG Mutagenicity  Other Genotoxic Effects . . . . . . . . . . yes yes yes yes yes yes yes yes 870.6100a Acute Delayed Neurotox. ( hen) . . . . . . . . . . . . . . . . 870.6100b 90 Day Neurotoxicity ( hen) . . . . . . . . . . . . . . . . . . . 870.6200a Acute Neurotox. Screening Battery ( rat) . . . . . . . . . 870.6200b 90 Day Neuro. Screening Battery ( rat) . . . . . . . . . . . 870.6300 Develop. Neuroc . . . . . . . . . . . . . . . . . . . . . . . . . . . . no no yes yes no   yes yes no 870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 870.7600 Dermal Penetration . . . . . . . . . . . . . . . . . . . . . . . . . yes no yes no Special Studies for Ocular Effects Acute Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subchronic Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . Six month Oral ( dog) . . . . . . . . . . . . . . . . . . . . . . . no no Page 50 of 58 a There is no inhalation exposure in the United States. Bitertanol is a non volatile pesticide used on imported bananas. b Not required where Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a. c Held in reserve pending review of the acute and 90 day neurotoxicity studies.

APPENDIX B: TOXICOLOGY STUDIES [ Executive Summaries]

Subchronic Studies with Bitertanol 90 day feeding study in Sprague Dawley rats ( MRID# 00157853)

EXECUTIVE SUMMARY: In a 90 day oral toxicity study ( MRID 00157853), bitertanol ( BAYCOR, 95%, a. i., Batch No. Pt 161600478) was administered in feed at concentrations of 0, 40, 200 or 1000 ppm to 15 Sprague Dawley rats/ sex/ group. Mean test substance consumption was 3.1, 15.9 and 81.8 mg/ kg/ day in males and 3.6, 18.6 and 88.2 mg/ kg/ day in females. Concentrations administered were based on data from a previous four week preliminary dosage study. Controls were fed untreated feed.

One male in the control group died at ten weeks from a circulatory disturbance; no deaths occurred in the treated animals. No treatment related clinical signs were observed in any animals.

Mean body weight and body weight gain indicated a dose dependent decrease in the treated animals. While low dose male and female rats had slight decreases in body weight and body weight gain compared to controls, the values were not of a magnitude to be considered toxicologically significant with values $ 94% of controls. Mid dose males and females had a decrease in body weight and body weight gain that was toxicologically significant. Mid dose male and female body weight started to decrease compared to controls at week three, remained lower than controls for the remainder of the study, with decreases within 10% of controls. Mean body weight gain in the mid dose males remained at 84 91% of controls with the lowest weight gain observed at weeks 3 6. Mid dose females had a mean body weight gain in weeks 0 3 that was 88% of controls, then decreased to 79% of controls in weeks 6 9, but was the same as controls, thereafter. The high dose male body weight was 81% of controls in the first week, dropped to 80% of controls through week six and averaged about 83% of controls through week thirteen. Total mean body weight gain in the high dose males for the entire thirteen weeks was 74% of controls and ranged from 56 to 115% with no trend in time established. High dose female mean body weight was 85% of controls during week one, then decreased to 83% of controls for the remainder of the study. Mean body weight gain for high dose females was the lowest in weeks 0 3 at 58% of controls and increased to 88% of controls during weeks 9 13.

Low and mid dose male and female rats had values similar to controls for food and water consumption, and low dose animals were similar to controls in food efficiency. In high dose males, food consumption was decreased ( 77 % of controls) during week one but then improved to approximately 90% of the control values for the remainder of the study. Food consumption in high dose females was also decreased compared to controls ( 76%) in week one but increased to 83% of controls by study termination. Water consumption for the high dose male and female rats was the lowest in week one, 71 and 77% of controls, respectively, and never increased above 80% of controls in males or 86% in females for the remainder of the study. Overall, food efficiency was 88 and 90% of controls in mid dose male and female rats, respectively and 87 and 86% in high dose male and female rats, respectively.

Hematology results showed both the high dose male and female rats had a statistically significant decrease ( p < 0.05) in the number of red blood cells with a corresponding increase in reticulocytes. The hematocrit was significantly decreased in the female rats in the high dose but Page 51 of 58 not in the males. These differences; however, did not demonstrate any dose related trends. Treated males were not observed to have any dose related differences in their clinical chemistry values. However, in high dose females, clinical chemistry values for lactate dehydrogenase ( LDH), aspartate aminotransferase ( AST, SGOT) and alkaline phosphatase ( ALP) values showed a statistically significant increase ( p < 0.05). In mid dose females, SGOT and ALP were also significantly increased.

Organ weight differences were observed only in the high dose animals. Relative liver and spleen organ weights were increased, + 23 and + 26 % of controls, respectively, in high dose males. Absolute and relative liver and spleen organ weights were statistically increased in the high dose female rats; absolute weights by + 16% for both liver and spleen and relative by + 39 and + 37%, respectively. Gross examination of the animals found a slight enlargement of the liver and adrenals in both the male and females in the high dose group. Histopathology examination found lesions related to these enlargements; however, severity of the lesions was not provided. Liver changes indicating hepatotoxicity included: swelling of hepatocytes ( 9/ 15 males and 10/ 15 females), fatty degeneration of liver cells ( 1/ 15 males and 8/ 15 females) and bile duct hyperplasia ( 1/ 15 males and 5/ 15 females). In the adrenal, there were enlarged cortical cells ( 14/ 15 males and 15/ 15 females) with increased fatty deposition ( 6/ 15 males and 10/ 15 females). Other lesions found in the highdose group were keratosis of the mucosal epithelium of the esophagus ( 9/ 15 males and 11/ 15 females) and stomach ( 10/ 15 males and 6/ 15 females). Few, if any, differences in organ weights, gross or histopathological lesions associated with treatment were seen in any animals in the control, low or mid dose groups.

The lowest observed adverse effect level ( LOAEL) for oral systemic toxicity in rats for bitertanol is 200 ppm, ( 15.9 or 18.6 mg/ kg/ day in males and females, respectively), based on a decrease in body weight and body weight gain. The no observed adverse effect level ( NOAEL) for systemic toxicity is 40 ppm, ( 3.1 or 3.6 mg/ kg/ day in males and females, respectively).

This study is Acceptable/ Guideline and satisfies the requirements for a subchronic oral toxicity study in rats [ OPPTS 870.3100 ( § 82 1)]. Although ophthalmological examinations were not conducted, eye were examined histologically and individual animal histopathology was acceptable.

Comments: This is a revised Executive Summary. This reviewer disagrees with the previous reviewer on the NOAEL and LOAEL values. The previous reviewer set the LOAEL at 40 ppm and the NOAEL to be undetermined. This reviewer agrees that there is a dose related decrease to body weight and body weight gain but the values are not toxicologically significant at the 40 ppm concentration, especially in the females. A table with the addition of body weight gain with additional time points was added to this revision to support this evaluation.

90 day feeding study Wister rats ( MRID# 00025647)

EXECUTIVE SUMMARY: In a 90 day oral toxicity study ( MRID 00025647), KWG 0599 ( purity not provided; batch no. 16001/ 77) was administered to 15 Wistar W. 74 rats/ sex/ dose in the diet at concentrations of 0, 30, 100 or 300 ppm ( equivalent to 0, 2.46, 8.16 or 24.84 mg/ kg/ day, respectively, for males and 0, 3.25, 10.15 or 31.60 mg/ kg/ day, respectively, for females).

There were no significant compound related effects based on the assessment of mortality, clinical signs of toxicity, behavior, body weights, food consumption, urinalysis, hematology, clinical chemistry, gross necropsy and histopathology. The test animals could have tolerated higher dosages of KWG 0599. However, there was a nominal body weight gain decrement in males and females through out treatment at 300 ppm of upto 8% and 12% by termination.

The tentative NOAEL is 100 ppm [ M/ F: 8.2/ 10.2 mg/ kg/ day]. The tentative LOAEL is 300 ppm Page 52 of 58 [ M/ F: 24.8/ 31.6 mg/ kg/ day] based on a consistent body weight gain decrement of upto 8% and 12% in males and females by termination, respectively.

This 90 day oral toxicity study in the rat is Unacceptable/ Guideline/ not upgradable and does no satisfy the guideline requirement for a 90 day oral toxicity study ( OPPTS 870.3100; OECD 408) in rat. Although no concentration analysis for test material in the feed was conducted, the effects from this study are similar to the NOAEL/ LOAEL and effects from MRID# 00157853 where analysis of test material in the feed was conducted. MRID# 0002547 supports MRID# 00157853. Since the same lot#/ batch# was used in MRID# 0002548 where purity was reported as used in MRID# 0002547, the purity is not an issue. However, the diet preparation, concentration, stability, and homogeneity data were not provided. Repeating the study is unnecessary because another 90 day study in rats with bitertanol is acceptable.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were not provided. This study was done prior to the and the guideline requirements of OPPTS 870.3100 and publication of FIFRA GLP Standards ( 11/ 29/ 83). The pesticide is sufficiently stable, and the limits on the purity indicate that the purity is satisfactory, but the lack of validation of the dose levels used is more problematic.

90 day feeding study in dogs ( MRID# 00025648)

EXECUTIVE SUMMARY: In a 90 day oral toxicity study ( MRID 00025648) KWG 0599 [ Bitertanol ( 90.2% a. i., batch/ lot 16001/ 77)] was administered by capsule to groups of 4 male and 4 female beagle dogs/ group at concentrations of 0, 1.0, 5.0, or 25.0 mg/ kg/ day.

Treatment with the test material at concentrations $ 5 mg/ kg/ day induced a dose and timedependent effect on the physical appearance of male and female dogs. Skin redness, alopecia, scale and scab formation, and mucosal irritation developed on most mid and high dose dogs. conjunctivitis was found on most mid and high dose dogs and was often accompanied with lacrimation. Three high dose dogs developed conjunctival keratitis by study end. The body weight of high dose male and female dogs was significantly decreased from week 7 through the end of the study, although food intake was not decreased. Likewise, a net decrease of total weight gain of male and female high dose dogs was statistically significant from control. No biologically significant differences in body weight gain were found in the low and mid dose treatment groups.

Treatment with the test material induced a slight increases in the activity of ALT and ALP in highdose animals. However, other liver related activities, such as glutamate dehydrogenase and AST were not significantly increased. A slight increase in liver total cytochrome P450 activity was found. No clearly demonstrable increase in the tissue activity of N demethylase activity or other significant treatment related effects were found. At necropsy, all female dogs in the 5 mg/ kg group and all male and female dogs in the 25 mg/ kg/ day group had thin hair coats, particularly on the chest and/ or stomach. The coat of all female high dose dogs was dirty and sticky, particularly on the edges of the ears. The prostate gland of high dose male dogs was noted to be small, and the thymus gland of three high dose female dogs was severely atrophied. Consistent with the increased total cytochrome P450 activity in both sexes of high dose dogs, the relative weight, but not the absolute liver weight was statistically increased ~ 13% in males and 22% in females, suggestive of an adaptive response.

Treatment of male and female dogs with 25 mg/ kg KWG 0599 decreased the absolute thymus weight and both absolute and relative prostate weight of mid and high dose male dogs. Microscopically, the prostate gland of all high dose dogs and one mid dose dog was only slightly developed with the tubuloalveolar section having a small lumen and containing no secretions. No treatment related effects were noted microscopically in the thymus. The stratum epithelium was Page 53 of 58 minimally distended in high dose male and female dogs and one mid dose male and female dog. In many cases, minimal cornification, particularly in follicles where the hair had fallen out, was observed.

Based on the prostatic effects in mid and high dose male dogs and the dermal and conjunctival effects on mid and high dose male and female dogs, the KWG 0599 LOAEL is 5 mg/ kg/ day. The NOAEL for KWG 0599 is 1 mg/ kg/ day.

This 90 day oral toxicity study in the dog is Acceptable/ Guideline and satisfies the guideline requirement for a 90 day oral toxicity study ( OPPTS 870.3150; OECD 409) in the dog. Signed and dated GLP, Quality Assurance, and Confidentiality statements were not included since the study was done prior to the original publication of FIFRA GLP Standards ( 11/ 29/ 83). However, sufficient numbers of animals were used/ group and individual animal data were provided.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were not provided.

21/ 28 Day dermal study in NZW rabbits ( MRID# 00149829)

EXECUTIVE SUMMARY: In a 21 day dermal toxicity study ( MRID 00149829), KWG 0599 ( bitertanol, 95.8%, a. i., Batch No. 233296990) was applied to the shaved skin of six New Zealand White rabbits/ sex/ dose at concentrations of 0 ( controls), 50, or 250 mg/ kg bw/ day, 6 hours/ day, 5 days/ week for three consecutive weeks. Skin in three rabbits in each group was abraded prior to treatment and three were left intact. MRID 40163204 was provided as a supplemental submission on the technical problems associated with application of higher doses in the original study.

There were no treatment related deaths or clinical signs of systemic toxicity in the rabbits. No effects on body weight, hematology, clinical chemistry, urinalysis, liver homogenate examination, or organ weight were observed in either treated or control animals. The histopathological examination showed lesions that were related only to dermal irritation.

Based on the results of this study, the systemic LOAEL for KWG 0599 ( bitertanol) in male and female rabbits can not be identified, and the systemic NOAEL is $ 250 mg/ kg/ day.

Evidence of mild dermal irritation in the form of redness was observed. Scoring for redness severity ranged from 0 ( no redness) to 4 ( deep redness with some corrosion). Dermal irritation was never scored greater than 3 ( moderate to severe redness) in any group. Treated male rabbits were observed to have a dose related difference in severity of redness with scores being slightly higher for abraded skin. In the first five days, high dose male rabbits with abraded skin had a mean redness score of 3 versus the low dose group with a mean of 2 ( slight to moderate redness). Male rabbits with intact skin had mean scores of < 1 to 1 ( slight, barely perceptible redness) on days 4 7 in the low dose group and 1 2 in the high dose group during the same time period. Females had slightly higher redness scores in abraded skin compared to intact skin but there was not a doseresponse All treated rabbits had dermal scores of # 1 by day 7 of the study. Control animals with abraded skin had redness scores of 1 3 for days 0 3 due to the physical act of abrading done pretreatment, but redness was not observed in the controls with intact skin. No treatment related effect on skin thickness was observed in any of the rabbits, treated or controls, when measured with calipers.

Gross examination at necropsy showed no treatment related, systemic or dermal lesions in any rabbits. Histopathological examination showed lesions limited to treated skin in the treated animals. No lesions were observed in the control group or in the untreated skin of the treated animals. The histopathological lesion observed from treatment was a mild epithelial proliferation Page 54 of 58 of the epidermis in the form of acanthosis with slight hyperkeratosis. This effect was seen in all treated animals ( intact and abraded skin) at the same severity level, mild.

Based on the results of this study, the dermal LOAEL for KWG 0599 ( bitertanol) in male and female rabbits is 50 mg/ kg/ day, and the dermal NOAEL is not identified.

This 21 day dermal toxicity study in rabbits is Acceptable/ Guideline. It satisfies the guideline requirement for a 21/ 28 day dermal toxicity study ( OPPTS 870.3200; OECD 410) in rabbits. This study is believed to be adequate to show no systemic effects, although previously classified as Supplementary in TXR# 0004638 and 0006528 because the explanation of the upper dose level was inadequate. The following explanation was accepted; " increasing the dose level would have exceeded the capacity for a stationary film on the treated area."

COMPLIANCE: Signed and dated GLP, and Data Confidentiality statements were provided. No Quality Assurance statements were provided.

Two week non guideline liver toxicity study in Wister rats ( MRID# 00149829)

EXECUTIVE SUMMARY: In a 14 day study ( MRID 00163455), suspensions of KWG 0599 ( 95.8%; Batch No. 233296990) were administered to 10 Wistar ( Bor WISW) ( SPF Cpb) rats/ sex/ dose by gavage at concentrations of 0, 30, 100 or 300 mg/ kg/ day. The study was designed to assess the potential effects of orally administered KWG 0599 on the liver of rats; therefore, a limited number of parameters were investigated.

There were no significant treatment related effects on mortality, clinical signs, behavior, hematology or gross pathology. A treatment related decrease in terminal body weight was statistically significant beginning at 30 mg/ kg/ day in females and 100 mg/ kg/ day in males; corresponding body weight gain was decreased in both sexes.

Slight induction of liver microsomal enzymes beginning at 100 mg/ kg/ day was based on increased O demethylase ( p# 0.01) activity in males and N demethylase activity in females as well as increased total cytochrome P 450 activity and increased absolute and/ or relative liver weights in both sexes. Hepatocellular hypertrophy with cytoplasmic granules was also reported at this dosage.

Additional significant treatment related effects in the liver include isolated Councilman bodies at 100 mg/ kg/ day in females and 300 mg/ kg/ day in males, bile duct proliferation at $ 100 mg/ kg/ day in both sexes, and isolated mitoses at 300 mg/ kg/ day in females. No treatment related effects were seen in liver of males and females receiving 30 mg KWG 0599/ kg/ day.

This subacute oral toxicity study in the rat is Acceptable/ Non guideline and satisfies the intent of the study. Signed and dated GLP and Quality Assurance statements were not included since the study was done prior to the original publication of FIFRA GLP Standards ( 11/ 29/ 83). However, sufficient numbers of animals were used/ group and individual animal data were provided.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were not provided.

Dermal Penetration in New Zealand White Rabbits ( MRID# 00150149]

EXECUTIVE SUMMARY: In a dermal absorption study ( MRID# 00150149) 200 mg of 50% formulation of bitertanol and 50 µ Ci of radiolabled bitertanol were applied to the shaved backs of 4 NZW rabbits/ sex/ group for 24 hours and occluded [ about 2.5 mg/ cm2]. After 24 hours the sites Page 55 of 58 were washed and urine and feces were collected over each 24 hour period for 13 days and processed for counting and the amount of radio label excreted in male and female urine and feces during each 24 hour period counted. At the end of 13 days, skin from the application site was removed and processed for radio label counting.

During the first 24 hours only 0.73% of the dose applied was excreted from males and 0.53% of the dose applied was excreted from females. Excretion was complete in 13 days.

The author calculated the amount adsorbed as a percentage of the mean of the total excreted in the urine and feces of male and female rabbits and reported as follows. The total excreted after 13 days from males ranged from 3.18 to 5.98 µ Ci or 6% to 12% of the dose applied. The total excreted after 13 days from females ranged from 5.21 to 11.67 µ Ci or 10 to 23% of the dosed applied. The author estimated that about 10% absorption represents a worst case scenario.

Using the mean of the total excreted in the urine, feces and remaining in the skin of males and female rabbits the reviewer calculated that a mean of 4.13 µ Ci or 8.1% of the dose applied to males and 7.02 µ Ci or 13.8% of the dose applied to females was accounted for. This left 92% of the dose to males and 86% of dose to females that was not accounted for. [ Although most of this unaccount for radiolabel was probably washed from the skin 24 hours after application, this is an unverifible assumption.] This percentage of unaccounted for radio label is unsatisfactory in a dermal penetration study where the dermal penetration could be as high as about 90% or as low as about 10%.

The study is unacceptable/ not upgradeable for a guideline dermal absorption study. The study lack multiple dose levels and did not account for the radio label applied.

COMPLIANCE: Signed and dated GLP, and Data Confidentiality statements were provided. Quality Assurance statements were provided.

Metabolism and Pharmacokinetics in Wister rats ( MRID# 0025733 & 00129560)

EXECUTIVE SUMMARY: Two studies were conducted to assess the metabolism and disposition of [ 14C phenyl UL] BAYCOR ( Bitertanol) in rats [ MRID 00129560 & 00025733]. In MRID 00129560, groups of five male and female rats were given single or multiple low ( 100 mg/ kg) oral doses, a single low ( 100 mg/ kg) intravenous dose, or a single high ( 1000 mg/ kg) dose of [ 14C phenyl UL] BAYCOR (> 99% radiochemical purity; no lot/ batch no.) combined with nonlabeled material ( 93.9% chemical purity, no lot/ batch no). The metabolism and disposition of the test material was assessed over a 168 hour time frame. An earlier study ( MRID 00025733) examined the metabolism and disposition of [ 14C phenyl UL] BAYCOR (> 99% radiochemical purity; no lot/ batch no.) and non labeled material ( 93.9% chemical purity, no lot/ batch no) in five male and five female rats. Unfortunately neither study used bitertanol labeled in the triazole group.

Recovery of radioactivity was acceptable in both studies ( 92 104% and 99%). Both studies affirmed the relatively rapid absorption of [ 14C phenyl UL] BAYCOR ( Bitertanol) and that excretion was primarily via the feces ( 81 98% and 92%, respectively) over the 168 hr experimental period. Urinary excretion ( 4 11% and  8% in the two studies) was secondary to fecal elimination. Saturated absorption at the high dose ( 1000 mg/ kg) was evident by a plateau in plasma radioactivity levels ( and by estimated kinetic parameters) and an increase in the fecal excretion of parent compound. A minor gender related variance in absorption and elimination constants and plasma elimination halftime was observed for the multiple dose group but not for other treatment groups. No other gender related variability was observed. Neither study reported excretion via expired air. In both studies, tissue radioactivity was minimal and not suggestive of bioaccumulation of the test material or its metabolites. Page 56 of 58 Both studies provided information on the identification of metabolites ( MRID 00025733 lacked details and a data table pertaining to metabolite quantification) that implied extensive metabolism of BAYCOR. Both parent compound and numerous metabolites ( of which 12 were identified in addition to two isomers of BAYCOR) were detected. The metabolites identified in fecal samples appeared to account for  34 72% of radioactivity recovered in the feces ( 81 98% of the dose) in that matrix. A notable amount of administered radioactivity ( 50% of total) remained unidentified and probably unextractable in the feces. Since the triazole ring was not labeled, the triazole metabolite if present was not detected. [ Triazole could not be detected in other triazole ring containing pesticides when the triazole ring was not labeled.] For the urine, the metabolite profile was less complex but contained similar metabolites as found in the feces. The urinary metabolites, however, were quantitatively, less significant due to urinary excretion accounting for only 4 11% of the total dose. The effort to extract and subsequently characterize the radioactivity in the excreta appeared to have been thorough, however. Fecal excretion in males and females was as high in the i. v. as the oral dosing studies showing high biliary excretion of the test material.

These studies ( MRID 00025733 and 00129560) on the metabolism and disposition of [ 14Cphenyl UL] BAYCOR ( Bitertanol) are classified Acceptable/ Guideline and satisfy the 85 1 Guideline Requirement for a metabolism study [ OPPTS 870.7485 OECD 417]. However, failure to label the triazole ring may require additional metabolic data. Although conducted prior to GLP guidelines, the reviewed studies utilized and adequate number of animals of each gender, demonstrated acceptable mass balance accounting of radioactivity, and adequately described the metabolism and disposition of the BAYCOR ( Bitertanol) in rats following multiple dose regimens including single low ( 100 mg/ kg) oral and intravenous doses, multiple low doses, and a single high ( 1000 mg/ kg) oral dose.

COMPLIANCE: These studies were conducted in 1979 ( MRID 00025733) and 1979 1983 ( MRID 00129560), both prior to GLP Guideline requirements. No quality Assurance or Data Confidentiality Claim statements were provided. Page 57 of 58 APPENDIX C: Names and Structures of Rat Metabolites in MRID# 00129560 & 00025733 TABLE C 1. Fecal metabolites (% of total recovered) in rats given [ 14C phenyl UL] BAYCOR Metabolite Metabolite # a A 100 mg/ kg iv B 100 mg/ kg oral C 100 mg/ kg oral, repeat D 1000 mg/ kg oral Male Female Male Female Male Female Male Female BAYCOR II 1 0.7 0.7 4.3 2.2 3.9 1.5 28.8 31.0 BAYCOR I 2 1.1 0.7 4.2 2.1 2.9 1.4 26.5 28.1 p hydroxy BAYCOR II 3 4.0 4.1 3.2 3.8 2.7 3.5 1.6 1.4 p hydroxy BAYCOR I 4 4.2 3.2 3.0 2.3 1.8 1.8 2.2 1.4 p hydroxy m methoxy BAYCOR I 5 3.0 1.8 5.0 1.9 0.1  1.6 0.8 BAYCOR alcohol II 6 1.5 1.2 1.6 1.0 1.0 1.1 0.7 0.3 m, m dihydroxy BAYCOR II 7 1.7 3.4 1.9 4.6 1.9 3.0 0.7 1.3 m, m dihydroxy BAYCOR I 8 2.1 5.0 3.3 5.3 4.5 6.0 1.4 2.0 p hydroxy BAYCOR alcohol II 9 2.3 1.7 3.5 2.7 4.2 1.8 0.8 0.7 p hydroxy BAYCOR alcohol I 10 1.5 1.2 1.9 1.9 1.9 1.3 0.7 0.7 BAYCOR acid II 11 0.6 0.5 0.6 1.5 0.6 0.9 0.2 0.3 BAYCOR acid I 12 4.3 1.5 2.5 1.7 3.6 2.4 1.1 0.7 p hydroxy BAYCOR acid II 13 2.8 2.0 0.9 2.3 0.7 1.8 1.2 1.1 p hydroxy BAYCOR acid I 14 5.5 5.9 5.4 6.9 4.4 6.2 2.3 2.4 Conjugates 0.6 1.1 0.6 0.9 0.8 1.1 0.6 0.7 Total identified b 35.9 34.0 41.9 41.1 35.0 33.8 70.4 72.9 Unidentified b 64.1 66.0 58.1 58.9 65.0 66.2 29.6 27.1 Total accounted b 100 100 100 100 100 100 100 100 a Refers to the number under the structures in the figure on the following page. b percent of radioactivity recovered in feces. Page 58 of 58 Figure 1. Proposed metabolic pathway for [ 14C phenyl UL] BAYCOR ( Bitertanol) in rats. Figure taken from page 48 of MRID 00129560.


[Federal Register: October 9, 2007 (Volume 72, Number 194)]
[Notices]
[Page 57320-57321]
[DOCID:fr09oc07-67]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2197-073; Project No. 2206-030]

Alcoa Generating, Inc., NC; Progress Energy Carolinas, North
Carolina; Notice of Availability of the Draft Environmental Impact
Statement for the Yadkin Project and the Yadkin-Pee Dee River Project

September 28, 2007.
    In accordance with the National Environmental Policy Act of 1969
and the Federal Energy Regulatory Commission's (Commission)
regulations, 18 CFR part 380 (Order No. 486, 52 FR 47897), the Office
of Energy Projects has reviewed the applications for relicense for the
Yadkin Project (FERC No. 2197) and the Yadkin-Pee Dee River Project
(FERC No. 2206), located on the Yadkin and Pee Dee rivers in central
North Carolina near Charlotte, North Carolina and has prepared a Draft
Environmental Impact Statement (draft EIS) for the projects.
    The existing 210-megawatt (MW) Yadkin Project and the existing
108.6-MW Yadkin-Pee Dee River Project do not occupy any federal lands.
    In the draft EIS, staff evaluates the applicants' proposals and
alternatives for relicensing the projects. Staff's analysis includes
evaluation of settlement agreements filed with the Commission for both
projects which

replaced the Proposed Actions originally filed with the license
applications. The draft EIS documents the views of governmental
agencies, non-governmental organizations, affected Indian tribes, the
public, the license applicants, and Commission staff.
    Comments should be filed with: Kimberly D. Bose, Secretary, Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426. All comments must be filed within 60 days of the notice in the
Federal Register, and should reference either Project No. 2197-073
(Yadkin Project) or Project No. 2206-030 (Yadkin-Pee Dee River
Project). Comments may be filed electronically via the Internet in lieu
of paper. The Commission strongly encourages electronic filings. See 18
CFR 385.2001(a)(1)(iii) and instructions on the Commission's Web site
at http:// www.ferc.gov under the eLibrary link.

    Anyone may intervene in this proceeding based on this draft EIS (18
CFR 380.10). You may also file your request to intervene
electronically. You do not need intervenor status to have the
Commission consider your comments.
    Copies of the draft EIS are available for review in the
Commission's Public Reference Branch, Room 2A, located at 888 First
Street, NE., Washington, DC 20426. The draft EIS also may be viewed on
the Internet at http://www.ferc.gov under the eLibrary link. Enter the

docket number (either P-2197 or P-2206) to access the document. For
assistance, contact FERC Online Support at<EMAIL_ADDRESS>or toll-free at 1-866-208-3676, or for TTY,<PHONE_NUMBER>.
    CD versions of the draft EIS have been mailed to everone on the
mailing list for the projects. Copies of the CD, as well as a limited
number of paper copies, are available from the Public Reference Room
identified above.
    You may also register online at http:// www.ferc.gov/docs-filing/

esubscription.asp to be notified via e-mail of new filings and
issuances related to these or other pending projects. For assistance,
contact FERC Online Support.
    For further information, contact Stephen Bowler at<PHONE_NUMBER>
or
<EMAIL_ADDRESS>or Lee Emery at<PHONE_NUMBER> or<EMAIL_ADDRESS>

Kimberly D. Bose,
Secretary.
[FR Doc. E7-19782 Filed 10-5-07; 8:45 am]

BILLING CODE 6717-01-P