WPCK 2JB NL Zames RomanaMs RomanTimes Roman BoldTimes Roman ItalicP"S^*8DSS888S^*8*.SSSSSSSSSS..^^^Jxooxf]xx8Axfxx]xo]fxxxxf8.8NS8JSJSJ8SS..S.SSSS8A.SSxSSJP!PZ8*888888888888S.xJxJxJxJxJooJfJfJfJfJ8.8.8.8.xSxSxSxSxSxSxSxSxSxSxJxSxSxSxS]SxJxJoJoJoJoJxSfJfJfJfJxSxSxSxSxSxS8S8S888SA8xSf.f8f8f.xSxSxSxSxSxo8o8o8]A]A]A]Af8f8xSxSxSxSxxSfJfJN:*LS8JSSSSS.4}}S2S}2JJS88SS]]8J2t^^\\^^ee*C^.wR)Ewn\1fy\r\S{v\rQMS PS 810QMPS810.PRS]\  PChhhhP2=|L8&~#|]s Roman Bold"S^*8]SS888S_*8*.SSSSSSSSSS88___SxoxxofASoxfx]oxxxxo8.8aS8S]J]J8S].8].]S]]JA8]SxSSJB%BW8*888888888888].xSxSxSxSxSxxJoJoJoJoJA.A.A.A.x]SSSSx]x]x]x]xSxSSSxSxSf]xSxSxJxJxJxJx]oJoJoJoJSSSSS]A]A]A8A]S8]o.o8o8o.x]x]x]SSxxJxJxJ]A]A]A]Ao8o8x]x]x]x]xxSoJoJN:*ZS8SSSSSS27}}S2}}S}2.SSS88SS]]8S2t__\\__ee*C_.wR)Ewn\1fy\r\]{v\rTimes RomanTimes Roman BoldTimes Roman ItalicCourierTimes RomanTimes Roman BoldTimes Roman ItalicCourierCourier BoldTimes RomanTimes Roman BoldTimes Roman ItalicCourierCourier BoldCourier ObliqueTimes Roman Bold ItalicH8!r 8\  PC,P2LoL L US"S^*8FSS888Sq*8*.SSSSSSSSSS88qqqSffoxffxx8Jo]oxfxfS]xff]]A.AFS8SSJSJ.SS..J.xSSSSAA.SJoJJAC.CZ8*888888888888S.fSfSfSfSfSooJfJfJfJfJ8.8.8.8.oSxSxSxSxSxSxSxSxS]JfSxSxS]JxSfSfSfSoJoJoJoJxSfJfJfJfJxSxSxSxSxSxS8S8S888SJ8oJ].]8]8].oSoSoSxSxSofAfAfASASASASA]8]8xSxSxSxSo]J]A]AN:*WSASSSSSS.4}}S2S}2$]]S88SSSS8]2tqq\\qqee*Cq.wR)Ewn\1fy\r\S{v\r"S^!)22SN!!!28!2222222222888,\HCCH=8HH!'H=YHH8HC8=HH^HH=!!/2!,2,2,!222N2222!'22H22,006!!!d!!!!!!!!!!2H,H,H,H,H,YCC,=,=,=,=,!!!!H2H2H2H2H2H2H2H2H2H2H,H2H2H2H282H,H,C,C,C,C,H2=,=,=,=,H2H2H2H2H2H2!2!2!!!2'!H2==!=!=H2H2H2H2H2YHC!C!C!8'8'8'8'=!=!H2H2H2H2^HH2=,=,N#-2!,22222KK2LL2K,,2d!!22b88d!,dt887788c<6660"66X@K@ >6668 6 `Kpy.]8*:H]\  PCPqy.a8* _a4  p(AC<{,\8*-\*f9 xCX H8!r 8\  PC,PH:! [ :4  p(AC,<I7!  7*f9 xC,XTg/ZZZ0dZ6X@K@ g/ZZZ8dZ `KT>6660"66X@K@ >6668 6 `Kg/ZZZE7 dZ6Nh[KHz-]8*U ]9 xIC88888].xSxSxSxSxSxxJoJoJoJoJA.A.A.A.x]SSSSx]x]x]x]xSxSSSxSxSf]xSxSxJ2I  #]\  PC:HP#6 X01Í Í<X01Í Í 6  yO 6 / October 8, 1992 6  yO  6  d  yO 2 Part III 6  yO 6 '! Environmental Protection Agency 6  yO( 6  d  yO  Daminozide; Notice of Final Determination for Non-Food Uses and Termination of the Daminozide Special 3Review 6  zNh D(This reprint was prepared from the electronic file that accompanied the original signed documents 7transmitted to the Office of the Federal Register. This file was certified to be a true copy of the originals.) 6  yO  (This document appeared at 57 FR 46436-46445.) 6 0*(( 6  yO 6 XU yO   Federal Register / Vol. 57 No. 196 / Thursday, October 8, 1992 / Notices d 6Ԛ ENVIRONMENTAL PROTECTION AGENCY  yO  [OPP - 30000/40D; FRL - 4163 - 7]  yO  Daminozide: Notice of Final Determination for Non-Food Uses and Termination of the Daminozide Special 3Review 6  yO@ 6  AGENCY: Environmental Protection Agency (EPA).  yO  ACTION: Final determination and termination of Special Review. d  yO  SUMMARY: This Notice concludes the Special Review of the non-food uses of daminozide and announces the Agency's decision to retain these registrations without requiring modification to the label. This Notice also contains the Agency's revised estimate of the dietary risks based on the conclusions of the 2 - year UDMH cancer studies in mice and rats.  yO@  ADDRESSES: Requests for a hearing must be submitted to: Hearing Clerk (A - 110), Environmental Protection Agency, 401 M St., SW., Washington, DC, 20460. Additional information supporting this action is available for public inspection from 8 a.m. to 4 p.m., Monday through Friday, except legal holidays in the Public Response and Program Resource Branch, Field Operations Division, (H7506C), Office of Pesticide Programs, Environmental Protection Agency, Room 1132, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202.  yO$  FOR FURTHER INFORMATION CONTACT: By Mail: Thomas Moriarty, Special Review Branch, Special Review and Reregistration Division (H7508W), Office of Pesticide Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office Location and Telephone Number: Third Floor, CS #1, 2800 Jefferson Davis Highway, Arlington, VA 22202 (703) 308 - 8035.  yO  SUPPLEMENTARY INFORMATION:  {O Electronic Availability: This document is available as an electronic file on The Federal Bulletin Board at 9 a.m.  yO on the date of publication in the Federal Register . By modem dial 202-512-1387 or call 202-512-1530 for disks or paper copies. This file is available in Postscript, Wordperfect 5.1 and ASCII. This Notice announces EPA's decision to retain the non-food use registrations of products which contain daminozide as the active ingredient. This Notice concludes EPA's administrative Special Review of the risks and benefits of daminozide which was initiated in a Federal Register notice of July 1984 (49 FR 29186). A notice of Preliminary Determination (PD 2/3) was issued in May 1989 (54 FR 22558), and supporting documents, including the Technical Support Document (TSD), for the PD 2/3 were made available to any requesting party at that time. The Agency received a request by the sole registrant of daminozide products, Uniroyal Chemical Company, in October 1989, to voluntarily withdraw all food-use registrations of daminozide. A notice was published in November 1989 (54 FR 47492) which canceled all food use registrations of daminozide as of November 17, 1989. This Notice concludes EPA's special review of the non-food uses of daminozide. This Notice is organized into nine units. Unit I is an introduction providing background information and the legal basis for this action. Unit II is a summary of previous regulatory actions concerning the registration of daminozide products. Unit III presents EPA's summary of the toxicological concerns, cancer classification, and comments received in response to EPA's PD2/3. Unit IV contains EPA's exposure assessment, final worker risk estimates and additional comments received in response to the PD 2/3. Unit V contains the benefits associated with daminozide and comments received in response to the PD 2/3. Unit VI contains EPA's reassessment of the dietary risks of  yO daminozide based on the refined cancer potency factor (Q1*) and Unit VII summarizes EPA's risk/benefit determination and announces EPA's regulatory action. Finally, Unit VIII announces the availability of the Public Docket and Unit IX lists references contained in this document.  yO / I. Introduction 6  yO 6  Daminozide is the common name for butanedioic acid mono (2,2-dimethylhydrazine). The sole registrant, Uniroyal Chemical Company (Uniroyal), produces four products, B-Nine, B-Nine SP, Alar 85, and Alar Technical, which contain daminozide as the active ingredient. Daminozide is a systemic growth regulator registered only for use on ornamental and bedding plants. Daminozide also was registered for use on food crops; however, Uniroyal Chemical Company voluntarily canceled all food use registrations of daminozide on November 14, 1989.  {Or  Legal background.Before a pesticide product may be lawfully sold or distributed in either intrastate or interstate commerce, the product must be registered by EPA (FIFRA sections 3(a) and 12(a)(1)). A registration is a license allowing a pesticide product to be sold and distributed for specified uses in accordance with specified use instructions, precautions, and other terms and conditions of a registration. In order to obtain a registration for a pesticide under FIFRA, an applicant must demonstrate that the pesticide satisfies the statutory standard for registration. The standard requires, among other things, that the pesticide perform its intended function without causing ``unreasonable adverse effects on the environment.'' The term ``unreasonable adverse effects on the environment'' is defined in FIFRA section 2(bb), as ``any unreasonable risk to man or the environment, taking into account the economic, social and environmental costs and benefits of the use of any pesticide.'' This standard requires a finding that the benefits of the use of the pesticide exceed the risks of use when the pesticide is used in compliance with the terms and conditions of registration or in accordance with commonly recognized practices. The burden of proving that a pesticide satisfies the statutory standard is on the proponent of registration and continues as long as the registration remains in effect. Under FIFRA section 6, the Administrator may issue a Notice of Intent to Cancel the registration of a pesticide product whenever it is determined that the pesticide product causes unreasonable adverse effects on the environment. EPA created the Special Review process to facilitate the identification of pesticide uses which may not satisfy the statutory requirements for registration and to provide an#0*%% informal procedure to gather and evaluate information about the risks and benefits of these uses. A Special Review is initiated if a pesticide meets or exceeds the risk criteria set out in the regulations at 40 CFR  yO part 154. EPA announces that a Special Review is initiated by issuing a notice in the Federal Register . Registrants and other interested persons are invited to review the data upon which the Special Review is based and to submit data and information to rebut EPA's conclusions by showing that EPA's initial determination was in error, or by showing that use of the pesticide is not likely to result in any significant risk to human health or the environment. In addition to submitting rebuttal evidence, persons wishing to comment may submit relevant information to aid in the determination of whether the economic, social, and environmental benefits of the pesticide outweigh the risks of use. After reviewing the comments received and other relevant material obtained during the Special Review process, EPA makes a decision on the future status of registrations of the pesticide. The Special Review process may be concluded in various ways depending upon the outcome of EPA's risk/benefit assessment. If EPA concludes that all of its risk concerns have been adequately rebutted, the pesticide registration will be maintained unchanged, or if all its risk concerns are adequately addressed through label changes, a special review may be terminated after such label changes. If, however, all risk concerns are not rebutted, EPA will proceed to a full risk/benefit assessment. In determining whether the use of a pesticide poses risks which are greater than its benefits, EPA considers possible changes to the terms and conditions of registration which can reduce risks, and what impacts such modifications may have on the benefits of use. If EPA determines that such changes reduce risks to the level where the benefits outweigh the risks, it may require that such changes be made in the terms and conditions of the registration. Alternatively, EPA may determine that no changes in the terms and conditions of a registration will adequately assure that use of the pesticide will not pose any unreasonable adverse effects. If EPA makes such a determination, it may seek cancellation, and, if necessary, suspension. In either case, EPA must issue a Notice of Intent to Suspend or a Notice of Intent to Cancel the registrations. If the Notice requires changes in the terms and conditions of registration, cancellation may be avoided by making the specified changes set forth in the Notice, if possible. Adversely affected persons, including registrants and applicants for registration, may also request a hearing on the suspension or cancellation of a specified registration or use.  yOP + II. Regulatory History 6  {M 6  A. Rebuttable Presumption Against Registration  {Op  In June 1984, EPA (the Agency) issued a Notice of Rebuttable Presumption Against Registration (RPAR) for Daminozide which initiated what is now called the Special Review Process (40 CFR part 154). The RPAR included the Notice of Initiation of Special Review (PD 1) (49 FR 29186, July 18, 1984), and the Pesticide Registration Standard and Guidance Document. At that time, the Agency was concerned about carcinogenic risk to the general population through dietary exposure to daminozide. Data available at that time indicated that daminozide was carcinogenic in laboratory mice and rats. The Agency was specifically concerned about risk from unsymmetrical dimethylhydrazine (UDMH). UDMH, a known carcinogen in laboratory animals, is a contaminant of commercial daminozide and a metabolite of daminozide once it enters the body. EPA believed, however, that the risks associated with the non-food uses of daminozide were not significant. The Agency noted that daminozide was not rapidly absorbed through the skin and exposure to applicators was low (Ref. 1). Through the PD 1, the Agency solicited information from registrants, applicants, and interested parties to help conduct a full risk/benefit analysis of daminozide. Information which the Agency solicited included information on the importance of daminozide to agriculture and information regarding alternative growth regulators such as their efficacy and use patterns.  {M# B. Draft Preliminary and Final Determination (PD 2/3/4), Data Call-In, and Tolerance Extension.#0*%%Ԍ {O ԙ In September 1985 EPA submitted a Draft PD 2/3/4 to the Scientific Advisory Panel (SAP) and the U.S. Department of Agriculture, as required by FIFRA. The Agency intended to proceed with a PD 2/3/4 in order to expedite the special review of daminozide. (A PD 2/3/4 allows the Agency to propose and finalize a regulatory action in one step whereas it is usually completed in two; first by proposing a regulatory action (PD 2/3) then by finalizing a regulatory action (PD 4)). The SAP believed that the animal cancer data were insufficient to support a quantitative risk assessment and recommended that EPA require additional data before taking regulatory action on daminozide. Although EPA is not legally bound by the SAP's opinion, the Panel is an integral part of Agency decisions. In this case, EPA accepted the Panel's recommendations and did not proceed with the Draft PD 2/3/4 but required additional data, and took a number of steps to reduce risk to the general population as discussed below. A Data Call-In Notice was issued in 1986 which required a number of additional studies including cancer studies in mice and rats, a greenhouse worker exposure study, and a market basket survey to measure levels of daminozide and UDMH on produce in the grocery store (Ref. 2). To reduce risk to the general population, the Agency reduced the application rate of daminozide on apples and added to the label an advisory statement which cautioned against the use of daminozide on apples intended for processing. (Levels of UDMH increase when apples are processed). EPA also reduced the tolerance for daminozide residues on apples from 30 ppm to 20 ppm and set the tolerance to expire on July 31, 1987. The Agency intended to reevaluate the daminozide tolerance on apples after the preliminary results of the residue and market basket survey data were available. However, data available at that time (July 1987), showed that the tolerances could not be lowered without making some legally treated apples over tolerance and therefore, subject to seizure. Thus, EPA extended the 20 ppm apple tolerance until January 31, 1989 (51 FR 12889). In early 1989, the Agency reevaluated the tolerance in light of the interim results of the cancer studies. In January 1989, EPA estimated, based on the interim results of the UDMH cancer studies in rat and mice, that  yO the dietary risk to the general population from daminozide/UDMH was 4.9 x 10−5. In considering the estimated risk, EPA believed that regulatory action should be pursued but that the daminozide tolerance, due to expire January 31, 1989, could be extended for an additional 18 months without posing an unreasonable risk to the general population.  {M C. Preliminary Determination to Cancel Certain Daminozide Product Registrations and Draft Notice of Intent to Cancel (PD 2/3)  {O:  In preparing the PD 2/3, which was issued in May 1989 (54 FR 22558), EPA reviewed all comments and data submitted in response to the PD 1, the historical toxicity data, and the interim results of the UDMH cancer studies required through the 1986 Data Call-In. The Agency's primary concern about exposure to daminozide/UDMH was cancer. Although EPA had classified both UDMH and daminozide as Group B2, probable human, carcinogens, (Ref. 3), EPA had identified UDMH as the primary agent of concern. At that time EPA did not estimate risk from daminozide, as it did for UDMH. Although daminozide produced the same types of tumors as did UDMH (hemangiomas/hemangiosarcomas), the incidences of tumors showed trends but no statistical significance by pairwise comparison with controls (Ref. 3). The interim results of the UDMH cancer studies in mice and rats were received in March 1988. Based on the  yOD report from the mouse study, EPA calculated an interim UDMH cancer potency factor (Q1*). (Cancer potency is a quantitative measure or estimate of the relationship between exposure to increasing doses of the chemical substance in question and the increased severity of the carcinogenic effect, such as the number of tumors). EPA believed that  yO! vascular tumors (hemangiosarcoma) were appropriate to use in calculating the interim Q1* because: (1) It is a relatively uncommon malignant tumor and has a low background rate in laboratory mice and rats; and (2) it is the same type of tumor seen in the earlier UDMH studies (Toth 1973, Toth 1977a, Toth 1977b, and Haun 1984) (Refs. 4, 5, 6, and 7).#0*%%Ԍ yO  Dietary risk was estimated using the interim (Q1*) and exposure estimates derived from levels of daminozide residues on treated foods, as observed in the market basket survey, and consumption patterns. EPA estimated dietary  yO risk to the general population from exposure to UDMH to be 4.9 x 10−5. Full descriptions of exposure estimates and risk calculations, including exposure and risk calculations to various subpopulations, are contained in the Technical Support Document (TSD) (Ref. 3). Risk from the non-food uses of daminozide was estimated using exposure estimates from a surrogate worker exposure study. Although Uniroyal submitted a daminozide worker exposure study in 1986, it was found to be inadequate to assess exposure, therefore, EPA used surrogate data (Sumagic PRG [Merricks, 1987]) it had on hand to estimate daminozide exposure to greenhouse workers. The Agency estimated risk to a worker performing the three  yO job functions of mixer, loader, and applicator, to be 2 x 10−6 (Ref. 3). The Agency also conducted a preliminary analysis of the benefits associated with the use of daminozide on both food and non-food crops. The analysis was conducted to determine the potential economic impacts to consumers, retailers, and producers if daminozide was not available. The Agency also considered the biological effects of daminozide, methods of application, and projected biological and economic impacts if daminozide were canceled, as well as the most likely chemical and non-chemical alternatives if daminozide were not available. EPA's preliminary benefit analysis of the following sites is contained in the TSD: apples (several varieties), peanuts, cherries, grapes, peaches, nectarines, pears and tomatoes (tomato transplants), and the non-food uses of daminozide. EPA believed that the carcinogenic risk posed to the general population from the food uses of daminozide outweighed the benefits and therefore proposed to cancel all food-use registrations of daminozide. However, EPA proposed to retain the non-food uses of daminozide without modification to the label because it believed that the risks posed to greenhouse workers were outweighed by the benefits.  {M0 D. Notice of Receipt of Request to Cancel and Termination of Special Review of Food Uses, and Final Tolerance Rule  {O  In October 1989, Uniroyal Chemical Company requested voluntary cancellation of all food-use registrations of daminozide. On November 14, 1989, the Agency published a notice (54 FR 47492) announcing its receipt of this request. That notice announced Uniroyal's commitment to submit the final report of the 2 - year UDMH cancer studies and also announced EPA's intention to conduct a final dietary and worker risk assessment based on the conclusions of these studies. Subsequently, the Agency received the final reports of the UDMH cancer studies. In addition, Uniroyal Chemical Company voluntarily submitted worker exposure and metabolism data. The final dietary and worker risk assessments, based on these data, are contained in Units III, IV, VI, and VII of this Notice. The Agency issued the Proposed Rule to revoke tolerances for daminozide on September 7, 1989 (54 FR 37278) the final tolerance rule for daminozide was published on March 19, 1990 (55 FR 10218), which set all tolerances for daminozide residues on food and feed crops at zero as of May 31, 1991.  {M" E. Conclusion of Special Review (PD 4)  {O  EPA's assessment and final decision regarding the risks and benefits for the non-food uses of daminozide are set forth in this document. This Notice also contains the Agency's reassessment of the dietary risks of daminozide. Based on both newly received data (including the final report of the rat and mouse cancer studies, new worker exposure data, and metabolism data), and historical daminozide data, EPA has determined that benefits from daminozide use on ornamental and bedding crops outweigh the risks to workers. Accordingly, EPA is announcing its decision to retain all non-food use registrations of daminozide without change to the label. Additionally, dietary risks have been reestimated using the final report of the UDMH cancer study in mice. EPA maintains that the dietary risk posed to the general population in 1989 was unreasonable and the Agency does not intend to change its regulatory position on the food-uses of daminozide. A more detailed discussion of the risks and benefits associated with the non-food#0*%% uses is contained in the latter part of this Notice.  yO  III. Summary of Toxicological Concerns and Agency Evaluation of Comments 6  yO  6  The principal effect of concern with daminozide is the carcinogenic potential of UDMH. In 1989, EPA based its Preliminary Determination on the interim results of the UDMH cancer studies in rats and mice (Uniroyal 1988c, 1988d, 1988e). The final report of these studies has been submitted and EPA finds these data appropriate for cancer risk assessment (Ref. 8). EPA has considered, as a whole, the data from both the interim and the final reports of the cancer studies in evaluating the carcinogenic potential of daminozide and UDMH.  {M A. Carcinogenicity  {O`  1. Hazard identification. In one study (Uniroyal 1988c), Fisher 344 rats were administered UDMH in their drinking water at concentration levels of 0, 1, 50, or 100 ppm for 2 years. Gross findings included a dose related increase in cloudy corneas in both sexes which was not statistically significant. Non-neoplastic lesions were not observed in the test animals with the exception of bile duct hyperplasia and inflammation of the liver in the highest dosed males and in the mid-dose and high-dose females. The females also showed a statistically significant increasing trend of liver tumors (hepatocellular carcinomas/adenocarcinomas) and of combined liver tumors (hepatocellular adenomas and carcinomas/adenocarcinomas). Females also exhibited a significant increase in combined adenomas and carcinomas in the 50 and 100 ppm concentration groups when compared to controls. There were no other dose-related increases of neoplasms at other sites in females (Ref. 9). A second study (Uniroyal 1988d), was conducted in which CD-1 mice were administered UDMH in their drinking water for 2 years at concentration levels of 0, 1, 5, or 10 ppm in males and 0, 1, 5, or 20 ppm in females. In the second year of the study, survival decreased in both sexes in all dose groups. However, only the top dose of both the males and females showed a substantial decrease in survival when compared to controls at termination. At week 78, the male mice showed a noticeable decrease in the survival (ranging from 62 percent to 86 percent), when compared to controls. There was an increase in the incidence of brown pigment in the liver of both males and females in the mid-dose and high-dose groups between 12 and 24 months. Both males and females also showed a significant increase in the number of combined lung tumors (bronchioloalveolar adenoma and/or carcinoma). Male and female mice also showed an increase in the occurrence of bronchioloalveolar adenomas (Ref. 9). In the third study (Uniroyal 1988e), CD - 1 mice were administered UDMH at concentration levels of 0, 40, or 80 ppm in drinking water. The majority of deaths of the test animals occurred in the second year of the study. While there was a significant decrease in the survival of males only in the 80 ppm dose group, the females showed a significant decrease in survival in both the 40 ppm and 80 ppm dose groups. There was a biologically significant dose-related decrease in water consumption in male mice receiving 40 and 80 ppm when compared to controls. There was an increased incidence of lung tumors (alveolar/bronchiolar adenomas) and vascular liver tumors (hemangioma and hemangiosarcomas) which were considered dose related. In the 80 ppm dose group, both sexes showed both a pair-wise comparison, and a significant increasing trend in hemangiosarcomas and bronchioloalveolar tumors. In pair-wise comparison to the controls with the 40 ppm dose group, there was a significant increasing trend of vascular tumors (hemangiosarcomas) and combined vascular and lung adenomas (hemangiomas and lung adenomas/ carcinomas). The males in the 40 ppm dose group also showed an increase in the incidence of combined vascular tumors (hemangiomas and hemangioma sarcomas), combined lung tumors (lung adenomas/carcinomas), and combined hepatocellular tumors (adenomas and/or carcinomas). Female mice in the 80 ppm dose group showed significant increased trends and significant pair-wise comparison to controls for vascular tumors (hemangiosarcomas), combined vascular tumors (hemangiomas and hemangiosarcomas), lung tumors (bronchioloalveolar adenomas) and combined lung tumors (bronchioloalveolar adenomas and bronchioloalveolar carcinomas). In pair-wise comparison to controls, the 40 ppm dose group showed#0*%% a significant increase in vascular tumors (hemangiosarcomas), combined vascular tumors (hemangiomas and hemangioma sarcomas), in hepatocellular adenomas, in lung tumors (bronchioloalveolar adenomas) and combined lung tumors (bronchioloalveolar adenomas and/or carcinomas) (Ref. 9)  {OX  2. Metabolism. A metabolism study in miniature swine was submitted to the Agency in 1987 (Ref. 10). Daminozide was administered in a single 5 mg/kg oral dose and after 96 hours was found in almost all tissues at  yO levels up to 73 ppb, with the liver and kidney containing the highest levels. Analysis indicated that both 14C-UDMH  yO and 14C-dimethylnitrosamine (DMN), which are derived from 14C-daminozide, were excreted in the urine. From urinalysis, EPA estimated that only about 16 percent of the oral dose could be shown to be absorbed and approximately 1 percent (1 ppm) of daminozide is metabolized to UDMH. DMN levels in the urine, collected in the first 24 hours, ranged from 0.01 to 0.69 ppm.  {O  3. Mutagenicity. While daminozide has been demonstrated to be negative for mutagenicity in a number of studies, UDMH has shown positive mutagenic activity in various other studies which have been submitted to the Agency. The Agency also notes that the open literature reports UDMH as positive for mutagenicity. Based on the available information, the Agency remains concerned about the mutagenic potential of UDMH (Refs. 11, 12, 13, 14, 15, and 16), although the available data does not conclusively indicate whether UDMH is mutagenic. In addition, further metabolism of UDMH can result in the formation of DMN, a well known mutagen.  {OL B. Unit Risk (Q1*)  yO  EPA calculated the final Q1* based on the incidence of hemangiosarcomas from all sites of the male CD - 1 mouse study (the combined report of Uniroyal 1988d and Uniroyal 1988e) (Ref. 17). The Agency did not combine the incidence of the hemangioma with that of the incidence of the hemangiosarcoma in deriving the cancer potency factor because the data were insufficient to demonstrate evidence that the benign hemangioma progressed to the malignant hemangiosarcoma (Ref. 18). The number of hemangiomas were few and, even if included, would only marginally affect the unit risk estimate. The Agency is also aware of the increased incidence of lung tumors in both the lower dose CD - 1 mouse study  yOV and in the higher dose CD - 1 mouse study. However, the refined unit risk estimate of UDMH (the final UDMH Q1*) did not reflect the incidence of these tumors for the following reasons: (1) Historical incidences of lung tumors in the CD - 1 male mouse were high, ranging from 17 percent to 52 percent; (2) incidences of lung adenomas and lung carcinomas in the two highest dose groups (40 and 80 ppm) were significantly higher than controls but were not dose-related; (3) the lung tumors were found only at interim or terminal sacrifice, or when animals died at unscheduled times during the study; (4) the hemangiosarcoma, which has a low background incidence in CD - 1 mice, was a rapidly fatal tumor that was observed throughout the study; and, (5) the lung tumors were not able to be correctly evaluated by the same statistical method as the hemangiosarcoma (Ref. 18). The unit risk estimate of lung tumors alone, of hemangiosarcomas alone, and of the combined incidence of lung tumors and hemangiosarcomas were computed. The unit risk estimate of the combined tumors was within one order of magnitude of that of the unit risk estimate of the hemangiosarcoma. Use of either the combined unit risk estimate or that of the hemangiosarcoma alone would have a similar impact on the final regulatory decision.  yO  Finally, the Agency did not use data from the rat study to estimate a UDMH Q1* because only a small number of tumors occurred in only one sex and only at relatively high doses. The Agency believes that the responses observed in the rat study contrasted with the concerns raised by the responses seen in the mouse studies (Ref. 18).  yO  A separate cancer potency factor was calculated using data from male mice (0.46 (mg/kg/day)−1) and data  yO from the female mice (0.31 (mg/kg/day)−1). EPA used the more conservative Q1* from the male mice, 0.46  yO! (mg/kg/day)−1, for the final risk assessment (Ref. 19). Because both sexes of mice had statistically significant increases in mortality with increasing doses of UDMH, hemangiosarcomas from all sites were evaluated by Peto's Prevalence test and the cancer potency factor was evaluated by the time-to-tumor Weibull83 model (Ref. 17). #0*%%Ԍ {M C. Cancer Classification  {O  EPA classified UDMH and the parent compound daminozide as Group B2 carcinogens using the weight-of-the-evidence approach and following the classification scheme set forth in EPA's Carcinogen Risk Assessment Guidelines (51 FR 33992, September 24, 1986). ``Weight-of-the-evidence'' is an approach the Agency uses to evaluate how likely an agent is to be a human carcinogen by taking into consideration the quality and adequacy of the data and the kinds and consistency of responses induced by a suspect carcinogen. Using this approach the Agency has determined that there is sufficient evidence from animals to consider the agent(s) probable human carcinogens. Evidence is ``sufficient'' for an agent to be classified as a probable human carcinogen if there is an increased incidence of tumors: (a) In multiple species or strains of test animals; or (b) in multiple experiments, for example, with different dose levels or routes of administration; or (c) to an unusual degree in a single experiment with regard to high incidence, unusual site or type of tumor, or early age at onset. UDMH is an inherent component of commercial daminozide and daminozide also breaks down to UDMH. The Agency, therefore, has classified both the metabolite, UDMH, and the parent, daminozide, as B2 carcinogens (Ref. 9) based on the following evidence: (1) Administration of UDMH to female rats for 2 years was associated with a significant increase of combined liver tumors (carcinomas, and combined adenomas and carcinomas). In male and female mice, there was a statistically significant increase in the incidence of lung tumors. (2) Administration of UDMH to male and female mice was associated with a significant increased incidence of vascular tumors (hemangiosarcomas and combined hemangiomas and hemangiosarcomas) at the mid-dose and high-dose levels. (3) UDMH is structurally related to other hydrazine compounds (such as 1,2 dimethylhydrazine and monomethylhydrazine) which produce vascular and lung tumors. (4) Data from a metabolism study in miniature pigs indicated the presence of DMN in the urine. DMN has been reported to produce vascular and pulmonary tumors identical to those evoked by both daminozide and UDMH. (5) The mutagenicity concern for both UDMH and DMN also supports the Agency's cancer classification.  {M D. Comments and EPA Response  {O  In response to the PD 2/3, EPA received comments regarding the Agency's evaluation of daminozide (Ref. 20). Several comments were submitted regarding the Agency's toxicological evaluation of daminozide/UDMH. A summary of these comments and the Agency's response follows.  {O  Comment. Uniroyal believes that the Group B2 cancer classification of daminozide is inappropriate and that the weight-of-the-evidence supports a finding that daminozide is not carcinogenic. Uniroyal cited a 1988 study in which rats were administered daminozide in doses up to 10,000 ppm with no reported carcinogenic effects related to the administration of daminozide. Uniroyal also believes that several studies (Toth 77 and NCI 78), which the Agency used to support its regulatory decision, are not appropriate for cancer risk assessment because of irregularities in the design of the studies and in the way the studies were conducted.  {O  EPA Response. With respect to the cancer classification of daminozide, the Agency recognizes that the cancer study in rats, as cited above, did not produce an overt incidence of tumors, as compared to the responses observed in mice. Additionally, the Agency notes that the gastrointestinal tract of various animal species to which alar is exposed, vary considerably and some species are more able to tolerate metabolic insult while others have a greater capability to cause (by metabolic conversion) or allow (due to appropriate pH condition) the breakdown of daminozide to UDMH. Since daminozide has been shown to breakdown to UDMH in several species, e.g., mice, guinea pig and swine, although not in the rat, the Agency believes that it is only appropriate that both the parent compound, daminozide, and the metabolite compound, UDMH, be classified as Group B2 carcinogens. With respect to the Agency's use of the Toth 77 and NCI 78 studies, the Agency did not base its 1989 proposed#0*%% regulatory decision on these two studies, rather the Agency used these two studies only as support for its proposed regulatory decision. (Indeed, the Scientific Advisory Panel recommended that the Agency not perform a quantitative risk assessment based on these studies.) The Agency, therefore, called for more definitive cancer data through a Data Call In, issued in 1986. The cancer studies in mice and rats provided the basis for the Agency's 1989 proposed regulatory decision.  {O  Comment. Uniroyal believes that the dose levels used in the higher-dose cancer study in mice (40 or 80 ppm) exceed the Maximum Tolerated Dose (MTD), and therefore, the study is inappropriate to use for human health risk assessment. Uniroyal contends that the administered dose levels produced extreme levels of toxicity in the test animals, resulting in an increased rate of mortality. Uniroyal believes the high rate of mortality in the test animals makes data produced from this study highly questionable.  {O  EPA Response. The Agency requested an additional carcinogenicity study in mice at doses of 0, 40, or 80 ppm because it did not believe that the MTD would be achieved with doses of 10 or 20 ppm of UDMH in the lower dose studies. The Agency consulted with other governmental testing facilities knowledgeable in setting test dose levels in cancer studies in order to establish dosing levels which should be administered to show whether UDMH was in fact carcinogenic. Although the top doses produced some toxicity, the Agency believes that the high mortality, resulting from tumor rupture, cannot be attributed to exceedance of the MTD. Additionally, data from both higher dose and lower dose cancer studies with UDMH, when considered together show a good dose relationship with statistical significance, thereby arguing against the MTD being exceeded. The Agency, therefore, considered it appropriate to use the data from both the higher dose and the lower dose studies to assess human risk.  {O  Comment. Uniroyal believes that the open literature on UDMH mutagenicity, which supports EPA's concern, is not accurate. UDMH mutagenicity data, as reported in the open literature, show that mutagenic responses are associated with cytotoxicity and are found only in studies where the test material was contaminated with dimethylnitrosamine (DMN).  {O  EPA Response. The Agency believes that at least a portion of UDMH is nitrosated in humans, as it is in some animals, such as mice, due to the gastric acid secretions of a low pH. The Agency realizes that nitrosation does not occur in all mutagenicity studies. However, the Agency maintains a concern for the mutagenic potential of UDMH because it is capable of nitrosating, in the human, to DMN which is a known mutagenic agent.  yO (v IV. Worker Exposure and Risk 6  yO@ 6  At the time of the PD 2/3, the Agency made a number of assumptions in estimating worker exposure to UDMH because of the limited data available at that time. Since then, the Agency has received a number of studies which have allowed EPA to refine the exposure assessment. Exposure to UDMH comes from two sources: (1) Conversion of daminozide to UDMH when it is ingested or absorbed through the skin or lungs; and (2) presence of UDMH as a contaminant in the commercial product and conversion of daminozide to UDMH when left standing in the mixing tank. The total risk from UDMH is estimated by adding together the individual risk from each source of exposure to UDMH.  {M A. Worker Exposure  {O  A worker exposure study submitted by Uniroyal in 1990 measured dermal and inhalation exposure to daminozide from application to ornamentals in a greenhouse. Exposure was monitored separately for the mixer/loader job function and the applicator job function. The Agency calculates the unit of exposure to daminozide by dividing the total dermal and inhalation exposure by the volume of pesticide handled. Actual dermal exposure to the body (exposure to the skin under the clothing) was measured using whole body dosimeters (long cotton briefs worn under the workers' typical clothing and over# 0*%% the workers' underwear). Dermal exposure to the face and neck was measured by extracts from swabs and exposure to the hands was measured from washing in detergent or rinsing in distilled water. Total dermal exposure was measured as the sum of all the residues from the upper and lower body dosimeters and residues measured from the facial and neck swab and hand rinse (Ref. 21). Inhalation exposure was measured with an air sampling pump attached to the collar of the worker. Calculations for inhalation exposure were based on a respiration rate of 45 liters/minute for all job functions (Ref. 21). Based on information provided by commercial growers and Uniroyal, EPA used the following parameters to estimate exposure to workers in both large and small greenhouses: (1) Workers in a large-greenhouse operation handle approximately 24 pounds of daminozide annually and small-greenhouse workers handle 10 pounds annually; (2) maximum exposure to a worker was estimated assuming that a worker will have a combined job function of mixer, loader, and applicator; (3) daminozide is not applied on consecutive days and the maximum period of exposure for any one application is 5 hours; (4) maximum concentration of the active ingredient is used (5,000 ppm solution), and is applied two times per year on multiple crops; and (5) daminozide is applied as a fine spray (as opposed to a coarse spray) which results in higher exposure (Ref. 22).  {O  1. Exposure to UDMH metabolized from daminozide. Based on the miniature pig metabolism study, EPA has determined that upon entering the gut, about 1 percent of daminozide is metabolized to UDMH (Ref. 10). However, a worker's dermal and/or inhalation exposure to daminozide most likely does not result in metabolic conversion of daminozide to UDMH in the gut but elsewhere in the body e.g., the bloodstream. Because the exact rate of metabolic conversion in the body is not known, EPA assumes it to be the same as the 1 percent rate at which daminozide is metabolized to UDMH in the gut. EPA believes that this may be an overestimation because the metabolic conversion rate in the gut is generally higher (due to pH), than in other parts of the body. A worker's exposure to UDMH which is metabolically converted from daminozide is summarized in Column A of Tables 1a and 1b. in Unit. IV.A.2 of this notice.  {O  2. Exposure to UDMH from contamination and hydrolysis of daminozide.The other source of UDMH exposure is from that amount of UDMH which is present as a contaminant of the commercial daminozide product. Commercial daminozide is comprised of 0.005 percent UDMH (Ref. 3). Exposure to UDMH also comes from the conversion (hydrolysis) of daminozide to UDMH when a solution of daminozide is mixed and stands in the tank before being used. EPA calculates that 0.012 percent of a daminozide solution hydrolyzes to UDMH when allowed to stand in the tank for 24 hours (the daminozide label states that spray and stock solutions must be used within 24 hours) (Ref. 22). Estimated exposure to UDMH as a contaminant, and UDMH as a hydrolysis product, is calculated as 0.005 percent and 0.012 percent respectively, of exposure to the parent compound, daminozide. A worker's dermal exposure to UDMH as a contaminant and hydrolysis product of daminozide is summarized in columns B and C of  yO the following Table 1a:#dZ6X@K@# 3'3'Standard'3'3Standard810qaڰ  0*%%  g/,  Table 1a.-- Dermal Exposure to Daminozide and UDMH (in mg/kg/year, for combined function of mixer/loader/applicator)  Daminozide UDMH  A B C Site  Exposure to 1 percent UDMH 0.005 percent UDMH as UDMH hydrolyzed from daminozide(parent) metabolized (in the part of the parent the parent (0.012 body from the parent) (contaminant) percent)   g/4 Large Greenhouses..... 0.18 1.8 x 10−3  9.0 x 2.2 x  g/  10−6 10−5  g/ Small Greenhouses..... 0.075 0.75 x 10−3  3.8 x 9.0 x  g/  10−6 10−6  '3'3Standard810q3'3'Standard810qM۰ z x #]\  PC:HP# A worker's inhalation exposure to UDMH which is metabolically converted from daminozide, which is a contaminant of commercial daminozide and is hydrolized from commercial daminozide is summarized in columns  yO  A, B, and C, respectively of the following Table 1b:#dZ6X@K@# 3'3'Standard810q'3'3Standard810qaڰ   0*%%  g/,  Table 1b.-- Inhalation Exposure to Daminozide and UDMH (in mg/kg/year, for combined function of mixer/loader/applicator)  Daminozide UDMH  A B C Site  Exposure to daminozide 1 percent UDMH 0.005 percent UDMH as UDMH hydrolyzed from (parent) metabolized (in the part of the parent the parent (0.012 body from the parent) (contaminant) percent)   g/4 Large Greenhouses..... 0.12 1.2 x 10−3  6.0 x 1.4 x  g/  10−6 10−5  g/ Small Greenhouses..... 0.049 4.9 x 10−4  2.5 x 5.9 x  g/  10−6 10−6  '3'3Standard810q3'3'Standard810qM۰ z x #]\  PC:HP#  {M B. Absorption  {O   1. UDMH as a contaminant and hydrolyzed from daminozide. The UDMH which is a contaminant of daminozide and which is hydrolyzed from daminozide comes into contact with the worker as UDMH per se and therefore, the rate of dermal absorption of UDMH is necessary to determine the dose. A dermal absorption study was recently submitted by Uniroyal which demonstrated dermal absorption and bioavailability of UDMH in rats (Ref. 23). Based on this study, the bioavailability of UDMH for the treatment group which most closely matched a worker's potential exposure ranged from 11 percent to 24 percent. EPA used a UDMH dermal absorption rate of 20 percent as a reasonable worst-case scenario (Ref. 24). The Agency assumes that 100 percent of the UDMH which is present as a contaminant of daminozide or is hydrolyzed from daminozide is absorbed into the lungs.  {O*  2. UDMH which is metabolically converted from daminozide. Metabolic conversion of daminozide to UDMH occurs once daminozide has entered the body. The rate of dermal absorption of daminozide is known to be 1 percent and the amount of daminozide which is metabolically converted to UDMH once it enters the body, is assumed to be 1 percent (Ref. 25). EPA also assumes that 100 percent of that which is metabolically converted from daminozide to UDMH is absorbed into the lungs (Ref. 24).  {M C. Risk Characterization  {O4  Lifetime risk to workers may be estimated by converting exposure estimates to a lifetime average daily dose  yO (LADD) and multiplying by the refined UDMH Q1* of 0.46 (mg/kg/day)−1. The LADD converts yearly exposure to an average daily dose over a worker's lifetime (EPA assumes a professional applicator works 35 years of a 70 - year lifetime). The Agency has calculated risk to workers using an approach which measures exposure to UDMH. Exposure to UDMH comes from three sources; as a contaminant of daminozide, as a hydrolysis product of daminozide and as a metabolic break down product of daminozide. Inhalation and dermal risk from UDMH which is metabolically converted from daminozide is broken down in  yO the following Table 2a:#dZ6X@K@# 3'3'Standard810q'3'3Standard810qaڰ  0*%%  g/,  Table 2a.-- Risk from UDMH Which is Metabolically Converted from Daminozide   g/X  Q1 * (mg/kg/  g/  Site Dose\1\ (mg/kg/day) LADD (mg/kg/day) day−1) Lifetime Risk  Large Greenhouse......  g/  Inhalation.......... 4.8 x 10−4 6.6 x 0.46 3.0 x 10−7  g/F  10−7  g/r  Dermal.......... 7.2 x 10−6 9.9 X 0.46 4.6 x 10−9  g/  10−9 Small Greenhouse  g/  Inhalation.......... 2.0 x 10−4 2.7 x 0.46 1.2 x 10−7  g/`  10−7  g/  Dermal.......... 3.0 x 10−6 4.1 x 0.46 1.9 x 10−9  g/"  10−9  \1\ Dose values are derived from Column A of Table 1a and 1b. Inhalation values are adjusted for molecular weight (UDMH is 40 percent by weight of daminozide). Dermal values are adjusted for molecular weight and dermal absorption (daminozide is dermally adsorbed at a rate of 1 percent). '3'3Standard810q3'3'Standard810qM۰ x #]\  PC:HP# Inhalation and dermal risk from UDMH which is a contaminant of, and hydrolized from commercial daminozide  yOX is broken down in the following Table 2b:#dZ6X@K@# 3'3'Standard810q'3'3Standard810qaڰ X0*%%  g/,  Table 2b.-- Risk from UDMH as a Contaminant and Hydrolysis Products of Daminozide   g/X  Q1 * (mg/kg/  g/  Site Dose\1\ (mg/kg/day) LADD (mg/kg/day) day−1) Lifetime Risk  Large Greenhouse......  g/  Inhalation.......... 1.2 x 10−5 1.6 x 0.46 7.4 x 10−9  g/F  10−8  g/r  Dermal.......... 3.6 x 10−6 4.9 X 0.46 2.3 x 10−9  g/  10−9 Small Greenhouse  g/  Inhalation.......... 4.9 x 10−6 6.7 x 0.46 3.1 x 10−9  g/`  10−9  g/  Dermal.......... 1.5 x 10−6 2.0 x 0.46 9.2 x  g/"  10−9  10−10  \1\ Dose values are derived by adding values from Columns B and C of Tables 1a and 1b. Inhalation values are taken from Column C and adjusted by 40 percent and added to Column B, dermal values are taken from Column B adjusted by 20 percent and added to Column C which is adjusted by 20 percent and 40 percent. '3'3Standard810q3'3'Standard810qM۰ x #]\  PC:HP# Risk from UDMH is the sum of the risks posed by UDMH from all three sources of exposure to UDMH. Incorporating a number of worst-case assumptions stated earlier in this Notice, EPA estimates upper-bound lifetime  yO  risk to workers in large greenhouses to be 3.1 x 10−7 and to workers in small greenhouses to be 1.2 x 10−7,  yO as summarized in the following Table 3 (Ref. 24):#dZ6X@K@#  g/F  Table 3.--Total Lifetime Risk from UDMH\1\   g/r  Site Risk   g/ Large Greenhouses..................... 3.1 x 10−7  g/ Small Greenhouses................. 1.2 x 10−7  \1\ Includes risk from all sources, combined inhalation and dermal exposure and for the combined function of mixer/loader and applicator. #]\  PC:HP#  yOt D. Risk From Daminozide The Agency has regulated daminozide based on a risk estimate using an approach that measures exposure to UDMH. The Agency has also conducted an alternative UDMH risk assessment based on an approach that measures the effects of daminozide per se, since daminozide is also a Group B2 carcinogen. The Agency used a daminozide  yO\ Q1* and estimates of exposure to daminozide to estimate worker risk. Based on this alternative approach, the Agency  yO$ estimates upper-bound lifetime risk to workers to be 1.5 x 10−6 and 5.8 x 10−7, for large and small greenhouses respectively. Although the Agency has performed this alternative risk assessment based on daminozide, the Agency believes that the preferable method to estimating risk is to measure exposure from UDMH per se. Therefore, the Agency has based its regulatory decision on risk estimates which come from measuring exposure to  {OD UDMH. The risk estimate based on daminozide is explained in full detail in the Addendum to the Daminozide Risk  {O Assessment, available in the public docket.  {M E. Comments and EPA's Response  {O0  Only one comment was received regarding the Agency's non-dietary risk assessment. This comment and the Agency's response are summarized below.  {O  Comment. Uniroyal believes that exposure estimates taken from the surrogate worker exposure study, (Sumagic PRG [Merricks, 1987]), which the Agency used to estimate exposure for the PD 2/3, are too high. Uniroyal also cites a surrogate study available in the open literature which shows that exposure values to workers are lower than those used by the Agency.  {O  Response. At the time of the PD 2/3, the Agency chose to use the surrogate data which were available and considered appropriate instead of searching through the open literature for another appropriate exposure study. As stated earlier in this Notice, EPA found that risk to greenhouse workers, based on the surrogate exposure data, was acceptable. The current exposure assessment incorporates a number of assumptions which are different from those incorporated into the exposure estimates of the PD 2/3; therefore, a direct comparison between the two is not possible. However, although the present exposure estimates and those contained in the PD 2/3 are based on different assumptions, EPA believes that the present exposure estimates are the most accurate measure of exposure available.^$0*%%Ԍ yO ԙj  V. Summary of Benefits Assessment and Agency Evaluation of Comments 6  yO 6  The benefits of a pesticide product are characterized by estimating the potential economic impact to industry, retailers, and consumers if that product were no longer available and more expensive or less efficacious alternatives are used. Daminozide is a plant growth regulator used on a number of bedding plants and other crops including the following: chrysanthemums, azaleas, easter lilies, and hydrangeas. Daminozide is used to create a more compact plant with greener foliage (i.e., thicker and less elongated stems), to increase plant longevity, and to facilitate plant transport. Growers like daminozide because of its predictable effects and ease of application (``spray to run-off''). In 1989, EPA estimated that 90 percent of all potted chrysanthemums and 40 percent to 50 percent of the 65 million square feet of bedding plants were treated with daminozide. EPA believes that the use of daminozide on bedding plants, mums, and poinsettias has remained relatively constant. There are four likely chemical alternatives to daminozide: uniconazole, ancymidol, chlormequat, and paclobutrazol. In addition, there are non-chemical controls such as withholding water or fertilizer, controlling light, and maintaining lower room temperatures. No single chemical alternative, however, can produce the same effects as daminozide. All the chemical alternatives are limited by either a narrower use spectrum, phytotoxic effects, or higher costs. Non-chemical controls are also considered less desirable because of adverse effects on the plants such as delayed flowering, discoloration, and smaller leaves. To produce the same effects as daminozide, several chemical alternatives would have to be used in combination. The result would be increased cost (estimated to range from 10 to 20 times higher) and a lower quality of plant. EPA currently estimates that the potential economic loss from cancellation of daminozide would be no less than $15 million and could be considerably higher (Ref. 26). This estimate is based on the incremental increase in costs resulting from the substitution of alternatives for daminozide.  {O  Comments and EPA's Response.The Agency received one written comment in response to the PD 2/3 regarding the Agency's benefits analysis. This comment and the Agency's response are summarized below:  {O  Comment. Uniroyal stated that EPA underestimated the benefits of daminozide use on ornamentals. The Society of American Florists and the Professional Plant Growers Association also submitted written comments in support of this position.  {O  Response. Although Uniroyal agreed with EPA's estimate of percent crop treated, Uniroyal's figures for gross poundage of daminozide used on ornamentals are higher than those used by the Agency. EPA accepts the Uniroyal number for usage of daminozide on ornamentals. Uniroyal also states that, based on the opinions of five university horticulturists and extension personnel, the added economic value to certain crops treated with daminozide ranges from 10 percent to 75 percent. However, without information on consumer acceptance and willingness to pay for treated versus non-treated plants, it is not possible to judge the accuracy of these estimates.  yO& "  VI. Final Assessment of the Dietary Risks 6  yO 6  In the Notice of Voluntary Cancellation (54 FR 47492), EPA stated that it would revise its dietary risk assessment based on the final report of the UDMH cancer studies. As stated earlier in this document, EPA has reviewed the final  yOF UDMH cancer data and has refined the UDMH Q1*. Using this refined Q1* (0.46 (mg/kg/day)−1), and the dietary exposure estimates contained in the PD 2/3, EPA has revised the upper-bound lifetime dietary risk estimate in the  yO PD 2/3 of 4.9 x 10−5 for the general population to 2.6 x 10−5 (Ref. 27). In light of the revised lifetime dietary  yO! risk estimate of 2.6 x 10−5, and the benefits of the food uses as estimated in 1989, EPA believes that it would have pursued the same course of action as that taken in 1989. Therefore, the revised dietary risk assessment does not change the Agency's regulatory or scientific position on the food-uses of daminozide. In general, the Agency's risk assessment methodology may overestimate risk. However, it has been designed to#0*%% avoid underestimating risk and, therefore, allows the Agency to act in a protective manner. The revised dietary risk assessment supports EPA's 1989 position that the dietary risks posed by the food uses of daminozide generally presented an unreasonable risk to human health. The Agency believes that its proposed regulatory action in 1989 on the food uses of daminozide was protective of public health.  yO " VII. Risk/Benefit Analysis and Announcement of Termination of the Daminozide Special Review. 6  yOx 6  Based on the information summarized and presented in this Notice, EPA has determined that the non-food uses of daminozide, as currently registered, do not pose an unreasonable risk to workers (mixer/loaders and/ or applicators). Given the magnitude of the benefits from the non-food uses of daminozide and the negligible risks posed to persons exposed to daminozide while working with it, EPA is announcing its decision to allow the continued uses of daminozide on the non-food use crops as presently registered.  yO`  The Agency estimates the lifetime risk to workers from exposure to UDMH to be 10-7 and estimates that the potential economic impacts from cancellation of daminozide would be no less than $15 million but could be considerably higher. The cost-effectiveness (C-E) coefficient is a tool used to compare the estimated loss of benefits from cancellation of daminozide to the estimated reduction in carcinogenic risk from a particular use. It is an estimate of the societal cost per cancer case avoided. EPA has estimated that the C-E of cancellation of the non-food uses of daminozide is approximately $1 billion per theoretical cancer case avoided (Ref. 28). The Agency recognizes that the C-E coefficient has limitations and uses it only as a guide, not a decision tool, in the risk/benefit analysis determination.  yOh #| VIII. Availability of the Public Docket 6  yO 6  Pursuant to 40 CFR 154.15, the Agency has established a public docket (OPP - 30000/40D) for the Daminozide Special Review. This public docket includes: (1) This Notice; (2) any other notices pertinent to the Daminozide Special Review; (3) non-Confidential Business Information (CBI) documents and copies of written comments or other materials submitted to the Agency in response to this Notice or any other Notice, and any other documents regarding daminozide submitted at any time during the Special Review process by any person outside the government; (4) a transcript of all public meetings held by the Agency for the purpose of gathering information on daminozide; (5) memoranda describing each meeting held during the Special Review process between Agency personnel and any person outside the government pertaining to daminozide; and (6) a current index of materials in the public docket.  yO / IX. References 6  yO 6  (1) U.S. Environmental Protection Agency (USEPA). (1984) Daminozide Registration Standard and Guidance Document. (2) U.S. Environmental Protection Agency (USEPA). (1986) Daminozide Data Call-In. February 10, 1986. (3) U.S. Environmental Protection Agency (USEPA). (1989) Daminozide Technical Support Document. (4) Toth, B. (1973) ``1,1-Dimethylhydrazine (unsymmetrical) Carcinogenesis in Mice. Light Microscopic and  {Ox Ultrastructural Studies on Neoplastic Blood Vessels.'' Journal of the National Cancer Institute, 50:181 - 187. GS0032001. (5) Toth, B. (1977a) The Large Bowl Carcinogenic Effects of Hydrazines and Related Compounds Occuring in Nature and in the Environment. Cancer Supplement, (40):2427. (6) Toth, B. (1977b) ``Induction of Tumors in Mice with the Herbicide, Succinic Acid 2,2 dimethylhydrazine.''  {Ob" Cancer Research, 37: 3497 - 3500. (7) Haun, A. (1984) Inhalation Studies of UDMH Air Force Aerospace Medical Res. Lab. TR 85 - 020. (8) Amendment to Final Report of the 2 - Year UDMH Mouse Study (MRID 41368301), Final report of UDMH#0*%% High Dose Mouse Study (MRID 413798001). (9) U.S. Environmental Protection Agency (USEPA). (1991) Third Peer Review of Daminozide and its Metabolite/Breakdown Product 1,2-Dimethylhydrazine. (10) Uniroyal Chemical Company, Inc. (1987d) Metabolism of Daminozide in Miniature Swine, Analysis for UDMH in Liver Tissue. Final Report submitted by Mitros, K., Doweyko, A.M. and Burger, R.N., December 1987 (MRID 404519 - 01). (11) Bignami, M., Conti, G., Crebelli, R. and Carere, A. (1981) ``Growth mediated metabolic activation of  {Ox promutagens in Aspergillus nidulans.'' Mutation Research, 80: 265 - 272. (12) Brunsick, D. and Matheson, D.W. (1976) Mutagen and Oncogen Study on 1,1 dimethylhydrazine. Prepared for the Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Kensingon, MD. NTIS: AD - A035475. (13) Parodi, S., DeFlora, S., Cavanna, M., Pino, A., Robbiano, L., Dennicelli, C. and Brambillia, G. (1981)  {Ob ``DNA-Damaging Activity in vivo and Bacterial Mutagenicity of Sixteen Hydrazine Derivatives as Related  {O, Quantitatively to their Carcinogenicity.'' Cancer Research. 41: 1469. (14) Rogers, A.M, and Back, K.C. (1981). ``Comparative Mutagenicity of Hydrazine and 3 Methylated  {O Derivatives in L5178V Mouse Lymphoma Cells.'' Mutation Research. 89: 1321 - 328.  {O  (15) Seiler, J.P. (1977b). ``Nitrosation in vitro and in vivo by Sodium Nitrite and Mutagenicity of Nitrogenous  {OR Pesticides.'' Mutation Research. 48(5): 225 - 236. (16) Suter, W. and Jaeger, I. (1982). ``Comparative Evaluation of Different Pairs of DNA Repair-Deficient and DNA Repair-Proficient Bacterial Tester Strains for Rapid Detection of Chemical Mutagens and Carcinogens,''  {O Mutation Research. 97: 1 - 18. (17) Fisher, B. (1991) Memorandum to Henry Spencer (USEPA). Qualitative Risk Assessment, Low High Dose 2-Year Dietary Studies in CD - 1 Mice. (18) Spencer, H. (1992) Memorandum to Penny-Fenner Crisp (USEPA). Additional Comments Addressing Concerns of J. Cogliano On The PD 4, Draft Notice of Final Determination For Daminozide By T. Moriarty. (19) Chow, F. (1991) Memorandum to Tom Moriarty (USEPA). Daminozide RiskAssessment. (20) Uniroyal Chemical Company, Inc., (1989) Written Comments to Preliminary Determination to Cancel Certain Daminozide Product Registrations. D - 11012A. (21) Bacchus, S. (1991) Memorandum to Paul Parsons (USEPA). Evaluation of Uniroyal Worker Exposure Study for Daminozide and Exposure Assessment for Labeled Uses, Assessment of Greenhouse Worker Exposure. (22) Bacchus, S. (1991) Memorandum to Tom Moriarty (USEPA). Comments on Uniroyal's Response to PD 2/3 on Daminozide and Response to Questions Raised at the Daminozide Meeting, 9/12/91: Previous Estimates and Recently Submitted Worker Exposure Study for Labeled Uses of Daminozide on Greenhouse Ornamentals. (23) Uniroyal Chemical Company, Inc., (1990) Dermal Absorption Study of B-Nine SP(400 - 110) in Rats (MRID 41795601). (24) Chow, F. (1991) Memorandum to Tom Moriarty (USEPA). Addendum to Daminozide Risk Assessment. (25) Spencer, H. (1987) Memorandum to Walter Waldrop (USEPA). Transmittal of Dermal Absorption Study of Alar in Male Sprague-Dawley Rats (MRID 402145 - 01). (26) Jennings, A. (1992) Memorandum to Daniel Barolo (USEPA). Benefits Analysis Update for the Use of Daminozide on Ornamentals. (27) Chow, F. (1991) Memorandum to Tom Moriarty (USEPA). Dietary Exposure Analysis for Daminozide/UDMH. (28) Moriarty, T. (1992) Memorandum to the File/Public Docket: Addendum to the Cost Effectiveness Memorandum on Daminozide. Dated: September 28, 1992. #0*%%Ԍ yO / Victor J. Kimm,  {M 6 D  Acting Assistant Administrator for Prevention, Pesticides and Toxic Substances. 6  yOX 6 [FR Doc. 92 - 24511 Filed 10 - 7 - 92; 8:45 am]  yO   BILLING CODE 6560 - 50 - F