99-22455. Notice of Filing Pesticide Petitions to Establish a Tolerance for Certain Pesticide Chemicals in or on Food  

  • [Federal Register Volume 64, Number 169 (Wednesday, September 1, 1999)]
    [Notices]
    [Pages 47795-47806]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 99-22455]
    
    
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    ENVIRONMENTAL PROTECTION AGENCY
    
    [PF-885; FRL-6096-8]
    
    
    Notice of Filing Pesticide Petitions to Establish a Tolerance for 
    Certain Pesticide Chemicals in or on Food
    
    AGENCY: Environmental Protection Agency (EPA).
    
    ACTION: Notice.
    
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    SUMMARY: This notice announces the initial filing of pesticide 
    petitions proposing the establishment of regulations for residues of 
    certain pesticide chemicals in or on various food commodities.
    
    DATES: Comments, identified by docket control number [PF-885], must be 
    received on or before October 1, 1999.
    
    ADDRESSES: Comments may be submitted by mail, electronically, or in 
    person. Please follow the detailed instructions for each method as 
    provided in Unit I.C. of the SUPPLEMENTARY INFORMATION section. To 
    ensure proper receipt by EPA, it is imperative that you identify docket 
    control number PF-885 in the subject line on the first page of your 
    response.
    
    
    [[Page 47796]]
    
    
    FOR FURTHER INFORMATION CONTACT:  By mail: Shaja Brothers, Registration 
    Support Branch, Registration Division (7505C), Office of Pesticide 
    Programs, Environmental Protection Agency, 401 M St., SW., Washington, 
    DC 20460; telephone number: (703) 308-3194; and e-mail address: 
    brothers.shaja@epa.gov.
        For technical questions, contact the appropriate Product Manager: 
    Joseph Tavano, telephone number: (703) 305-6411 and e-mail address: 
    tavano.joseph@epa.gov.; or Cynthia Giles-Parker (PM 22), telephone 
    number: (703) 305-7740 and e-mail address: parker.cynthia@epa.gov.
    
    SUPPLEMENTARY INFORMATION:
    
    I. General Information
    
    A. Does this Action Apply to Me?
    
        You may be affected by this action if you are an agricultural 
    producer, food manufacturer or pesticide manufacturer. Potentially 
    affected categories and entities may include, but are not limited to:
    
     
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                                                              Examples of
               Categories                    NAICS            potentially
                                                           affected entities
    ------------------------------------------------------------------------
    Industry                          111                 Crop production
     
                                      112                 Animal production
     
                                      311                 Food manufacturing
                                      32532               Pesticide
                                                           manufacturing
    ------------------------------------------------------------------------
    
        This listing is not intended to be exhaustive, but rather provides 
    a guide for readers regarding entities likely to be affected by this 
    action. Other types of entities not listed in the table could also be 
    affected. The North American Industrial Classification System (NAICS) 
    codes have been provided to assist you and others in determining 
    whether or not this action might apply to certain entities. If you have 
    questions regarding the applicability of this action to a particular 
    entity, consult the person listed in the ``FOR FURTHER INFORMATION 
    CONTACT'' section.
    
    B. How Can I Get Additional Information, Including Copies of this 
    Document and Other Related Documents?
    
        1. Electronically. You may obtain electronic copies of this 
    document, and certain other related documents that might be available 
    electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
    To access this document, on the Home Page select ``Laws and 
    Regulations'' and then look up the entry for this document under the 
    ``Federal Register--Environmental Documents.'' You can also go directly 
    to the Federal Register listings at http://www.epa.gov/fedrgstr/.
        2. In person. The Agency has established an official record for 
    this action under docket control number PF-885. The official record 
    consists of the documents specifically referenced in this action, any 
    public comments received during an applicable comment period, and other 
    information related to this action, including any information claimed 
    as confidential business information (CBI). This official record 
    includes the documents that are physically located in the docket, as 
    well as the documents that are referenced in those documents. The 
    public version of the official record does not include any information 
    claimed as CBI. The public version of the official record, which 
    includes printed, paper versions of any electronic comments submitted 
    during an applicable comment period, is available for inspection in the 
    Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
    Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
    a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
    PIRIB telephone number is (703) 305-5805.
    
    C. How and to Whom Do I Submit Comments?
    
        You may submit comments through the mail, in person, or 
    electronically. To ensure proper receipt by EPA, it is imperative that 
    you identify docket control number PF-885 in the subject line on the 
    first page of your response.
        1. By mail. Submit your comments to: Public Information and Records 
    Integrity Branch (PIRIB), Information Resources and Services Division 
    (7502C), Office of Pesticide Programs (OPP), Environmental Protection 
    Agency, 401 M St., SW., Washington, DC 20460.
        2. In person or by courier. Deliver your comments to: Public 
    Information and Records Integrity Branch (PIRIB), Information Resources 
    and Services Division (7502C), Office of Pesticide Programs (OPP), 
    Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
    Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
    a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
    PIRIB telephone number is (703) 305-5805.
        3. Electronically. You may submit your comments electronically by 
    E-mail to: opp-docket@epa.gov ,'' or you can submit a computer disk 
    as described above. Do not submit any information electronically that 
    you consider to be CBI. Avoid the use of special characters and any 
    form of encryption. Electronic submissions will be accepted in 
    Wordperfect 5.1/6.1 or ASCII file format. All comments in electronic 
    form must be identified by docket control number PF-885. Electronic 
    comments may also be filed online at many Federal Depository Libraries.
    
    D. How Should I Handle CBI That I Want to Submit to the Agency?
    
        Do not submit any information electronically that you consider to 
    be CBI. You may claim information that you submit to EPA in response to 
    this document as CBI by marking any part or all of that information as 
    CBI. Information so marked will not be disclosed except in accordance 
    with procedures set forth in 40 CFR part 2. In addition to one complete 
    version of the comment that includes any information claimed as CBI, a 
    copy of the comment that does not contain the information claimed as 
    CBI must be submitted for inclusion in the public version of the 
    official record. Information not marked confidential will be included 
    in the public version of the official record without prior notice. If 
    you have any questions about CBI or the procedures for claiming CBI, 
    please consult the person identified in the ``FOR FURTHER INFORMATION 
    CONTACT'' section.
    
    E. What Should I Consider as I Prepare My Comments for EPA?
    
        You may find the following suggestions helpful for preparing your 
    comments:
         1. Explain your views as clearly as possible
         2. Describe any assumptions that you used.
         3. Provide copies of any technical information and/or data you 
    used that support your views.
         4. If you estimate potential burden or costs, explain how you 
    arrived at the estimate that you provide.
         5. Provide specific examples to illustrate your concerns.
         6. Make sure to submit your comments by the deadline in this 
    notice.
         7. To ensure proper receipt by EPA, be sure to identify the docket 
    control number assigned to this action in the subject line on the first 
    page of your response. You may also provide the name, date, and Federal 
    Register citation.
    
    II. What Action is the Agency Taking?
    
        EPA has received pesticide petitions as follows proposing the 
    establishment and/or amendment of regulations for residues of certain 
    pesticide chemicals in or on various food commodities
    
    [[Page 47797]]
    
    under section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 
    21 U.S.C. 346a. EPA has determined that these petitions contain data or 
    information regarding the elements set forth in section 408(d)(2); 
    however, EPA has not fully evaluated the sufficiency of the submitted 
    data at this time or whether the data supports granting of the 
    petition. Additional data may be needed before EPA rules on the 
    petition.
    
    List of Subjects
    
        Environmental protection, Agricultural commodities, Feed additives, 
    Food additives, Pesticides and pests, Reporting and recordkeeping 
    requirements.
    
        Dated: August 19, 1999.
    
    James Jones,
    
    Director, Registration Division, Office of Pesticide Programs.
    
    Summaries of Petitions
    
        Petitioner summaries of the pesticide petitions are printed below 
    as required bysection 408(d)(3) of the FFDCA. The summaries of the 
    petitions were prepared by the petitioners and represent the views of 
    the petitioners. EPA is publishing the petition summaries verbatim 
    without editing them in any way. The petition summary announces the 
    availability of a description of the analytical methods available to 
    EPA for the detection and measurement of the pesticide chemical 
    residues or an explanation of why no such method is needed.
    
    1. IR-4 Project
    
     PP 6E4603, 6E4787, and 7E4878
    
        EPA has received pesticide petitions [PP 6E4603, 6E4787, and 
    7E4878] from the Interregional Research Project Number 4 (IR-4), New 
    Jersey Agricultural Experiment Station, P. O. Box 231 Rutgers 
    University, New Brunswick, NJ 08903 proposing pursuant to section 
    408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 
    346a(d), to amend 40 CFR part 180 by establishing tolerances for 
    combined residues of the herbicide, pendimethalin [N-(1-ethylpropyl)-
    3,4-dimethyl-2,6-dinitrobenzenamine, and its 3, 5-dinitrobenzyl alcohol 
    metabolite (CL 202347) in or on the food commodities as follows:
        1 PP 6E4603. Proposes the establishment of a tolerance for carrots 
    at 0.5 parts per million (ppm).
        2 PP 6E4787. Proposes the establishment of a tolerance for citrus 
    fruit crop group at 0.1 ppm.
        3. PP 7E4878. Proposes the establishment of tolerances, with 
    regional registration for peppermint and spearmint tops at 0.2 ppm, and 
    peppermint and spearmint oil at 1.0 ppm. Registration will be limited 
    to Idaho, Oregon, and Washington based on the geographical 
    representation of the residue data submitted to EPA.
        EPA has determined that the petitions contain data or information 
    regarding the elements set forth in section 408(d)(2) of the FFDCA; 
    however, EPA has not fully evaluated the sufficiency of the submitted 
    data at this time or whether the data support granting of the 
    petitions. Additional data may be needed before EPA rules on the 
    petitions.
    
    A. Residue Chemistry
    
        1. Plant metabolism. The qualitative nature of the residues of 
    pendimethalin in plants is understood based on adequate studies 
    conducted with [14 C]-pendimethalin on various crops. 
    Pendimethalin and its 3,5-dinitrobenzyl alcohol metabolite (CL202347) 
    are the only residues of concern.
        2. Analytical method. Section 408 (b)(3) of the amended FFDCA 
    requires EPA to determine that there is a practical method for 
    detecting and measuring levels of the pesticide chemical residue in or 
    on food and that the tolerance be set at a level at or above limit of 
    detection of the designated method. The Gas Chromatography (GC) of 
    pendimethalin and (CL202347) analytical methods, M691 and M692, are 
    proposed as the enforcement methods for the residues in carrots; M1999 
    is the proposed method for citrus fruit crop group, and processed 
    citrus commodities; and M1930.01 has been proposed for mint and mint 
    oil. All methods utilize electron capture detectors and have a limit of 
    quantitation (LOQ) of 0.05 ppm for the respective residues of concern.
        3. Magnitude of residues--i. Residue field trials were conducted in 
    seven major carrot producing states in the United States at both the 1x 
    rate of 2 pounds (lbs) active ingredient/acre (ai/A) and an exaggerated 
    rate of 4 lbs ai/A (2x the typical application rate). Maximum 
    pendimethalin residues recovered from carrot samples treated with these 
    applications were 0.10 ppm from the 1x treatment and 0.16 ppm from the 
    2x treatment. For the alcohol metabolite, CL202347, the maximum 
    recovered residues ranged from 0.29 ppm from the 1x treatment to 0.44 
    ppm from the 2x treatment. The registrant believes that the results 
    from these studies support the proposed tolerance of 0.5 ppm 
    pendimethalin in or on carrots.
        ii. Residue field trials were conducted on oranges, grapefruits, 
    and lemons in major citrus fruit crop group producing states in the 
    United States at a 1.5x rate of 6 lbs ai/A and an exaggerated 3x rate 
    of 12 lbs ai/A. The plots were treated with pendimethalin at a variety 
    of different intervals prior to harvest. The raw agricultural commodity 
    (RAC) samples were also processed into wet and dried pulp, molasses, 
    oil and juice. RAC samples taken from plots treated one day prior to 
    harvest, a worst case residue situation, resulted in residues of 0.008 
    ppm (in grapefruit) or less. No residues were recovered from wet pulp 
    and juice samples at the 0.005 ppm level. Residues of pendimethalin 
    were recovered at 0.005 ppm in dried pulp, 0.009 ppm in molasses and 
    0.026 ppm in orange oil. It should be noted that data for wet pulp and 
    molasses are no longer required as per Table I of the Residue Chemistry 
    Test Guidelines EPA OPPTS 860.1000. The registrant believes that the 
    results from these studies are adequate to support the proposed 
    tolerance of 0.1 ppm pendimethalin in or on citrus fruit crop group, 
    and in processed citrus commodities.
        iii. Residue field trials were conducted in two major mint 
    producing states in the United States at both the 1x rate of 2 lbs ai/A 
    and an exaggerated rate of 10 lbs ai/A (5x the typical application 
    rate). Fresh mint foliage samples were either harvested and directly 
    analyzed or processed into mint oil before analyses. The registrant 
    believes that the results from these studies support the proposed 
    tolerances of 0.2 ppm pendimethalin in mint foliage (leaves and stems) 
    and 1.0 ppm pendimethalin in mint oil.
    
    B. Toxicological Profile
    
        1. Acute toxicity. The acute oral lethal dose (LD50) 
    values for pendimethalin technical in the Wistar rat are 1,250 
    milligrams/kilograms/body weight (mg/kg/bwt) (males) and 1,050 mg/kg/
    bwt (females). The acute dermal LD50 was greater than 5,000 
    mg/kg in New Zealand white rabbits. The 4-hour rat inhalation lethal 
    concentration (LC50) was > 320 milligram per liter (mg/L) 
    (nominal concentration). Pendimethalin was shown to be slightly 
    irritating to rabbit eyes and non-irritating to rabbit skin. 
    Pendimethalin did not cause skin sensitization in guinea pigs.
        2. Genotoxicity. Extensive mutagenicity studies conducted to 
    investigate point and gene mutations, DNA damage and chromosomal 
    aberration, using in vitro and in vivo test systems show pendimethalin 
    to be non-genotoxic.
    
    [[Page 47798]]
    
        3. Reproductive and developmental toxicity. Results from a 2-
    generation rat reproduction study showed the no-observed adverse effect 
    level (NOAEL) for parental and reproductive toxicity to be 2,500 ppm 
    (172 mg/kg bwt/day) and the lowest-observed adverse effect level 
    (LOAEL) to be 5,000 ppm (346 mg/kg/bwt/day). No developmental toxicity 
    was observed in either the rat or rabbit developmental toxicity 
    studies, nor was there any evidence in the 2-generation rat 
    reproduction study that there was developmental or reproductive 
    toxicity at dose levels below those in which parental toxicity was 
    observed. For rabbits, the developmental toxicity NOAEL was > 60 mg/kg/
    day, the highest dose tested (HDT). The maternal NOAEL was > 60 mg/kg/
    day, based on mortality observed at 125 mg/kg/day in a pilot study. For 
    rats, there were no maternal or developmental effects at any dose level 
    and the NOAELs for both maternal and developmental effects were 
     500 mg/kg/day, the HDT.
        4. Subchronic toxicity. A 90-day feeding study was conducted in 
    rats and dogs. The NOAELs for these studies were 500 ppm (50 mg/kg/bwt/
    day) and 2,500 ppm (62.5 mg/kg/bwt/day) for the rat and dog studies, 
    respectively.
        5. Chronic toxicity. The chronic toxicity of pendimethalin has been 
    extensively investigated in three species (i. e., the rat, mouse, and 
    dog). The results are as follows:
        i. Rats. In an initial 2-year feeding study in Sprague-Dawley rats, 
    conducted at dose levels of 0, 100, 500, and 5,000 ppm (corresponding 
    to dietary intakes of 0, 5, 25, and 250 mg/kg/bwt/day, respectively), a 
    clear NOAEL was established at 500 ppm (25 mg/kg/bwt/day). The LOAEL 
    was set at 5,000 ppm (250 mg/kg/bwt/day) based on decreased survival, 
    body weight gain and food consumption, increased gamma glutamyl 
    transferase and cholesterol, an increase in absolute and/or relative 
    liver weight, generalized icterus, dark adipose tissue in females, 
    diffusely dark thyroids and follicular cell hyperplasia of the thyroid. 
    In a second 2-year feeding study in rats, conducted at dose levels of 
    0, 1,250, 2,500, 3,750, and 5,000 ppm (corresponding to dietary intakes 
    of 0, 51, 103, 154, and 213 mg/kg/bwt/day, respectively), a NOAEL was 
    not determined. The LOAEL of less than or equal to 1,250 ppm 
    ( 51 mg/kg/bwt/day) was based on non-neoplastic thyroid 
    follicular cell changes and increased liver weight.
        ii. Mouse. Pendimethalin technical was administered at dietary 
    concentrations of 100, 500, and 5,000 ppm (corresponding to dose levels 
    of 12.3, 62.3 and 622.1 mg/kg/bwt/day in males and 15.6, 78.3, and 
    806.9 mg/kg/ bwt/day in females) to CD-1 mice for 18-months. In this 
    study, the NOAEL was 500 ppm (62.3 mg/kg/bwt/day) and the LOAEL, based 
    on mortality, body weight decrease, organ weight changes and 
    amyloidosis, was 5,000 ppm (622.1 mg/kg/ bwt/day).
        iii. Dog. In a 2-year oral (capsule) study, conducted at dose 
    levels of 0, 12.5, 50 and 200 mg/kg/bwt/day, the NOAEL was equal to or 
    greater than the maximum dose tested  200 mg/kg/bwt/day with 
    no LOAEL established.
        Pendimethalin has been classified as a Group C, ``possible human 
    carcinogen,'' chemical by EPA based on a statistically significant 
    increased trend and pairwise comparison between the high dose group and 
    controls for thyroid follicular cell adenomas in male and female rats. 
    EPA recommended using the chronic population adjusted dose (cPAD) 
    approach for quantification of human risk. Therefore, the cPAD is 
    deemed protective of all chronic human health effects, including 
    cancer.
        6. Animal metabolism. Adequate goat and poultry metabolism studies 
    are available for pendimethalin. As no poultry feed items are 
    associated with carrots, citrus fruit crop group processed citrus 
    commodities, or mint, poultry metabolism studies are not relevant to 
    this petition. In addition, the registrant has determined that there is 
    no reasonable expectation of finite pendimethalin residues of concern 
    in animal commodities as a result of use on multiple crops and no 
    tolerances for pendimethalin residues of concern in livestock 
    commodities are needed.
        7. Endocrine disruption. Collective results from several 
    mechanistic studies provide support that pendimethalin disrupts 
    thyroid-pituitary hormonal balance. An analysis of the data obtained 
    from these studies supports fluctuations in thyroid hormones (T3 and/or 
    T4) at dietary concentrations of 500 ppm (31 mg/kg/bwt/day) and 
    greater. However, no fluctuations in thyroid hormones were observed at 
    100 ppm (10 mg/kg/bwt/day) in either of the 14-day special feeding 
    studies, supporting a NOAEL for thyroid effects of 100 ppm or 10 mg/kg/
    bwt/day. As the cPAD is based on the NOAEL of 10 mg/kg/bwt/day obtained 
    from these studies, thyroid hormonal changes are already accounted for 
    in the characterization of the potential risks to humans. Moreover, 
    because of species differences in thyroid gland physiology, slight 
    fluctuations in thyroid hormone levels noted in rats may not be 
    applicable to humans. In addition, collective organ weights and 
    histopathological findings from the 2-generation rat reproduction 
    study, as well as from the subchronic and chronic toxicity studies in 3 
    different animal species demonstrate no apparent estrogenic effects or 
    treatment-related effects on any other component of the endocrine 
    system.
    
    C. Aggregate Exposure
    
        Pendimethalin is widely used as a pre-emergent herbicide to control 
    broad-leaf weeds in both food and non-food crops, as well as non-
    agricultural use sites including residential lawns. In examining 
    aggregate exposure, FQPA directs EPA to consider available information 
    concerning exposures from the pesticide residue in food and water 
    (dietary) and all other non-occupational exposures. The primary non-
    food sources of exposure the Agency evaluates include drinking water 
    (whether from groundwater or surface water), and exposure through 
    pesticide use in gardens, lawns, or buildings (residential and other 
    indoor uses). The potential for aggregate exposure from all registered 
    and proposed uses is discussed below:
        1. Dietary (food) exposure. Tolerances have been established (40 
    CFR 180.361) for the combined residues of pendimethalin and its 3,5-
    dinitrobenzyl alcohol metabolite (CL 202347) in or on a variety of food 
    commodities at levels ranging from 0.05 ppm in rice grain to 0.1 ppm in 
    corn, peanuts, soybeans and other commodities. Based on conservative 
    assumptions of tolerance level residues and 100% crop treatment with 
    pendimethalin, the EPA's Dietary Exposure Evaluation Model (DEEM) 
    estimates chronic dietary exposure to pendimethalin from all currently 
    registered uses to be only 0.00042 mg/kg/day (< 1%="" cpad)="" for="" the="" overall="" u.="" s.="" population.="" the="" estimated="" most="" highly="" exposed="" deem="" subgroup="" for="" pendimethalin="" is="" non-nursing="" infants="" at="" a="" level="" of="" 0.00140="" mg/kg/day="">< 2%).="" additional="" maximum="" dietary="" contributions,="" (of="" up="" to="" 0.000498="" mg/kg/="" bwt/day="" and="" 0.001294="" mg/kg/bwt/day="" for="" the="" general="" u.s.="" population="" and="" for="" non-nursing="" infants="" less="" than="" 1-year="" old,="" respectively)="" anticipated="" from="" use="" on="" carrots="" and="" citrus="" fruit="" crop="" group="" will="" still="" utilize="">< 1%="" (actual="" 0.5%)="" and="">< 2%="" (actual="" 1.3%)="" of="" the="" cpad="" for="" the="" respective="" population="" subgroups.="" the="" additional="" dietary="" burden="" that="" will="" result="" from="" the="" pendimethalin="" tolerances="" in="" mint="" and="" mint="" oil="" will="" also="" be="" insignificant.="" thus,="" the="" american="" cyanamid="" company="" believes="" that="" there="" should="" be="" no="" reason="" for="" concern="" from="" the="" additional="" dietary="" burden="" that="" will="" result="" from="" the="" proposed="" tolerances="" of="" pendimethalin="" in="" carrots,="" citrus="" fruit="" [[page="" 47799]]="" crop="" group,="" and="" mint="" because="" the="" contribution="" to="" the="" cpad="" will="" be="" insignificant.="" i.="" drinking="" water.="" pendimethalin="" has="" low="" water="" solubility="" and="" a="" strong="" absorption="" to="" soil,="" which="" makes="" it="" essentially="" immobile="" in="" all="" soil="" types.="" therefore,="" american="" cyanamid="" company="" concludes="" that="" there="" is="" no="" concern="" for="" the="" potential="" for="" pendimethalin="" to="" runoff="" to="" surface="" water="" or="" leach="" to="" ground="" water.="" no="" maximum="" concentration="" level="" and="" no="" health="" advisory="" level="" has="" been="" established="" for="" residues="" of="" pendimethalin="" in="" drinking="" water.="" a="" pendimethalin="" drinking="" water="" exposure="" analysis="" for="" a="" 10="" kg="" child="" shows="" that="" a="" chronic="" exposure="" from="" a="" worst="" case="" dietary="" intake="" (drinking="" water="" only)="" of="" 0.0018="" mg/kg/day="" would="" utilize="">< 2%="" of="" the="" cpad.="" thus,="" the="" american="" cyanamid="" company="" believes="" that="" contributions="" to="" the="" dietary="" burden="" from="" residues="" of="" pendimethalin="" in="" water,="" alone,="" would="" be="" inconsequential.="" 2.="" non-dietary="" exposure.="" pendimethalin="" is="" currently="" registered="" for="" use="" on="" the="" following="" residential="" and="" non-food="" sites:="" ornamental="" lawns,="" grasses,="" ground="" covers,="" turf,="" and="" ornamental="" plantings,="" which="" are="" short-="" and="" intermediate-term="" non-occupational="" exposure="" scenarios.="" thus,="" the="" american="" cyanamid="" company="" believes="" that="" the="" estimates="" margins="" of="" exposure="" (moes)="" for="" residential="" applicators="" (moe="833)" and="" residential="" post-application="" exposures="" to="" children="" (moe="111)" are="" more="" than="" adequate.="" d.="" cumulative="" effects="" the="" agency="" has="" not="" yet="" published="" guidelines="" to="" determine="" whether="" pendimethalin="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances="" or="" how="" to="" include="" this="" pesticide="" in="" a="" cumulative="" risk="" assessment.="" unlike="" other="" pesticides="" for="" which="" epa="" has="" followed="" a="" cumulative="" risk="" approach="" based="" on="" a="" common="" mechanism="" of="" toxicity,="" pendimethalin="" does="" not="" appear="" to="" produce="" a="" toxic="" metabolite="" produced="" by="" other="" substances.="" for="" the="" purposes="" of="" this="" tolerance="" action,="" the="" american="" cyanamid="" company="" assumes="" that="" pendimethalin="" does="" not="" have="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" the="" american="" cyanamid="" company="" concludes="" that="" the="" total="" aggregate="" exposure="" to="" pendimethalin="" from="" food="" will="" utilizes="" less="" than="" 1%="" of="" the="" cpad="" for="" the="" overall="" u.s.="" population.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" cpad="" because="" the="" cpad="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" despite="" the="" potential="" for="" exposure="" to="" pendimethalin="" in="" drinking="" water="" and="" from="" non-dietary="" non-occupational="" exposures,="" the="" american="" cyanamid="" company="" does="" not="" expect="" the="" aggregate="" exposure="" to="" exceed="" 100%="" of="" the="" cpad.="" the="" registrant="" concludes="" that="" the="" aggregate="" risks="" estimated="" from="" the="" following="" three="" scenarios:="" (i)="">< 4%="" of="" the="" cpad="" for="" chronic="" dietary="" exposures="" (food="" plus="" water),="" (ii)="" moe="680" for="" chronic="" dietary="" exposures="" (food="" plus="" water)="" plus="" residential="" applicator="" exposures,="" and="" (iii)="" moe="107" for="" chronic="" dietary="" exposures="" (food="" plus="" water)="" plus="" residential="" post-application="" exposures="" to="" children,="" do="" not="" exceed="" the="" agency's="" levels="" of="" concern.="" thus,="" the="" american="" cyanamid="" company="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" pendimethalin="" residues="" as="" a="" result="" of="" the="" establishment="" of="" the="" proposed="" tolerance="" in="" carrots,="" citrus="" fruit="" crop="" group,="" and="" processed="" citrus="" commodities,="" mint="" and="" mint="" oil.="" 2.="" infants="" and="" children.="" the="" major="" identifiable="" subgroup="" with="" the="" highest="" aggregate="" exposure="" is="" non-nursing="" infants="" less="" than="" 1-year="" old.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" pendimethalin,="" the="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit,="" and="" a="" 2-generation="" reproduction="" study="" in="" the="" rat="" has="" been="" considered.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" resulting="" from="" maternal="" pesticide="" exposure="" during="" prenatal="" development.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" on="" the="" reproductive="" capabilities="" of="" parental="" animals="" from="" exposure="" to="" the="" pesticide="" as="" well="" as="" additional="" data="" on="" systemic="" toxicity.="" the="" prenatal="" and="" postnatal="" toxicology="" data="" base="" for="" pendimethalin="" is="" complete="" with="" respect="" to="" current="" toxicological="" data="" requirements.="" the="" data="" base="" does="" not="" indicate="" a="" potential="" for="" increased="" sensitivity="" from="" prenatal="" or="" postnatal="" exposure.="" as="" mentioned="" in="" item="" b.3.="" above,="" no="" developmental="" toxicity="" was="" observed="" in="" either="" the="" rat="" or="" rabbit="" developmental="" toxicity="" studies,="" nor="" was="" there="" any="" evidence="" in="" the="" 2-="" generation="" rat="" reproduction="" study="" that="" there="" was="" developmental="" or="" reproductive="" toxicity="" at="" dose="" levels="" below="" those="" in="" which="" parental="" toxicity="" was="" observed.="" for="" rabbits,="" the="" developmental="" toxicity="" noael="" was=""> 60 mg/kg/day, the HDT. The maternal NOAEL was > 60 mg/kg/day, 
    based mortality observed at 125 mg/kg/day in a pilot study. For rats, 
    there were no maternal or developmental effects at any dose level and 
    the NOAELs for both maternal and developmental effects were  
    500 mg/kg/day, the HDT. In the 2-generation reproductive toxicity study 
    in rats, the parental and reproductive NOAELs were 172 mg/kg/day. The 
    reproductive LOAEL of 346 mg/kg/day was based on decreased pup weight, 
    which occurred in the presence of parental (systemic) toxicity at 346 
    mg/kg/day.
        FFDCA section 408 provides that EPA may apply an additional tenfold 
    margin of safety for infants and children in the case of threshold 
    effects to account for prenatal and postnatal toxicity and the 
    completeness of the data base. Based on current toxicological data 
    requirements, the toxicology data base for pendimethalin is complete. 
    Furthermore, the reproductive NOAEL of 172 mg/kg/day is seventeen-fold 
    higher than the NOAEL of 10 mg/kg/day used for the cPAD. Additionally, 
    the reproductive LOAEL occurred in the presence of parental (systemic) 
    toxicity, and there was no evidence of developmental toxicity in either 
    the rat or the rabbit studies. Therefore, the American Cyanamid Company 
    believes that these proposed tolerances do not represent any 
    unacceptable prenatal or postnatal risk to infants and children.
        Using the conservative exposure assumptions described above, and 
    based on previous EPA reports, the American Cyanamid Company has 
    concluded that aggregate exposure to pendimethalin from food will 
    utilize less than 2% of the cPAD for infants and children. EPA 
    generally has no concern for exposures below 100% of the cPAD because 
    the cPAD represents the level at or below which daily aggregate dietary 
    exposure over a lifetime will not pose appreciable risks to human 
    health. Despite the potential for exposure to pendimethalin in drinking 
    water and from non-dietary, non-occupational exposure, the American 
    Cyanamid Company does not expect the aggregate exposure to exceed 100% 
    of the cPAD. Thus, the registrant concludes that there is a reasonable 
    certainty that no harm will result to infants and children from 
    aggregate exposure to pendimethalin residues.
    
     F. International Tolerances
    
         There are no Codex, Canadian or Mexican International Maximum 
    Residue Levels established for residues of pendimethalin in carrots, 
    citrus fruit
    
    [[Page 47800]]
    
    crop group and processed citrus commodities, or mint at this time.
    
    2. Rohm and Haas Company
    
    PP 7F4824
    
        EPA has received a pesticide petition (PP 7F4824) from Rohm and 
    Haas Company, 100 Independence Mall West, Phila., PA 19106-2399 
    proposing, pursuant to section 408(d) of the Federal Food, Drug, and 
    Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
    establishing a tolerance for indirect or inadvertent residues of 
    tebufenozide [benzoic acid, 3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-
    ethylbenzoyl) hydrazide] and its metabolite [Benzoic acid, 3,5-
    dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl] 
    hydrazide] in or on the RAC grass forage, fodder and hay at 0.5 parts 
    per million (ppm) and forage, fodder, straw and hay of nongrass animal 
    feeds at 0.5 ppm. EPA has determined that the petition contains data or 
    information regarding the elements set forth in section 408(d)(2) of 
    the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
    submitted data at this time or whether the data supports granting of 
    the petition. Additional data may be needed before EPA rules on the 
    petition.
    
    A. Residue Chemistry
    
        1. Plant metabolism. The metabolism of tebufenozide in plants 
    (grapes, apples, rice and sugar beets) is adequately understood for the 
    purpose of this tolerance. The metabolism of tebufenozide in all crops 
    was similar and involves oxidation of the alkyl substituents of the 
    aromatic rings primarily at the benzylic positions. The extent of 
    metabolism and degree of oxidation are a function of time from 
    application to harvest. In all crops, parent compound comprised the 
    majority of the total dosage. None of the metabolites were in excess of 
    10% of the total dosage. Tebufenozide, the metabolite, benzoic acid, 
    3,5-dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl, and 
    sugar conjugates of the metabolite were detected in a confined rotation 
    crop study.
        2. Analytical method. Validated high performance liquid 
    chromatographic (HPLC) analytical methods using ultraviolet (UV) or 
    mass selective (MS) detection are employed for measuring residues of 
    tebufenozide and its metabolite in grains, forage, fodder, stover, hay, 
    and straw. The methods involve extraction by blending with solvents, 
    purification of the extracts by liquid-liquid partitions and final 
    purification of the residues using solid phase extraction column 
    chromatography. The limit of quantitation (LOQ) of the method for all 
    matrices is 0.02 ppm for tebufenozide and its metabolite.
        3. Magnitude of residues. Field rotation crop residue trials were 
    conducted and residues of tebufenozide and its metabolite were 
    measured. Results of analyses showed that residues of tebufenozide and 
    its metabolite will not exceed 0.1 ppm in forage of legumes and 0.5 ppm 
    in forage, hay or straw of cereal grains.
    
    B. Toxicological Profile
    
        1. Acute toxicity--Acute toxicity studies with technical grade. 
    Oral LD50 in the rat is > 5 grams for males and females - 
    Toxicity Category IV; dermal LD50 in the rat is = 5,000 mg/
    kg for males and females - Toxicity Category III; inhalation 
    LD50 in the rat is > 4.5 mg/l - Toxicity Category III; 
    primary eye irritation study in the rabbit is a non-irritant; primary 
    skin irritation in the rabbit > 5 mg - Toxicity Category IV. 
    Tebufenozide is not a sensitizer.
        2. Genotoxicty. Several mutagenicity tests which were all negative. 
    These include an Ames assay with and without metabolic activation, an 
    in vivo cytogenetic assay in rat bone marrow cells, and in vitro 
    chromosome aberration assay in CHO cells, a CHO/HGPRT assay, a reverse 
    mutation assay with E. Coli, and an unscheduled DNA synthesis (UDS) 
    assay in rat hepatocytes.
        3. Reproductive and developmental toxicity--i. In a prenatal 
    developmental toxicity study in Sprague-Dawley rats 25/group 
    Tebufenozide was administered on gestation days 6-15 by gavage in 
    aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day 
    and a dose volume of 10 ml/kg. There was no evidence of maternal or 
    developmental toxicity; the maternal and developmental toxicity NOAEL 
    was 1,000 mg/kg/day.
        ii. In a prenatal developmental toxicity study conducted in New 
    Zealand white rabbits 20/group Tebufenozide was administered in 5 ml/kg 
    of aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/
    day on gestation days 7-19. No evidence of maternal or developmental 
    toxicity was observed; the maternal and developmental toxicity NOAEL 
    was 1,000 mg/kg/day.
        iii. In a 1993 2-generation reproduction study in Sprague-Dawley 
    rats Tebufenozide was administered at dietary concentrations of 0, 10, 
    150, or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males and 0, 
    0.9, 12.8, or 171.1 mg/kg/day for females). The parental systemic NOAEL 
    was 10 ppm (0.8/0.9 mg/kg/day for males and females, respectively) and 
    the lowest observed adverse effect level (LOAEL) was 150 ppm (11.5/12.8 
    mg/kg/day for males and females, respectively) based on decreased body 
    weight, body weight gain, and food consumption in males, and increased 
    incidence and/or severity of splenic pigmentation. In addition, there 
    was an increased incidence and severity of extramedullary hematopoiesis 
    at 2,000 ppm. The reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day 
    for males and females, respectively) and the LOAEL was 2,000 ppm 
    (154.8/171.1 mg/kg/day for males and females, respectively) based on an 
    increase in the number of pregnant females with increased gestation 
    duration and dystocia. Effects in the offspring consisted of decreased 
    number of pups per litter on postnatal days 0 and/or 4 at 2,000 ppm 
    (154.8/171.1 mg/kg/day for males and females, respectively) with a NOEL 
    of 150 ppm (11.5/12.8 mg/kg/day for males and females, respectively).
        In a 1995 2-generation reproduction study in rats Tebufenozide was 
    administered at dietary concentrations of 0, 25, 200, or 2,000 ppm (0, 
    1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 mg/
    kg/day for females). For parental systemic toxicity, the NOAEL was 25 
    ppm (1.6/1.8 mg/kg/day in males and females, respectively), and the 
    LOAEL was 200 ppm (12.6/14.6 mg/kg/day in males and females), based on 
    histopathological findings (congestion and extramedullary 
    hematopoiesis) in the spleen. Additionally, at 2,000 ppm (126.0/143.2 
    mg/kg/day in M/F), treatment-related findings included reduced parental 
    body weight gain and increased incidence of hemosiderin-laden cells in 
    the spleen. Columnar changes in the vaginal squamous epithelium and 
    reduced uterine and ovarian weights were also observed at 2,000 ppm, 
    but the toxicological significance was unknown. For offspring, the 
    systemic NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in males and females), 
    and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on 
    decreased body weight on postnatal days 14 and 21.
        4. Subchronic toxicity. In a 21-day dermal toxicity study, Crl: CD 
    rats (6/sex/dose) received repeated dermal administration of either the 
    technical 96.1% product RH-75,992 at 1,000 mg/kg/day limit-dose or the 
    formulation 23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 1,000 
    mg/kg/day, 6 hours/day, 5 days/week for 21 days. Under conditions of 
    this study, RH-75,992
    
    [[Page 47801]]
    
    Technical or RH-75,992 2F demonstrated no systemic toxicity or dermal 
    irritation at the HDT 1,000 mg/kg/ during the 21-day study. Based on 
    these results, the NOAEL for systemic toxicity and dermal irritation in 
    both sexes is 1,000 mg/kg/day HDT. A LOAEL for systemic toxicity and 
    dermal irritation was not established.
        5. Chronic toxicity-- i. A 1-year dog feeding study with a (LOAEL) 
    of 250 ppm, 9 mg/kg/day for male and female dogs based on decreases in 
    red blood cells (RBC), HCT, and HGB, increases in Heinz bodies, 
    methemoglobin, MCV, MCH, reticulocytes, platelets, plasma total 
    bilirubin, spleen weight, and spleen/body weight ratio, and liver/body 
    weight ratio. Hematopoiesis and sinusoidal engorgement occurred in the 
    spleen, and hyperplasia occurred in the marrow of the femur and 
    sternum. The liver showed an increased pigment in the Kupffer cells. 
    The NOAEL for systemic toxicity in both sexes is 50 ppm (1.9 mg/kg/
    day).
        ii. An 18-month mouse carcinogenicity study with no carcinogenicity 
    observed at dosage levels up to and including 1,000 ppm.
        iii. A 2-year rat carcinogenicity with no carcinogenicity observed 
    at dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 
    mg/kg/day for males and females, respectively).
        6. Animal metabolism. The pharmacokinetics and metabolism of 
    tebufenozide were studied in female Sprague-Dawley rats (3-6/sex/group) 
    receiving a single oral dose of 3 or 250 mg/kg of RH-5992 
    14C labeled in one of three positions (A-ring, B-ring or N-
    butylcarbon). The extent of absorption was not established. The 
    majority of the radiolabeled material was eliminated or excreted in the 
    feces within 48 hours within 48 hours; small amounts (1 to 7% of the 
    administered dose) were excreted in the urine and only traces were 
    excreted in expired air or remained in the tissues. There was no 
    tendency for bioaccumulation. Absorption and excretion were rapid. A 
    total of 11 metabolites, in addition to the parent compound, were 
    identified in the feces; the parent compound accounted for 96 to 99% of 
    the administered radioactivity in the high dose group and 35 to 43% in 
    the low dose group. No parent compound was found in the urine; urinary 
    metabolites were not characterized. The identity of several fecal 
    metabolites was confirmed by mass spectral analysis and other fecal 
    metabolites were tentatively identified by cochromatography with 
    synthetic standards. A pathway of metabolism was proposed based on 
    these data. Metabolism proceeded primarily by oxidation of the three 
    benzyl carbons, two methyl groups on the B-ring and an ethyl group on 
    the A-ring to alcohols, aldehydes or acids. The type of metabolite 
    produced varies depending on the position oxidized and extent of 
    oxidation. The butyl group on the quaternary nitrogen also can be 
    cleaved (minor), but there was no fragmentation of the molecule between 
    the benzyl rings.
        No qualitative differences in metabolism were observed between 
    sexes, when high or low dose groups were compared or when different 
    labeled versions of the molecule were compared.
        7. Metabolite toxicology. The absorption and metabolism of 
    tebufenozide were studied in a group of male and female bile-duct 
    cannulated rats. Over a 72 hour period, biliary excretion accounted for 
    30% male to 34% female of the administered dose while urinary excretion 
    accounted for about 5% of the administered dose and the carcass 
    accounted for < 0.5%="" of="" the="" administered="" dose="" for="" both="" males="" and="" females.="" thus="" systemic="" absorption="" (percent="" of="" dose="" recovered="" in="" the="" bile,="" urine="" and="" carcass)="" was="" 35%="" male="" to="" 39%="" female.="" the="" majority="" of="" the="" radioactivity="" in="" the="" bile="" (20%="" male="" to="" 24%="" female="" of="" the="" administered="" dose)="" was="" excreted="" within="" the="" first="" 6="" hours="" post-dosing="" indicating="" rapid="" absorption.="" furthermore,="" urinary="" excretion="" of="" the="" metabolites="" was="" essentially="" complete="" within="" 24="" hours="" post-dosing.="" a="" large="" amount="" [67%="" (female)="" to="" 70%="" (male)="" of="" the="" administered="" dose="" was="" unabsorbed="" and="" excreted="" in="" the="" feces="" by="" 72="" hours.="" total="" recovery="" of="" radioactivity="" was="" 105%="" of="" the="" administered="" dose.="" a="" total="" of="" 13="" metabolites="" were="" identified="" in="" the="" bile;="" the="" parent="" compound="" was="" not="" identified,="" i.e.,="" unabsorbed="" compound,="" nor="" were="" the="" primary="" oxidation="" products="" seen="" in="" the="" feces="" in="" the="" pharmacokinetics="" study.="" the="" proposed="" metabolic="" pathway="" proceeded="" primarily="" by="" oxidation="" of="" the="" benzylic="" carbons="" to="" alcohols,="" aldehydes="" or="" acids.="" bile="" contained="" most="" of="" the="" other="" highly="" oxidizedproducts="" found="" in="" the="" feces.="" the="" most="" significant="" individual="" bile="" metabolites="" accounted="" for="" 5%="" to="" 18%="" of="" the="" total="" radioactivity="" (female="" and/or="" male).="" bile="" also="" contained="" the="" previously="" undetected="" (in="" the="" pharmacokinetics="" study]="" ``a''="" ring="" ketone="" and="" the="" ``b''="" ring="" diol.="" the="" other="" major="" components="" were="" characterized="" as="" high="" molecular="" weight="" conjugates.="" no="" individual="" bile="" metabolite="" accounted="" for=""> 5% of the total administered dose. Total bile 
    radioactivity accounted for about 17% of the total administered dose.
        No major qualitative differences in biliary metabolites were 
    observed between sexes. The metabolic profile in the bile was similar 
    to the metabolic profile in the feces and urine.
    
    C. Aggregate Exposure
    
        1. Dietary exposure-- From food and feed uses. Tolerances have been 
    established (40 CFR 180.482) for the residues of tebufenozide, in or on 
    walnuts at 0.1 ppm, pome fruit at 1.5 ppm, pecans at 0.01, kiwifruit at 
    0.5ppm, leafy and cole crop vegetables at 10 ppm and wine grapes at 0.5 
    ppm. Numerous section 18 tolerances have been established at levels 
    ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip tops. The 
    current petition requests establishment of tolerances due to indirect 
    or inadvertent residues of tebufenozide and its metabolite in or on 
    grass forage, fodder and hay and forage, fodder, straw and hay of 
    nongrass animal feeds Risk assessments were conducted by Rohm and Haas 
    to assess dietary exposures and risks from tebufenozide, benzoic acid, 
    3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide and are 
    presented in the followingdiscussion:
        i. Food--Acute exposure and risk. Acute dietary risk assessments 
    are performed for a food-use pesticide if a toxicological study has 
    indicated the possibility of an effect of concern occurring as a result 
    of a one day or single exposure. Toxicity observed in oral toxicity 
    studies were not attributable to a single dose (exposure). No neuro- or 
    systemic toxicity was observed in rats given a single oral 
    administration of tebufenozide at 0, 500, 1,000 or 2,000 mg/kg. No 
    maternal or developmental toxicity was observed following oral 
    administration of tebufenozide at 1,000 mg/kg/day (limit-dose) during 
    gestation to pregnant rats or rabbits. This risk is considered to be 
    negligible.
        ii. Chronic exposure and risk. The RfD used for the chronic dietary 
    analysis is 0.018 mg/kg/day. In conducting this chronic dietary (food) 
    exposure assessment, Rohm and Haas used (a) tolerance level residues 
    for pecans, walnuts, wine and sherry, imported apples and all other 
    commodities with established or pending tebufenozide tolerances; and 
    (b) percent crop-treated (%CT) information on some of these crops. 
    Further refinement using anticipated residue values and additional %CT 
    information would result in a lower estimate of chronic dietary 
    exposure. The Novigen DEEM system was used for this chronic dietary 
    exposure analysis. The subgroups listed below are (c) the U.S. 
    Population (48
    
    [[Page 47802]]
    
    States); (d) those for infants and children; and (e) the other 
    subgroups (adult) for which the percentage of the reference dose (RfD) 
    occupied is greater than that occupied by the subgroup U.S. population 
    (48 States). The results are summarized below:
    
    ------------------------------------------------------------------------
                   Groups                          %RfD (percentage)
    ------------------------------------------------------------------------
    U.S. Population.....................                               10.0%
    All Infants (< 1-year)..............="" 12.2%="" nursing="" infants="">< 1-year="" old)......="" 5.7%="" non-nursing="" infants="">< 1-year="" old)..="" 15.0%="" children="" (1-6="" years="" old)............="" 22.5%="" children="" (7-12="" years="" old)...........="" 14.1%="" females="" (13="" +="" years="" old,="" nursing)...="" 10.1%="" u.s.="" population="" autumn="" season.......="" 10.3%="" u.s.="" population="" winter="" season.......="" 10.1%="" non-hispanic="" blacks.................="" 10.4%="" non-hispanic="" other="" than="" black="" or="" 11.0%="" white..............................="" northeast="" region....................="" 10.3%="" southern="" region.....................="" 10.1%="" western="" region......................="" 10.5%="" pacific="" region......................="" 10.7%="" ------------------------------------------------------------------------="" iii.="" drinking="" water--="" i.="" acute="" exposure="" and="" risk.="" because="" no="" acute="" dietary="" endpoint="" was="" determined,="" rohm="" and="" haas="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" of="" no="" harm="" from="" acute="" exposure="" from="" drinking="" water.="" iv.="" chronic="" exposure="" and="" risk.="" submitted="" environmental="" fate="" studies="" suggest="" that="" tebufenozide="" is="" moderately="" persistent="" to="" persistent="" and="" mobile.="" under="" certain="" conditions="" tebufenozide="" appears="" to="" have="" the="" potential="" to="" contaminate="" ground="" and="" surface="" water="" through="" runoff="" and="" leaching;="" subsequently="" potentially="" contaminating="" drinking="" water.="" there="" are="" no="" established="" maximum="" contaminant="" levels="" (mcl)="" for="" residues="" of="" tebufenozide="" in="" drinking="" water="" and="" no="" health="" advisories="" (ha)="" have="" been="" issued="" for="" tebufenozide="" therefore="" these="" could="" not="" be="" used="" as="" comparative="" values="" for="" risk="" assessment.="" therefore,="" potential="" residue="" levels="" for="" drinking="" water="" exposure="" were="" calculated="" previously="" by="" epa="" using="" geneec="" (surface="" water)="" and="" scigrow="" (ground="" water)="" for="" human="" health="" risk="" assessment.="" because="" of="" the="" wide="" range="" of="" half-life="" values="" (66-729="" days)="" reported="" for="" the="" aerobic="" soil="" metabolism="" input="" parameter="" a="" range="" of="" potential="" exposure="" values="" were="" calculated.="" in="" each="" case="" the="" worst="" case="" upper="" bound="" exposure="" limits="" were="" then="" compared="" to="" appropriate="" chronic="" drinking="" water="" level="" of="" concern="" (dwloc).="" in="" each="" case="" the="" calculated="" exposures="" based="" on="" model="" data="" were="" below="" the="" dwloc.="" 2.="" non-dietary="" exposure.="" tebufenozide="" is="" not="" currently="" registered="" for="" use="" on="" any="" residential="" non-food="" sites.="" therefore="" ,="" there="" is="" no="" chronic,="" short-="" or="" intermediate-term="" exposure="" scenario.="" d.="" cumulative="" effects="" section="" 408(b)(2)(d)(v)="" requires="" that,="" when="" considering="" whether="" to="" establish,="" modify,="" or="" revoke="" a="" tolerance,="" the="" agency="" consider="" ``available="" information''="" concerning="" the="" cumulative="" effects="" of="" a="" particular="" pesticide's="" residues="" and="" ``other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity.''="" the="" agency="" believes="" that="" ``available="" information''="" in="" this="" context="" might="" include="" not="" only="" toxicity,="" chemistry,="" and="" exposure="" data,="" but="" also="" scientific="" policies="" and="" methodologies="" for="" understanding="" common="" mechanisms="" of="" toxicity="" and="" conducting="" cumulative="" risk="" assessments.="" for="" most="" pesticides,="" although="" the="" agency="" has="" some="" information="" in="" its="" files="" that="" may="" turn="" out="" to="" be="" helpful="" in="" eventually="" determining="" whether="" a="" pesticide="" shares="" a="" common="" mechanism="" of="" toxicity="" with="" any="" other="" substances,="" epa="" does="" not="" at="" this="" time="" have="" the="" methodologies="" to="" resolve="" the="" complex="" scientific="" issues="" concerning="" common="" mechanism="" of="" toxicity="" in="" a="" meaningful="" way.="" epa="" has="" begun="" a="" pilot="" process="" to="" study="" this="" issue="" further="" through="" the="" examination="" of="" particular="" classes="" of="" pesticides.="" the="" agency="" hopes="" that="" the="" results="" of="" this="" pilot="" process="" will="" increase="" the="" agency's="" scientific="" understanding="" of="" this="" question="" such="" that="" epa="" will="" be="" able="" to="" develop="" and="" apply="" scientific="" principles="" for="" better="" determining="" which="" chemicals="" have="" a="" common="" mechanism="" of="" toxicity="" and="" evaluating="" the="" cumulative="" effects="" of="" such="" chemicals.="" the="" agency="" anticipates,="" however,="" that="" even="" as="" its="" understanding="" of="" the="" science="" of="" common="" mechanisms="" increases,="" decisions="" on="" specific="" classes="" of="" chemicals="" will="" be="" heavily="" dependent="" on="" chemical="" specific="" data,="" much="" of="" which="" may="" not="" be="" presently="" available.="" although="" at="" present="" the="" agency="" does="" not="" know="" how="" to="" apply="" the="" information="" in="" its="" files="" concerning="" common="" mechanism="" issues="" to="" most="" risk="" assessments,="" there="" are="" pesticides="" as="" to="" which="" the="" common="" mechanism="" issues="" can="" be="" resolved.="" these="" pesticides="" include="" pesticides="" that="" are="" toxicologically="" dissimilar="" to="" existing="" chemical="" substances="" (in="" which="" case="" the="" agency="" can="" conclude="" that="" it="" is="" unlikely="" that="" a="" pesticide="" shares="" a="" common="" mechanism="" of="" activity="" with="" other="" substances)="" and="" pesticides="" that="" produce="" a="" common="" toxic="" metabolite="" (in="" which="" case="" common="" mechanism="" of="" activity="" will="" be="" assumed).="" epa="" does="" not="" have,="" at="" this="" time,="" available="" data="" to="" determine="" whether="" tebufenozide,="" benzoic="" acid,="" 3,5-dimethyl-1-(1,1-dimethylethyl)-="" 2-(4-ethylbenzoyl)="" hydrazide="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances="" or="" how="" to="" include="" this="" pesticide="" in="" a="" cumulative="" risk="" assessment.="" unlike="" other="" pesticides="" for="" which="" epa="" has="" followed="" a="" cumulative="" risk="" approach="" based="" on="" a="" common="" mechanism="" of="" toxicity,="" tebufenozide,="" benzoic="" acid,="" 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-="" ethylbenzoyl)="" hydrazide="" does="" not="" appear="" to="" produce="" a="" toxic="" metabolite="" produced="" by="" other="" substances.="" for="" the="" purposes="" of="" this="" tolerance="" action,="" therefore,="" rohm="" and="" haas="" has="" not="" assumed="" that="" tebufenozide,="" benzoic="" acid,="" 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)="" hydrazide="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" e.="" safety="" determination="" 1.="" u.s.="" population--="" i.="" acute="" risk.="" since="" no="" acute="" toxicological="" endpoints="" were="" established,="" no="" acute="" aggregate="" risk="" exists.="" [[page="" 47803]]="" ii.="" chronic="" risk.="" using="" the="" conservative="" exposure="" assumptions="" described="" above,="" and="" taking="" into="" account="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" rohm="" and="" haas="" has="" concluded="" that="" dietary="" (food="" only)="" exposure="" to="" tebufenozide="" will="" utilize="" 10.0%="" of="" the="" rfd="" for="" the="" u.s.="" population.="" submitted="" environmental="" fate="" studies="" suggest="" that="" tebufenozide="" is="" moderately="" persistent="" to="" persistent="" and="" mobile;="" thus,="" tebufenozide="" could="" potentially="" leach="" to="" groundwater="" and="" runoff="" to="" surface="" water="" under="" certain="" environmental="" conditions.="" the="" modeling="" data="" for="" tebufenozide="" indicate="" levels="" less="" than="" opp's="" drinking="" water="" levels="" concern="" (dwloc).="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" there="" are="" no="" registered="" residential="" uses="" of="" tebufenozide.="" since="" there="" is="" no="" potential="" for="" exposure="" to="" tebufenozide="" from="" residential="" uses,="" rohm="" and="" haas="" does="" not="" expect="" the="" aggregate="" exposure="" to="" exceed="" 100%="" of="" the="" rfd.="" iii.="" short-="" and="" intermediate-term="" risk.="" short-="" and="" intermediate-="" term="" aggregate="" exposure="" takes="" into="" account="" chronic="" dietary="" food="" and="" water="" (considered="" to="" be="" a="" background="" exposure="" level)="" plus="" indoor="" and="" outdoor="" residential="" exposure.="" since="" there="" are="" currently="" no="" registered="" indoor="" or="" outdoor="" residential="" non-dietary="" uses="" of="" tebufenozide="" and="" no="" short-="" or="" intermediate-term="" toxic="" endpoints,="" short-="" or="" intermediate-="" term="" aggregate="" risk="" does="" not="" exist.="" 2.="" infants="" and="" children--="" i.="" in="" general.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" tebufenozide,="" benzoic="" acid,="" 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-="" ethylbenzoyl)="" hydrazide,="" epa="" previously="" considered="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit="" and="" a="" 2-generation="" reproduction="" study="" in="" the="" rat.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" resulting="" from="" maternal="" pesticide="" exposure="" gestation.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" data="" on="" systemic="" toxicity.="" ffdca="" section="" 408="" provides="" that="" epa="" shall="" apply="" an="" additional="" tenfold="" margin="" of="" safety="" for="" infants="" and="" children="" in="" the="" case="" of="" threshold="" effects="" to="" account="" for="" prenatal="" and="" postnatal="" toxicity="" and="" the="" completeness="" of="" the="" data="" base="" unless="" epa="" determines="" that="" a="" different="" margin="" of="" safety="" will="" be="" safe="" for="" infants="" and="" children.="" margins="" of="" safety="" are="" incorporated="" into="" epa="" risk="" assessments="" either="" directly="" through="" use="" of="" a="" moe="" analysis="" or="" through="" using="" uncertainty="" (safety)="" factors="" in="" calculating="" a="" dose="" level="" that="" poses="" no="" appreciable="" risk="" to="" humans.="" epa="" believes="" that="" reliable="" data="" support="" using="" the="" standard="" uncertainty="" factor="" (usually="" 100="" for="" combined="" inter-="" and="" intra-="" species="" variability))="" and="" not="" the="" additional="" tenfold="" moe/uncertainty="" factor="" when="" epa="" has="" a="" complete="" data="" base="" under="" existing="" guidelines="" and="" when="" the="" severity="" of="" the="" effect="" in="" infants="" or="" children="" or="" the="" potency="" or="" unusual="" toxic="" properties="" of="" a="" compound="" do="" not="" raise="" concerns="" regarding="" the="" adequacy="" of="" the="" standard="" moe/safety="" factor.="" the="" toxicology="" data="" base="" for="" tebufenozide="" is="" complete="" and="" includes="" acceptable="" developmental="" toxicity="" studies="" in="" both="" rats="" and="" rabbits="" as="" well="" as="" a="" 2-generation="" reproductive="" toxicity="" studies="" in="" rats.="" the="" epa="" determined="" that="" the="" data="" provided="" no="" indication="" of="" increased="" sensitivity="" of="" rats="" or="" rabbits="" to="" in="" utero="" and/or="" postnatal="" exposure="" to="" tebufenozide.="" no="" maternal="" or="" developmental="" findings="" were="" observed="" in="" the="" prenatal="" developmental="" toxicity="" studies="" at="" doses="" up="" to="" 1,000="" mg/kg/day="" in="" rats="" and="" rabbits.="" in="" the="" 2-generation="" reproduction="" studies="" in="" rats,="" effects="" occurred="" at="" the="" same="" or="" lower="" treatment="" levels="" in="" the="" adults="" as="" in="" the="" offspring.="" rohm="" and="" haas="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" tebufenozide,="" benzoic="" acid,="" 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-="" ethylbenzoyl)="" hydrazide="" residues.="" f.="" international="" tolerances="" there="" are="" currently="" no="" codex,="" canadian="" or="" mexican="" maximum="" residue="" levels="" (mrls)="" established="" for="" tebufenozide="" in="" rotation="" crops="" so="" no="" harmonization="" issues="" are="" required="" for="" this="" action.="" 3.="" rohm="" and="" haas="" company="" pp="" 9f5058="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 9f5058)="" from="" rohm="" and="" haas="" company,="" 100="" independence="" mall="" west,="" philadelphia,="" pa="" proposing,="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (ffdca),="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" combined="" residues="" of="" rh-117281="" technical="" benzamide-3,5-="" dichloro-n-(3-chloro-1-ethyl-1-methyl-2oxopropyl)-4-methyl="" and="" metabolites="" 3,5-dichloro-4-hydroxy="" methyl-benzoic="" acid="" and="" 3,5-="" dichloro-1,4-benzene="" dicarboxylic="" (rh-141452="" and="" rh-141455)="" in="" or="" on="" the="" raw="" agricultural="" commodity="" (rac)="" potatoes="" at="" 0.1="" parts="" per="" million="" (ppm),="" grapes="" at="" 5="" ppm,="" and="" raisins="" at="" 15="" ppm.="" epa="" has="" determined="" that="" the="" petition="" contains="" data="" or="" information="" regarding="" the="" elements="" set="" forth="" in="" section="" 408(d)(2)="" of="" the="" ffdca;="" however,="" epa="" has="" not="" fully="" evaluated="" the="" sufficiency="" of="" the="" submitted="" data="" at="" this="" time="" or="" whether="" the="" data="" supports="" granting="" of="" the="" petition.="" additional="" data="" may="" be="" needed="" before="" epa="" rules="" on="" the="" petition.="" a.="" residue="" chemistry="" 1.="" plant="" metabolism.="" the="" metabolism="" of="" rh-117281="" technical="" in="" plants="" (grapes="" and="" potatoes)="" is="" adequately="" understood="" for="" the="" purposes="" of="" these="" tolerances.="" there="" were="" no="" significant="" metabolites="" other="" than="" the="" parent="" compound="" in="" grapes.="" residues="" in="" grapes="" were="" surface="" residues="" of="" parent="" rh-117281="" and="" minor="" amounts="" of="" hydrolysis="" and="" photolysis="" degradates.="" in="" potatoes,="" two="" minor="" rat="" metabolites,="" rh-141452="" and="" rh-="" 141455,="" comprised="" the="" majority="" of="" the="" residue.="" no="" other="" metabolites="" were="" present="" in="" excess="" of="" 10%="" of="" the="" total="" dosage.="" it="" is="" most="" likely="" that="" the="" source="" of="" these="" residues="" is="" extremely="" low="" level="" uptake="" of="" highly="" degraded="" metabolites="" from="" the="" soil,="" rather="" than="" metabolism="" within="" the="" plant,="" since="" these="" compounds="" are="" highly="" metabolized,="" but="" there="" are="" no="" intermediate="" products="" found="" in="" the="" potato.="" 2.="" animal="" metabolism.="" the="" metabolism="" of="" rh-117281="" technical="" in="" food-producing="" animals="" (dairy="" goats)="" is="" adequately="" understood.="" hen="" metabolism="" is="" not="" required="" for="" the="" current="" submission="" because="" no="" components="" of="" grape="" or="" potato="" are="" fed="" to="" poultry.="" metabolism="" in="" laboratory="" and="" food-producing="" animals="" was="" similar="" and="" extensive,="" occurring="" through="" multiple="" pathways="" involving="" primary="" hydrolysis,="" glutathione-mediated="" reactions,="" and="" reductive="" dehalogenation;="" secondary="" oxidation;="" and="" terminal="" glucuronic="" and="" amino="" acid="" conjugation.="" rh-="" 117281="" technical="" and="" its="" residues="" are="" rapidly="" excreted="" in="" animals.="" no="" significant="" residues="" in="" these="" food="" commodities.="" 3.="" analytical="" method.="" tolerance="" enforcement="" methods="" using="" gas="" chromatography/electron="" capture="" detection="" (gc/ecd)="" or="" gas="" chromatography/mass="" selective="" detection="" (gc/msd),="" have="" been="" developed="" for="" rh-117281="" in="" grapes,="" grape="" juice="" and="" raisins.="" the="" limit="" of="" quantification="" (loq)="" is="" 0.01="" ppm="" for="" all="" matrices.="" average="" recoveries="" are="" 95.8-106%="" for="" grapes,="" 84.2-101%="" for="" juice,="" and="" 85.9-108%="" for="" raisins,="" over="" the="" range="" of="" fortifications.="" [[page="" 47804]]="" a="" tolerance="" enforcement="" method="" using="" gcecd="" or="" gc/msd="" detection="" has="" also="" been="" developed="" for="" rh-117281="" in="" potatoes="" and="" for="" the="" metabolites="" rh-141452="" and="" rh-141455="" in="" potatoes,="" potato="" chips="" and="" potato="" flakes.="" the="" loq="" for="" all="" analytes="" is="" 0.02="" ppm="" for="" all="" matrices.="" the="" methods="" involve="" extraction="" with="" solvent,="" filtration,="" liquid-="" liquid="" partition,="" and="" final="" purification="" of="" the="" residues="" using="" solid="" phase="" column="" chromatography.="" an="" independent="" validation="" of="" the="" methods="" has="" been="" completed.="" 4.="" magnitude="" of="" residues--i.="" grape.="" twelve="" field="" residue="" trials="" were="" conducted="" over="" two="" seasons="" in="" four="" states="" at="" either="" 1.25="" lb="" active="" ingredient="" (a.i)/acre="" and="" 2.50="" lb="" a.i./acre="" (1.40="" kiligram/hectare="" kg/="" ha="" and="" 2.81="" kg/ha)="" or="" 2.0="" lbs="" a.i/acre="" and="" 4.0="" lbs="" a.i="" acre="" (2.25="" kg/ha="" and="" 4.49="" kg/ha).="" ten="" applications="" were="" made="" in="" each="" trial.="" in="" two="" of="" the="" trials,="" fruit="" was="" harvested="" at="" 0,="" 7,="" 14,="" and="" 21="" days="" after="" the="" final="" application.="" in="" the="" remaining="" trials,="" samples="" were="" taken="" at="" 13="" or="" 14="" days="" after="" the="" final="" application.="" the="" proposed="" seasonal="" use="" rate="" is="" 1.6="" lb="" a.i/acre="" (1.8="" kg/ha)="" with="" a="" 14-="" day="" pre-harvest="" interval="" (phi).="" samples="" were="" analyzed="" for="" residues="" of="" rh-117281.="" residue="" levels="" in="" the="" 34="" samples="" from="" the="" 2.0="" or="" 2.5="" lb/acre="" (2.25="" and="" 2.81="" kg/ha)="" rates="" and="" 13="" or="" 14="" day="" phi="" ranged="" from="" 0.218="" to="" 4.52="" ppm.="" the="" average="" residue="" was="" 0.88="" ppm.="" these="" data="" support="" a="" permanent="" tolerance="" of="" 5.0="" ppm="" on="" grapes.="" grape="" juice="" (clarified="" and="" unclarified)="" and="" raisins="" were="" generated="" from="" two="" rac="" samples="" from="" one="" residue="" trial.="" residues="" in="" grape="" juice="" were="" much="" lower="" than="" in="" the="" whole="" fruit,="" roughly="" 10%="" of="" the="" levels="" in="" the="" rac.="" residues="" concentrated="" in="" the="" raisins.="" the="" data="" support="" a="" permanent="" tolerance="" of="" 15="" ppm="" on="" raisins.="" ii.="" potatoes.="" sixteen="" field="" residue="" trials="" were="" conducted="" over="" two="" seasons="" in="" 10="" states="" at="" either="" 1.25="" lb="" a.i./acre="" and="" 2.50="" lb="" a.i/a="" (1.40="" kg/ha="" and="" 2.81="" kg/ha)="" or="" 2.0="" lbs="" a.i./acre="" and="" 4.0="" lbs="" a.i./acre="" (2.25="" kg/ha="" and="" 4.49="" kg/ha).="" ten="" applications="" were="" made="" in="" each="" trial.="" in="" two="" of="" the="" trials,="" tubers="" were="" harvested="" at="" 0,="" 3,="" 7,="" and="" 14="" days="" after="" the="" final="" application.="" in="" the="" remaining="" trials,="" samples="" were="" taken="" at="" 3="" days="" after="" the="" final="" application.="" the="" proposed="" maximum="" seasonal="" use="" rate="" is="" 1.6="" lb="" a.i./acre="" (1.8="" kg/ha)="" with="" a="" 3-day="" phi.="" samples="" were="" analyzed="" for="" parent="" rh-117281="" and="" the="" two="" metabolites="" rh-="" 141452="" and="" rh-141455.="" samples="" were="" below="" the="" loq="" in="" nearly="" all="" cases.="" these="" residues="" support="" the="" establishment="" of="" a="" permanent="" tolerance="" of="" 0.1="" ppm="" on="" potatoes.="" twelve="" residue="" trials="" were="" conducted="" in="" 7="" regions="" in="" canada="" during="" 1998="" at="" 2.0="" kg/ha="" and="" a="" phi="" of="" 3-days.="" there="" were="" no="" residues="" of="" any="" analyte="" above="" the="" loq="" of="" 0.02="" ppm="" in="" any="" sample.="" a="" potato="" process="" study="" was="" conducted.="" residues="" of="" two="" metabolites="" concentrated="" in="" flakes,="" consistent="" with="" loss="" of="" water="" from="" the="" potato.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" rh-117281="" technical="" was="" practically="" non-toxic="" by="" ingestion="" of="" a="" singe="" oral="" dose="" in="" rats="" and="" mice="" lethal="" dose="">50) > 5,000 milligram/kilogram (mg/kg), practically non-
    toxic by dermal application to rats (LD50 > 2,000 mg/kg), 
    and practically non-toxic to rats after a 4-hour inhalation exposure 
    with an LC50 value of > 5.3 milligrams per liter (mg/L) 
    (highest attainable concentration ), is not considered to be a primary 
    eye irritant or a skin irritant and is not a dermal sensitizer. The 
    technical material was non irritating to skin after single applications 
    and moderately irritating to eyes. RH-117281 Technical produced delayed 
    contact hypersensitivity in the guinea pig at concentrations of 2,500 
    ppm and higher. An acute neurotoxicity study in rats did not produce 
    any neurotoxic or neuropathologic effects with a NOAEL > 2,000 mg/kg.
        2. Genotoxicity. RH-117281 was nonmutagenic in a standard battery 
    of tests. In in vitro assays, RH-117281 showed no evidence of mutagenic 
    activity in an Ames and CHO/HGPRT assays for gene mutation, and no 
    evidence of structural chromosomal aberrations in the CHO in vitro 
    cytogenetic study. As predicted by its antitubulin mode of action, 
    mitotic accumulation and polyploidy were noted at cytotoxic doses in 
    the in vitro chromosomal assay. However, there was no evidence of 
    structural or numerical chromosomal aberrations when RH-117281 
    Technical was tested in vivo in the mouse micronucleus test.
        3. Reproductive and developmental toxicity. NOAELs for 
    developmental and maternal toxicity to RH-117281 Technical were 
    established at 1,000 mg/kg/day, highest dose tested (HDT) in both the 
    rat and rabbit. No signs of developmental toxicity were exhibited.
        In a 2-generation reproduction study in the rat, RH-117281 
    Technical had no adverse effects on reproductive performance or pup 
    development at doses up to and exceeding 1474 mg/kg/day, the limit dose 
    tested (LDT). This NOAEL was 20-fold higher than the NOAEL for adult 
    toxicity of 71 mg/kg/day. A delay in periweaning weight gain and 
    associated spleen effects in the F1 and F2a litters were shown in the 
    F2b litters to be a secondary effect related to feed refusal due to 
    palatability of the treated diets, and not to a systemic toxic effect. 
    The consequences of feed refusal due to palatability do not constitute 
    an adverse effect relevant to human health risk assessment.
        4. Subchronic toxicity. The NOAEL in a 90-day rat subchronic 
    feeding study was 1,509 mg/kg/day in males and 1,622 mg/kg/day in 
    females (HDT). RH-117281 Technical did not produce neurotoxic or 
    neuropathologic effects.
        In a 90-day feeding study with mice, the NOAEL was 436 mg/kg/day in 
    males and 574 mg/kg/day in females based on a slight decrease in weight 
    gain among the females only at the LOAEL of 1,666 mg/kg/day.
        A 90-day dog feeding study gave a NOAEL of 55 mg/kg/day in males 
    and 62 mg/kg/day in females based on increased liver weights without a 
    corresponding clinical or histopathologic change in females only at 322 
    mg/kg/day.
        No signs of systemic toxicity were observed when RH-117281 
    Technical was administered dermally to rats for 28 days at a limit dose 
    of 1,000 mg/kg/day. This occurred despite skin irritation at all doses 
    tested (150, 400, and 1,000 mg/kg/day). Similarly, in vivo dermal 
    absorption was shown to be low regardless of concentration or 
    formulation type (i.e. < 1-6%="" of="" theadministered="" dose="" was="" systemically="" absorbed="" after="" 24="" hours).="" 5.="" chronic="" toxicity.="" in="" a="" combined="" rat="" chronic/oncogenicity="" study,="" the="" noael="" for="" chronic="" toxicity="" was="" 51="" mg/kg/day="" in="" males="" and="" 65="" mg/kg/="" day="" based="" on="" an="" equivocal="" increase="" in="" relative="" liver="" weight="" at="" a="" loael="" of="" 328="" mg/kg/day="" in="" females="" at="" the="" interim="" sacrifice="" only.="" the="" noael="" was="" considered="" to="" be="" 1,058="" mg/kg/day="" in="" males="" and="" 1,331="" mg/kg/day="" in="" females="" (hdt,="" limit="" dose).="" no="" carcinogenicity="" was="" observed.="" an="" 18-month="" mouse="" carcinogenicity="" study="" showed="" no="" signs="" of="" carcinogenicity="" or="" of="" any="" other="" compound-related="" effect="" at="" dosage="" levels="" up="" to="" 1,021="" mg/kg/day="" in="" males="" and="" 1,289="" mg/kg/day="" in="" females="" hdt,="" limit="" dose).="" the="" noael="" in="" a="" 1-year="" feeding="" study="" in="" dogs="" was="" 255="" mg/kg/day="" in="" males="" and="" 48="" mg/kg/day="" in="" females="" based="" on="" minimal="" effects="" on="" body="" weight="" (bwt)="" and="" body="" weight="" gain="" and="" increased="" liver="" weights="" in="" females="" only="" at="" a="" loael="" of="" 278="" mg/kg/day.="" 6.="" animal="" metabolism.="" in="" pharmacokinetic="" and="" metabolism="" studies="" in="" the="" rat,="" rh-117281="" technical="" [[page="" 47805]]="" was="" rapidly="" and="" extensively="" absorbed,="" metabolized="" and="" excreted="" following="" oral="" exposure.="" a="" total="" of="" approximately="" 60%="" of="" the="" administered="" dose="" was="" systemically="" absorbed.="" plasma="" levels="" peaked="" within="" 8="" hours="" of="" dosing,="" and="" declined="" with="" a="" half-life="" of="" 12-14="" hours,="" consistent="" with="" the="" nearly="" complete="" excretion="" within="" 48="" hours.="" no="" evidence="" of="" accumulation="" of="" the="" parent="" compound="" or="" its="" metabolites="" was="" observed.="" the="" predominant="" route="" of="" excretion="" was="" hepatobiliary.="" metabolism="" was="" found="" to="" occur="" through="" multiple="" pathways="" involving="" primary="" hydrolysis,="" glutathione-mediated="" reactions,="" and="" reductive="" dehalogenation;="" secondary="" oxidation="" on="" both="" the="" aromatic="" methyl="" and="" the="" aliphatic="" side-chain;="" and="" terminal="" glucuronic="" acid="" and="" amino="" acid="" conjugation.="" altogether,="" 32="" separate="" metabolites="" were="" identified;="" no="" single="" metabolite="" other="" than="" parent="" rh-117281="" accounted="" for="" more="" than="" 10%="" of="" the="" administered="" dose.="" the="" rapid="" metabolism="" and="" excretion="" of="" rh-="" 117281="" technical="" was="" a="" major="" factor="" explaining="" the="" compound's="" overall="" remarkably="" low="" toxicity="" profile="" in="" animals.="" 7.="" metabolite="" toxicology.="" of="" these="" multiple="" pathways,="" all="" three="" are="" common="" to="" both="" laboratory="" (rat)="" and="" food-producing="" animals="" (goat).="" extensive="" degradation="" and="" elimination="" occurs="" in="" animals="" such="" that="" residues="" are="" unlikely="" to="" accumulate="" in="" humans="" or="" animals="" exposed="" to="" these="" residues="" through="" the="" diet.="" there="" were="" no="" significant="" metabolites="" other="" than="" the="" parent="" rh-117281="" in="" grapes.="" two="" minor="" metabolites="" in="" the="" rat="" constituted="" a="" major="" portion="" of="" the="" residue="" in="" potato="" tubers="" in="" the="">14 C-metabolism study. RH-141452 and RH-141455 are not 
    considered toxicologically significant as they were practically non-
    toxic after acute oral administration in mice, non mutagenic in the 
    Ames test, and rapidly excreted essentially unchanged in rats. Actual 
    residues in field trials never exceeded trace levels approximating the 
    LOQ.
        8. Endocrine disruption. Based on structure-activity and mode of 
    action information as well as the lack of developmental and 
    reproductive toxicity, RH-117281 Technical is unlikely to exhibit 
    endocrine activity. There was no evidence of a functional or 
    histopathologic change in the male or female reproductive tract, and no 
    indicators of an endocrine effect of any kind below limit doses in 
    mammalian subchronic or chronic studies or in mammalian and avian 
    reproduction studies. A slight thyroid effect at the limit dose (994-
    1139 mg/kg/day) in the subchronic dog studies was secondary to liver 
    hypertrophy and enlargement at that dose. Collectively, the weight of 
    evidence provides no indication of an endocrine effect of RH-117281 
    Technical.
        9. Toxicological endpoints-- i. Acute and short term dietary. No 
    endpoint of concern was identified for acute or short term (1-7 day) 
    dietary exposure to RH-117281 Technical, and no acute or short term 
    risk assessment is required.
        ii. Chronic dietary. The proposed RfD for RH-117281 Technical is 
    0.5 mg/kg/day, based on application of a 100-fold uncertainty factor to 
    the chronic NOAELs in the rat and dog of 51 and 48 mg/kg/day, 
    respectively.
        iii. Carcinogen classification. There was no evidence of oncogenic 
    potential in two well-conducted lifetime feeding studies in rats and 
    mice, at doses up to and including the limit dose. Thus, RH-117281 
    Technical should be classified as ``unlikely'' to have carcinogenic 
    potential.
    
    C. Aggregate Exposure
    
        1. Dietary (food) exposure. Tolerances are proposed for the 
    residues of RH-117281 Technical in or on potatoes (0.1 ppm), grapes (5 
    ppm), and raisins (15 ppm). The goat metabolism study demonstrated that 
    there is no reasonable expectation of transfer of residues of RH-117281 
    Technical into meat or milk from potatoes. There are no grape feed 
    commodities fed to livestock, and no potato or grape feed commodities 
    fed to poultry. There are no other established or proposed United 
    States tolerances for RH-117281 Technical, and no currently registered 
    uses in the United States. Risk assessments were conducted by Rohm and 
    Haas to assess dietary exposures and risks from RH-117281 Technical as 
    follows:
        i. Acute exposure and risk. No acute endpoint was identified for 
    RH-117281 Technical and no acute risk assessment is required.
        ii. Chronic exposure and risk. For chronic dietary risk assessment, 
    the proposed tolerance values, as well as anticipated (average) 
    residues and processing factors, were used and the assumption that 100% 
    of all potatoes and grapes will contain residues of RH-117281 Technical 
    at the tolerance or anticipated residue levels. Potential chronic 
    exposures were estimated using USDA food consumption data from the 
    1989-1992 survey. With the proposed tolerances and anticipated residue 
    levels for RH-117281 Technical, the percentage of the 0.5 mg/kg/day 
    reference dose (RfD) utilized as follows:
    
    ----------------------------------------------------------------------------------------------------------------
                      Group                     AnticipatedResidues Total % RfD      Tolerance Levels Total % RfD
    ----------------------------------------------------------------------------------------------------------------
    U.S. Population 48 States...............                                 0.5                                 0.1
    Nursing Infants < 1="" year="" old............="" 1.0="" 0.2="" non-nursing="" infants="">< 1-year="" old........="" 1.2="">< 0.1="" children="" 1-6="" years="" old..................="" 1.7="" .1="" children="" 7-12="" years="" old="" 0.5="" 0.1="" ----------------------------------------------------------------------------------------------------------------="" the="" chronic="" dietary="" risks="" from="" these="" uses="" do="" not="" exceed="" epa's="" level="" of="" concern.="" 2.="" drinking="" water.="" no="" direct="" information="" is="" available="" on="" potential="" for="" exposure="" to="" rh-117281="" technical="" from="" drinking="" water.="" however,="" exposure="" from="" drinking="" water="" is="" unlikely="" to="" occur="" as="" a="" result="" of="" the="" uses="" on="" potatoes="" or="" grapes.="" submitted="" environmental="" fate="" studies="" indicat0e="" that="" rh-117281="" technical="" dissipates="" rapidly="" from="" the="" environment="" under="" all="" conditions="" tested,="" and="" that="" is="" not="" mobile="" and="" poses="" no="" threat="" to="" groundwater.="" furthermore,="" its="" environmental="" metabolites="" are="" very="" snort-lived="" and="" also="" have="" no="" potential="" to="" leach.="" there="" is="" no="" established="" maximum="" concentration="" level="" (mcl)="" for="" residues="" of="" rh-117281="" technical="" in="" drinking="" water,="" and="" no="" drinking="" water="" health="" advisory="" levels="" have="" been="" established.="" there="" is="" no="" entry="" for="" rh-117281="" technical="" in="" the="" ``pesticides="" in="" groundwater="" database''="" (epa="" 734-12-001,="" september="" 1992).="" i.="" chronic="" exposure="" and="" risk.="" nevertheless,="" to="" assess="" an="" upper="" bound="" on="" the="" potential="" for="" exposure="" from="" drinking="" water,="" chronic="" exposure="" to="" rh-117281="" technical="" in="" drinking="" water="" was="" estimated="" using="" the="" generic="" expected="" environmental="" concentration="" (geneec)="" v1.2="" and="" sci-="" grow="" models,="" as="" directed="" in="" the="" office="" of="" pesticide="" program's="" interim="" approach="" for="" addressing="" drinking="" water="" exposure.="" geneec="" is="" a="" highly="" conservative="" model="" used="" to="" estimate="" residue="" concentrations="" in="" surface="" water.="" sci="GROW" is="" an="" equally="" [[page="" 47806]]="" conservative="" model="" used="" to="" estimate="" residue="" concentrations="" in="" shallow,="" highly="" vulnerable="" groundwater="" (i.e.,="" sites="" with="" sandy="" soils="" and="" depth="" to="" groundwater="" of="" 10="" to="" 20="" feet).="" as="" indicated="" in="" epa's="" drinking="" water="" exposure="" guidance,="" a="" very="" small="" percentage="" of="" people="" in="" the="" united="" states="" would="" derive="" their="" drinking="" water="" from="" such="" sources.="" geneec="" (56-="" day="" average)="" and="" sci-grow="" water="" exposure="" values="" utilizes="" substantially="" less="" than="" 1%="" of="" the="" rfd="" for="" adults="" and="" children.="" 3.="" non-dietary="" exposure.="" rh-117281="" technical="" is="" not="" currently="" registered="" for="" any="" indoor="" or="" outdoor="" residential="" or="" structural="" uses,="" and="" no="" application="" is="" pending;="" therefore,="" no="" non-dietary="" non-="" occupational="" exposure="" is="" anticipated.="" 4.="" aggregate="" exposure="" and="" risk.="" the="" anticipated="" exposure="" from="" food="" and="" drinking="" water="" combined="" is="">< 2%="" of="" the="" rfd,="" and="" there="" is="" no="" expectation="" of="" other="" non-occupational="" exposure.="" thus,="" aggregate="" exposure="" of="" rh-117281="" technical="" does="" not="" exceed="" epa's="" level="" of="" concern,="" and="" is="" essentially="" negligible.="" d.="" cumulative="" effects="" at="" this="" time,="" no="" data="" are="" available="" to="" determine="" whether="" rh-117281="" technical="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" thus,="" it="" is="" not="" appropriate="" to="" include="" this="" fungicide="" in="" a="" cumulative="" risk="" assessment.="" unlike="" other="" pesticides="" for="" which="" epa="" has="" followed="" a="" cumulative="" risk="" approach="" based="" on="" a="" common="" mechanism="" of="" toxicity,="" rh-="" 117281="" technical="" does="" not="" appear="" to="" produce="" a="" toxic="" metabolite="" produced="" by="" other="" substances.="" in="" addition,="" the="" toxicity="" studies="" submitted="" to="" support="" this="" petition="" indicate="" that="" rh-117281="" has="" only="" limited="" toxic="" potential.="" no="" toxic="" endpoints="" of="" potential="" concern="" were="" identified.="" for="" the="" purposes="" of="" this="" tolerance="" action,="" therefore,="" rh-117281="" technical="" [benzamide-3,5-dichloro-n-(3-clair-1-ethyl-1-methyl-2-oxopropyl)-4-="" methyl]="" is="" assumed="" not="" to="" have="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" e.="" safety="" determination="" 1.="" u.s.="" population--="" i.="" acute="" exposure="" and="" risk.="" since="" no="" acute="" endpoint="" was="" identified="" for="" rh-117281="" technical,="" no="" acute="" risk="" assessment="" is="" required.="" ii.="" chronic="" exposure="" and="" risk.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" taking="" into="" account="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" the="" percentage="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" the="" dietary="" (food="" only)="" exposure="" to="" residues="" of="" rh-="" 117281="" technical="" from="" the="" proposed="" tolerances="" is="" 0.5%="" (tolerance="" levels)="" and="" 0.1%="" (anticipated="" residues)="" for="" the="" u.s.="" population.="" aggregate="" exposure="" (food="" and="" water)="" are="" expected="" to="" be="">< 1%="" rfd.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" rohm="" and="" haas="" concludes="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" rh-117281="" technical="" residues="" to="" the="" u.s.="" population.="" 2.="" infants="" and="" children--i.="" general.="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" rh-117281="" technical="" is="" assessed="" using="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit="" and="" 2-generation="" reproduction="" studies="" in="" the="" rat.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" resulting="" from="" maternal="" pesticide="" exposure="" during="" gestation.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" data="" on="" systemic="" toxicity.="" ii.="" developmental="" toxicity="" studies--rats.="" in="" a="" developmental="" toxicity="" study="" in="" rats,="" the="" maternal="" noael="" was="" 1,000="" mg/kg/day,="" hdt,="" and="" the="" developmental="" (pup)="" noael="" was="" 1,000="" mg/kg/day="" hdt.="" rabbits.="" in="" a="" developmental="" toxicity="" study="" in="" rats,="" the="" maternal="" noael="" was="" 1,000="" mg/kg/day="" hdt,="" and="" the="" developmental="" (pup)="" noael="" was="" 1,000="" mg/kg/day="" hdt.="" iii.="" reproductive="" toxicity="" study--rats.="" in="" a="" multigeneration="" reproductive="" toxicity="" study="" in="" rats,="" theparental="" (systemic)="" noael="" was="" 71="" mg/kg/day,="" based="" on="" an="" equivocal="" liver="" effect="" at="" the="" lowest="" observed="" adverse="" effect="" levels="" (loael)="" of="" 360="" mg/kg/day.="" the="" noael="" for="" reproductive="" and="" developmental="" effects="" was="" 1,471="" mg/kg/day="" hdt.="" no="" adverse="" reproductive="" or="" developmental="" effects="" were="" observed.="" iv.="" prenatal="" and="" postnatal="" sensitivity.="" no="" developmental="" or="" reproductive="" effects="" were="" demonstrated="" for="" rh-117281="" technical="" as="" a="" result="" of="" systemic="" exposure="" at="" up="" to="" limit="" doses="" of="" 1,000="" and="" 1,471="" mg/="" kg/day.="" additionally,="" these="" noaels="" are="" greater="" than="" 20-fold="" higher="" than="" the="" noaels="" of="" 48-51="" mg/kg/day="" from="" the="" dog="" and="" rat="" chronic="" studies="" which="" are="" the="" basis="" of="" the="" rfd.="" these="" developmental="" and="" reproductive="" studies="" indicate="" that="" developing="" and="" maturing="" animals="" are="" not="" more="" sensitive="" either="" pre="" or="" postnatally="" than="" other="" age="" groups="" to="" rh-117281="" technical;="" i.e.,="" rh-117281="" technical="" does="" not="" exhibit="" additional="" pre="" or="" postnatal="" sensitivity.="" thus,="" reliable="" data="" indicate="" that="" an="" additional="" fqpa="" uncertainty="" factor="" is="" not="" necessary="" to="" insure="" an="" adequate="" margin="" of="" safety="" for="" protection="" of="" infants="" and="" children.="" a.="" acute="" exposure="" and="" risk.="" no="" acute="" endpoint="" was="" identified="" for="" rh-117281="" technical,="" and="" therefore="" no="" acute="" risk="" assessment="" is="" required.="" b.="" chronic="" exposure="" and="" risk.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" taking="" into="" account="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" the="" percentage="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" dietary="" (food="" only)="" exposure="" to="" residues="" of="" rh-="" 117281="" technical="" from="" the="" proposed="" tolerances="" is="" 1.0%="" (tolerance="" levels)="" and="" 0.2%="" (anticipated="" residues)="" for="" children,="" 1-infants="">< 1-="" year)="" and="" 1.7%="" (tolerance="" levels)="" and="" 0.1%="" (anticipated="" residues)="" for="" children,="" 1-6="" years="" old,="" the="" most="" highly="" exposed="" subgroups.="" aggregate="" exposure="" (food="" and="" water)="" are="" expected="" to="" be="">< 2%="" rfd.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime.="" f.="" international="" tolerances="" there="" are="" currently="" no="" codex,="" canadian="" or="" mexican="" maximum="" residue="" levels="" (mrls)="" established="" for="" rh-117281="" technical="" in="" potatoes,="" potato="" chips="" or="" flakes,="" grapes="" or="" raisins.="" thus,="" no="" harmonization="" issues="" are="" required="" to="" be="" resolved="" for="" this="" action.="" g.="" rotation="" crop="" restrictions="" an="" outdoor=""> C rotation crop study was conducted, in 
    which leafy, root, and grain crops and soybeans were planted back 30, 
    137, 210, and 365 days following four applications. No individual 
    metabolite comprised greater than or equal to 0.01 ppm in any matrix.
    [FR Doc. 99-22455 Filed 8-31-99; 8:45 am]
    BILLING CODE 6560-50-F
    
    
    

Document Information

Published:
09/01/1999
Department:
Environmental Protection Agency
Entry Type:
Notice
Action:
Notice.
Document Number:
99-22455
Dates:
Comments, identified by docket control number [PF-885], must be received on or before October 1, 1999.
Pages:
47795-47806 (12 pages)
Docket Numbers:
PF-885, FRL-6096-8
PDF File:
99-22455.pdf