99-5823. Notice of Filing of Pesticide Petitions  

  • [Federal Register Volume 64, Number 46 (Wednesday, March 10, 1999)]
    [Notices]
    [Pages 11874-11879]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 99-5823]
    
    
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    ENVIRONMENTAL PROTECTION AGENCY
    
    [PF-862; FRL-6063-3]
    
    
    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-862, must 
    be received on or before April 9, 1999. 
    ADDRESSES: By mail submit written comments to: Information and Records 
    Integrity Branch, Public Information and Services Divison (7502C), 
    Office of Pesticides Programs, Environmental Protection Agency, 401 M 
    St., SW., Washington, DC 20460. In person bring comments to: Rm. 119, 
    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. 119 at the 
    address
    
    [[Page 11875]]
    
    given above, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding 
    legal holidays.
    
    FOR FURTHER INFORMATION CONTACT: Mary L. Waller, Fungicide Branch, 
    Registration Division (7505C), Office of Pesticide Programs, 
    Environmental Protection Agency, 401 M St., SW, Washington, DC 20460. 
    Office location, telephone number, and e-mail address: Rm. 249, Crystal 
    Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
    6117; e-mail:waller. mary@epamail.epa.gov.
    SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as 
    follows proposing the establishment and/or amendment of regulations for 
    residues of certain pesticide chemical 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 this petition 
    contains 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.
        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-862] (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 5.1/6.1 file format or 
    ASCII file format. All comments and data in electronic form must be 
    identified by the docket control number [PF-862] and appropriate 
    petition number. Electronic comments on this notice 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: February 22, 1999.
    
    James Jones,
    
    Director, Registration Division, Office of Pesticide Programs.
    
    Summary of Petition
    
        The petitioner summaries of the pesticide petitions are printed 
    below as required by section 408(d)(3) of the FFDCA. The summary of 
    each petition was prepared by the petitioner and represents the views 
    of the petitioner. 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. American Cyanamid Company
    
    PP 7F4816
    
        EPA has received a pesticide petition (PP 7F4816) from American 
    Cyanamid Company, P.O. Box 400 Princeton, NJ 08543-0400 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 residues of dimethomorph, (E,Z)4-[3-(4-chlorophenyl)-3-
    (3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholine in or on the raw 
    agricultural commodity cereal grains (Crop Group 15) and forage of 
    cereal grain crops (Crop Group 16) at 0.05 parts per million (ppm) and 
    fodder and straw of cereal grain crops (Crop Group 16) at 0.10 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 dimethomorph in plants is 
    adequately understood for the purposes of these tolerances. A 
    rotational crop study showed the potential for indirect or inadvertent 
    residues of dimethomorph in or on commodities of cereal crops.
        2. Analytical method. There is a practical method for measuring 
    0.050 ppm of dimethomorph in or on commodities of cereal crops. This 
    gas chromatography method with nitrogen-phosphorus detection (M3112) is 
    appropriate for enforcement purposes. Confirmation of residues is 
    provided by liquid chromatography/mass spectroscropy of the final 
    extract of this method.
        3. Magnitude of residues. The magnitude of residue studies were 
    conducted for wheat as a rotational crop to potatoes treated at 1.4 x 
    the maximum labeled rate. Residues found in these studies were below 
    the level of quantitation (LOQ) in the forage and grain samples from 
    all six trials and in the hay, and straw samples from four of the 
    trials. The maximum observed residue (sample means) was 0.057 ppm for 
    hay, and 0.086 ppm for straw for the other two trials. Therefore, at 
    the maximum labeled rate, residues of dimethomorph in or on hay are 
    expected to be below the LOQ (< 0.05="" ppm)="" and="" residues="" in="" or="" on="" straw="" are="" expected="" to="" be="" less="" than="" 0.10="" ppm.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" an="" acute="" oral="" toxicity="" study="" in="" the="" sprague-="" dawley="" rat="" for="" dimethomorph="" technical="" with="" a="">50 of 4,300 
    milligram per kilogram bodyweight (mg/kg bwt) for males and 3,500 mg/kg 
    bwt for females. Based upon EPA toxicity criteria, the acute oral 
    toxicity category for dimethomorph technical is Category III or 
    slightly toxic. Oral LD50 studies were conducted on the two 
    isomers (E and Z) alone: An acute oral toxicity study in the Wistar rat 
    for the E-isomer with a LD50 greater than 5,000 mg/kg bwt 
    for males and approximately 5,000 mg/kg bwt for females. An acute oral 
    toxicity study in the Wistar rat for the Z-isomer with a 
    LD50 greater than 5,000 mg/kg bwt for both males and 
    females. An acute dermal toxicity study in the Wistar rat for 
    dimethomorph technical with a dermal LD50 greater than 5,000 
    mg/kg bwt for both males and females. Based on the EPA toxicity 
    category criteria, the Acute dermal toxicity category for dimethomorph 
    is Category IV or relatively non-toxic. A 4-hour inhalation study in 
    Wistar rats for dimethomorph technical with a LC50 greater 
    than 4.2 milligram per liter (mg/L) for both males and females. Based 
    on the EPA toxicity category criteria, the acute inhalation toxicity 
    category for dimethomorph technical is Category IV or relatively non-
    toxic.
        2. Genotoxicty. Salmonella reverse gene mutation assays (2 studies) 
    were negative up to a limit dose of 5,000 g/plate. Chinese 
    hamster lung cells were negative in V79 cells up to toxic doses in 2 
    studies. Two Chinese hamster lung structural chromosomal studies were
    
    [[Page 11876]]
    
    reportedly positive for chromosomal aberrations at the highest dose 
    tested (HDT) (160 g/ml/-S9; 170 g/ml/+S9). 
    Dimethomorph induced only a weak response in increasing chromosome 
    aberrations in this test system. These results were not confirmed in 
    two micronucleus tests under in vivo conditions. Structural Chromosomal 
    Aberration studies were weakly positive, in human lymphocyte cultures, 
    but only in S9 activated cultures treated at the HDT (422 g/
    ml) which was strongly cytotoxic. Dimethomorph was negative in the 
    absence of activation at all doses and the positive in human lymphocyte 
    cultures was only in S9 activated cultures treated at the HDT (422 
    g/ml) which was strongly cytotoxic. Dimethomorph was negative 
    in the absence of activation at all doses and the positive clastogenic 
    response observed under the in vitro conditions was not confirmed in 
    two in vivo micronucleus assays. Micronucleus assay (2 studies) 
    indicated that dimethomorph was negative for inducing micronuclei in 
    bone marrow cells of mice following i.p. administration of doses up to 
    200 mg/kg or oral doses up to the limit dose of 5,000 mg/kg. Thus, 
    dimethomorph was found to be negative in these studies for causing 
    cytogenic damage in vivo. Dimethomorph was negative for inducing 
    unscheduled DNA synthesis in cultured rat liver cells at doses up to 
    250 /ml, a weak cytotoxic level. Dimethomorph was negative for 
    transformation in Syrian hamster embryo cells treated in the presence 
    and absence of activation up to cytotoxic concentrations (265 
    g/ml/+S9; 50 g/ml-S9).
        3. Reproductive and developmental toxicity. A rat developmental 
    toxicity study with a maternal toxicity lowest-observed-adverse-effect 
    Level (LOAEL) of 160 mg/kg/day and a maternal toxicity no-observed 
    adverse-effect level (NOAEL) of 60 mg/kg/day. The NOAEL for 
    developmental toxicity is 60 mg/kg/day. Dimethomorph is not teratogenic 
    in the Sprague-Dawley rat. A rabbit development toxicity study with 
    parental LOAEL for systemic toxicity of 80 mg/kg/day, and a NOAEL of 24 
    mg/kg/day. The NOAEL for fertility and reproductive function was 80 mg/
    kg/day, the HDT.
        4. Subchronic toxicity A 90-day dog dietary study in Sprague-Dawley 
    rats with a NOAEL of greater than or equal to 73 mg/kg/day in males and 
    82 mg/kg/day in females, the HDT. A 90-day dog dietary study with a 
    NOAEL 15 mg/kg/day, and a LOAEL of 43 mg/kg/day.
        5. Chronic toxicity. A 2-year oncogenicity study in Sprague-Dawley 
    rats with a NOAEL for systemic toxicity of 9 mg/kg/day for males and 12 
    mg/kg/day for females. The LOAEL for systemic toxicity is 36 mg/kg/day 
    for males and 58 mg/kg/day for females. A 1-year chronic toxicity study 
    in dogs with a NOAEL of 14.7 mg/kg/day and a LOAEL of 44.6 mg/kg/day. A 
    2-year oncogenicity study in Sprague-Dawley rats with a NOAEL for 
    systemic toxicity of 9 mg/kg/day for males and 11 mg/kg/day for 
    females. The LOAEL for system toxicity was 34 mg/kg/day for males and 
    46 mg/kg/ day for females. There was no evidence of increased incidence 
    of neoplastic lesions in treated animals. The NOAEL for oncogenicity is 
    95 mg/kg/day for males and 132 mg/kg/day for females, the HDT. A 2-year 
    oncogenicity study in mice with a NOAEL for systemic toxicity of 100 
    mg/kg/day, and LOAEL of 1,000 mg/kg/day. There was no evidence of 
    increased incidence of neoplastic lesions in treated animals. The NOAEL 
    for oncogenicity is 1,000 mg/kg/day, the HDT.
        6. Animal metabolism. Results from livestock and rat metabolism 
    studies show that orally administered dimethomorph was rapidly excreted 
    by the animals. The principal route of elimination is the feces.
        7. Metabolite toxicology. There were no metabolites identified in 
    plant or animal commodities which require regulation.
        8. Endocrine disruption. There is no evidence of effects of 
    dimethomorph on the endocrine system. There were no changes noted in 
    organ weights for the pituitary, thyroid, ovaries or testes. There was 
    no increased incidence of mammary tumors observed. No effects on 
    fertility or reproduction were noted and there was no evidence of 
    related histopathological changes in reproductive or endocrine system 
    organs.
    
    C. Aggregate Exposure
    
        1. Dietary exposure. Dietary exposure should be based upon the 
    Theoretical Maximum Residue Concentration (TMRC) from the established 
    tolerances for residues of dimethomorph at 0.05 ppm in or on potato; 
    for the proposed tolerances for residues of dimethomorph at 2.0 ppm in 
    or on grapes; and 0.15 ppm on potatoes wet peel; for the proposed 
    tolerances for indirect and inadvertent residues of dimethomorph at 
    0.05 ppm in or on cereal grains, and in or on fodder and straw of 
    cereal grain crops, and from the time-limited tolerances (i.e. at 1.0 
    ppm for cantaloupes, cucumbers, squash, and watermelons) which were 
    established under Section 18 emergency exempt ions and which are not 
    due to expire at or near completion of this regulatory action.
        i. Food. The goat and poultry metabolism studies demonstrate that 
    there is no reasonable expectation of transfer of residues to meat, 
    milk, poultry, or eggs from potato, grape, and cereal crop commodities. 
    Therefore, no consumption data associated with meat, milk, poultry or 
    eggs should be included in the calculation of the TMRC. Except for the 
    permanent tolerances on potato tubers, there are no other permanent 
    U.S. tolerances for dimethomorph.
        ii. Drinking water. The predicted dimethomorph surface and ground 
    water concentrations are well below the drinking water level of 
    concern. Using the SCI-GROW model to generate the Estimated 
    Environmental Concentration (EEC) of dimethomorph residues in ground 
    water, the projected EEC is 0.26 parts per billion (ppb). Using the 
    Generic Estimated Environmental Concentration (GENEEC) model to 
    estimate acute and chronic EECs of dimethomorph residues in surface 
    water, the projected EEC ranged from a peak of 28 ppb to a 56 day 
    concentration of 24 ppb. The level of concern for chronic exposure to 
    residues of dimethomorph range from 960 ppb for children 1-6 years old 
    to 3,400 ppb for the U.S. population and males 13 years and older. 
    Therefore, American Cyanamid believes that exposure from water is below 
    the level of concern for all of the populations examined. In addition, 
    American Cyanamid believes that the aggregate (food, and water) chronic 
    exposure for infants, children, and adults does not exceed the level of 
    concern and adverse health effects from chronic exposure to 
    dimethomorph in food, and water are not expected in these populations.
        2. Non-dietary exposure. In the United States, dimethomorph is 
    registered only for use on potatoes. Thus, there is no potential for 
    non-dietary exposure.
    
    D. Cumulative Effects
    
        There is no information to indicate that any toxic effects produced 
    by dimethomorph would be cumulative with those of any other chemical. 
    The fungicidal mode of action of dimethomorph is unique; dimethomorph 
    inhibits cell wall formation only in Oomycete fungi. The result is 
    lysis of the cell wall which kills growing cells and inhibits spore 
    formation in mature hyphae. This unique mode of action and limited pest 
    spectrum suggest that there is little or no potential for cumulative 
    toxic effects in mammals. In addition, the toxicity studies submitted 
    to support this
    
    [[Page 11877]]
    
    petition do not indicate that dimethomorph is a particularly toxic 
    compound.
    
    E. Safety Determination
    
        1. U.S. population. The established reference dose (RfD) is 0.1 mg/
    kg bwt/day, based on a NOAEL of 10 mg/kg bwt/day from a 2-year dietary 
    toxicity study in rats that demonstrated decreased bwt, and liver foci 
    in females. The established RfD is also based on an uncertainty factor 
    of 100. The TMRC from the established tolerances for residues in or on 
    potato along with the current Section 18 time-limited tolerances 
    (cantaloupes, watermelons, cucumbers, and squash, as well as expiring 
    tolerances for tomato commodities) utilizes less than 4% of the RfD for 
    all population subgroups. The TMRC for grapes and cereal grains is not 
    expected to cause the RfD to be exceeded.
        2. Infants and children. American Cyanamid believes that the 
    results of the studies submitted to support this package provide no 
    evidence that dimethomorph caused reproductive, developmental or 
    fetotoxic effects. No such effects were noted at dose levels which were 
    not maternally toxic. The NOAELs observed in the developmental and 
    reproductive studies were 6 to 65 times higher than the NOAEL (10 mg/kg 
    bwt/day) used to establish the RfD. There is no evidence to indicate 
    that children or infants would be more sensitive than adults to toxic 
    effects caused by exposure to dimethomorph.
    
    F. International Tolerances
    
        No Codex maximum residue levels (MRLs) have been established for 
    dimethomorph to date.
    
    2. BASF Corporation
    
    PP 7F4880
    
        EPA has received a pesticide petition (7F4880) from BASF 
    Corporation, 26 Davis Drive, Post Office Box 13528, Research Triangle 
    Park, North Carolina 27709-3528, 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 kresoxim-methyl (methyl (E)-2-methoxyimino-2-[2-(o-
    tolyloxymethyl) phenyl] acetate) and the glycoside conjugates of its 
    metabolites 2-[o-(o-hydroxymethylphenoxymethyl) phenyl]-2-
    (methoxyimino) acetic acid and 2-[o-(p-hydroxy-o-methylphenoxymethyl) 
    phenyl]-2-(methoxyimino) acetic acid in or on the raw agricultural 
    commodities pome fruit, grapes and pecans at 0.30 parts per million 
    (ppm) for pome fruit, 1.0 ppm for grapes, 0.15 ppm for pecans and 0.70 
    ppm for apple pomace. 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. BASF Corporation notes that metabolism in 
    plants is understood.
        2. Analytical method. The proposed analytical method involves 
    extraction, enzyme hydrolysis, partition, clean-up and detection of 
    residues by high performance liquid chromotography using ultra-violet 
    (HPLC/UV) detection.
        3. Magnitude of residues. Twelve grape residue trials were 
    conducted in six States. Residues of kresoxim-methyl and its two 
    metabolites were measured by HPLC/UV. The analytical method had a limit 
    of detection (LOD) of 0.05 ppm for each of the three analytes. Residues 
    ranged from < 0.15="" ppm="" to="" 0.79="" ppm.="" nineteen="" apple="" residue="" trials="" were="" conducted="" in="" 12="" states.="" residues="" of="" kresoxim-methyl="" and="" its="" two="" metabolites="" were="" measured="" by="" hplc/uv.="" the="" analytical="" method="" had="" a="" lod="" of="" 0.05="" ppm="" for="" each="" of="" the="" three="" analytes.="" residue="" of="" parent="" and="" metabolites="" ranged="" from="">< 0.15="" to="" 0.23="" ppm.="" eight="" pear="" residue="" trials="" were="" conducted="" in="" five="" states.="" residues="" of="" kresoxim-methyl="" and="" its="" two="" metabolites="" were="" measured="" by="" hplc/uv.="" the="" analytical="" method="" had="" a="" lod="" of="" 0.05="" ppm="" for="" each="" of="" the="" three="" analytes.="" residues="" of="" parent="" plus="" metabolites="" ranged="" from="">< 0.15="" to="" 0.26="" ppm.="" six="" pecan="" residue="" trials="" were="" conducted="" in="" five="" states.="" residues="" of="" kresoxim-methyl="" and="" its="" two="" metabolites="" were="" measured="" by="" hplc/uv.="" the="" analytical="" method="" had="" a="" lod="" of="" 0.05="" ppm="" for="" each="" of="" the="" three="" analytes.="" no="" residue="" of="" parent="" or="" metabolites="" was="" found="" in="" any="" sample="" above="" the="" lod.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity--acute/subchronic="" toxicology.="" based="" on="" available="" acute="" toxicity="" data,="" kresoxim-methyl="" does="" not="" pose="" any="" acute="" toxicity="" risks.="" acute="" toxicology="" studies="" place="" technical-grade="" kresoxim-methyl="" in="" toxicity="" category="" iv="" for="" acute="" oral="" and="" category="" iii="" for="" acute="" dermal="" and="" acute="" inhalation="" toxicity.="" the="" material="" is="" not="" an="" eye="" irritant,="" a="" primary="" dermal="" irritant="" or="" a="" skin="" sensitizer.="" additionally,="" in="" acute="" and="" subchronic="" neurotoxicity="" studies,="" kresoxim-methyl="" did="" not="" show="" any="" signs="" of="" neurotoxicity="" at="" dose="" levels="" up="" to="" and="" including="" 2,000,="" and="" 1,267="" milligram/kilogram/day="" (mg/kg/day),="" respectively.="" 2.="" genotoxicty.="" with="" regard="" to="" the="" liver="" tumors,="" kresoxim-methyl="" is="" not="" a="" genotoxic="" agent="" and="" is="" not="" an="" initiator="" of="" the="" carcinogenic="" process.="" the="" increased="" incidence="" of="" liver="" tumors="" in="" rats="" is="" the="" result="" of="" liver="" tumor="" promoting="" properties="" of="" the="" test="" substance.="" 3.="" reproductive="" and="" developmental="" toxicity--i.="" reproductive="" toxicity.="" the="" 2-generation="" reproduction="" study="" with="" rats="" resulted="" in="" a="" reproductive="" no-observed="" adverse="" effect="" level="" (noael)="" of="" 1,625="" mg/kg/="" day,="" and="" a="" maternal="" noael="" of="" 100="" mg/kg/day.="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 2="" year="" feeding="" study="" in="" rats="" used="" to="" establish="" the="" reference="" dose="" (rfd).="" ii.="" developmental="" toxicity.="" the="" teratogenicity="" study="" in="" rats="" resulted="" in="" a="" developmental="" toxicity="" noael="" of="" 1,000="" mg/kg/day,="" and="" a="" maternal="" toxicity="" noael="" of="" 1,000="" mg/kg/day.="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 2="" year="" feeding="" study="" in="" rats="" used="" to="" establish="" the="" rfd.="" 4.="" subchronic="" toxicity--i.="" acute/subchronic="" toxicology.="" based="" on="" available="" acute="" toxicity="" data,="" kresoxim-methyl="" does="" not="" pose="" any="" acute="" toxicity="" risks.="" acute="" toxicology="" studies="" place="" technical-grade="" kresoxim-methyl="" in="" toxicity="" category="" iv="" for="" acute="" oral="" and="" category="" iii="" for="" acute="" dermal="" and="" acute="" inhalation="" toxicity.="" the="" material="" is="" not="" an="" eye="" irritant,="" a="" primary="" dermal="" irritant="" or="" a="" skin="" sensitizer.="" additionally,="" in="" acute="" and="" subchronic="" neurotoxicity="" studies,="" kresoxim-="" methyl="" did="" not="" show="" any="" signs="" of="" neurotoxicity="" at="" dose="" levels="" up="" to="" and="" including="" 2,000="" and="" 1,267="" mg/kg/day,="" respectively.="" ii.="" subchronic="" toxicology--a.="" teratology="" -="" rat.="" a="" teratogenicity="" study="" in="" the="" rat="" with="" doses="" at="" 100,="" 400,="" and="" 1,000="" mg/kg/day="" by="" gavage="" was="" performed="" with="" a="" maternal="" noael="" of="" 1,000="" mg/kg/day="" and="" fetal="" noael="" of="" 1,000="" mg/kg/day.="" b.="" teratology="" -="" rabbits.="" a="" teratogenicity="" study="" in="" the="" rabbit="" with="" doses="" at="" 100,="" 400,="" and="" 1,000="" mg/kg/day="" by="" gavage="" was="" performed="" with="" a="" maternal="" noael="" of="" 1,000="" mg/kg/day="" and="" fetal="" noael="" of="" 1,000="" mg/kg/day.="" c.="" mutagenicity.="" modified="" ames="" test="" (2="" studies;="" point="" mutation):="" negative;="" in="" vitro="" chinese="" hamster="" ovary="" hypoxanthine="" guanine="" phophoribosyl="" transferase="" (cho/hgprt)="" (point="" [[page="" 11878]]="" mutation):="" negative;="" in="" vitro="" cytogenetics="" chromosome="" damage="" human="" lymphocytes:="" negative;="" in="" vivo="" chromosome="" mouse="" micronucleus:="" negative;="" in="" vitro="" dna="" damage="" &="" repair="" rat="" hepatocytes:="" negative;="" uds="" ex="" vivo="" dna="" damage="" &="" repair="" wistar="" rats="" (single="" oral="" dose):="" negative;="" uds="" ex="" vivo="" dna="" damage="" &="" repair="" wistar="" rats="" (3="" week="" feeding):="" negative.="" 5.="" chronic="" toxicity--i.="" threshold="" effects.="" based="" on="" review="" of="" the="" available="" data,="" basf="" believes="" the="" rfd="" for="" kresoxim-methyl="" will="" be="" based="" on="" the="" 2="" year="" feeding="" study="" in="" rats="" with="" a="" threshold="" noael="" of="" 36="" mg/kg/="" day="" in="" males,="" and="" 47="" mg/kg/day="" in="" females.="" using="" an="" uncertainty="" factor="" of="" 100,="" the="" rfd="" is="" calculated="" to="" be="" 0.36="" mg/kg/day.="" ii.="" non-threshold="" effects="" -="" carcinogenicity.="" kresoxim-methyl="" was="" shown="" to="" be="" non-carcinogenic="" in="" mice.="" in="" the="" rat="" carcinogenicity="" study,="" a="" statistically="" significant="" increase="" in="" liver="" tumors="" was="" observed="" in="" both="" male="" and="" female="" animals="" at="" 370="" and="" 746="" mg/kg/day,="" and="" 503="" and="" 985="" mg/kg/day="" dose="" levels,="" respectively.="" kresoxim-methyl="" is="" not="" a="" genotoxic="" agent="" and="" mechanistic="" studies="" have="" shown="" that="" the="" increased="" incidence="" of="" liver="" tumors="" in="" rats="" is="" the="" result="" of="" liver="" tumor="" promoting="" properties="" of="" the="" test="" substance.="" kresoxim-methyl="" is="" not="" an="" initiator="" of="" the="" carcinogenic="" process.="" based="" on="" the="" available="" data,="" the="" mechanism="" of="" promotion="" is="" the="" induction="" of="" liver="" cell="" proliferation="" of="" the="" test="" substance.="" the="" data="" available="" also="" indicate="" that="" dose="" levels="" which="" do="" not="" induce="" liver="" toxicity="" neither="" induce="" cell="" proliferation="" nor="" enhance="" the="" carcinogenic="" process.="" therefore,="" a="" threshold="" for="" liver="" carcinogenicity="" in="" rats="" can="" be="" defined="" to="" be="" approximately="" 40="" mg/kg/="" day.="" based="" on="" the="" results="" of="" the="" carcinogenicity="" study="" in="" mice,="" the="" results="" of="" genotoxicity="" testing,="" the="" results="" of="" the="" 24="" month="" chronic="" feeding/oncogenicity="" study="" in="" rats;="" and="" auxiliary="" mechanistic="" data="" showing="" that="" kresoxim-methyl="" is="" not="" an="" initiator="" of="" the="" carcinogenic="" process,="" basf="" believes="" that="" the="" threshold="" approach="" to="" regulating="" kresoxim-methyl="" is="" appropriate.="" c.="" toxicity="" data="" supporting="" kresoxim-methyl="" tolerances="" 1.="" chronic="" feeding--i.="" nonrodent.="" a="" 12="" month="" feeding="" study="" in="" the="" dog="" with="" doses="" of="" 29,="" 142,="" and="" 738="" mg/kg/day="" was="" performed="" with="" a="" noael="" of="" 138="" mg/kg/day="" for="" males,="" and="" 761="" mg/kg/day="" for="" females.="" the="" only="" effect="" observed="" was="" reduced="" body="" weights="" (bwt)="" in="" male="" dogs="" at="" the="" highest="" dose="" tested="" (hdt).="" ii.="" chronic="" feeding/oncogenicity="" -="" rats.="" a="" 24="" month="" chronic="" feeding/oncogenicity="" study="" in="" the="" rat="" with="" doses="" at="" 9,="" 36,="" 370,="" and="" 746="" mg/kg/day="" for="" males="" and="" 12,="" 48,="" 503,="" and="" 985="" mg/kg/day="" for="" females="" was="" performed="" with="" a="" noael="" of="" 36="" mg/kg/day="" in="" males,="" and="" 47="" mg/kg/day="" in="" females.="" reduced="" bwt="" changes="" were="" observed="" in="" male,="" and="" female="" rats="" in="" the="" highest="" two="" dose="" groups.="" histopathologically,="" changes="" in="" the="" liver="" were="" observed="" in="" either="" or="" both="" of="" the="" highest="" two="" dose="" groups="" for="" male,="" and="" female="" rats.="" these="" changes="" consisted="" of="" increased="" liver="" weight,="" increased="" hepatocellular="" hypertrophy,="" increased="" incidence="" and="" severity="" of="" eosinophilic="" foci="" of="" hepatocellular="" alterations,="" and="" increased="" incidence="" and="" degree="" of="" severity="" of="" bile="" duct="" proliferation.="" associated="" with="" the="" liver,="" an="" increase="" of="" serum-gamma-="" glutamyltransferase="" values="" was="" observed.="" a="" statistically="" significant="" increase="" in="" liver="" tumors="" was="" observed="" in="" both="" male,="" and="" female="" animals="" at="" 370="" mg/kg/day="" and="" 985="" mg/kg/day,="" respectively.="" with="" regard="" to="" the="" liver="" tumors,="" kresoxim-methyl="" is="" not="" a="" genotoxic="" agent="" and="" is="" not="" an="" initiator="" of="" the="" carcinogenic="" process.="" the="" increased="" incidence="" of="" liver="" tumors="" in="" rats="" is="" the="" result="" of="" liver="" tumor="" promoting="" properties="" of="" the="" test="" substance.="" based="" on="" the="" available="" data,="" the="" mechanism="" of="" promotion="" is="" the="" induction="" of="" liver="" cell="" proliferation="" of="" the="" test="" substance.="" the="" data="" available="" also="" indicate="" that="" dose="" levels="" which="" do="" not="" induce="" liver="" toxicity="" neither="" induce="" cell="" proliferation="" nor="" enhance="" the="" carcinogenic="" process.="" therefore,="" a="" threshold="" for="" liver="" carcinogenicity="" in="" rats="" can="" be="" defined="" to="" be="" approximately="" 40="" mg/kg/day.="" iii.="" oncogenicity="" -="" mice.="" a="" mouse="" oncogenicity="" study="" using="" dosage="" levels="" at="" 60,="" 304,="" and="" 1,305="" mg/kg/day="" for="" males,="" and="" 81,="" 410,="" and="" 1,662="" mg/kg/day="" for="" females="" was="" performed="" with="" a="" noael="" of="" 304="" mg/kg/day="" for="" males,="" and="" 81="" mg/kg/day="" for="" females,="" with="" no="" evidence="" of="" oncogenicity.="" bwt="" changes="" were="" observed="" in="" both="" male,="" and="" female="" mice="" in="" the="" highest="" dose="" group="" and="" only="" in="" the="" females="" in="" the="" 410="" mg/kg/day="" group.="" histopathology="" was="" limited="" only="" to="" the="" highest="" dose="" group="" and="" consisted="" of="" increased="" incidence="" of="" renal="" papillary="" necrosis="" for="" both="" male,="" and="" female="" mice="" and="" increased="" incidence="" and="" higher="" degree="" of="" severity="" of="" liver="" amyloidosis="" in="" females="" only.="" iv.="" 2-generation="" reproduction="" -="" rats.="" a="" 2-generation="" reproductive="" study="" in="" the="" rat="" with="" doses="" at="" 5,="" 100,="" 407,="" and="" 1,625="" mg/kg/day="" was="" performed="" with="" a="" noael="" of="" 100="" mg/kg/day="" for="" parental="" and="" developmental="" toxicity,="" and="" a="" noael="" of="" 1,625="" mg/kg/day="" for="" reproduction="" toxicity.="" decreased="" body="" weight="" was="" seen="" in="" both="" the="" pups="" and="" parents.="" reduced="" serum-gamma-glutamyltransferase="" was="" seen="" in="" f0="" males="" and="" both="" sexes="" of="" the="" f1="" generation,="" and="" reduced="" kidney="" weights="" were="" seen="" in="" the="" f1="" generation="" at="" the="" 407="" and="" 1,625="" mg/kg/day="" dose="" levels.="" decreased="" fat="" storage="" was="" observed="" in="" f0="" and="" f1="" male="" livers="" at="" the="" 407="" and="" 1,625="" mg/="" kg/day="" dose="" levels.="" 6.="" animal="" metabolism.="" basf="" corporation="" notes="" that="" metabolism="" in="" animals="" is="" understood.="" d.="" aggregate="" exposure="" 1.="" dietary="" exposure.="" for="" purposes="" of="" assessing="" the="" potential="" chronic="" dietary="" exposure,="" basf="" has="" estimated="" aggregate="" exposure="" based="" on="" the="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" from="" the="" proposed="" tolerance="" for="" kresoxim-methyl="" on="" pome="" fruit="" at="" 0.30="" ppm,="" grapes="" at="" 1.0="" ppm,="" and="" pecans="" at="" 0.15="" ppm.="" the="" tmrc="" is="" a="" ``worse="" case''="" estimate="" of="" dietary="" exposure="" since="" it="" is="" assumed="" that="" 100%="" of="" all="" crops="" for="" which="" tolerances="" are="" established="" are="" treated="" and="" that="" pesticide="" residues="" are="" always="" found="" at="" the="" tolerance="" levels.="" i.="" food.="" dietary="" exposure="" to="" residues="" of="" kresoxim-methyl="" in="" or="" on="" food="" will="" be="" limited="" to="" residues="" on="" pome="" fruit,="" grapes,="" and="" pecans.="" apple="" pomace="" is="" fed="" to="" animals;="" thus="" exposure="" of="" humans="" to="" residues="" in="" apple="" pomace="" might="" result="" if="" such="" residues="" carry="" through="" to="" meat,="" milk,="" poultry,="" or="" eggs.="" however,="" basf="" has="" concluded="" that="" there="" is="" no="" reasonable="" expectation="" that="" measurable="" residues="" of="" kresoxim-methyl="" will="" occur="" in="" meat,="" milk,="" poultry,="" or="" eggs="" from="" this="" use.="" there="" are="" no="" other="" established="" u.s.="" tolerances="" for="" kresoxim-methyl,="" and="" there="" are="" no="" currently="" registered="" uses="" for="" kresoxim-methyl="" on="" food="" or="" feed="" crops="" in="" the="" u.s.="" dietary="" exposure="" to="" residues="" of="" kresoxim-methyl="" from="" the="" proposed="" tolerances="" on="" pome="" fruit,="" grapes,="" and="" pecans="" would="" account="" for="" less="" than="" 0.15%="" of="" the="" rfd="" (.36="" mg/kg/day)="" for="" the="" general="" population="" of="" the="" u.s.="" the="" most="" highly="" exposed="" group="" in="" the="" subpopulation="" groups="" would="" be="" non-nursing="" infants="">< 1="" year="" old,="" which="" uses="" 0.88%="" of="" the="" rfd.="" ii.="" drinking="" water.="" other="" potential="" sources="" of="" exposure="" for="" the="" general="" population="" to="" residues="" of="" kresoxim-methyl="" are="" residues="" in="" drinking="" water="" and="" exposure="" from="" non-occupational="" sources.="" based="" on="" the="" available="" studies,="" basf="" does="" not="" anticipate="" exposure="" to="" residues="" of="" kresoxim-methyl="" in="" drinking="" water.="" there="" is="" no="" established="" maximum="" concentration="" level="" (mcl)="" for="" residues="" of="" kresoxim-methyl="" in="" [[page="" 11879]]="" drinking="" water="" under="" the="" safe="" drinking="" water="" act="" (sdwa).="" 2.="" non-dietary="" exposure.="" kresoxim-methyl="" is="" currently="" registered="" for="" use="" in="" greenhouses="" on="" ornamental="" plants.="" the="" potential="" for="" non-="" occupational="" exposure="" to="" the="" general="" population="" is="" not="" significant.="" e.="" cumulative="" effects="" basf="" has="" considered="" the="" potential="" for="" cumulative="" effects="" of="" kresoxim-methyl="" and="" other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity.="" no="" evidence="" or="" information="" exists="" to="" suggest="" that="" toxic="" effects="" produced="" by="" kresoxim-methyl="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemical="" compound.="" f.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" the="" reliability="" of="" the="" toxicity="" data,="" basf="" has="" estimated="" that="" aggregate="" exposure="" to="" kresoxim-methyl="" will="" utilize="" less="" than="" 0.15%="" of="" the="" rfd="" for="" the="" total="" u.s.="" population.="" basf="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" the="" aggregate="" exposure="" to="" residues="" of="" kresoxim-methyl,="" including="" anticipated="" dietary="" exposure="" and="" non-="" occupational="" exposures.="" 2.="" infants="" and="" children--i.="" developmental="" toxicity.="" the="" teratogenicity="" study="" in="" rats="" resulted="" in="" a="" developmental="" toxicity="" noael="" of="" 1,000="" mg/kg/day,="" and="" a="" maternal="" toxicity="" noael="" of="" 1,000="" mg/kg/day.="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 2="" year="" feeding="" study="" in="" rats="" used="" to="" establish="" the="" rfd.="" the="" teratogenicity="" study="" in="" rabbits="" resulted="" in="" a="" developmental="" toxicity="" noael="" of="" 1,000="" mg/kg/day,="" and="" a="" maternal="" toxicity="" noael="" of="" 1,000="" mg/kg/day.="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 2="" year="" feeding="" study="" in="" rats="" used="" to="" establish="" the="" rfd.="" ii.="" reproductive="" toxicity.="" the="" 2-generation="" reproduction="" study="" with="" rats="" resulted="" in="" a="" reproductive="" noael="" of="" 1,625="" mg/kg/day,="" and="" a="" maternal="" noael="" of="" 100="" mg/kg/day.="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 2="" year="" feeding="" study="" in="" rats="" used="" to="" establish="" the="" rfd.="" iii.="" reference="" dose.="" since="" developmental="" and="" reproductive="" toxicity="" occurs="" at="" levels="" at="" or="" above="" the="" levels="" shown="" to="" exhibit="" parental="" toxicity="" and="" since="" these="" levels="" are="" significantly="" higher="" than="" those="" used="" to="" calculate="" the="" rfd,="" basf="" believes="" the="" rfd="" of="" 0.36="" mg/kg/day="" is="" an="" appropriate="" measure="" of="" safety="" for="" infants="" and="" children.="" using="" the="" conservative="" exposure="" assumptions="" described="" above,="" basf="" has="" concluded="" that="" the="" portion="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" aggregate="" exposure="" to="" residues="" of="" kresoxim-methyl="" resulting="" from="" the="" proposed="" tolerances="" will="" be="" less="" than="" 1%="" for="" all="" populations="" of="" infants="" and="" children.="" the="" most="" highly="" exposed="" group="" in="" the="" subpopulation="" groups="" would="" be="" non-nursing="" infant="">< 1-year="" old,="" which="" uses="" 0.88%="" of="" the="" rfd.="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" basf="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" the="" residues="" of="" kresoxim-methyl,="" including="" all="" anticipated="" dietary="" exposure="" and="" all="" other="" non-="" occupational="" exposures.="" g.="" international="" tolerances="" a="" maximum="" residue="" level="" has="" not="" been="" established="" for="" kresoxim-="" methyl="" by="" the="" codex="" alimentarius="" commission.="" [fr="" doc.="" 99-5823="" filed="" 3-9-99;="" 8:45="" am]="" billing="" code="" 6560-50-f="">

Document Information

Published:
03/10/1999
Department:
Environmental Protection Agency
Entry Type:
Notice
Action:
Notice.
Document Number:
99-5823
Dates:
Comments, identified by the docket control number PF-862, must be received on or before April 9, 1999.
Pages:
11874-11879 (6 pages)
Docket Numbers:
PF-862, FRL-6063-3
PDF File:
99-5823.pdf