65 FR 173 pgs. 54006-54014 - Notice of Filing a Pesticide Petition to Establish aTolerance for a Certain Pesticide Chemical in or on Food
Type: NOTICEVolume: 65Number: 173Pages: 54006 - 54014
Docket number: [PF-966; FRL-6738-6]
FR document: [FR Doc. 00-22816 Filed 9-5-00; 8:45 am]
Agency: Environmental Protection Agency
Official PDF Version: PDF Version
ENVIRONMENTAL PROTECTION AGENCY
[PF-966; FRL-6738-6]
Notice of Filing a Pesticide Petition to Establish aTolerance for a Certain Pesticide Chemical in or on Food
AGENCY:
Environmental Protection Agency (EPA).
ACTION:
Notice.
SUMMARY:
This notice announces the initial filing ofa pesticide petition proposing the establishment of regulationsfor residues of a certain pesticide chemical in or on variousfood commodities.
DATES:
Comments, identified by docket controlnumber PF-966, must be received on or before October 6, 2000.
ADDRESSES:
Comments may be submitted by mail,electronically, or in person. Please follow the detailedinstructions for each method as provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure proper receiptby EPA, it is imperative that you identify docket control numberPF-966 in the subject line on the first page of yourresponse.
FOR FURTHER INFORMATION CONTACT:
By mail: JoanneMiller, Registration Division (7505C), Office of PesticidePrograms, Environmental Protection Agency, 1200 PennsylvaniaAve., NW., Washington, DC 20460; telephone number: (703)305-6224; e-mail address: miller.joanne@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agriculturalproducer, food manufacturer or pesticide manufacturer.Potentially affected categories and entities may include, but arenot limited to:
| Categories | NAICS codes | Examples of potentially affected entities |
|---|---|---|
| Industry | 111 | Crop production |
| 112 | Animal production | |
| 311 | Food manufacturing | |
| 32532 | Pesticide manufacturing |
This listing is not intended to be exhaustive, but ratherprovides a guide for readers regarding entities likely to beaffected by this action. Other types of entities not listed inthe table could also be affected. The North American IndustrialClassification System (NAICS) codes have been provided to assistyou and others in determining whether or not this action mightapply to certain entities. If you have questions regarding theapplicability of this action to a particular entity, consult theperson listed under FOR FURTHER INFORMATIONCONTACT.
B. How Can I Get Additional Information, Including Copies ofthis Document and Other Related Documents?
1. Electronically . You may obtain electroniccopies of this document, and certain other related documents thatmight be available electronically, from the EPA Internet HomePage at http://www.epa.gov/. To access this document, on the HomePage select "Laws and Regulations,""Regulations and Proposed Rules," and then look upthe entry for this document under the " FederalRegister -Environmental Documents." You can alsogo directly to the Federal Register listings athttp://www.epa.gov/fedrgstr/.
2. In person . The Agency has established anofficial record for this action under docket control numberPF-966. The official record consists of the documentsspecifically referenced in this action, any public commentsreceived during an applicable comment period, and otherinformation related to this action, including any informationclaimed as confidential business information (CBI). This officialrecord includes the documents that are physically located in thedocket, as well as the documents that are referenced in thosedocuments. The public version of the official record does notinclude any information claimed as CBI. The public version of theofficial record, which includes printed, paper versions of any electronic comments submitted during an applicable commentperiod, is available for inspection in the Public Information andRecords Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2,1921 Jefferson Davis Highway, Arlington, VA, from 8:30 a.m. to 4p.m., Monday through Friday, excluding legal holidays. The PIRIBtelephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, orelectronically. To ensure proper receipt by EPA, it is imperativethat you identify docket control number PF-966 in thesubject line on the first page of your response.
1. By mail . Submit your comments to: PublicInformation and Records Integrity Branch (PIRIB), InformationResources and Services Division (7502C), Office of PesticidePrograms (OPP), Environmental Protection Agency, 1200Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier . Deliver yourcomments to: Public Information and Records Integrity Branch(PIRIB), Information Resources and Services Division (7502C),Office of Pesticide Programs (OPP), Environmental ProtectionAgency, Rm. 119, Crystal Mall #2, 1921 Jefferson DavisHighway, Arlington, VA. The PIRIB is open from 8:30 a.m. to 4p.m., Monday through Friday, excluding legal holidays. The PIRIBtelephone number is (703) 305-5805.
3. Electronically . You may submit your commentselectronically by e-mail to:"opp-docket@epa.gov", or you can submit acomputer disk as described above. Do not submit any informationelectronically that you consider to be CBI. Avoid the use ofspecial characters and any form of encryption. Electronicsubmissions will be accepted in Wordperfect 6.1/8.0 or ASCII fileformat. All comments in electronic form must be identified bydocket control number PF-966. Electronic comments may alsobe filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to theAgency?
Do not submit any information electronically that you considerto be CBI. You may claim information that you submit to EPA inresponse to this document as CBI by marking any part or all ofthat information as CBI. Information so marked will not bedisclosed except in accordance with procedures set forth in 40CFR part 2. In addition to one complete version of the commentthat includes any information claimed as CBI, a copy of thecomment that does not contain the information claimed as CBI mustbe submitted for inclusion in the public version of the officialrecord. Information not marked confidential will be included inthe public version of the official record without prior notice.If you have any questions about CBI or the procedures forclaiming CBI, please consult the person identified under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparingyour comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data youused that support your views.
4. If you estimate potential burden or costs, explain how youarrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in thisnotice.
7. To ensure proper receipt by EPA, be sure to identify thedocket control number assigned to this action in the subject lineon the first page of your response. You may also provide thename, date, and Federal Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing theestablishment and/or amendment of regulations for residues ofcertain pesticide chemical in or on various food commoditiesunder section 408 of the Federal Food, Drug, and Cosmetic Act(FFDCA), 21 U.S.C. 346a. EPA has determined that this petitioncontains data or information regarding the elements set forth insection 408(d)(2); however, EPA has not fully evaluated thesufficiency of the submitted data at this time or whether thedata support granting of the petition. Additional data may beneeded before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feedadditives, Food additives, Pesticides and pests, Reporting andrecordkeeping requirements.
Dated: August 23, 2000.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printedbelow as required by section 408(d)(3) of the FFDCA. The summaryof the petition was prepared by the petitioner and represents theview of the petitioner. The petition summary announces theavailability of a description of the analytical methods availableto EPA for the detection and measurement of the pesticidechemical residues or an explanation of why no such method isneeded.
Valent U.S.A. Company
PP 7F4841 and PP 0F6171
EPA has received the pesticide petitions (PP 7F4841 andOF6171) from Valent U.S.A Company, 1333 North CaliforniaBoulevard, Suite 600, Walnut Creek, California 94596-8025proposing, pursuant to section 408(d) of the Federal Food, Drug,and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part180 by establishing a tolerance for residues of2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2 H -1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro-1 H -isoindole-1,3(2 H )-dione in or on theraw agricultural commodities soybean seed and peanut nutmeat at0.01 parts per million (ppm) and on sugarcane cane at 0.2 ppm.EPA has determined that the petition contains data or informationregarding the elements set forth in section 408(d)(2) of theFFDCA; however, EPA has not fully evaluated the sufficiency ofthe submitted data at this time or whether the data supportsgranting of the petition. Additional data may be needed beforeEPA rules on the petition.
A. Residue Chemistry
Summary . Radiocarbon plant and animalmetabolism studies have demonstrated that the residue of concernis adequately understood for the purposes of these tolerances andis best defined as parent, flumioxazin. Practical, validatedresidue methodology is available to analyze all appropriatematrices for flumioxazin residue with a limit of quantification(LOQ) of 0.01 ppm, adequate to enforce all proposed tolerances.The potential magnitude of residues of flumioxazin has beenevaluated in peanuts, soybeans, and sugarcane and in appropriateprocessed products and animals. These studies are adequate to support appropriate tolerances and dietary risk analyses.
1. Plant metabolism . Metabolism of14 C-flumioxazin labelled in the phenyl- ortetrahydrophthalimido-rings has been studied in soybeans andpeanuts. Flumioxazin was rapidly and extensively metabolized tomany metabolites in both plants. Even with exaggerated treatment,individual metabolites and parent were only found at very lowconcentrations. Comparisons of metabolites detected andquantified from plants and animals show that there are nosignificant aglycones in plants which are not also present in theexcreta or tissues of animals. The residue of concern is bestdefined as the parent.
2. Ruminant and poultry metabolism . Metabolismstudies in goats and hens treated at very exaggerated doses(approximately 1,000X) demonstrated that transfer of administered14 C-flumioxazin residues to tissues was low (0.05 ppmin goats, 0.7 ppm in eggs).
3. Analytical method . Practical analyticalmethods for detecting and measuring levels of flumioxazin havebeen developed and validated in/on all appropriate agriculturalcommodities and respective processing fractions. The extractionmethodology has been validated using aged radiochemical residuesamples from14 C-metabolism studies. The enforcementmethod has been validated in soybean at an independent laboratoryand by EPA. The LOQ of flumioxazin in the methods is 0.01 ppmwhich will allow monitoring of food with residues at the levelsproposed for the tolerances.
4. Magnitude of residues - i. Soybean . Forty-two field trials in soybeans were conductedin 1989 through 1993 in EPA Regions II (2 trials), IV (9 trials,and V (31 trials), representing approximately 99%% of theU.S. soybean growing region. Treatments ranged from 0.09 to 0.47pounds active ingredient per acre, 1- to 5-times theproposed application rate. No residues of flumioxazin weredetected in soybean seed from any of the trials, even whenapplication rates were five times the proposed label rate.Analysis for the major plant metabolite, 1-OH-HPA, was conductedon seed samples from 13 residue trials. In all cases no residuesof the degradate were found, including two trials conducted at a5X treatment rate.
No residues of flumioxazin were found in any of the processedcommodities in two processing studies of soybeans treated at5-times the proposed label rate. In one of the processingstudies, no residue of 1-OH-HPA was found in any processedfraction.
All these data support a proposed tolerance for flumioxazinin/on soybean seed at 0.01 ppm, the LOQ of the enforcementmethod. No separate tolerances are needed for soybean processedcommodities.
ii. Peanut . Sixteen field trials in peanutswere conducted in 1992, 1993, and 1996 in EPA Regions II (eighttrials), III (three trials), IV (three trials), and VIII (twotrials), representing virtually all of the U.S. peanut growingregion. Treatments ranged from 0.09 to 0.47 pounds active peracre, 1- to 5-times the proposed application rate. No residues offlumioxazin were detected in any peanut seed sample from any ofthe trials, even when application rates were five times theproposed label rate. Analysis for the major plant metabolite,1-OH-HPA, was conducted on seed samples from one 5X processingtrial. No residues of the degradate were found.
No residues of flumioxazin were found in any of the processedcommodities in two processing studies of peanuts treated at5-times the proposed label rate. One of the processingstudies was analyzed for degradate, no residue of 1-OH-HPA wasfound in any processed fraction.
All these data support a proposed tolerance for flumioxazinin/on peanut seed at 0.01 ppm, the LOQ of the enforcement method.No separate tolerances are needed for peanut processedcommodities.
iii. Sugarcane . Nine field trials in sugarcanewere conducted in 1998 in EPA Regions III (4 trials), IV (3trials), VI (1 trial), and XIII (1 trial), representative of allof the U.S. sugarcane growing regions. Treatments ranged from0.37 to 1.12 pounds active per acre, 1- to 3-times theproposed application rate for high organic soils. Finite residuesof flumioxazin were detected in 14 of 18 duplicate samples.Residues of flumioxazin averaged 0.039 ppm (standard deviation= 0.033 ppm) from the trials conducted at the proposedmaximum application rate. Analysis for the major plantmetabolite, 1-OH-HPA, was conducted on all cane samples includingthose from the two 3X processing trials. No residues of thedegradate were found in any cane sample.
No residues of flumioxazin or its degradate were found in theprocessed commodity refined sugar. In molasses, produced fromcane treated at 3-times the proposed label rate,flumioxazin was detected (0.055 ppm) at approximately half of theconcentration in the starting sugarcane. The degradate, 1-OH-HPA,was also detected in molasses (0.036 ppm). Because thesedetections were in a processed sample from cane treated at 3X,and are still less than the proposed RAC tolerance, no separateprocessed product tolerances are necessary.
All these data support a proposed tolerance for flumioxazinin/on sugarcane at 0.2 ppm. No separate tolerances for parent ordegradate are needed for processed commodities.
iv. Secondary residues . Using proposedtolerances to calculate the maximum feed exposure to fed animals,and using the very low potential for residue transferdemonstrated in the goat and hen metabolism studies, detectablesecondary residues in animal tissues, milk, and eggs are notexpected. Therefore, no cow or hen residue feeding studies wereperformed, and tolerances are not proposed for these commodities.
v. Rotational crops . The results of a confinedrotational crops accumulation study indicate that no rotationalcrop planting restrictions or rotational crop tolerances arerequired.
B. Toxicological Profile
Summary . A full battery of toxicology testinghas been performed on flumioxazin including acute, chronic,oncogenicity, developmental, mutagenicity, and reproductiveeffects. Flumioxazin has low toxicity via oral and dermal routesand is not carcinogenic. Overall, it does not present a genetichazard. Although developmental and reproductive effects wereobserved in rats, acute and chronic dietary assessments andworker exposure assessments demonstrate large margins of safetywhen worst case exposures are compared to the proposed toxicendpoints, along with appropriate uncertainty factors. Valentproposes a chronic population adjusted dose (cPAD) of 0.018milligrams/kilograms/day (mg/kg/day) for adults and 0.0018mg/kg/day for women of child bearing age and infants and childrenbased on the no observed adverse effect level (NOAEL) of 1.8mg/kg/day for males in the rat 2-year chronic toxicityoncogenicity study. Valent also proposes 3.0 mg/kg/day as theacute oral endpoint based on the developmental toxicity NOAELfrom the rat oral developmental toxicity study.
1. Acute toxicity . The acute toxicity oftechnical grade flumioxazin is low by all routes. The battery ofacute toxicity studies place flumioxazin in Toxicity CategoryIII.
i. No abnormal clinical signs, body weight changes, or grosspathological findings were observed and no rats died followingadministration of an oral dose of 5 gram/kilogram (g/kg) offlumioxazin technical. The LD 50 was greater than 5g/kg.
ii. No deaths, abnormal clinical signs, body weightchanges, or gross pathological findings were observed in ratsexposed to a 2.0 g/kg dermal dose of flumioxazin technical. TheLD 50 was greater than 2.0 g/kg.
iii. Rats were exposed to a dust aerosol of flumioxazintechnical for four hours at measured concentrations of 1.55 or3.93 milligram per liter (mg/l), the maximum attainableconcentration. Irregular respiration, bradypnea and a decrease inspontaneous activity were observed in many of the rats, but theseeffects disappeared within two hours after termination of theexposure. No deaths, body weight changes, gross pathologicalfindings or histopathological changes in the respiratory organswere observed. The LC 50 for flumioxazin technicalwas determined to be greater than 3.93 mg/l.
iv. Flumioxazin technical produced minimal eye irritation inrabbits which cleared within 48 hours.
v. Flumioxazin technical did not produce any signs of skinirritation in abraded or intact skin of rabbits.
vi. Flumioxazin technical was not a skin sensitizer whentested in guinea pigs using the Magnussen and Kligmanmaximization test methodology.
2. Genotoxicity . Flumioxazin does not presenta genetic hazard. Flumioxazin was evaluated in the followingtests for mutagenicity:
i. A reverse gene mutation assay in Salmonellatyphimurium and Escherichia coli was negativewith or without metabolic activation.
ii. An in vitro chromosome aberration assayusing Chinese hamster ovary (CHO) cells was negative in theabsence of metabolic activation. However, an increase in cellswith aberrations was observed at doses of 1 × 10 -4 M and higher in the presence of S9.
iii. An in vivo chromosomal aberration studyin the rat was negative. No significant increase in theincidence of chromosomal aberrations in bone marrow cells wasobserved following treatments as high as 5,000 mg/kg.
iv. An in vitro unscheduled DNA synthesis(UDS) assay with rat hepatocytes was negative.
v. A mouse micronucleus assay was negative followingintraperitoneal injection of 5,000 mg/kg.
3. Reproductive and developmental toxicity .Flumioxazin shows developmental toxicity in the absence ofmaternal toxicity in rats. Mechanistic studies demonstrate thatthe effect is specifically related to the inhibition of hemesynthesis, that the effect shows considerable speciesspecificity, and that the rat is a conservative surrogate speciesfor the potential for developmental toxicity in man. Nodevelopmental toxicity was observed in rabbits. Developmentaltoxicity to the pups was seen in the rat reproduction study atdoses that were not toxic to the parental animals.
i. Rat - Developmentaltoxicity . A pilot dose range-finding study was conducted todetermine appropriate doses for the definitive oral developmentaltoxicity study. Flumioxazin technical was administered by oralgavage at dosages of 0, 30, 100, 200 and 500 mg/kg/day topregnant rats on days 6 through 15 of gestation. No animals diedduring the course of this study and maternal toxicity was limitedto decreased weight gain associated with high embryolethalityobserved in all dose groups. Fetuses obtained from the 30mg/kg/day dams had significantly reduced body weights and werefound to have both skeletal and visceral abnormalities primarilywavy ribs and ventricular septal defects (VSD). Because of thehigh degree of embryolethality at doses of 100 mg/kg/day andgreater, the highest dose selected for the definitive study was30 mg/kg/day.
In the definitive study, pregnant rats were administered oraldoses of 0, 1, 3, 10 or 30 mg/kg/day of flumioxazin technical ondays 6 through 15 of gestation. No maternal deaths were observedat any dosage and no treatment-related effects on clinical signsor food consumption were noted. A decrease in maternal bodyweight gain was found at 30 mg/kg/day. The number of live fetusesand fetal body weights were decreased in the 30 mg/kg/day groupand the incidence of embryo mortality tended to be higher but wasnot statistically significant. No effects on the number ofimplantations, sex ratios, or external abnormalities were found.The incidence of fetuses with cardiovascular abnormalities,primarily VSD, was increased in the 30 mg/kg/day group. Otherdevelopmental effects observed at 30 mg/kg/day included anincrease in the incidence of wavy ribs and curvature of thescapula, and a decrease in the number of ossified sacrococcygealvertebral bodies. Based on these findings, a maternal NOAEL of 30mg/kg/day and a developmental NOAEL of 3 mg/kg/day are proposed.
In a range-finding dermal developmental toxicity studyflumioxazin technical was administered dermally at levels of 100,200, 400 and 800 mg/kg/day in corn oil. No adverse effects on thedams were observed at doses up to 800 mg/kg/day. Because of thehigh degree of embryolethality at doses of 400 mg/kg/day andgreater, the highest dose selected for the definitive study was300 mg/kg/day.
On days 6-15 of gestation, pregnant rats were exposeddermally to dose levels of 30, 100, or 300 mg/kg/day offlumioxazin technical in corn oil. No adverse effects wereobserved in the dams throughout the study. Increased fetalmortality was accompanied by decreases in the number of livefetuses and fetal body weights at doses of 300 mg/kg/day. Noexternal abnormalities were observed at any dose level. Anincrease in cardiovascular abnormalities, primarily VSD, anincrease in wavy ribs and a decrease in the number of ossifiedsacrococcygeal vertebral bodies was observed at 300 mg/kg/day.Based on these results, a maternal NOAEL of 300 mg/kg/day and adevelopmental NOAEL of 30 mg/kg/day are proposed.
To measure the dermal penetration of flumioxazin under theconditions of the dermal teratology study, 13-day pregnantrats were dermally exposed to phenyl-14 C-flumioxazin. Thesystemic absorption ranged from 3.8%% at 2 hours to6.9%% of the recovered14 C at 48 hours.
ii. Mechanistic Studies . A series of scientificstudies were conducted to examine the mechanism and speciesdifferences in the production of developmental toxicity byflumioxazin. This research demonstrates clear species differencesbetween rats, rabbits, mice, and (in vitro) humans and indicatesa high degree of correlation between the interruption of hemesynthesis and the production of developmental toxicity in rats.The data support that the rat is a conservative model for use inthe risk assessment for humans. Specifically the studiesdemonstrate that:
• Flumioxazin interferes with normal heme biosynthesisresulting in sidroblastic anemia and porphyria in adult rats.
•14 C-Flumioxazin administered to pregnant ratson day 12 of gestation crosses the placenta and reaches the ratfetus at maximum levels of radiocarbon (and flumioxazin), 4 hourslater.
• No clear pattern of adsorption, distribution,metabolism, or excretion was evident which could account for thespecies-specific development toxicity in rats.
• The critical period of sensitivity to thedevelopmental effects of flumioxazin in rats is day 12 ofgestation. This correlates with the peak period of protoporphyrinIX (PPIX) accumulation in maternal rat liver and the rat fetus.
• A histological examination of rat fetus indicatedsigns of fetal anemia within 6 hours after dosing, but nohistological changes in the fetal rat heart were observed until36 or 48 hour after treatment. No effects were observed in rabbitfetus treated in the same manner as the rats.
• Other observations in the pathogenesis of thedevelopmental effects of flumioxazin in rat fetuses included:enlarged heart, edema, anemia (decreased red blood cell count andhemoglobin), delayed closure of the interventricular foramen,reduced serum protein and incomplete/delayed ossification of theribs.
• The observation of enlarged heart, edema and anemiapreceding the occurrence of fetal mortality suggest these effectsmay be instrumental in the cause of fetal deaths.
• The occurrence of an enlarged heart preceding thefailure of interventricular foramen closure could be related tothe pathogenesis rather than a direct toxic effect of flumioxazinon cardiac tissue.
• A strong correlation exists between PPIXaccumulation, an indicator of disrupted heme synthesis, anddevelopmental toxicity. Evidence of this correlation exists onthe basis of species differences between rats and rabbits; thecritical period of sensitivity in the rat; and compound-specificdifferences with two chemicals structurally related toflumioxazin, one which produces developmental effects in rats andone which does not.
iii. Rabbits . In a pilot dose range-findingstudy in rabbits, flumioxazin technical was administered torabbits on days 7 through 19 of gestation via oral intubation atdosages of 0, 300, 500, 1,000 and 1,500 mg/kg/day. Clinicalobservations were recorded and on day 29 of gestation, all doeswere sacrificed, caesarean sectioned, and examined for grosslesions, number of corpora lutea, and number and placement ofimplantation sites, early and late resorptions and live and deadfetuses. No deaths, abortions or premature deliveries occurredduring this study. Dosages of flumioxazin technical as high as1,500 mg/kg/day did not result in significant clinical ornecropsy observations nor affect maternal body weight gains orfeed consumption values. Similarly, there were no adverse effectsof dosages of flumioxazin technical up to 1,500 mg/kg/day onembryo-fetal viability, sex ratios, body weights or externalmorphology.
Based on these results, pregnant rabbits were administered0, 300, 1,000, or 3,000 mg/kg/day of flumioxazin technical ondays 7-19 of gestation by oral gavage. The highest dose waswell in excess of the 1,000 mg/kg/day limit dose fordevelopmental toxicity studies. The 3,000 mg/kg/day dosage tendedto reduce maternal body weight gains and relative and absolutefeed consumption values. No gross lesions were produced at anydose level. The 3,000 mg/kg/day dosage group litters tended tohave reduced fetal body weights but these differences were notstatistically different. No fetal external, soft tissue, orskeletal malformations or variants were attributable to the testsubstance. Based on these data, the maternal NOAEL was 1,000mg/kg/day and the developmental NOAEL was 3,000 mg/kg/day.
iv. Reproduction . Two pilot range-finding ratreproduction studies were conducted with flumioxazin technical atdosages from 100 to 5,000 ppm in the diet. In the definitive2-generation reproduction study in the rat dietary levelsof 0, 50, 100, 200 and 300 ppm established a systemic NOAEL of200 ppm based on increased clinical signs (both sexes andgenerations); mortality, gross and histopathology findings in theliver (F 1 females); decreased body weight/weightgain (F 0 and F 1 females duringgestation, F 1 males during premating) and decreasedfood consumption (F 0 and F 1 femalesduring lactation). The reproductive NOAEL of 100 ppm was mainlybased on developmental toxicity at 200 ppm. Observed at 200 ppmwere a decreased number of liveborn pups and reduced pup bodyweights. At 300 ppm the following effects were observed:decreased pup body weight (both generations); decreased number oflive pups/litter and viability index (both generations);increased incidence of abnormalities of the reproductive organs(predominately atrophied or hypoplastic testes and/orepididymides in F 1 males); decreased gestationindex (F 0 females); decreased mating and fertilityindices (F 1 males) and increased clinical signs(F 1 pups).
4. Subchronic toxicity . Subchronic toxicitystudies conducted with flumioxazin technical in the rat (oral anddermal), mouse and dog indicate a low level of toxicity. Effectsobserved at high dose levels consisted primarily of anemia andhistological changes in the spleen, liver and bone marrow relatedto the anemia.
i. Rats . A 90-day subchronic toxicitystudy was conducted in rats, with dietary intake levels of 0, 30,300, 1,000 and 3,000 ppm flumioxazin technical (98.4%%purity). The NOAEL of 300 ppm was based on decreased bodyweights; anemia; increases in absolute and/or relative liver,kidney, brain heart and thyroid weights; and histological changesin the spleen, liver and bone marrow related to the anemia.
A second 90-day subchronic toxicity study wasconducted with a sample of Flumioxazin Technical of typicalpurity (94.8%) at dietary concentrations of 0, 30, 300, 1,000 and3,000 ppm. The NOAEL was 30 ppm based on anemia and relatedhematological changes; increases in liver, heart, kidney andthyroid weights; and histological changes in the spleen, liverand bone marrow related to the anemia.
ii. Mice . Dose levels for the mouseoncogenicity study were selected on the basis of results from a4-week study of flumioxazin in the diets of mice at levelsof 0, 1,000, 3,000 and 10,000 ppm. In this range-finding study,increases in absolute and/or relative liver weights were notedfor males at 10,000 ppm and at 3,000 and 10,000 ppm for females.
iii. Dogs . A 90-day study was conductedin dogs given gelatin capsules containing 0, 10, 100 or 1,000mg/kg/day. The NOAEL of 10 mg/kg/day for this study was based ona slight prolongation of activated partial thromboplastin time;increased total cholesterol and phospholipid and elevatedalkaline phosphatase activity; increased absolute and relativeliver weights; and histological changes in the liver.
iv. A 21-day dermal toxicity study was conducted inrats at dose levels of 0, 100, 200 or 1,000 mg/kg/day. The NOAELwas determined to be 300 mg/kg/day based on significantlydecreased hemoglobin and hematocrit values for females.
5. Chronic toxicity . Flumioxazin technicalhas been tested in chronic studies with dogs, rats and mice.Valent proposes a chronic oral endpoint of 1.8 mg/kg bw/day,based on the NOAEL for male rats in the 2-year chronictoxicity oncogenicity feeding study.
i. Rats . In a 2-year study in rats,flumioxazin technical administered in the diet at levels of 0,50, 500, and 1,000 ppm produced anemia and chronic nephropathy inrats of the 500 and 1,000 ppm groups. The anemia lastedthroughout the treatment period, however, it was not progressivenor aplastic in nature. No evidence of an oncogenic effect wasobserved in rats and the NOAEL for this study was 50 ppm (1.8mg/kg/day for males and 2.2 mg/kg/day for females).
ii. Mice . Flumioxazin technical wasadministered to mice at doses of 0, 300, 3,000, and 7,000 ppm indiet for 78 weeks. An increased incidence of hypertrophy ofcentrilobular hepatocytes was observed in males of the 3,000 and7,000 ppm groups. Increases in the incidence of diffusehypertrophy and single cell necrosis of hepatocytes were observedin females of the 3,000 and 7,000 ppm groups. There was noevidence of any treatment-related effect on the incidence oftumors. Flumioxazin technical was not carcinogenic to mice, andthe NOAEL for this study was 300 ppm (31.1 mg/kg/day for malesand 36.6 mg/kg/day for females).
iii. Dogs . Flumioxazin technical wasadministered to dogs in capsules at daily doses of 0, 10, 100,and 1,000 mg/kg bw/day for 1-year. Treatment-relatedchanges in blood biochemistry included increased totalcholesterol and phospholipid values, elevated alpha-2-globulinratio at 1,000 mg/kg/day and increased alkaline phosphataseactivity in the 100 and 1,000 mg/kg/day groups. The absoluteand/or relative liver weights were elevated in one animal in the100 mg/kg/day group and four animals of the 1,000 mg/kg/daygroup. Minimal treatment-related histological changes were notedin the livers of animals at the 1,000 mg/kg/day group. Based onthese data the NOAEL was determined to be 10 mg/kg/day.
iv. Carcinogenicity . Flumioxazin is not acarcinogen. Adequately designed studies with both rats and micehave shown that repeated high dose exposures produced anemia,liver effects and nephropathy, but did not produce cancer in testanimals. No oncogenic response was observed in a rat two-yearchronic feeding/oncogenicity study or in a 78 week study on mice.Valent anticipates that the oncogenicity classification offlumioxazin will be "E" (no evidence ofcarcinogenicity for humans).
6. Animal metabolism . The absorption, tissuedistribution, metabolism and excretion ofphenyl-14 C-labeled flumioxazin were studied in rats aftersingle oral doses of 1 or 100 mg/kg, and after a single oral doseof 1 mg/kg following 14 daily oral doses at 1 mg/kg of unlabelledmaterial. For all dose groups, most (97.9-102.3%%) of theadministered radiolabel was excreted in the urine and feceswithin seven days after radiolabeled test material dosing.Radiocarbon tissue residue levels were generally low on theseventh day post-dosing. Radiocarbon residues were higher inblood cells than tissues. Tissue14 C-residue levels,including those for fat, were lower than blood levels whichsuggests little potential for bioaccumulation. Urinaryradiocarbon excretion was greater in females than males in alldose groups.
Flumioxazin was extensively metabolized by rats and 35metabolites were detected and quantitated. The main metabolicreactions in rats were (1) hydroxylation of thetetrahydrophthalimide moiety; (2) incorporation of the sulfonicacid group into the tetrahydrophthalimide moiety; (3) cleavage ofthe imide linkage; (4) cleavage of the benzoxazinoneamide and;(5) acetylation of the aniline nitrogen group.
7. Metabolite toxicology . Metabolism studiesof flumioxazin in rats, goats, hens, soybeans, and peanuts, aswell as the fish bioaccumulation study demonstrate that theparent is very rapidly metabolized and, in animals, eliminated.The metabolites detected and quantified from plants and animalsshow that there are no significant aglycones in plants which arenot also present in the excreta or tissues of animals. Becauseparent and metabolites are not retained in the body, thepotential for acute toxicity from in situ formed metabolites islow. The potential for chronic toxicity is adequately tested bychronic exposure to the parent at the MTD and consequent chronicexposure to the internally formed metabolites.
8. Endocrine disruption . No special studiesto investigate the potential for estrogenic or other endocrineeffects of flumioxazin have been performed. However, assummarized above, a large and detailed toxicology data baseexists for the compound including studies in all requiredcategories. These studies include acute, sub-chronic, chronic,developmental, and reproductive toxicology studies includingdetailed histology and histopathology of numerous tissues,including endocrine organs, following repeated or long termexposures. These studies are considered capable of revealingendocrine effects. The results of all of these studies show noevidence of any endocrine-mediated effects and no pathology ofthe endocrine organs. Consequently, it is concluded thatflumioxazin does not possess estrogenic or endocrine disruptingproperties.
C. Aggregate Exposure
1. Dietary exposure . A full battery oftoxicology testing including studies of acute, chronic,oncogenicity, developmental, mutagenicity, and reproductiveeffects is available for flumioxazin. EPA has not had theopportunity to review all of the toxicity studies on flumioxazinand has not established toxic endpoints. Thus, in these riskassessments Valent proposes as chronic oral toxic endpoint theNOAEL for males from the rat chronic/oncogenicity feeding study,1.8 mg/kg/day; and as the acute oral toxic endpoint the NOAEL(proposed by EPA) from the rat oral developmental toxicity studyof 3.0 mg/kg/day. Because the acute oral endpoint is for fetaltoxicity to rats, Valent has chosen to use the full, extra 10Xuncertainty factor for appropriate sub-groups of the populationas mandated by FQPA.
i. Food . Acute dietary exposure toflumioxazin residues was calculated for the U.S. population,Women 13 years and older, and five children subgroups. Thecalculated exposure values are very conservative becausetolerance-level residues and 100%% of the crop treated areassumed. The calculated exposures and margins of exposure (MOE)for the higher exposed proportions of the subgroups are listed intable 1 below. In all cases, margins of exposure relative to theacute endpoint from the rat oral developmental toxicity studyexceed 1,000.
| Population Subgroup | 95th percentile | Exposure (mg/kg/day) | MOE | 99.9th percentile | Exposure (mg/kg/day) | MOE |
|---|---|---|---|---|---|---|
| Total U.S.Population | 0.000226 | 13,260 | 0.000791 | 3,791 | ||
| Women 13 Years andOlder | 0.000146 | 20,592 | 0.000379 | 7,916 | ||
| Children 7 to 12Years | 0.000295 | 10,165 | 0.000758 | 3,956 | ||
| Children 1 to 6Years | 0.000397 | 7,559 | 0.000937 | 3.202 | ||
| All Infants | 0.000801 | 3,744 | 0.001414 | 2,121 | ||
| Non-Nursing Infants(Less than 1 yr old) | 0.000861 | 3,483 | 0.001417 | 2,117 | ||
| Nursing Infants (Less than 1 yr old) | 0.000338 | 8,877 | 0.001244 | 2,411 |
ii. Chronic dietary exposures to flumioxazin residues wascalculated for the U.S. population and 25 population subgroups.This Tier I analysis assumes tolerance-level residues and100%% of the crops treated. The results from severalrepresentative subgroups are listed in table 2 below. Allcalculated chronic dietary exposures were below 13%% of thec-PAD. The c-PAD was defined as the NOAEL from the rat oral2-year combined chronic toxicity oncogenicity study (1.8mg/kg/day for males) divided by the 100X uncertainty factor forthe adult exposures (0.018 mg/kg/day), or divided by 1,000 toinclude the extra 10X uncertainty factor for adult females ofchild-bearing age and infant and children population subgroups(0.0018 mg/kg/day). Generally speaking, the Agency has no causefor concern if total residue contribution for published andproposed tolerances is less than 100%% of the c-PAD.
| Population Subgroup | Exposure (mg/kg/day) | Percent of cPAD |
|---|---|---|
| Total U.S. Population(total) (0.018) * | 0.000075 | 0.42 |
| Females 13+(nursing) (0.0018) * | 0.000053 | 2.94 |
| Females 13+(pregnant/not nursing) (0.0018) * | 0.000070 | 3.89 |
| Children 7-12 yrs(0.018) * | 0.000132 | 0.73 |
| Children 1-6 yrs(0.0018) * | 0.000163 | 9.06 |
| All Infants (Less than1 Year) (0.0018) * | 0.000190 | 10.56 |
| Non-Nursing Infants(0.0018) * | 0.000229 | 12.72 |
| Nursing Infants (0.0018) * | 0.000058 | 3.22 |
| * cPAD value used to calculate percentof occupancy. | ||
iii. Drinking water . Since flumioxazin isapplied outdoors to growing agricultural crops, the potentialexists for the parent or its metabolites to reach ground orsurface water that may be used for drinking water. Because of thephysical properties of flumioxazin, it is unlikely thatflumioxazin or its metabolites can leach to potable groundwater.To quantify potential exposure from drinking water, surface waterconcentrations for flumioxazin were estimated using genericexpected environmental concentration (GENEEC) 1.2. Because K OC could not be measured directly inadsorption-desorption studies because of chemical stability,GENEEC values representative of a range of K OC values were modeled. The simulation that was selected for theseexposure estimates used a K OC of 150, indicatinghigh mobility. The peak GEEC concentration predicted in thesimulated pond water was 12.59 ppb. Using standard assumptionsabout body weight and water consumption, the acute exposure fromthis drinking water would be 0.00036 and 0.0013 mg/kg/day foradults and children, respectively. The 56-day GEEC concentrationpredicted in the simulated pond water was 0.45 ppb. Chronicexposure from this drinking water would be 0.0000129 and 0.000045mg/kg/day for adults and children, respectively; 2.5%% ofthe c-PAD of 0.0018 mg/kg/day for children. Based on this worsecase analysis, the contribution of drinking water to the dietaryexposure is comparable to that from food, but the risk is stillnegligible.
2. Non-dietary exposure . Flumioxazin isproposed only for agricultural uses and no homeowner, turf, orindustrial uses. Thus, no non-dietary risk assessment is needed.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider"available information" concerning the cumulativeeffects of a particular pesticide's residues and "othersubstances that have a common mechanism of toxicity."Available information in this context include not only toxicity,chemistry, and exposure data, but also scientific policies andmethodologies for understanding common mechanisms of toxicity andconducting cumulative risk assessments. For most pesticides,although the Agency has some information in its files that mayturn out to be helpful in eventually determining whether apesticide shares a common mechanism of toxicity with any othersubstances, EPA does not at this time have the methodologies toresolve the complex scientific issues concerning common mechanismof toxicity in a meaningful way.
There are other pesticidal compounds that are structurallyrelated to flumioxazin and have similar effects on animals. Inconsideration of potential cumulative effects of flumioxazin andother substances that may have a common mechanism of toxicity,there are currently no available data or other reliableinformation indicating that any toxic effects produced byflumioxazin would be cumulative with those of other chemicalcompounds. Thus, only the potential risks of flumioxazin havebeen considered in this assessment of aggregate exposure andeffects.
Valent will submit information for EPA to consider concerningpotential cumulative effects of flumioxazin consistent with theschedule established by EPA in the Federal Register (August 4, 1997) (62 FR 42020) (FRL-5734-4) andother subsequent EPA publications pursuant to the Food QualityProtection Act (FQPA).
E. Safety Determination
The FQPA of 1996 introduced a new standard of safety, areasonable certainty of no harm. To make this determination, atthis time the Agency should consider only the incremental risk offlumioxazin in its exposure assessment. Since the potentialchronic and acute exposures to flumioxazin are small (much lessthan 100%% of c-PAD, MOE much more greater than 1,000) theprovisions of the FQPA of 1996 will not be violated.
1. U.S. population - i. Acuterisk . The potential acute exposure from food to the U.S.population and various non-child/infant population subgroups(shown above) provide MOE values exceeding 1,000. Addition of theworse case, but small "background" dietary exposurefrom water reduces the MOE value at the 99.9 percentile from3,791 to 2,606. In a conservative policy, the Agency has no causefor concern if total acute exposure to adults calculated for the99.9th percentile yields a MOE of 100 or larger. For Women ofchild bearing age where an MOE of 1,000 or larger is appropriate,the addition of water to the diet of women, 13 years and older,reduces the MOE (99.9 percentile) from 20,592 to 7,916. It can beconcluded that there is a reasonable certainty that no harm willresult to the overall U.S. Population and many non- child/infantsubgroups from aggregate, acute exposure to flumioxazin residues.
ii. Chronic risk . Using the dietary exposureassessment procedures described above for flumioxazin, calculatedchronic dietary exposure resulting from residue exposure fromproposed uses of flumioxazin is minimal. The estimated chronicdietary exposure from food for the overall U.S. Population andmany non-child/infant subgroups is 0.42 to 3.89%% of theappropriate c-PAD. Addition of the small but worse casepotential exposure from drinking water (calculated above)increases exposure by 0.000013 mg/kg /day and the maximumoccupancy of the c-PAD from 3.89%% to 5.22%% (women13 +). Generally, the Agency has no cause for concern if totalresidue contribution is less than 100%% of the appropriatec-PAD. It can be concluded that there is a reasonable certaintythat no harm will result to the overall U.S. Population and manynon-child/infant subgroups from aggregate, chronic exposure toflumioxazin residues.
2. Infants and children - Safetyfactor for infants and children . In assessing the potentialfor additional sensitivity of infants and children to residues offlumioxazin, FFDCA section 408 provides that EPA shall apply anadditional margin of safety, up to ten-fold, for added protectionfor infants and children in the case of threshold effects unlessEPA determines that a different margin of safety will be safe forinfants and children.
i. Children . The toxicological data base forevaluating prenatal and postnatal toxicity for flumioxazin iscomplete with respect to current data requirements. Developmentaltoxicity was observed by both oral and dermal routes in rats.Therefore, reliable data support use of the standard 100-folduncertainty factor and an additional uncertainty factor of 10Xfor flumioxazin to be further protective of infants and children.
ii. Developmental toxicity studies .Flumioxazin shows developmental toxicity in the absence ofmaternal toxicity in rats. Mechanistic studies demonstrate thatthe effect is specifically related to the inhibition of hemesynthesis, that the effect shows considerable speciesspecificity, and that the rat is a conservative surrogate speciesfor the potential for developmental toxicity in man. Nodevelopmental toxicity was observed in rabbits. Developmentaltoxicity to the pups was seen in the rat reproduction study atdoses that were not toxic to the parental animals.
a. Rats . In the definitive rat oraldevelopmental toxicity study, pregnant rats were administeredoral doses of 0, 1, 3, 10 or 30 mg/kg/day of flumioxazintechnical on days 6 through 15 of gestation. No maternal deathswere observed at any dosage and no treatment-related effects onclinical signs or food consumption were noted. A decrease inmaternal bodyweight gain was found at 30 mg/kg/day. The number of live fetusesand fetal body weights were decreased in the 30 mg/kg/day groupand the incidence of embryo mortality tended to be higher but wasnot statistically significant. No effects on the number ofimplantations, sex ratios, or external abnormalities were found.The incidence of fetuses with cardiovascular abnormalities,primarily VSD, was increased in the 30 mg/kg/day group. Otherdevelopmentaleffects observed at 30 mg/kg/day included an increase in theincidence of wavy ribs and curvature of the scapula, and adecrease in the number of ossified sacrococcygeal vertebralbodies. Based on these findings, a maternal NOAEL of 30 mg/kg/dayand a developmental NOAEL of 3 mg/kg/day are proposed.
On days 6-15 of gestation, pregnant rats were exposeddermally to dose levels of 30, 100, or 300 mg/kg/day offlumioxazin technical in corn oil. No adverse effects wereobserved in the dams throughout the study. Increased fetalmortality was accompanied by decreases in the number of livefetuses and fetal body weights at doses of 300 mg/kg/day. Noexternal abnormalities were observed at any dose level. Anincrease in cardiovascular abnormalities, primarily VSD, anincrease in wavy ribs and a decrease in the number of ossifiedsacrococcygeal vertebral bodies was observed at 300 mg/kg/day.Based on these results, a maternal NOAEL of 300 mg/kg/day and adevelopmental NOAEL of 30 mg/kg/day are proposed.
To measure the dermal penetration of flumioxazin under theconditions of the dermal teratology study, 13-day pregnantrats were dermally exposed to phenyl-14 C-flumioxazin. Thesystemic absorption ranged from 3.8%% at 2 hours to6.9%% of the recovered14 C at 48 hours.
b. Mechanistic Studies . A series of scientificstudies were conducted to examine the mechanism and speciesdifferences in the production of developmental toxicity byflumioxazin. This research demonstrates clear species differencesbetween rats, rabbits, mice, and ( in vitro ) humansand indicates a high degree of correlation between theinterruption of heme synthesis and the production ofdevelopmental toxicity in rats. The data support that the rat isa conservative model for use in the risk assessment for humans.Specifically the studies demonstrate that:
• Flumioxazin interferes with normal heme biosynthesisresulting in sidroblastic anemia and porphyria in adult rats.
•14 C-Flumioxazin administered to pregnant ratson day 12 of gestation crosses the placenta and reaches the ratfetus at maximum levels of radiocarbon (and flumioxazin), 4 hourslater.
• No clear pattern of adsorption, distribution,metabolism, or excretion was evident which could account for thespecies-specific development toxicity in rats.
• The critical period of sensitivity to thedevelopmental effects of flumioxazin in rats is day 12 ofgestation. This correlates with the peak period of protoporphyrinIX (PPIX) accumulation in maternal rat liver and the rat fetus.
• A histological examination of rat fetus indicatedsigns of fetal anemia within 6 hours after dosing, but no histological changes in the fetal rat heart were observed until36 or 48 hour after treatment. No effects were observed in rabbitfetus treated in the same manner as the rats.
• Other observations in the pathogenesis of thedevelopmental effects of flumioxazin in rat fetuses included:enlarged heart, edema, anemia (decreased red blood cell count andhemoglobin), delayed closure of the interventricular foramen,reduced serum protein and incomplete/delayed ossification of theribs.
• The observation of enlarged heart, edema and anemiapreceding the occurrence of fetal mortality suggest these effectsmay be instrumental in the cause of fetal deaths.
• The occurrence of an enlarged heart preceding thefailure of interventricular foramen closure could be related tothe pathogenesis rather than a direct toxic effect of flumioxazinon cardiac tissue.
• A strong correlation exists between PPIXaccumulation, an indicator of disrupted heme synthesis, anddevelopmental toxicity. Evidence of this correlation exists onthe basis of species differences between rats and rabbits; thecritical period of sensitivity in the rat; and compound-specificdifferences with two chemicals structurally related toflumioxazin, one which produces developmental effects in rats andone which does not.
c. Rabbits. Pregnant rabbits wereadministered 0, 300, 1,000, or 3,000 mg/kg/day of flumioxazintechnical on days 7-19 of gestation by oral gavage. The highestdose was well in excess of the 1,000 mg/kg/day limit dose fordevelopmental toxicity studies. The 3,000 mg/kg/day dosage tendedto reduce maternal body weight gains and relative and absolutefeed consumption values. No gross lesions were produced at anydose level. The 3,000 mg/kg/day dosage group litters tended tohave reduced fetal body weights but these differences were notstatistically different. No fetal external, soft tissue, orskeletal malformations or variants were attributable to the testsubstance. Based on these data, the maternal NOAEL was 1,000mg/kg/day and the developmental NOAEL was 3,000 mg/kg/day.
iii. Reproductive toxicity study. In the2-generation reproduction study in the rat dietary levelsof 0, 50, 100, 200 and 300 ppm established a systemic NOAEL of200 ppm based on increased clinical signs (both sexes andgenerations); mortality, gross and histopathology findings in theliver (F 1 females); decreased body weight/weightgain (F 0 and F 1 females duringgestation, F 1 males during premating) and decreasedfood consumption (F 0 and F 1 femalesduring lactation). The reproductive NOAEL of 100 ppm was mainlybased on developmental toxicity at 200 ppm. Observed at 200 ppmwere a decreased number of liveborn pups and reduced pup bodyweights. At 300 ppm the following effects were observed:decreased pup body weight (both generations); decreased number oflive pups/litter and viability index (both generations);increased incidence of abnormalities of the reproductive organs(predominately atrophied or hypoplastic testes and/orepididymides in F 1 males); decreased gestationindex (F 0 females); decreased mating and fertilityindices (F 1 males) and increased clinical signs(F 1 pups).
iv. Prenatal and postnatal sensitivity. Flumioxazin interferes with normal heme biosynthesis resulting insidroblastic anemia and porphyria in adult rats. Clear speciesdifferences between rats, rabbits, mice, and ( invitro ) humans were demonstrated. There is a high degree ofcorrelation between the interruption of heme synthesis,consequent PPIX accumulation, and the production of developmentaltoxicity in rats. The data support that the rat is a conservativemodel for use in the risk assessment for humans.
v. Acute exposure and risk . The potentialacute exposure from food to the various child and infantpopulation subgroups (shown above) all provide MOE valuesexceeding 1,000. Addition of the worse case, but small"background" dietary exposure from water (0.00126mg/kg/day) to the 99.9 percentile food exposure for infantsreduces the MOE value from 2,117 to 1,121. In a conservativepolicy with the addition of the FQPA extra 10X uncertaintyfactor, the Agency has no cause for concern if total acuteexposure to infants and children calculated for the 99.9thpercentile yields a MOE of 1,000 or larger. It can be concludedthat there is a reasonable certainty that no harm will result toinfants and children from aggregate, acute exposure toflumioxazin residues.
vi. Chronic exposure and risk. Using theconservative exposure assumptions described above, the percentageof the c-PAD that will be utilized by dietary (food only)exposure to residues of flumioxazin ranges from 0.73%% forchildren 7-12 years, to 12.72%% for Non-Nursing Infants.Adding the worse case potential incremental exposure to infantsand children from flumioxazin in drinking water (0.000045mg/kg/day) increases the aggregate, chronic dietary exposure by2.5%%. The addition of the exposure attributable todrinking water increases the occupancy of the c-PAD forNon-Nursing Infants to 15.22%%. EPA generally has noconcern for exposures below 100%% of the c-PAD because theC-PAD, in this case including the extra 10X FQPA uncertaintyfactor, represents the level at or below which daily aggregatedietary exposure over a lifetime will not pose appreciable risksto human health. It can be concluded that there is a reasonablecertainty that no harm will result to infants and children fromaggregate, chronic exposure to flumioxazin residues.
vii. Determination of safety - Safety determination summary . Aggregate acute orchronic dietary exposure to various sub-populations of childrenand adults demonstrate acceptable risk. Chronic dietary exposuresto flumioxazin occupy considerably less than 100% of theappropriate c-PAD, and all acute dietary MOE values exceed 1,000.Chronic and acute dietary risk to children from flumioxazinshould not be of concern. Further, flumioxazin has onlyagricultural uses and no other uses, such as indoor pest control,homeowner or turf, that could lead to unique, enhanced exposuresto vulnerable sub-groups of the population. It can be concludedthat there is a reasonable certainty that no harm will result tothe U.S. Population or to any sub-group of the U.S. population,including infants and children, from aggregate chronic oraggregate acute exposures to flumioxazin residues resulting fromproposed uses.
F. International Tolerances
Flumioxazin has not been evaluated by the JMPR and there areno Codex Maximum Residue Limits (MRL) for flumioxazin. MRL valuesshown in the following table 3 have been established to allow theuses of flumioxazin in the following countries.
| Country | Crop | Maximum residue limits (ppm) |
|---|---|---|
| Brazil | Soybean | 0.05 |
| Argentina | Soybean | 0.015 |
| Sunflower | 0.02 | |
| Paraguay | Soybean | 0.02 |
| South Africa | Soybean | 0.02 |
| Groundnut | 0.02 |
[FR Doc. 00-22816 Filed 9-5-00; 8:45 am]
BILLING CODE6560-50-S