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CFR Citation: 40 CFR Part 180

OPP ID: [OPP-2003-0125; FRL-7302-3]

NOTICE: PROPOSED RULES

ACTION: Pesticides; tolerances in food, animal feeds, and raw agricultural commodities:

DOCUMENT ACTION: Proposed rule.

SUBJECT CATEGORY: Indoxacarb; Proposed Pesticide Tolerance

DATES: Comments, identified by docket ID number OPP-2003-0125, must be received on or before May 1, 2003.

DOCUMENT SUMMARY: This document proposes to establish a temporary tolerance for combined residues of Indoxacarb, (S)methyl 7chloro2,5dihydro2 [[(methoxy carbonyl) [4(trifluor omethoxy)phenyl]amino]carbonyl] indeno[1,2e][1,3,4]oxadiazine4a(3H)carboxylate + its Renantiomer [(R)methyl 7chloro2,5dihydro2[[(methoxycarbonyl)[4(trifluoro methoxy)phenyl]amino]carbonyl]indeno [1,2e][1,3,4]oxadiazine4a(3H) carboxylate in or on peaches under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA). This action is in response to university extension specialists, DuPont Crop Protection, and EPA's combined efforts to generate the information necessary for use of the reduced risk pesticide, Indoxacarb, on peaches for control of oriental fruit moth and plum cuculio. This proposed temporary tolerance supports a noncrop destruct experimental use permit (EUP) under section 5 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) authorizing use of Indoxacarb on peaches in Georgia, Michigan, New Jersey, Pennsylvania, South Carolina, and West Virginia. This regulation proposes to establish a maximum permissible level for residues of Indoxacarb in this food commodity pursuant to section 408(e) of FFDCA, as amended by FQPA.

SUMMARY: Indoxacarb,

SUPPLEMENTAL INFORMATION

A. Does this Action Apply to Me?

You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are not limited to: [sbull] Crop production (NAICS Code 111)
[sbull] Animal production (NAICS Code 112)
[sbull] Food manufacturing (NAICS Code 311)

[sbull] Pesticide manufacturing (NAICS Code 32532)

This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entities. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?

1. Docket. EPA has established an official public docket for this action under docket identification (ID) number OPP20030125. The official public docket consists of the documents specifically referenced in this action, any public comments received, and other information related to this action. Although a part of the official docket, the public docket does not include Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. The official public docket is the collection of materials that is available for public viewing at the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The docket telephone number is (703) 3055805.

2. Electronic access. You may access this Federal Register document electronically through the EPA Internet under the ``Federal Register'' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of 40 CFR part 180 is available at http://www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180_00.html , a
beta site currently under development. To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gov/opptsfrs/home/guidelin.htm.

An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Once in the system, select ``search,'' then key in the appropriate docket ID number.

Certain types of information will not be placed in the EPA Dockets. Information claimed as CBI and other information whose disclosure is restricted by statute, which is not
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included in the official public docket, will not be available for public viewing in EPA's electronic public docket. EPA's policy is that copyrighted material will not be placed in EPA's electronic public docket but will be available only in printed, paper form in the official public docket. To the extent feasible, publicly available docket materials will be made available in EPA's electronic public docket. When a document is selected from the index list in EPA Dockets, the system will identify whether the document is available for viewing in EPA's electronic public docket. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I.B. EPA intends to work towards providing electronic access to all of the publicly available docket materials through EPA's electronic public docket.

For public commenters, it is important to note that EPA's policy is that public comments, whether submitted electronically or in paper, will be made available for public viewing in EPA's electronic public docket as EPA receives them and without change, unless the comment contains copyrighted material, CBI, or other information whose disclosure is restricted by statute. When EPA identifies a comment containing copyrighted material, EPA will provide a reference to that material in the version of the comment that is placed in EPA's electronic public docket. The entire printed comment, including the copyrighted material, will be available in the public docket.

Public comments submitted on computer disks that are mailed or delivered to the docket will be transferred to EPA's electronic public docket. Public comments that are mailed or delivered to the Docket will be scanned and placed in EPA's electronic public docket. Where practical, physical objects will be photographed, and the photograph will be placed in EPA's electronic public docket along with a brief description written by the docket staff.

C. How and To Whom Do I Submit Comments?

You may submit comments electronically, by mail, or through hand delivery/courier. To ensure proper receipt by EPA, identify the appropriate docket ID number in the subject line on the first page of your comment. Please ensure that your comments are submitted within the specified comment period. Comments received after the close of the comment period will be marked ``late.'' EPA is not required to consider these late comments. If you wish to submit CBI or information that is otherwise protected by statute, please follow the instructions in Unit I.D. Do not use EPA Dockets or email to submit CBI or information protected by statute.

1. Electronically. If you submit an electronic comment as prescribed in this unit, EPA recommends that you include your name, mailing address, and an e mail address or other contact information in the body of your comment. Also include this contact information on the outside of any disk or CD ROM you submit, and in any cover letter accompanying the disk or CD ROM. This ensures that you can be identified as the submitter of the comment and allows EPA to contact you in case EPA cannot read your comment due to technical difficulties or needs further information on the substance of your comment. EPA's policy is that EPA will not edit your comment, and any identifying or contact information provided in the body of a comment will be included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment.

i. EPA Dockets. Your use of EPA's electronic public docket to submit comments to EPA electronically is EPA's preferred method for receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket , and follow the online instructions for submitting comments. Once in the system, select ``search,'' and then key in docket ID number OPP20030125. The system is an ``anonymous access'' system, which means EPA will not know your identity, email address, or other contact information unless you provide it in the body of your comment.

ii. Email. Comments may be sent by email to oppdocket@epa.gov, Attention: Docket ID Number OPP20030125. In contrast to EPA's electronic public docket, EPA's email system is not an ``anonymous access'' system. If you send an email comment directly to the docket without going through EPA's electronic public docket, EPA's email system automatically captures your email address. Email addresses that are automatically captured by EPA's email system are included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket.

iii. Disk or CD ROM. You may submit comments on a disk or CD ROM that you mail to the mailing address identified in Unit I.C.2. These electronic submissions will be accepted in WordPerfect or ASCII file format. Avoid the use of special characters and any form of encryption.

2. By mail. Send your comments to: Public Information and Records Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 204600001, Attention: Docket ID Number OPP20030125.

3. By hand delivery or courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall 2, 1921 Jefferson Davis Hwy., Arlington, VA., Attention: Docket ID Number OPP20030125. Such deliveries are only accepted during the docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI To the Agency?

Do not submit information that you consider to be CBI electronically through EPA's electronic public docket or by email. You may claim information that you submit to EPA as CBI by marking any part or all of that information as CBI (if you submit CBI on disk or CD ROM, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is CBI). Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2.

In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket and EPA's electronic public docket. If you submit the copy that does not contain CBI on disk or CD ROM, mark the outside of the disk or CD ROM clearly that it does not contain CBI. Information not marked as CBI will be included in the public docket and EPA's electronic public docket without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed 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 preparing your comments:

1. Explain your views as clearly as possible.
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2. Describe any assumptions that you used.

3. Provide copies of any technical information and/or data you used that support your views.

4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide.

5. Provide specific examples to illustrate your concerns.

6. Offer alternative ways to improve the proposed rule or collection activity.

7. Make sure to submit your comments by the deadline in this document.

8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation.

II. Background and Statutory Findings

EPA, in cooperation with DuPont Crop Protection and university extension specialists, under section 408(e) of the FFDCA, 21 U.S.C. 346a, is proposing to establish a tolerance for combined residues of the insecticide Indoxacarb, in or on peaches at 10.0 parts per million (ppm). This action is in response to university extension specialists, DuPont, and EPA's combined efforts to generate the information necessary for registration of the reduced risk pesticide, Indoxacarb, on peaches for control of oriental fruit moth and plum cuculio. This proposed temporary tolerance supports a noncrop destruct experimental use permit (EUP) under section 5 of FIFRA authorizing use of Indoxacarb on peaches in Georgia, Michigan, New Jersey, Pennsylvania, South Carolina, and West Virginia. Section 5 of FIFRA authorizes EPA to issue an experimental use permit for a pesticide. This provision was not amended by FQPA. EPA has established regulations governing such experimental use permits in 40 CFR part 172. Section 408(r) of FFDCA authorizes EPA to issue temporary tolerances for pesticide residues from FIFRA experimental use permits.

Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) of the FFDCA defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of the FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue * * *''

EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. For further discussion of the regulatory requirements of section 408 of the FFDCA and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997). III. Aggregate Risk Assessment and Determination of Safety

Consistent with section 408(b)(2)(D) of the FFDCA, EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure, consistent with section 408(b)(2) of the FFDCA, for a tolerance for combined residues of Indoxacarb on peaches at 10.0 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance follows.

A. Toxicological Profile

EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. The nature of the toxic effects caused by Indoxacarb are discussed in Table 1 of this unit as well as the noobservedadverse effectlevel (NOAEL) and the lowestobservedadverseeffectlevel (LOAEL) from the toxicity studies reviewed.
Table 1. Subchronic, Chronic, and Other Toxicity Guideline No. Study Type Results 870.3100 90Day oral toxicity DPXMP062 rodents NOAEL = M 3.1 mg/kg/day F 2.1 mg/kg/day LOAEL = M 6.0 mg/kg/day, F 3.8 mg/kg/day based on decreased body weight, body weight gain, food consumption and food efficiency. 870.3150 90Day oral toxicity in DPXJW062 nonrodents NOAEL = 5.0 mg/kg/day LOAEL = 19 mg/kg/day based on hemolytic anemia, as indicated by decrease in HGB, RBCs; increases in platelets, increased reticulocytes; and secondary histopathologic findings indicative of blood breakdown (pigment in Kupffer cells, renal tubular epithelium, and spleen and bone marrow macrophages); increase in splenic EMH; and RBC hyperplasia in bone marrow in dogs. 870.3200 21/28Day dermal toxicity DPXMP062 NOAEL = 2,000 mg/kg/day LOAEL = >2,000 mg/kg/day in rats. DPXMP062 NOAEL = 50 mg/kg/day LOAEL = 500 mg/kg/day based on decreased body weights, body weight gains, food consumption, and food efficiency in F*, and changes in hematology parameters (increased reticulocytes), the spleen (increased absolute and relative weight M* only, gross discoloration), clinical signs of toxicity in both sexes in rats. [[Page 18585]]
870.3700 Prenatal developmental in DPXMP062 rodents Maternal NOAEL = 2.0 mg/kg/day LOAEL = 4.0 mg/kg/day based on decreased mean body weights, body weight gains, food consumption. Developmental NOAEL = 2.0 mg/kg/day LOAEL = 4.0 mg/kg/day based on decreased fetal weights. DPXJW062 Maternal NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on mortality, clinical signs, and decreased mean body weights, body weight gains, and food consumption. Developmental NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on decreased numbers of live fetuses/litter. DPXJW062 Maternal NOAEL = 1.1 mg/kg/day LOAEL = 2.2 mg/kg/day based on decreased mean body weights, body weight gains, food consumption, and food efficiency. Developmental NOAEL = 1.1 kg/day LOAEL = 2.2 mg/kg/day based on decreased fetal body weights. 870.3700 Prenatal developmental in DPXJW062 rabbits nonrodents Maternal NOAEL = 500 mg/kg/day LOAEL = 1,000 mg/kg/day based on slight decreases in maternal body weight gain and food consumption. Developmental NOAEL = 500 mg/kg/day LOAEL = 1,000 mg/kg/day based on decreased fetal body weights and reduced ossification of the sternebrae. 870.3800 Reproduction and fertility DPXJW062 effects Parental/Systemic NOAEL = 1.5 mg/kg/day LOAEL = 4.4 mg/kg/day based on decreased body weights, body weight gains, and food consumption of F0 females, and increased spleen weights in the F0 and F1 females Reproductive NOAEL = 6.4 mg/kg/day LOAEL = 6.4 mg/kg/day Offspring NOAEL = 1.5 mg/kg/day LOAEL = 4.4 mg/kg/day based on decrease in the body weights of the F1 pups during lactation. 870.4100 Chronic toxicity rodents DPXJW062 NOAEL = M 5, F 2.1 mg/kg/day LOAEL = M 10, F 3.6 mg/kg/day based on decr. body weight, body weight gain, and food consumption and food efficiency; decreased HCT, HGB and RBC at 6 months in F only. no evidence of carcinogenic potential 870.4100 Chronic toxicity dogs DPXJW062 NOAEL = M 2.3, F 2.4 mg/kg/day LOAEL = M 18, F 19 mg/kg/day based on decr. HCT, HGB and RBC; increased Heinz bodies and reticulocytes and associated secondary microscopic changes in the liver, kidneys, spleen, and bone marrow; increased absolute and relative liver weights. 870.4200 Carcinogenicity rats DPXJW062 see 870.4100. No evidence of carcinogenicity 870.4300 Carcinogenicity mice DPXJW062 NOAEL = M 2.6, F4.0 mg/kg/day LOAEL = M 14, F 20 mg/kg/day based on decreased body weight, body weight gain, and food efficiency and clinical signs indicative of neurotoxicity. No evidence of carcinogenicity 870.5100 Gene Mutation DPXMP062 strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 105,000 [mu]g/plate DPXJW062 strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 105,000 [mu]g/plate. [[Page 18586]]
870.5300 Gene Mutation DPXMP062 negative for mutagenic activity for the following concentration ranges: 3.1250 [mu]g/mL (S9); 3.1250 [mu]g/mL (+S9) DPXJW062 negative for mutagenic activity for the following concentration ranges: Negative;1001,000 [mu]g/mL (S9); 100 1,000 [mu]g/mL (+S9), precipitate >=1,000 [mu]g/mL 870.5375 Cytogenetics DPXMP062 no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 15.71,000 [mu]g/mL (+/S9) DPXJW062 no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 19300 [mu]g/mL ( S9), 19150 [mu]g/mL (+S9); partial insoluble and cytotoxicity >=150 [mu]g/mL 870.5395 Cytogenetics DPXMP062 no evidence of mutagenicity for the following dose ranges: 3,0004,000 mg/kg males; 1,0002,000 mg/kg females DPXJW062 no evidence of mutagenicity at 2,500 or 5,000 mg/kg 870.5550 Other Effects DPXMP062 no evidence of mutagenic activity at the following concentration range: 1.56200 [mu]g/mL; cytotoxicity was seen at concentrations of >=100 [mu]g/mL DPXJW062 No evidence of mutagenic activity at the following concentration range: 0.150 [mu]g/mL, cytotoxicity observed at >=50 [mu]g/mL 870.6200 Acute neurotoxicity DPXMP062 screening battery NOAEL = M 100, F 12.5 mg/kg LOAEL = M 200 mg/kg based on decreased body weight gain, decreased food consumption, decreased forelimb grip strength, and decreased foot splay. F 50 mg/kg based on decreased body weight, body weight gain, and food consumption DPXJW062 NOAEL= M > 2,000 mg/kg = F < 500 mg/kg LOAEL > M 2,000 mg/kg F < 500 mg/kg based on clinical signs, decreased body weight gains and food consumption, and FOB effects 870.6200 Subchronic neurotoxicity DPXMP062 screening battery NOAEL = M 0.57, F 0.68 mg/kg/day LOAEL = M 5.6, F 3.3 mg/kg/day based on decreased body weight and alopecia 870.7485 Metabolism and Both DPXMP062 and DPXJW062 were pharmacokinetics extensively metabolized and the metabolites were eliminated in urine, feces, and bile. The metabolite profile for DPXJW062 was dose dependent and varied quantitatively between males and females. Differences in metabolite profiles were also observed for the different label positions (indanone and trifluoromethoxyphenyl rings). All biliary metabolites undergo further biotransformation in the gut. The proposed metabolic pathway for both DPXMP062 and DPXJW062 has multiple metabolites bearing one of the two ring structures (see 870 4100 chronic toxicity rodents above). B. Toxicological Endpoints

The dose at which no adverse effects are observed (the NOAEL) from the toxicology study identified as appropriate for use in risk assessment is used to estimate the toxicological level of concern (LOC). However, the lowest dose at which adverse effects of concern are identified (the LOAEL) is sometimes used for risk assessment if no NOAEL was achieved in the toxicology study selected. An uncertainty factor (UF) is applied to reflect uncertainties inherent in the extrapolation from laboratory animal data to humans and in the variations in sensitivity among members of the human population as well as other unknowns. An UF of 100 is routinely used, 10X to account for interspecies differences and 10X for intra species differences.

For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (acute RfD or chronic RfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factor is retained due to concerns unique to the FQPA, this additional factor is applied to the RfD by dividing the RfD by such additional factor. The acute or chronic Population Adjusted Dose (aPAD or cPAD) is a modification of the RfD to accommodate this type of FQPA Safety Factor (SF).

For nondietary risk assessments (other than cancer) the UF is used to determine the LOC. For example, when 100 is the appropriate UF (10X to account for interspecies differences and 10X for intraspecies differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and compared to the LOC.

The linear default risk methodology (Q*) is the primary method currently
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used by the Agency to quantify carcinogenic risk. The Q* approach assumes that any amount of exposure will lead to some degree of cancer risk. A Q* is calculated and used to estimate risk which represents a probability of occurrence of additional cancer cases (e.g., risk is expressed as 1 x 10⁶ or one in a million). Under certain specific circumstances, MOE calculations will be used for the carcinogenic risk assessment. In this nonlinear approach, a ``point of departure'' is identified below which carcinogenic effects are not expected. The point of departure is typically a NOAEL based on an endpoint related to cancer effects though it may be a different value derived from the dose response curve. To estimate risk, a ratio of the point of departure to exposure (MOEcancer = point of departure/exposures) is calculated. A summary of the toxicological endpoints for Indoxacarb used for human risk assessment is shown in Table 2 of this unit:
Table 2. Summary of Toxicological Dose and Endpoints for Indoxacarb for Use in Human Risk Assessment FQPA SF* and Level of Exposure Scenario Dose Used in Risk Concern for Risk Study and Toxicological Assessment, UF Assessment Effects Acute Dietary (females 1350 years of NOAEL = 2.0 mg/kg/day FQPA SF = 1 Developmental rat age) UF = 100............... aPAD = acute RfD/FQPA toxicity study. Acute RfD = 0.02 mg/kg. SF = 0.02 mg/kg/day. developmental LOAEL = 4.0 mg/kg/day based on decreased fetal body weight. Acute Dietary general population NOAEL = 12.5 mg/kg FQPA SF = 1 Acute oral rat including infants and children UF = 100............... aPAD = acute RfD/FQPA neurotoxicity study. Acute RfD = 0.12 mg/kg. SF = 0.12 mg/kg/day. LOAEL = 50 mg/kg based on decreased body weight and body weight gain in females. Chronic Dietary all populations NOAEL = 2.0 mg/kg/day FQPA SF = 1 90day rat subchronic UF = 100............... cPAD = chronic RfD/FQPA toxicity study, 90day Chronic RfD = 0.02 mg/ SF = 0.02 mg/kg/day. rat neurotoxicity kg/day. study, chronic/ carcinogenicity rat study. LOAEL = 3.3 mg/kg/day based on decreased body weight, alopecia, body weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months. 3.3 mg/kg/day is the lowest LOAEL of the three studies. ShortTerm Oral (17 days) oral study NOAEL= 2.0 LOC for MOE = 100 Developmental rat (Residential) mg/kg/day (Residential, includes toxicity study. the FQPA SF) Maternal LOAEL = 4.0 mg/ kg/day based on decreased mean maternal body weights, body weight gains, and food consumption. IntermediateTerm Oral (1 week oral study NOAEL= 2.0 LOC for MOE = 100 90day rat subchronic several months) (Residential) mg/kg/day (Residential, includes toxicity study. the FQPA SF) LOAEL = 3.8 mg/kg/day based on decreased body weight, body weight gain, food consumption and food efficiency. Short (17 days), Intermediate (1 dermal study NOAEL= 50 LOC for MOE = 100 28day rat dermal week several months), and Long mg/kg/day (Occupational) toxicity study. (several months lifetime) Term LOC for MOE = 100 LOAEL = 500 mg/kg/day Dermal (Occupational/Residential) (Residential, includes based on decreased the FQPA SF). body weights, body weight gains, food consumption, and food efficiency in females, and changes in hematology parameters (increased reticulocytes), the spleen (increased absolute and relative weight males only, gross discoloration), and clinical signs of toxicity in both sexes. ShortTerm Inhalation (17 days) oral study NOAEL= 2.0 LOC for MOE = 100 Rat developmental (Occupational/Residential) mg/kg/day (inhalation (Occupational) toxicity study. absorption rate = LOC for MOE = 100 Maternal LOAEL = 4.0 mg/ 100%) (Residential, includes kg/day based on the FQPA SF). decreased mean maternal body weights, body weight gains, and food consumption. IntermediateTerm Inhalation (1 week oral study NOAEL= 2.0 LOC for MOE = 100 90day rat subchronic several months) (Occupational/ mg/kg/day (inhalation (Occupational) toxicity study. Residential) absorption rate = LOC for MOE = 100 LOAEL = 3.8 mg/kg/day 100%) (Residential, includes based on decreased the FQPA SF). body weight, body weight gain, food consumption and food efficiency. LongTerm Inhalation (several months oral study NOAEL= 2.0 LOC for MOE = 100 90day rat subchronic lifetime) (Occupational/ mg/kg/day (inhalation (Occupational) toxicity study, 90day Residential) absorption rate =100%) LOC for MOE = 100 rat neurotoxicity (Residential, includes study, chronic/ the FQPA SF). carcinogenicity rat study. LOAEL = 3.3 mg/kg/day based on decreased body weight, body weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months. [[Page 18588]]
Cancer (oral, dermal, inhalation) ``not likely'' to be N/A no evidence of carcinogenic to humans carcinogenicity in either the rat or mouse in acceptable carcinogenicity studies and no evidence of mutagenicity. * The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique to the FQPA.

C. Exposure Assessment

1. Dietary exposure from food and feed uses. Tolerances have been established (40 CFR 180.564) for the combined residues of Indoxacarb, in or on a variety of raw agricultural commodities. Including tolerances already established for: alfalfa, forage at 10 ppm; alfalfa, hay at 50 ppm; apple at 1.0 ppm; apple, wet pomace at 3.0 ppm; brassica, head and stem, subgroup at 5.0 ppm; cattle, goat, horse, sheep, and hog fat at 1.5 ppm; cattle, goat, horse, sheep, and hog meat at 0.05 ppm; cattle, goat, horse, sheep , and hog meat byproducts at 0.03 ppm; corn, sweet, forage at 10 ppm; corn, sweet, kernel plus cob with husk removed at 0.02 ppm; corn, sweet stover at 15 ppm; cotton gin byproducts at 15 ppm; cotton, undelinted seed at 2.0 ppm; lettuce, head at 4.0 ppm; lettuce, head at 5.0 ppm; lettuce, leaf at 10.0 ppm; milk at 0.15 ppm; and milk, fat at 4.0 ppm; peanut at 0.01 ppm; peanut, hay at 40 ppm; pear at 0.20 ppm; potato at 0.01 ppm; soybean, seed at 0.8 ppm; soybean, aspirated grain fractions at 45 ppm; and vegetables, fruiting, group at 0.50 ppm. Risk assessments were conducted by EPA to assess dietary exposures from Indoxacarb in food as follows:

i. Acute exposure. Acute dietary risk assessments are performed for a fooduse pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a one day or single exposure. The Dietary Exposure Evaluation Model (DEEM[reg]) analysis evaluated the individual food consumption as reported by respondents in the USDA 19891992 nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity. The following assumptions were made for the acute exposure assessments: An acute Tier 2 (partially refined analysis) dietary assessment was performed with use of anticipated residues (ARs) from field trial data, processing factors (where applicable), and assumed 100% crop treated (CT) for all crops. ARs for meat, milk, poultry, and eggs (MMPE) raw agricultural commodities (RACs) were calculated also.

ii. Chronic exposure. In conducting this chronic dietary risk assessment the DEEM[reg] analysis evaluated the individual food consumption as reported by respondents in the USDA19891992 nationwide CSFII and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: Chronic exposure estimates are expressed in mg/kg bw/day and as a percent of the cPAD. The chronic dietary assessment assumed tolerance level residues, DEEM[reg] default processing factors, assumed 100% CT for all crops other than peaches, and 1% CT for the peach EUP (300 acres)(Tier 1).

iii. Cancer. There is no evidence for mutagenicity and there is no evidence of carcinogenicity in either the rat or mouse. Indoxacarb has been classified as ``not likely to be carcinogenic in humans'' by the Agency; therefore, no carcinogenic dietary risk analysis was performed.

iv. Anticipated residue and percent crop treated (PCT) information. Section 408(b)(2)(E) of the FFDCA authorizes EPA to use available data and information on the anticipated residue levels of pesticide residues in food and the actual levels of pesticide chemicals that have been measured in food. If EPA relies on such information, EPA must require that data be provided 5 years after the tolerance is established, modified, or left in effect, demonstrating that the levels in food are not above the levels anticipated. Following the initial data submission, EPA is authorized to require similar data on a time frame it deems appropriate. As required by section 408(b)(2)(E) of the FFDCA, EPA will issue a data callin for information relating to anticipated residues to be submitted no later than 5 years from the date of issuance of this tolerance.

Section 408(b)(2)(F) of the FFDCA states that the Agency may use data on the actual percent of food treated for assessing chronic dietary risk only if the Agency can make the following findings: Condition 1, that the data used are reliable and provide a valid basis to show what percentage of the food derived from such crop is likely to contain such pesticide residue; Condition 2, that the exposure estimate does not underestimate exposure for any significant subpopulation group; and Condition 3, if data are available on pesticide use and food consumption in a particular area, the exposure estimate does not understate exposure for the population in such area. In addition, the Agency must provide for periodic evaluation of any estimates used. To provide for the periodic evaluation of the estimate of PCT as required by section 408(b)(2)(F) of the FFDCA, EPA may require registrants to submit data on PCT.

The Agency used PCT information as follows:

Dietary exposure estimates were based on 1% PCT for peaches. This PCT of 1% was based on the fact that the 2year experimental use permit was issued for only 300 acres of peaches to be treated annually, which amounts to 0.2% of the total peach acreage in the United States. The reason for using 1% instead of 0.2% is to allow for any uncertainties in the residue evaluation. Before making this tolerance permanent, reevaluation of dietary exposure will be performed using all available information. Other commodities were assumed to be 100% treated.

The Agency believes that the three conditions previously discussed have been met. With respect to Condition 1, EPA finds that the PCT information described 1% for Indoxacarb used on peaches is reliable and has a valid basis. A 2year EUP has been issued for this use, which will allow for use of Indoxacarb on 300 acres of peaches in some eastern states. Before the use can be expanded for treatment of greater than 300 acres per year, permission from the Agency must be obtained. As to Conditions 2 and 3, regional consumption information and consumption information for significant subpopulations is taken into account through EPA's computerbased model for evaluating the exposure of significant subpopulations including several regional groups. Use of this consumption information in EPA's risk
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assessment process ensures that EPA's exposure estimate does not understate exposure for any significant subpopulation group and allows the Agency to be reasonably certain that no regional population is exposed to residue levels higher than those estimated by the Agency. Other than the data available through national food consumption surveys, EPA does not have available information on the regional consumption of food to which Indoxacarb may be applied in a particular area.

2. Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for Indoxacarb in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of Indoxacarb.

The Agency uses the Generic Estimated Environmental Concentration (GENEEC) or the Pesticide Root Zone/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and SCIGROW (screening concentration in ground water), which predicts pesticide concentrations in groundwater. In general, EPA will use GENEEC (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a screeninglevel assessment for surface water. The GENEEC model is a subset of the PRZM/EXAMS model that uses a specific highend runoff scenario for pesticides. GENEEC incorporates a farm pond scenario, while PRZM/EXAMS incorporate an index reservoir environment in place of the previous pond scenario. The PRZM/EXAMS model includes a percent crop area factor as an adjustment to account for the maximum percent crop coverage within a watershed or drainage basin.

None of these models include consideration of the impact processing (mixing, dilution, or treatment) of raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models by the Agency at this stage is to provide a coarse screen for sorting out pesticides for which it is highly unlikely that drinking water concentrations would ever exceed human health levels of concern.

Since the models used are considered to be screening tools in the risk assessment process, the Agency does not use estimated environmental concentrations (EECs) from these models to quantify drinking water exposure and risk as a percent reference dose (%RfD) or percent population adjusted dose (%PAD). Instead, drinking water levels of comparison (DWLOCs) are calculated and used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, and from residential uses. Since DWLOCs address total aggregate exposure to Indoxacarb they are further discussed in the aggregate risk sections below.

Based on the PRZM/EXAMS and SCIGROW models the estimated environmental concentrations (EECs) of Indoxacarb for acute exposures are estimated to be 13.7 parts per billion (ppb) for surface water and 0.02 ppb for ground water. The EECs for chronic exposures are estimated to be 3.7 ppb for surface water and 0.02 ppb for ground water.

3. From nondietary exposure. The term ``residential exposure'' is used in this document to refer to nonoccupational, nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Indoxacarb is not registered for use on any sites that would result in residential exposure.

4. Cumulative exposure to substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''

EPA does not have, at this time, available data to determine whether Indoxacarb has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, Indoxacarb does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that Indoxacarb has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the final rule for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997). D. Safety Factor for Infants and Children

1. In general. Section 408 of the FFDCA provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk assessments either directly through use of a MOE analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans.

2. Prenatal and postnatal sensitivity. There is no evidence for either qualitative or quantitative susceptibility. In all developmental studies, the developmental endpoint occurs at the maternal LOAEL or above. Although there is no rabbit developmental toxicity study with indoxacarb, a study is not required since: (1) studies both using methyl cellulose comparing JW062 in the rabbit and rat demonstrate that the toxicity profiles for the rat and rabbit are similar and that the rat is the more sensitive species; (2) range finding studies in the rat comparing indoxacarb and JW062 indicate that the maternal and external developmental toxicity are comparable; (3) a dietary developmental toxicity study in the rat with JW062 had comparable toxicity to the gavage indoxacarb rat developmental toxicity study. Developmental toxicity only occurred at levels at or above maternal toxicity.

The reproduction toxicity study with JW062 can be used to satisfy the requirement for an indoxacarb study because: 1) systemic toxicity is at similar doses and of similar magnitude to that observed in subchronic feeding studies with both indoxacarb and JW062; 2) based on the data base, the HIARC determined that there was support for using data from dietary studies conducted with JW062 to satisfy the data requirements for indoxacarb.

The Agency has required a developmental neurotoxicity study as confirmatory data due to:
[sbull] Clinical signs of neurotoxicity in several studies, males and females, mice and rats, at some doses that do not cause mortality; [sbull] Signs of neurotoxicity in the acute neurotoxicity study rat with indoxacarb (males and females), no mortality in males at neurotoxic doses;
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[sbull] Clinical signs of neurotoxicity in the 90day toxicity study rat indoxacarb (females), mortality;
[sbull] Clinical signs of neurotoxicity in the 90day toxicity study mouse with the racemic mixture, JW062 (males and females), no mortality in females at neurotoxic doses, mortality in males; [sbull] Clinical signs of neurotoxicity in the 18 month carcinogenicity study mouse with JW062 (males and females) high and mid dose, mortality at the high but no mortality at the mid dose; and [sbull] Clinical signs of neurotoxicity in the developmental toxicity study rat with JW062 (using methyl cellulose as the vehicle), at doses causing mortality.

3. Conclusion. The Agency concluded that the FQPA safety factor could be reducecd to 1X for Indoxacarb because:
[sbull] There is no indication of quantitative or qualitative increased susceptibility of rats or rabbits to in utero and/or postnatal exposure;
[sbull] The requirement of a developmental neurotoxicity study is not based on the criteria reflecting special concern for the developing fetuses or young which are generally used for requiring a DNT study and a safety factor (e.g.: neuropathy in adult animals; CNS malformations following prenatal exposure; brain weight or sexual maturation changes in offspring; and/or functional changes in offspring) and therefore does not warrant an FQPA safety factor; and [sbull] The dietary (food and drinking water) exposure assessments will not underestimate the potential exposures for infants and children [sbull] There are no registered residential uses at the current time.

E. Aggregate Risks and Determination of Safety

To estimate total aggregate exposure to a pesticide from food, drinking water, and residential uses, the Agency calculates drinking water level of comparison (DWLOCs) which are used as a point of comparison against the model estimates of a pesticide's concentration in water (EECs). DWLOC values are not regulatory standards for drinking water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food and residential uses. In calculating a DWLOC, the Agency determines how much of the acceptable exposure (i.e., the PAD) is available for exposure

FOR FURTHER INFORMATION CONTACT Rita Kumar, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave, NW., Washington, DC 204600001; telephone number: (703) 3088291; email address: kumar.rita@epa.gov.