97-12472. Notice of Filing of Pesticide Petitions  

  • [Federal Register Volume 62, Number 92 (Tuesday, May 13, 1997)]
    [Notices]
    [Pages 26305-26313]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 97-12472]
    
    
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    ENVIRONMENTAL PROTECTION AGENCY
    
    [PF-731; FRL-5714-3]
    
    
    Notice of Filing of Pesticide Petitions
    
    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 the docket control number PF-731, must 
    be received on or before June 12, 1997.
    ADDRESSES: By mail submit written comments to: Public Information and 
    Records Integrity Branch, Information Resources and Services Division 
    (7506C), Office of Pesticides Programs, Environmental Protection 
    Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
    to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
        Comments and data may also be submitted electronically by following 
    the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
    business information should be submitted through e-mail.
        Information submitted as a comment concerning this document may be 
    claimed confidential by marking any part or all of that information as 
    ``Confidential Business Information'' (CBI). CBI should not be 
    submitted through e-mail. Information marked as CBI will not be 
    disclosed except in accordance with procedures set forth in 40 CFR part 
    2. A copy of the comment that does not contain CBI must be submitted 
    for inclusion in the public record. Information not marked confidential 
    may be disclosed publicly by EPA without prior notice. All written 
    comments will be available for public inspection in Rm. 1132 at the 
    address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
    excluding legal holidays.
    
    FOR FURTHER INFORMATION CONTACT: By mail: Philip Errico, Product 
    Manager (PM-25), Registration Division (7505C), Office of Pesticide 
    Programs, Environmental Protection Agency, 401 M St., S.W., Washington, 
    D.C. 20460.
    
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     Office Location, telephone number, and e-mail address: Rm. 241 Crystal 
    Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
    6800; e-mail: errico.phil@epamail.epa.gov.
    SUPPLEMENTARY INFORMATION: 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 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 grantinig of 
    the petition. Additional data may be needed before EPA rules on the 
    petition.
        The official record for this notice of filing, as well as the 
    public version, has been established for this notice of filing under 
    docket control number [PF-731] (including comments and data submitted 
    electronically as described below). A public version of this record, 
    including printed, paper versions of electronic comments, which does 
    not include any information claimed as CBI, is available for inspection 
    from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
    holidays. The official record is located at the address in 
    ``ADDRESSES'' at the beginning of this document.
        Electronic comments can be sent directly to EPA at:
        opp-docket@epamail.epa.gov
    
    
        Electronic comments must be submitted as an ASCII file avoiding the 
    use of special characters and any form of encryption. Comment and data 
    will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
    file format. All comments and data in electronic form must be 
    identified by the docket number (insert docket number) and appropriate 
    petition number. Electronic comments on this proposed rule may be filed 
    online at many Federal Depository Libraries.
    
    List of Subjects
    
        Environmental protection, Agricultural commodities, Food additives, 
    Feed additives, Pesticides and pests, Reporting and recordkeeping 
    requirements.
    
        Dated: April 30, 1997.
    
    James Jones,
    
    Acting Director, Registration Division, Office of Pesticide Programs.
    
    Summaries of Petitions
    
        Petitioner summaries of the pesticide petitions are printed below 
    as required by section 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. DowElanco
    
    PP 4F4412
    
        EPA has received a pesticide petition (PP 4F4412) from DowElanco 
    9330 Zionsville Road Indianapolis, IN 46254 proposing pursuant to 
    section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 
    346a(d), to amend 40 CFR part 180 by establishing a tolerance for 
    inadvertent residues of the herbicide picloram in or on the raw 
    agricultural commodity grain sorghum grain, forage, and stover at 0.3, 
    0.2, and 0.5 ppm, respectively. The proposed analytical method is ACR 
    73.3.S2. Pursuant to the sect 408(d)(2)(A)(i) of the FFDCA, as amended, 
    Company has submitted the following summary of information, data and 
    arguments in support of their pesticide petition. This summary was 
    prepared by DowElanco and EPA has not fully evaluated the merits of the 
    petition. EPA edited the summary to clarify that the conclusions and 
    arguments were the petitioner's and not necessarily EPA's and to remove 
    certain extraneous material.
        Picloram provides control of deep rooted perennial weeds either in 
    grainland, fallowland or on CRP acres. With the addition of the 
    proposed tolerance, grain sorghum could be considered as a rotational 
    crop option for the producer. The Agency has completed the 
    reregistration review of picloram, culminating in publication of the 
    Reregistration Eligibility Decision (RED) for picloram which was 
    received on October 5, 1995. The RED concludes that picloram and its 
    derivatives can be used without causing unreasonable adverse effects to 
    humans or the environment. Therefore, all uses of products containing 
    picloram acid and its derivatives were judged eligible for 
    reregistration. In view of this comprehensive regulatory review, as 
    well as the lack of human dietary consumption of grain sorghum and the 
    negligible dietary impact on livestock associated with this proposed 
    use, establishment of these tolerances will not cause exposure to 
    exceed the levels at which there is an appreciable risk.
    
    A. Residue Chemistry
    
        1. Plant metabolism. The qualitative nature of the residue in 
    plants is understood based on a wheat metabolism study. The residue of 
    concern in wheat forage, straw and grain is conjugated picloram, which 
    is hydrolyzable by acid, base and B-glucosidase. The minor metabolites 
    that were identified in grain and straw were 4-amino-6-hydroxy-3,5-
    dichloropicolinic acid and 4-amino-2,3,5-trichloropyridine.
        2. Analytical method. The analytical portions of the magnitude of 
    residue studies were performed at DowElanco in Midland, MI. The 
    analytical method utilized for the determination of picloram residue 
    levels in the submitted studies was ACR 73.3.S2. There is a practical 
    analytical method for detecting and measuring levels of picloram in or 
    on food with a limit of quantitation that allows monitoring of food 
    with residues at or above the levels set in these tolerances. EPA has 
    provided information on this method to FDA. The method is available to 
    anyone who is interested in pesticide residue enforcement.
        3. Magnitude of residues.
    
      Table --Summary Of Residues Of Picloram (ppm) Found In Grain Sorghum  
    ------------------------------------------------------------------------
                      Matrix                                Range           
    ------------------------------------------------------------------------
    Grain                                       NDa0.23                     
    Forage                                      ND-0.17                     
    Fodder                                      ND-0.44                     
    ------------------------------------------------------------------------
    aND = less than one-half of the validated lower limit of quantitation of
      0.05 g/g in grain and 0.1 g/g in forage and fodder. 
    
    B. Toxicological Profile
    
        1. Acute toxicity. Studies for acute toxicity indicate that 
    picloram is classified as category III for acute oral toxicity, 
    category III for acute dermal toxicity, category I/II (depending on 
    whether acid or salts) for acute inhalation toxicity, category IV for 
    skin irritation potential, and category III for eye irritation 
    potential. The potassium salt is classified as a skin sensitizer. In 
    addition, picloram has a low vapor pressure.
        Picloram potassium salt has low acute toxicity. The rat oral 
    LD50 is 3,536
    
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    milligrams per kilogram (mg/kg) or greater for males and females. The 
    rabbit dermal LD50 is >2,000 mg/kg and the rat inhalation 
    LC50 is >1.63 mg/L air (the highest attainable 
    concentration). Picloram potassium salt is a positive skin sensitizer 
    in guinea pigs but is not a dermal irritant. Technical picloram 
    potassium salt is a moderate ocular irritant but ocular exposure to the 
    technical material would not normally be expected to occur to infants 
    or children or the general public. End use formulations of picloram 
    have similar low acute toxicity profiles plus low ocular toxicity as 
    well. Therefore based on the available acute toxicity data, picloram 
    does not pose any acute dietary risks.
        2. Genotoxicity. Picloram acid was evaluated in the Ames test using 
    Salmonella typhimurium. Doses ranged up to 5,000 ug/plate, with and 
    without metabolic activation. The test substance did not produce a 
    mutagenic response either in the presence or absence of activation.
        Picloram acid was evaluated for gene mutation in mammalian cells 
    (HGPRT/CHO). As evaluated up to toxic levels (750 ug/ml without 
    metabolic activation; 1,250 ug/ml with metabolic activation), the 
    compound was found to be negative for inducing forward mutation in 
    Chinese hamster ovary (CHO) cells.
        Picloram acid was evaluated for cytogenetic effects on bone marrow 
    cells of rats via intragastric administration at dosage levels of 0 
    (vehicle), 20, 200 or 2,000 mg/kg. The test material did not produce 
    cytogenetic effects in the study.
        Picloram acid was evaluated for genotoxic potential as administered 
    to primary rat hepatocyte cultures at concentrations of 0 (vehicle), 
    10, 33.3, 100, 333.3 or 1,000 ug/ml. The test material was negative for 
    unscheduled DNA synthesis (UDS, a measure of DNA damage/repair) treated 
    up to cytotoxic levels of (1,000 ug/ml).
        3. Reproductive and developmental toxicity. The HED RfD Peer Review 
    Committee concluded that there was no evidence, based on the available 
    data, that picloram and its salts were associated with significant 
    reproductive or developmental toxicity under the testing conditions.
        In the following developmental toxicity studies, the dose levels 
    that appear in parenthesis are picloram acid equivalents where the 
    conversion factor employed was 0.86 as applied to doses of potassium 
    salt.
        Picloram potassium salt was administered to New Zealand rabbits by 
    oral Savage at dosage levels of 0, 40, 200 and 400 milligram per 
    kilogram per day (mg/kg/day) (picloram acid equivalents) during days 6 
    to 18 of gestation. The maternal NOEL is 40 (34) mg/kg/day, where the 
    LOEL is 200 (172) mg/kg/day based on reduced maternal weight gain 
    during gestation. The developmental NOEL is 400 mg/kg/day and the LOEL 
    was not determined.
        The potassium salt of picloram was administered to CD rats by 
    gastric intubation at dosage levels of 0, 35 (30), 174 (150) and 347 
    (298) mg/kg/day during day 6-15 of gestation: The test vehicle was 
    distilled water. There was no evidence of developmental toxicity at 
    doses up to and including the high dose of 347 (298) mg/kg/day. The 
    maternal LOEL is 347 (298) mg/kg/day based upon excessive salivation in 
    the dams of the high dose group. Hence, the developmental toxicity NOEL 
    is greater than or equal to 347 (298) mg/kg/day. The maternal toxicity 
    LOEL is 347 (298) mg/kg/day and NOEL is 174 (150) mg/kg/day.
        Picloram acid was evaluated in a 2-generation reproduction study in 
    the CD rat. Dosage levels employed were 0, 20, 200 or 1,000 mg/kg/day. 
    The parental LOEL is 1,000 mg/kg/day based on histopathological lesions 
    in the kidney of males of both generations and some females. In males 
    of both generations, blood in the urine, decreased urine specific 
    gravity, increased absolute and relative kidney weight, and increased 
    body weight gain was observed at the high dose. The parental LOEL is 
    1,000 mg/kg/day and the NOEL is 200 mg/kg/day. The reproductive LOEL 
    was not identified and the NOEL is 1,000 mg/kg/day.
        4. Subchronic toxicity. In a 90-day oral toxicity study, picloram 
    acid was administered via the diet to groups of 15 F344 rats/sex/dose 
    at dosage levels of 0, 15, 50, 150, 300 or 500 mg/kg/day. Based upon 
    liver weight changes and minimal microscopic changes in the liver, the 
    systemic LOEL is 150 mg/kg/day. The NOEL is 50 mg/kg/day.
        In a 1982 6-month dog dietary study, picloram acid was evaluated at 
    dosage levels of 0, 7, 35 or 175 mg/kg/day. The systemic NOEL is 35 mg/
    kg/day and the LOEL is 175 mg/kg/day based on decreases in the 
    following: body weight gain, food consumption, liver weights 
    (relative), alkaline phosphatase and alanine transaminase. Increased 
    liver to body weight ratios and absolute weights were observed in only 
    two males at the 35 mg/kg/day dosage level.
        In a 21-day dermal toxicity study, the potassium salt of picloram 
    was administered dermally to groups of five New Zealand white rabbits 
    of each sex at doses of 0 (vehicle control), 75.3, 251 or 753 mg/kg/day 
    (O. 65, 217 or 650 mg/kg/day picloram acid equivalents) for a total of 
    15 applications over the 21-day period. The NOEL is greater than or 
    equal to 753 mg/kg/day for both sexes: hence, a LOEL was not 
    established for either sex. Although the limit dose of 1,000 mg/kg/day 
    was not achieved, practical difficulties precluded administering more 
    test material. The study revealed the non-systemic effects of dermal 
    irritation and very slight to well defined edema and/or erythema in 
    both sexes at all dose levels.
        5. Chronic toxicity. In a 1988 1-year chronic feeding study in the 
    dog, picloram acid was administered orally via the diet at dosage 
    levels of 0, 7, 35 or 175 mg/kg/day The LOEL is 175 mg/kg/day based on 
    increased liver weight (absolute and relative). The NOEL is 35 mg/kg/
    day.
        In a chronic toxicity/carcinogenicity feeding study conducted in 
    the F344 rat, picloram acid (technical grade 93% containing 197 ppm 
    hexachlorobenzene as an impurity) was evaluated at 0, 20, 60 or 200 mg/
    kg/day for 2 years. The chronic toxicity LOEL was 60 mg/kg/day as 
    evidenced by altered size and tinctorial properties of centrilobular 
    hepatocytes and increased absolute and/or relative liver weights in 
    both sexes. The NOEL was 20 mg/kg/day. The study was negative for 
    carcinogenicity, but due to concerns that a MTD may not have been 
    achieved and the fact that the test material contained 197 ppm 
    hexachlorobenzene impurity, the study was not considered to fulfill 
    adequately the carcinogenicity testing requirement.
        In response to the deficiencies cited in the study above, an 
    additional 2-year dietary chronic/carcinogenicity study was conducted 
    (in 1992) using F344 rats administered picloram acid at dosage levels 
    of 0, 250 or 500 mg/kg/day for 104 weeks. Chronic toxicity was observed 
    at 250 mg/kg/day among males only (increased incidence and severity of 
    glomerulonephritis, blood in urine, decreased specific gravity of 
    urine, increased size of hepatocytes that often had altered staining 
    properties). Among females there were chronic effects only at 500 mg/
    kg/day (increased glomerulonephropathy, increased absolute and relative 
    kidney weight). There was no evidence of carcinogenicity in this study. 
    It should be noted that use of the Osborne-Mendel rat was waived due to 
    lack of availability of the strain of rat. In addition, the level of 
    hexachlorobenzene in the test material employed in this study was 12 
    ppm. These two studies fulfill the guidelines 83-l(a) and 83-2(a) for 
    rats.
        In a 1992 2-year dietary carcinogenicity study in B6C3F1 mice,
    
    [[Page 26308]]
    
    picloram acid was evaluated at doses of 0, 100, 500 or 1,000 mg/kg/day. 
    The systemic NOEL in this study is 500 mg/kg/day based on a significant 
    increase in absolute and relative kidney weights in males (at the high 
    dose level). No histopathological lesions were found to corroborate 
    these changes. There was no evidence of carcinogenicity.
        The dose levels tested in the 1992 carcinogenicity studies in rats 
    and mice were considered adequate for carcinogenicity testing. The 
    treatment did not alter the spontaneous tumor profile in mice or 
    different strains of rats tested under the testing conditions. The 
    chemical was classified as a ``Group E - Evidence of Non-
    Carcinogenicity for humans.'' This classification applies to the 
    picloram acid and potassium salt forms for which acceptable 
    carcinogenicity studies were available for review by the HED 
    Carcinogenicity Peer Review Committee (5/26/88).
        Using its Guidelines for Carcinogen Risk Assessment published 
    September 24, 1986 (51 FR 33992), picloram is classified as Group ``E'' 
    for carcinogenicity (no evidence of carcinogenicity) based on the 
    results of the carcinogenicity studies. The dose levels tested in the 
    1992 carcinogenicity studies in rats and mice were considered adequate 
    for carcinogenicity testing. The treatment did not alter the 
    spontaneous tumor profile in mice or different strains of rats tested 
    under the testing conditions. The chemical was classified as a ``Group 
    E - Evidence of Non-Carcinogenicity for humans.'' This classification 
    applies to the picloram acid and potassium salt forms for which 
    acceptable carcinogenicity studies were available for review by the HED 
    Carcinogenicity Peer Review Committee (5/26/88). Thus, a cancer risk 
    assessment would not be appropriate.
        6. Animal metabolism. The absorption, distribution, metabolism and 
    excretion of picloram acid was evaluated in female rats administered a 
    single i.v. or oral gavage dose of 10 mg/kg, an oral gavage dose of 
    1,000 mg/kg 14C-picloram, or 1 mg/kg/day unlabeled picloram 
    by gavage for 14 days followed by a single oral gavage dose of 10 mg/kg 
    14C-picloram on day 15. The study demonstrates that 
    14C-picloram is rapidly absorbed, distributed and excreted 
    following oral and i.v. administration. This study alone is not 
    adequate; however, this study is acceptable when considered in 
    conjunction with a male rat metabolism study which yielded similar 
    results.
    
    C. Aggregate Exposure
    
        1. Dietary exposure-- i. Food. For purposes of assessing the 
    potential dietary exposure under these tolerances, aggregate exposure 
    is estimated based on the TMRC from the existing and future potential 
    tolerances for picloram on food crops. The TMRC is obtained by 
    multiplying the tolerance level residues (existing and proposed) by the 
    consumption data which estimates the amount of those food products 
    eaten by various population subgroups. Exposure of humans to residues 
    could also result if such residues are transferred to meat, milk, 
    poultry or eggs. The following assumptions were used in conducting this 
    exposure assessment: 100% of the crops were treated, the RAC residues 
    would be at the level of the tolerance, and certain processed food 
    residues would be at anticipated (average) levels based on processing 
    studies (see attached Dietary Risk Evaluation for Picloram). This 
    results in an overestimate of human exposure and a conservative 
    assessment of risk. As mentioned previously, 0.9% of the RfD is 
    utilized using these assumptions.
        The chronic dietary exposure/risk estimates for picloram are 
    extremely low. For the United States population as a whole, the 
    Theoretical Maximum Residue Contribution (TMRC) is 0.001845 milligrams 
    per kilogram of body weight per day (mg/kg bw/day), only 0.9% of the 
    RfD. For this same group, the Anticipated Residue Contribution (ARC) is 
    0.001053 mg/kg bw/day, only 0.5% of the RfD. The subgroup with the 
    greatest routine chronic exposure/risk is non-nursing infants (less 
    than 1 year old), which has a TMRC of 0.004753 mg/kg bw/day (2.4% of 
    the RfD) and an ARC of 0.003805 mg/kg bw/day (1.9% of the RfD).
        There is currently no form of sorghum observed in human consumption 
    surveys utilized by EPA in their DRES assessments. Therefore, sorghum 
    tolerances will have no effect on the human dietary consumption of 
    picloram, and the proposed action, as well as existing tolerances, pose 
    no concern with regards to chronic dietary exposure to food residues of 
    picloram.
        ii. Drinking water. An additional potential source of dietary 
    exposure to residues of pesticides are residues in drinking water. The 
    Maximum Contaminant Level for residues of picloram in drinking water 
    has been established at 500 g/L and a 1-10 day Health Advisory 
    of 20,000 g/L. Monitoring data available from the Pesticides 
    in Ground Water Database indicate that picloram has been detected in 
    ground water at concentrations ranging up to 30 g/L. Results 
    reported in this database typically were focused on highly vulnerable 
    areas and in many cases, the database reports information from poorly 
    constructed or damaged wells. These wells are at high risk because of 
    the potential for surface residues to be carried directly down the 
    casing into the ground water. Recognizing these high risk situations, 
    an analysis of this database shows that less than 3% of the wells 
    sampled were found to contain picloram. No distinction has been made 
    between point and non point sources of material. Many of the 
    detection's are known to be related to point source contamination 
    including spills at mixing/loading sites, near wells and back siphoning 
    events. Of the detection's which may have resulted from non-point 
    sources, none are documented to occur on sites where application would 
    be recommended based on current labeling. Nearly 99% of the ground 
    water detection's are at levels of less than 1% of the Maximum 
    Contaminant Level ( i.e., < 5="">g/L) established for human 
    consumption by the EPA Office of Drinking Water. The STORET database 
    maintained by the USEPA Office of Drinking Water indicates that 
    picloram has been reported in surface water samples before 1988. Of 
    these detections, 85% were at concentrations 0.13 g/L or lower 
    and the maximum was 4.6 g/L. The maximum concentration 
    reported was 4.6 g/L.
        The impact of potential residues of picloram in drinking water on 
    the aggregate risk of the herbicide is minimal. If it is assumed that 
    all of the drinking water in the U.S. contains 30 g/L of 
    picloram, the maximum observed in the groundwater data base, its 
    contribution to the TMRC would be 0.000280 mg/kg bw/day for the general 
    U.S. population, or 0.14% of the RfD. For the most sensitive population 
    subgroup, Non-nursing Infants (<1 yr.="" old),="" the="" contribution="" to="" the="" tmrc="" would="" be="" 0.002855="" mg/kg="" bw/day,="" or="" 1.4%="" of="" the="" rfd.="" in="" reality,="" the="" likelihood="" of="" drinking="" water="" being="" contaminated="" with="" picloram="" is="" extremely="" remote,="" and="" actual="" contribution="" to="" the="" dietary="" exposure="" of="" picloram="" is="" virtually="" nil.="" in="" summary,="" these="" data="" on="" potential="" water="" exposure="" indicate="" insignificant="" additional="" dietary="" intake="" and="" risk="" for="" picloram.="" 2.="" non-dietary="" exposure.="" this="" is="" a="" restricted="" use="" chemical="" that="" has="" no="" residential="" uses="" at="" this="" time;="" therefore,="" there="" are="" no="" human="" risks="" associated="" with="" residential="" uses.="" entry="" into="" a="" treated="" area="" soon="" after="" the="" application="" of="" picloram="" is="" expected="" to="" be="" rare="" given="" the="" cultural="" practices="" typically="" associated="" with="" the="" use-sites="" (rights-of-way,="" forestry,="" pastures,="" range="" [[page="" 26309]]="" lands,="" and="" small="" grains)="" defined="" by="" the="" picloram="" labels="" at="" this="" time.="" furthermore,="" if="" entry="" should="" occur,="" the="" potential="" exposures="" are="" expected="" to="" be="" minimal="" due="" to="" the="" characteristics="" of="" those="" use-sites="" d.="" cumulative="" effects="" the="" potential="" for="" cumulative="" effects="" of="" picloram="" and="" other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity="" was="" considered.="" the="" mammalian="" toxicity="" of="" picloram="" is="" well="" defined.="" however,="" the="" biochemical="" mechanism="" of="" toxicity="" of="" this="" compound="" is="" not="" well="" known.="" no="" reliable="" information="" exists="" to="" indicate="" that="" toxic="" effects="" produced="" by="" picloram="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemical="" compounds.="" therefore,="" consideration="" of="" a="" common="" mechanism="" of="" toxicity="" with="" other="" compounds="" is="" not="" appropriate.="" thus="" only="" the="" potential="" risks="" of="" picloram="" are="" considered="" in="" the="" aggregate="" exposure="" assessment.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" in="" the="" meeting="" of="" september="" 30,="" 1993,="" the="" opp="" rfd="" peer="" review="" committee="" recommended="" that="" the="" rfd="" for="" this="" chemical="" be="" based="" on="" a="" noel="" of="" 20="" mg/kg/day="" for="" a="" dose-related="" increase="" in="" size="" and="" altered="" tinctorial="" properties="" of="" centrilobular="" hepatocytes="" in="" males="" and="" females="" at="" 60="" and="" 200="" mg/kg/day="" in="" a="" chronic="" toxicity="" study="" in="" rats.="" an="" uncertainty="" factor="" (uf)="" of="" 100="" was="" used="" to="" account="" for="" the="" inter-="" species="" extrapolation="" and="" intra-species="" variability.="" on="" this="" basis,="" the="" rfd="" was="" calculated="" to="" be="" 0.20="" mg/kg/day.="" the="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" from="" existing="" tolerances="" is="" 0.001845="" mg/kg/="" day.="" existing="" tolerances="" utilize="" 0.9%="" of="" the="" rfd.="" it="" should="" be="" noted="" that="" no="" regulatory="" value="" has="" been="" established="" for="" this="" chemical="" by="" the="" world="" health="" organization="" (who)="" up="" to="" this="" date.="" the="" committee="" classified="" picloram="" as="" a="" ``group="" e''="" chemical,="" no="" evidence="" of="" carcinogenicity="" for="" humans.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" it="" is="" concluded="" that="" aggregate="" exposure="" to="" picloram="" will="" utilize="" approximately="" 1="" percent="" of="" the="" rfd="" for="" the="" u.s.="" population.="" generally,="" exposures="" below="" 100="" percent="" of="" the="" rfd="" are="" of="" no="" concern="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risk="" to="" human="" health.="" thus,="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" picloram="" residues.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" picloram,="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit="" and="" a="" 2-generation="" reproduction="" study="" in="" the="" rat="" were="" considered.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" during="" prenatal="" development="" resulting="" from="" pesticide="" exposure="" to="" one="" or="" both="" parents.="" reproduction="" studies="" provide:="" (1)="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" (2)="" data="" on="" systemic="" toxicity.="" developmental="" toxicity="" was="" studied="" using="" rats="" and="" rabbits.="" the="" developmental="" study="" in="" rats="" resulted="" in="" a="" developmental="" noel="" of="">298 
    mg/kg/day and a maternal toxicity NOEL of 280 mg/kg/day. A study in 
    rabbits resulted in a maternal NOEL of 34 mg/kg/day and a developmental 
    NOEL of 344 mg/kg/day. Based on all of the data for picloram, there is 
    no evidence of developmental toxicity at dose levels that do not result 
    in maternal toxicity.
        In a 2-generation reproduction study in rats, The NOEL for parental 
    systemic toxicity is 200 mg/kg/day. There was no effect on reproductive 
    parameters at 1,000 mg/kg/day nor was there an adverse effect on the 
    morphology, growth or viability of the offspring; thus, the 
    reproductive NOEL is 1,000 mg/kg/day.
        FFDCA section 408 provides that EPA may apply an additional safety 
    factor for infants and children in the case of threshold effects to 
    account for pre- and post-natal toxicity and the completeness of the 
    database. Based on the current toxicological data requirements, the 
    database relative to pre- and post-natal effects for children is 
    complete. Therefore, it is concluded that an additional uncertainty 
    factor is not warranted and that the RfD at 0.2 mg/kg/day is 
    appropriate for assessing aggregate risk to infants and children.
        Using the conservative exposure assumption previously described, it 
    is concluded that the percent of the RfD that will be utilized by 
    aggregate exposure to residues of picloram will be less than 4 percent 
    of the RfD for all populations and subgroups. Since this estimate 
    represents the ``worst case'' exposure for a given population (non-
    nursing infants, <1 year="" old),="" exposures="" will="" be="" less="" for="" all="" other="" sub-populations="" e.g.="" children,="" 1-6="" years.="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" it="" is="" concluded="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" picloram="" residues.="" other="" considerations="" f.="" international="" tolerances="" there="" are="" no="" codex="" maximum="" residue="" levels="" established="" for="" residues="" of="" picloram.="" 1.="" endocrine="" effects.="" an="" evaluation="" of="" the="" potential="" effects="" on="" the="" endocrine="" systems="" of="" mammals="" has="" not="" been="" determined;="" however,="" no="" evidence="" of="" such="" effects="" were="" reported="" in="" the="" chronic="" or="" reproductive="" toxicology="" studies="" described="" above.="" there="" was="" no="" observed="" pathology="" of="" the="" endocrine="" organs="" in="" these="" studies.="" there="" is="" no="" evidence="" at="" this="" time="" that="" picloram="" causes="" endocrine="" effects.="" 2.="" data="" gaps.="" data="" gaps="" currently="" exist="" for="" residue="" data="" for="" sorghum="" aspirated="" grain="" fractions.="" based="" on="" the="" toxicological="" data="" and="" the="" levels="" of="" exposure,="" epa="" has="" determined="" that="" the="" proposed="" tolerances="" will="" be="" safe.="" 2.="" novartis="" crop="" protection="" pp="" 6f4688="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 6f4688)="" from="" novartis="" crop="" protection,="" inc.,="" p.="" o.="" box="" 18300,="" greensboro,="" north="" carolina="" 27419,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act,="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" residues="" of="" the="" herbicide="" cga-277476,="" benzoic="" acid,="" 2-[[[[4,6-dimethyl-2-pyrimidinyl)-="" amino]carbonyl]amino]sulfonyl]-,3-oxetanylester="" in="" or="" on="" the="" raw="" agricultural="" commodity="" soybeans="" at="" 0.01="" ppm.="" the="" proposed="" analytical="" method="" involves="" homogenization,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" high="" performance="" liquid="" chromatography="" using="" uv="" detection.="" 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.="" as="" required="" by="" section="" 408(d)="" of="" the="" ffdca,="" as="" recently="" amended="" by="" the="" food="" quality="" protection="" act="" (fqpa)="" pub.l.="" 104-170,="" novartis="" crop="" protection="" included="" in="" the="" petition="" a="" summary="" of="" the="" petition="" and="" authorization="" for="" the="" summary="" to="" be="" published="" in="" the="" federal="" register="" in="" a="" notice="" of="" receipt="" of="" the="" petition.="" the="" summary="" represents="" the="" views="" of="" novartis="" crop="" protection.="" epa="" is="" in="" the="" process="" of="" evaluating="" the="" petition.="" as="" [[page="" 26310]]="" required="" by="" section="" 408(d)(3)="" of="" the="" ffdca,="" epa="" is="" including="" the="" summary="" as="" a="" part="" of="" this="" notice="" of="" filing.="" epa="" has="" made="" minor="" edits="" to="" the="" summary="" for="" the="" purpose="" of="" clarity.="" a.="" metabolism="" the="" qualitative="" nature="" of="" the="" metabolism="" of="" cga-277476="" in="" plants="" and="" animals="" is="" well="" understood="" for="" the="" purposes="" of="" the="" proposed="" tolerance.="" metabolism="" proceeds="" through="" hydrolysis="" of="" the="" oxetane="" ring="" with="" subsequent="" cleavage="" of="" the="" oxetane="" ester="" and="" the="" sulfonylurea="" bridge.="" metabolic="" pathways="" in="" plants="" (soybeans),="" rats,="" ruminants="" (goats),="" and="" poultry="" are="" similar.="" parent="" cga-277476="" is="" the="" residue="" of="" concern.="" b.="" analytical="" methodology="" novartis="" crop="" protection,="" inc.="" has="" submitted="" a="" practical="" analytical="" method="" involving="" homogenization,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" high="" performance="" liquid="" chromatography="" using="" uv="" detection.="" the="" methodology="" accounts="" for="" residues="" of="" cga-277476.="" the="" limit="" of="" quantitation="" (loq)="" for="" the="" method="" is="" 0.01="" ppm="" for="" cga-277476.="" this="" method="" has="" undergone="" a="" successful="" method="" trial="" and="" is="" available="" for="" enforcement.="" c.="" residue="" twenty="" field="" trials="" were="" conducted="" in="" typical="" soybean="" growing="" areas="" across="" the="" u.s.="" either="" a="" single="" preplant="" or="" preemergence="" application="" (57="" grams="" ai/a)="" or="" a="" split="" application="" made="" preemergence="" followed="" by="" a="" post="" broadcast="" application="" (total="" of="" 81="" grams="" ai/a)="" was="" made.="" no="" residues=""><0.01 ppm)="" were="" found="" in="" the="" dry="" beans="" (1x)="" and="" no="" residues="" were="" found="" in="" the="" processed="" commodities="" at="" rates="" up="" to="" 5x.="" no="" residues=""><0.01 ppm)="" were="" found="" in="" rotational="" crops="" treated="" at="" the="" 1x="" rate.="" a="" prohibition="" against="" grazing="" forage,="" hay="" and="" silage="" will="" be="" placed="" in="" the="" label,="" as="" will="" a="" 60="" day="" preharvest="" interval.="" d.="" international="" mrl's="" there="" are="" no="" codex="" alimentarius="" commission="" (codex)="" maximum="" residue="" levels="" (mrl's)="" established="" for="" residues="" of="" cga-277476="" in="" or="" on="" raw="" agricultural="" commodities.="" e.="" toxicological="" profile="" 1.="" acute="" toxicity.="" cga-277476="" has="" a="" low="" order="" of="" acute="" toxicity.="" the="" rat="" oral="">50 is > 5,000 mg/kg, the acute rabbit dermal 
    LD50 is > 2,000 mg/kg and the rat inhalation LC50 
    is > 5.08 mg/L. CGA 277476 is moderately irritating to the skin but not 
    irritating to the eye. It is not a skin sensitizer in guinea pigs. The 
    commercial formulation (75WG) of CGA-277476 has a similar acute 
    toxicity profile, with both technical and formulated product carrying a 
    Category III CAUTION Signal Word.
        2. Genotoxicity. Assays for genotoxicity were comprised of tests 
    evaluating the potential of CGA-277476 to induce point mutations 
    (Salmonella assay and a Chinese hamster V79 lung tissue assay), 
    chromosome aberrations (mouse micronucleus and a Chinese hamster ovary 
    study) and the ability to induce either scheduled or unscheduled DNA 
    synthesis in rat hepatocytes. The results indicate that CGA-277476 is 
    not mutagenic or clastogenic and does not induce unscheduled DNA 
    synthesis.
        3. Developmental/reproductive effects. The developmental and 
    teratogenic potential of CGA-277476 was investigated in rats and 
    rabbits. The results indicate that CGA-277476 was not maternally or 
    developmentally toxic in the rabbit. Minimal developmental toxicity was 
    observed at the limit dose (1,000 mg/kg) in the rat; the developmental 
    no observed effect level in the rat was 300 mg/kg/day. No evidence of 
    teratogenicity was observed at the limit dose of 1,000 mg/kg in either 
    the rat or rabbit.
        A 2-generation reproduction study was conducted with CGA-277476 at 
    feeding levels of 0, 20, 200, 5,000 or 20,000 ppm (0, 1, 10, 250 or 
    1,000 mg/kg/day). The reproductive NOEL was established at a feeding 
    level of 5,000 ppm (equivalent to approximately 250 mg/kg/day). Reduced 
    fertility observed at the highest dose tested (20,000 ppm) was 
    associated with degenerative changes in the seminiferous tubules and 
    atypical spematogenesis in males and severe effects on kidneys in 
    females. The NOEL for parental toxicity was established at the 200 ppm 
    feeding level based on slight effects on body weight parameters at the 
    next highest dose tested (i.e. 5,000 ppm).
        4. Subchronic toxicity. The subchronic toxicity of CGA-277476 was 
    evaluated in studies in the rat, mouse and dog at high doses. Target 
    organs included the liver, spleen, blood, kidney, urogenital tract, 
    testes, epididymis and peripheral nerves and muscles. No observable 
    effect levels have been established for all end-points in subchronic 
    studies. The dog appears to be the most sensitive species (NOEL = 40 
    ppm; 1 mg/kg) with treatment related effects on testes, peripheral 
    nerve and muscle appearing at doses  5,000 ppm ( 125 mg/kg/
    day).
        5. Chronic effects. The chronic toxicity of CGA-277476 was 
    investigated in long term studies in the rat, mouse and dog. Target 
    organs included the central and peripheral nervous systems, skeletal 
    muscle, liver, kidney, gallbladder, testes, and blood. No observed 
    effect levels (NOELS) have been established in each study. The dog is 
    the most sensitive species with a NOEL = 40 ppm (1.3 mg/kg/day). Based 
    on these data, it is expected the EPA will establish a RfD for CGA-
    277476 at 0.01 mg/kg/day using the NOEL of 1.3 mg/kg/day and an 
    uncertainty factor of 100.
        6. Carcinogenicity. The carcinogenicity studies conducted with CGA- 
    277476 showed no evidence of an oncogenic response in either mouse or 
    rat at doses that did not exceed the maximum tolerated dose. Dose 
    levels in the mouse study were 2.25, 150, 525, and 1,050 mg/kg/day. In 
    the rat study, dose levels were 1, 10, 100, 500, 750 (females), and 
    1,000 (males) mg/kg/day. At the end of the chronic rat study, a 
    statistically significant increased incidence of schwannomas was found 
    in the heart of the 1,000 mg/kg/day male rats (7/59) compared to the 
    control group (0/60). Based on the Guidelines for Carcinogenic Risk 
    Assessment published by EPA September 24, 1986 (51 FR 33992), Novartis 
    Crop Protection believes that CGA-277476 should be classified as Class 
    E because the neoplastic response (marginal increased incidence of 
    schwannomas) was observed only in male rats at a dose exceeding the 
    maximum tolerated dose of 500 mg/kg/day. No effect was observed at 
    doses  500 mg/kg/day.
    
    F. Threshold Effects
    
        1. Chronic effects. Based on the available chronic toxicity data, 
    it is expected the EPA will establish a RfD for CGA-277476 at 0.01 mg/
    kg/day based on the results obtained in the 1-year feeding study in 
    dogs using the No-Observed Effect Level (NOEL) of 1.3 mg/kg/day and an 
    uncertainty factor of 100.
        2. Acute toxicity. Based on the available acute toxicity data, 
    Novartis Crop Protection believes CGA-277476 does not pose any acute 
    dietary risks.
    
    G. Nonthreshold Effects.
    
         Carcinogenicity. Based on the Guidelines for Carcinogenic Risk 
    Assessment published by EPA September 24, 1986 (51 FR 33992), Novartis 
    Crop Protection believes that CGA-277476 should be classified as Class 
    E because the neoplastic response (marginal increased incidence of 
    schwannomas) was observed only in male rats at a dose exceeding the 
    maximum tolerated dose of 500 mg/kg/day. No effect was observed at 
    doses  500 mg/kg/day.
    
    [[Page 26311]]
    
    H. Endocrine Effects.
    
        CGA-277476 belongs to the sulfonylurea class of chemicals, one not 
    known or suspected of having adverse effects on the endocrine system. 
    Reduced fertility observed in high dose females (20,000 ppm) in the rat 
    reproduction study was associated with degenerative changes in the 
    seminiferous tubules and a typical spermatogenesis observed in high 
    dose males. Evidence of impaired spermatogenesis was also observed at 
    high doses ( 125 mg/kg/day) in the subchronic dog study.
    
    I. Aggregate Exposure
    
        1. Dietary exposure. For purposes of assessing the potential 
    dietary exposure to CGA-277476, Novartis Crop Protection has estimated 
    aggregate exposure based on the Theoretical Maximum Residue 
    Contribution from the use of CGA-277476 in or on raw agricultural 
    commodities for which tolerances have been proposed (0.01 ppm on 
    soybeans). In conducting this exposure assessment, Novartis has 
    conservatively assumed that 100% of soybeans will contain CGA-277476 
    residues at the proposed level of 0.01 ppm. No residues are anticipated 
    in animal commodities and therefore, tolerances in meat, meat 
    byproducts, milk, poultry and eggs are not proposed.
        2. Drinking water exposure. Another potential source of exposure of 
    the general population to residues of pesticides are residues in 
    drinking water. The potential for CGA-277476 to enter surface or ground 
    water sources of drinking water is limited because of the low use rate. 
    This is supported by the results of two small-scale prospective ground 
    water monitoring studies which did not show any quantifiable residues 
    of CGA-277476 in ground water samples. The Maximum Contaminant Level 
    Guideline (MCLG) calculated for CGA-277476 according to EPA's procedure 
    leads to an exposure value (7 ppb) substantially greater than any level 
    expected to reach ground water based on study results.
        3. Non-occupational exposure. Novartis Crop Protection has 
    evaluated the estimated non-occupational exposure to CGA-277476 and 
    concludes that the potential for non-occupational exposure to the 
    general population is unlikely because CGA-277476 is not planned to be 
    used in or around the home, including home lawns, schools, recreation 
    facilities or parks.
    
    J. Cumulative Risk.
    
        Novartis Crop Protection has also considered the potential for 
    cumulative effects of CGA-277476 and other chemicals belonging to this 
    chemical class (sulfonylureas) that may have a common mechanism of 
    toxicity. It is concluded that consideration of a common mechanism of 
    toxicity is not appropriate at this time because there is no reliable 
    data to establish whether a common mechanism exists.
    
    K. Safety Determinations.
    
        1. U.S. general population. Using the conservative exposure 
    assumptions described above, based on the completeness and reliability 
    of the toxicity data, Novartis Crop Protection has concluded that 
    aggregate exposure to CGA-277476 will utilize 0.07 percent of the RfD 
    for the U.S. population based on chronic toxicity endpoints. Because 
    EPA generally has no concern for exposures below 100 percent of the 
    RfD, it is concluded that there is a reasonable certainty that no harm 
    to the general population will result from aggregate exposure to CGA-
    277476.
        2. Infants and children. In assessing the potential for additional 
    sensitivity of infants and children to residues of CGA-277476, Novartis 
    Crop Protection has considered data discussed above from developmental 
    toxicity studies conducted with CGA-277476 in the rat and rabbit and a 
    2-generation rat reproduction study. The developmental toxicity studies 
    are designed to evaluate adverse effects on the developing organism 
    resulting from chemical exposure during prenatal development to one or 
    both parents. Reproduction studies provide information relating to 
    effects from exposure to a chemical on the reproductive capability of 
    mating animals and data on systemic toxicity.
        FFDCA section 408 provides that EPA may apply an additional safety 
    factor for infants and children in the case of threshold effects to 
    account for pre- and post-natal toxicity and the completeness of the 
    database. Based on the current toxicological data requirements, the 
    database relative to pre- and post-natal effects for children is 
    complete. Further, for CGA-277476, the NOEL of 1.3 mg/kg/day from the 
    chronic dog study, which was used to calculate the RfD (discussed 
    above), is at least an order of magnitude lower than the developmental 
    NOEL of 300 mg/kg/day from the rat teratogenicity study or the 
    reproductive NOEL of 250 mg/kg/day from the multigeneration 
    reproduction study. There is no evidence to suggest that developing 
    organisms are more sensitive to the effects of CGA-277476 than are 
    adults.
        However, Novartis Crop Protection has determined that when an 
    additional tenfold safety margin is used, the percent of the RfD that 
    will be utilized by aggregate exposure to residues of CGA-277476 is 0.8 
    percent for nursing infants less than 1 year old, 3.5 percent for non-
    nursing infants, 1.4 percent for children 1 to 6 years old and 1.1 
    percent for children 7 to 12 years old. Therefore, based on the 
    completeness and reliability of the toxicity data and the conservative 
    exposure assessment, it is concluded that there is a reasonable 
    certainty that no harm to infants and children will result from 
    aggregate exposure to CGA-277476 residues.
    
    3. Siemer and Associates
    
    PP 6F4789
    
        EPA has received a pesticide petition (PP 6F4789) from Siemer & 
    Associates, Inc. on behalf of National Chelating, 4672 West Jennifer, 
    Suite 103, Fresno, CA 93722, proposing pursuant to section 408(d) of 
    the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 
    CFR part 180 by establishing an exemption from the requirements for a 
    tolerance for ammonium thiosulfate when used for blossom thinning on 
    apples.
        Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended, 
    Siemer & Associates, Inc. on behalf of National Chelating has submitted 
    the following summary of information, data and arguments in support of 
    their pesticide petition. This summary was prepared by Siemer & 
    Associates, Inc. and EPA has not fully evaluated the merits of the 
    petition. EPA edited the summary to clarify that the conclusions and 
    arguments were the petitioner's and not necessarily EPA's and to remove 
    certain extraneous material.
        On August 30, 1996 Siemer & Associates on behalf of National 
    Chelating petitioned the EPA, under pesticide petition 6F4789, for a 
    permanent exemption from the requirements of a tolerance for ammonium 
    thiosulfate on apples.
        Section 408(b)(2)(A) of the amended Federal Food, Drug, and 
    Cosmetic Act allows the EPA to establish an exemption from the 
    requirements for a tolerance only if the Administrator determines that 
    there is a ``reasonable certainty that no harm will result from the 
    aggregate exposure to the pesticide chemical residue, including all 
    anticipated dietary exposures and all other exposures for which there 
    is reliable information.''
        The available information indicates that there is a reasonable 
    certainty that no harm will result from various types of exposure. 
    Requests for waivers from the requirements of performing studies for 
    known chemistry are presented and
    
    [[Page 26312]]
    
    substantiated. The following is a summary of the information submitted 
    to the EPA to support the establishment, under Section 408(b)(2)(D) of 
    the amended FFDCA, of a tolerance for ammonium thiosulfate on apples.
    
    A. Residue Chemistry
    
        1. Plant metabolism. The qualitative nature of the residues of 
    ammonium thiosulfate in apple is adequately understood. The requirement 
    for residue studies was waived by EPA based on the knowledge that 
    ammonium thiosulfate has been used as a soil applied and foliar applied 
    fertilizer for many years. Prior experience and numerous publications 
    teach that ammonium thiosulfate ionizes when placed into water, forming 
    an ammonium ion and a thiosulfate ion which further degrades to form 
    elemental sulfur and a sulfate ion. The sulfur is further oxidized to 
    form a sulfate ion. The ammonium and sulfate ions thus formed are 
    absorbed into the growing plant and moved into the naturally occurring 
    nitrogen and sulfate pools that occur naturally in growing plants. Once 
    applied to the plant, without isotope identification, it is not 
    possible to separate the ammonium and sulfate ions that will occur from 
    those that already occur naturally in the plant. On this basis, an 
    exemption from the requirements of a tolerance is justified. There is 
    no analytical method needed since there is no practical way to separate 
    the ammonium and sulfate ions from those that naturally occur.
        2. Analytical method. The need for an analytical method is waived 
    on the basis that there is no need for analyzing for the component of 
    ammonium and sulfate ion applied for blossom thinning purposes.
        3. Magnitude of residues. No residues of ammonium thiosulfate will 
    be identified separately from those ammonium and sulfate ions naturally 
    occurring. This result supports the proposed exemption from the 
    requirements for a tolerance.
    
    B. Toxicological Profile
    
        A request to waive the battery of mammalian toxicity studies for 
    ammonium thiosulfate is based on and justified by the following:
        1. Acute toxicity. Based on EPA criteria, ammonium thiosulfate 
    previously registered for a non-food use as an ornamental herbicide has 
    been shown to be relatively non-toxic and has been registered for non-
    food use purposes as a Category III herbicide. These data have 
    previously been supplied to the agency.
        2. Genotoxicity. A request for a waiver from the following 
    requirements is made on the basis that sodium thiosulfate is on the FDA 
    Generally Recognized as Safe (GRAS) list at 21 CFR 184.1807, and 
    ammonium thiosulfate is already exempted from the requirements of a 
    tolerance when used in accordance with good agricultural practices as 
    inert (or occasionally active) ingredients in pesticide formulations 
    applied to growing crops or to raw agricultural commodities after 
    harvest (at 40 CFR 180.1001(c)). Ammonium thiosulfate ionizes to form 
    ammonium ion and thiosulfate ion in water with neither of these ions 
    being mutagenic or genotoxic. On that basis the following tests are 
    requested to be waived.
        i. Gene Mutation - Ames.
        ii. In vitro Structural chromosomal aberration assay.
        iii. In vitro CHO/HGPRT assay.
        iv. In vivo micronucleus aberration assay.
        3. Reproductive and developmental toxicity. A request for waiving 
    the data requirements for the following is made on the basis listed 
    above for ``B''. In addition, all of the tests listed below rely on 
    feeding the test substance, to animals that have acidic stomachs. 
    Placing ammonium thiosulfate into an acidic environment will cause near 
    instantaneous ion formation giving rise to ammonium and thiosulfate 
    ions, which ultimately breaks down to elemental sulfur and sulfite. 
    These sulfur forms will be quickly oxidized under acidic conditions to 
    sulfate, which will be incorporated into the normal sulfate pool that 
    exists within the metabolic system of the various animal test systems. 
    The ammonium ion will react with the acidic component, most likely 
    forming ammonium chloride which will be metabolized in a well 
    understood pathway in the systems of the various animal test systems. 
    The new moiety formed in this acidic medium is the sulfite ion which 
    also is well understood and is quickly oxidized to sulfate. The FDA 
    instituted studies in 1975 and 1985 on the GRAS status of sulfite and, 
    as a result of these studies, has substantiated the GRAS status except 
    for a few individuals that might be allergic to sulfite. In this 
    proposed usage however, the sulfite will not reach the possibly 
    allergic people, since the sulfite will be metabolized to sulfate in 
    the plant system before reaching any sensitive people who may consume 
    the treated tissue. The data waivers requested are as follows:
        i. Teratology in rats.
        ii. Teratology in rabbits.
        iii. 2-Generation reproduction in rats.
        4. Subchronic Toxicity. The data requirements listed below are 
    requested to be waived on the basis illustrated above at paragraph 3.
        i. 28-Day dermal in rats.
        ii. 13-Week oral feeding in rats.
        iii. 90-Day oral feeding in dogs.
        5. Chronic toxicity. The data requirements listed below are 
    requested to be waived for reasons listed above at paragraph 3.
        i. 1-Year chronic toxicity in dogs.
        ii. 18-Month chronic toxicity & carcinogenicity in mice.
        iii. 24-Month chronic toxicity & carcinogenicity in rats.
        6. Animal metabolism. The metabolism of ammonium thiosulfate is 
    well understood in animals. As listed above, this substance rapidly 
    ionizes in the acidic portion of the animal gut, giving rise to 
    ammonium ion and sulfate ion. Both of these substances are required and 
    occur in the metabolism of animals.
        7. Metabolite toxicology. No toxicologically significant 
    metabolites will be detected in plant or animal metabolism studies 
    using ammonium thiosulfate. Therefore, no metabolites are required to 
    be regulated.
        8. Endocrine effects. There is no information available that 
    suggest that ammonium thiosulfate would be associated with endocrine 
    effects.
    
    C. Aggregate Exposure
    
        1. Dietary exposure--i. Food. There will be no residues of ammonium 
    thiosulfate that will reach any portion of the US population as a 
    result of using ammonium thiosulfate as a blossom thinner on apples. 
    The ammonium and sulfate ions that will arise will not be different 
    from the naturally occurring forms of the ions, which exceed by far the 
    amount that will be applied as a result of the use of the ammonium 
    thiosulfate.
        ii. Drinking water. Ammonium and sulfate ions that arise from 
    ammonium thiosulfate use will add no additional burden to the drinking 
    water. The end points of the two ions formed as a result of ammonium 
    thiosulfate use will both be used in plant nutrition. The ammonium form 
    of nitrogen resists leaching by binding to the colloid fraction in the 
    soil to resist ground water contamination. The amount of sulfate added 
    as a result of the described use will add an imperceptible amount to 
    the sulfate level already in existence in the soil.
        There is a reasonable certainty that no harm will result from 
    dietary exposure to ammonium thiosulfate, because dietary exposures to 
    residues on food cannot be differentiated from those that
    
    [[Page 26313]]
    
    will occur naturally in food, and exposure through drinking water is 
    expected to be insignificant.
        2. Non-dietary exposure. There is no non-dietary exposure expected, 
    since any ammonium thiosulfate finding its way onto the plants or 
    around any plants will be absorbed and metabolized into naturally 
    occurring plant constituents.
    
    D. Cumulative Effects
    
        There are no cumulative effects expected since the ammonium 
    thiosulfate metabolites are all incorporated into naturally occurring 
    constituents found in all plant systems.
    
    E. Safety Determination
    
        1. U.S. population. The natural occurrence of the metabolites of 
    the ammonium and sulfate ions in all plants and in humans is the basis 
    for the Generally Recognized As Safe characterization of the 
    thiosulfate ion and the use of the ammonium ion as a component in 
    nearly all fertilizers, supports the conclusion that there is a 
    ``reasonable certainty of no harm'' from aggregate exposure to ammonium 
    thiosulfate.
        2. Infants and children. No developmental, reproductive or 
    fetotoxic effects have been associated with ammonium thiosulfate and 
    its use as a fertilizer. The calculation of safety margins with respect 
    to ammonium thiosulfate is unnecessary since the ammonium and sulfate 
    ions that will arise from the use of ammonium thiosulfate will add only 
    slightly to the already naturally occurring nitrogen and sulfur pools 
    in existence in various plants. Since there will be no residues of 
    toxicological significance resulting from ammonium thiosulfate, 
    calculations of safety margins are not necessary based on the lack of 
    any unnatural residues.
    
    F. International Tolerances
    
        There is no Codex maximum residue level established for ammonium 
    thiosulfate on apple. However, ammonium thiosulfate is widely used as a 
    nutrient in many parts of the world.
    
    [FR Doc. 97-12472 Filed 5-12-97; 8:45 am]
    BILLING CODE 6560-50-F
    
    
    

Document Information

Published:
05/13/1997
Department:
Environmental Protection Agency
Entry Type:
Notice
Action:
Notice.
Document Number:
97-12472
Dates:
Comments, identified by the docket control number PF-731, must be received on or before June 12, 1997.
Pages:
26305-26313 (9 pages)
Docket Numbers:
PF-731, FRL-5714-3
PDF File:
97-12472.pdf