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CFR Citation: 40 CFR Part 180

RIN ID: RIN 2070-AB78

OPP ID: [OPP-301061; FRL-6746-5]

NOTICE: RULES

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

DOCUMENT ACTION: Final rule.

SUBJECT CATEGORY: Hexythiazox; Pesticide Tolerance

DATES: This regulation is effective September 29, 2000. Objections and requests for hearings, identified by docket control number OPP301061, must be received by EPA on or before November 28, 2000.

DOCUMENT SUMMARY: This regulation establishes a tolerance for residues of the ovicide/miticide hexythiazox (trans5(4chlorophenyl)Ncyclohexyl4 methyl2oxothiazolidine3carboxamide) and its metabolites containing the (4chlorophenyl)4methyl2oxo3thiazolidine moiety (expressed as parent) in or on wet apple pomace, almonds, strawberries, stone fruit (excluding plums), milk, fat and meat byproducts in cattle, goats, horses, swine, and sheep. It also increases the tolerance in apples and establishes a tolerance with regional registration in cotton. Gowan Company requested this tolerance under the Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality Protection Act of 1996.

SUMMARY: Hexythiazox,

SUPPLEMENTAL INFORMATION

A. Does this Action Apply to Me?

You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Examples of Potentially Categories NAICS Affected Entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing

This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also [[Page 58438]]
be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?

1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http://www.epa.gov/. To access this document, on the Home Page select ``Laws and Regulations,'' ``Regulations and Proposed Rules,'' and then look up the entry for this document under the ``Federal RegisterEnvironmental Documents.'' You can also go directly to the Federal Register listings at http://www.epa.gov/fedrgstr/. To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.gpo.gov/opptsfrs/home/guidelin.htm.

2. In person. The Agency has established an official record for this action under docket control number OPP301061. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 3055805. II. Background and Statutory Findings

Hexythiazox is the active ingredient in Savey Ovicide/Miticide 50 WP (EPA Reg. No. 10163208). Permanent tolerances are established under 40 CFR 180.448(a) for residues of hexythiazox and its metabolites containing the (4chlorophenyl)4methyl2oxo3thiazolidine moiety (expressed as parent) in/on apples at 0.02 parts per million (ppm), hops at 2.0 ppm, and pears at 0.3 ppm. Timelimited tolerances established under 40 CFR 180.448(b) for residues in/on undelinted cotton seed and cotton gin byproducts at 0.1 and 2.0 ppm expired on October 10, 1999. Additional timelimited tolerances for residues in/on dates (0.1 ppm), hops (2.0 ppm), and strawberries (3.0 ppm) established under 40 CFR 180.448(b) are set to expire on September 15, 2000.

In the Federal Register of July 31, 1996, 61 FR 39971, (FRL5384 6); April 30, 1997, 62 FR 23455, (FRL56008); January 28, 1998, 63 FR 4252, (FRL57636); and August 26, 1998, 63 FR 45487, (FRL60235), EPA issued a notice pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food Quality Protection Act of 1996 (FQPA) (Public Law 104170) announcing the filing of a pesticide petition (PP 6F4738, 8F4985) for tolerance by Gowan Company, P.O. Box 5569, Yuma AZ 853665569. This notice included a summary of the petition prepared by Gowan Company, the registrant. There were no comments received in response to the notice of filing.

The petition(s) requested that 40 CFR 180.448 be amended by establishing a tolerance for residues of the insecticide hexythiazox, in or on various food commodities as follows: (1) On July 31, 1996 PP 6F4738 proposed the establishment of tolerances for stone fruits (except plums) at 1 ppm; almond nutmeat at 0.2 ppm and almond hulls at 10 ppm; milk, cattle meat, and cattle fat at 0.05 ppm, and cattle meat by products at 0.1 ppm. On April 30, 1997, the petitioner refiled the petition pursuant to the Food Quality Protection Act (FQPA). On January 28, 1998, the petitioner amended the tolerance petition by proposing to establish a tolerance for stone fruits including plums at 1 ppm; prunes at 5 ppm; and all tree nuts at 0.2 ppm. Based upon EPA's review of the field residue data, the tolerance for almonds was changed from 0.2 ppm to 0.3 ppm. Also, the commodity terms almonds, nutmeat and almond hulls was changed to almond and almond, hulls. EPA was unable to complete its review of the field residue data for tree nuts and plums (prunes) and therefore is limiting tolerances to stone fruits (except plums) and almond at this time. Also, the commodity term Stone Fruits (except plums) was corrected to read Fruit, stone group (except plums). Based upon data from a ruminant feeding study, the tolerances proposed in milk, cattle fat and meat byproducts are too high and are reduced to 0.02 ppm. Tolerances for meat are not required. The petition was amended to specify tolerances in cattle, goats, horses, swine, and sheep fat and meat byproducts and milk at 0.02 ppm. (2) On August 26, 1998, PP 8F4985 proposed the establishment of tolerances for strawberries at 3.0 ppm; the increase of tolerances in apples from 0.02 ppm to 0.40 ppm; wet apple pomace at 0.70 ppm; cotton, undelinted seed at 0.20 ppm; and cotton gin byproducts at 3.0 ppm, geographically limited to California only. Based upon apple processing studies, the pomace tolerance of 0.70 ppm is too low and is revised to 0.80 ppm. The use on cotton is limited to California based on the geographical representation of the residue data submitted. Additional residue data would be required to expand the area of usage.

Hexythiazox is currently proposed for use on stone fruits (except plums) to control European red mites, Twospotted spider mites, McDaniel spider mite, Strawberry spider mites, Pacific spider mites, Pecan leaf scorch mites, and Willamette mites; almonds to control European red mites, Twospotted spider mites, McDaniel spider mites, Strawberry spider mites, Pacific spider mites, Pecan leaf scorch mites, and Willamette mites; strawberries to control Twospotted spider mites; apples to control European red mites, Twospotted spider mites, McDaniel spider mite, Pacific spider mites, and Willamette mites; and in cotton to control Twospotted spider mites, Strawberry spider mites, Pacific spider mites, and Carmine spider mites.

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) 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) 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
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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 and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997) (FRL57547).

III. Aggregate Risk Assessment and Determination of Safety

Consistent with section 408(b)(2)(D), 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), for a tolerance for residues of hexythiazox on stone fruits (except plums) at 1 ppm; almonds at 0.3 ppm and almond hulls at 10 ppm; milk at 0.02 ppm; fat of cattle, goats, horses, swine and sheep at 0.02 ppm; meat byproducts of cattle, goats, horses, swine and sheep at 0.02 ppm; strawberries at 3.0 ppm; wet apple pomace at 0.80 ppm; cotton, undelinted seed (CA only), at 0.20 ppm; and cotton gin byproducts (CA only) at 3.0 ppm. This regulation also increases the tolerance on apples from 0.02 ppm to 0.50 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 hexythiazox are discussed in the following Table 1 as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed.
Table 1.Subchronic, Chronic and Other Toxicity Guideline No. Study Type Results 870.3100 90Day oral toxicity rodents NOAEL = 8.1/5.4 mg/kg/day males, females LOAEL = 58.6/38.1 mg/kg/day, males, females based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculata. 870.3700a Prenatal developmental in Maternal NOAEL = 240 mg/kg/day rodents
LOAEL = 720 mg/kg/day based on decreased maternal body weight gain and decreased food consumption. Developmental NOAEL = 2,160 mg/kg/day LOAEL > 2,160 mg/kg/day. 870.3700b Prenatal developmental in Maternal NOAEL = 1080 mg/kg/day nonrodents
LOAEL = > 1,080 mg/kg/day. Developmental NOAEL = 1,080 mg/kg/day LOAEL = > 1,080 mg/kg/day. 870.3800 Reproduction and fertility Parental/Systemic NOAEL = 29.73/34.77 effects mg/kg/day, males/females LOAEL = 180.67/207.67 mg/kg/day, males/ females based on decreased body weight gain and increased absolute and relative liver, kidney, and adrenal weights. Reproductive NOAEL = > 180.67/207.67mg/ kg/day, males/females LOAEL >180.67/207.67 mg/kg/day, males/ females. Offspring NOAEL = 29.73/34.77 mg/kg/ day, males/females LOAEL = 180.67/207.67 mg/kg/day, males/ females based on decreased pup body weight during lactation, and delayed hair growth and/or eye opening. 870.4100b Chronic toxicity dogs NOAEL = 2.5 mg/kg/day LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology. 870.4300 Chronic Toxicity/ NOAEL = 23/29 mg/kg/day, males/females Carcinogenicity rats LOAEL = 163/207 mg/kg/day, males/ females based on decreased body weight and body weight gain and increased absolute and relative liver weights. No evidence of carcinogenicity 870.4300 Carcinogenicity mice NOAEL = 41.6/51.2 mg/kg/day, males/ females LOAEL = 267/318 mg/kg/day, males/ females based on decreased male body weight and body weight gain and increased absolute and relative liver weights in both sexes. Evidence of carcinogenicity (causes liver tumors in females) 870.5100 Gene Mutation (Salmonella The test was negative up to the highest typhimurium and Escherichia dose tested (6400 micrograms/plate +/ coli reverse gene mutation S9) assay)
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870.5300 Gene Mutation (In vitro Independently performed trials were mammalian cell forward gene negative up to precipitating doses ( mutation assay in CHO cells) micrograms/mL) and severely cytotoxic concentrations (200 micrograms/mL S9; 400 micrograms/mL + S9) 870.5375 Cytogenetics (In vitro The test was negative up to mammalian cell cytogenetic precipitating doses accompanied by assay in CHO cells) severe cytotoxicity ( 167 micrograms/ mL +/S9) 870.5395 Cytogenetics (In vivo mouse The results were inconclusive because a micronucleus assay) positive response, which was within the wide range of historical background data, was recorded for female mice at the midand high doses (500 and 10,000 mg/kg). The assay should be repeated to confirm or refute the equivocal results. 870.5550 Other Effects (In vitro UDS The test was negative up to a lethal assay in primary rat dose (250 micrograms/mL). hepatocytes
870.7485 Metabolism and Absorption and distribution of dosed pharmacokinetics radioactivity were rapid. The radioactive material was rapidly eliminated in the urine and feces; the majority of the radioactivity was eliminated within 24 hours. There were no observable differences in the total elimination of NA73 between male and female rats. The major route of elimination in both the male and female rats was by fecal excretion. The major metabolite found, PT18 (cis), accounted for 812% of the administered radioactivity in the low dose groups. Approximately 1120% and 6569% of the dosed radioactivity was identified as unchanged NA73 in the lowdose and highdose groups, respectively. All other metabolites were present at low concentrations (<2%). There was no apparent sex difference in metabolite formation. Significant levels of NA73 equivalent \14\C residues were detected in the fat, liver, and adrenals. A sex related difference in the residue levels of all tissues was observed, with residues in female tissues being twofold higher than those found in male tissues. 870.7485 Metabolism and Total recovery of radioactivity 72 pharmacokinetics hours after treatment accounted for 101.9103% of the dose. The distribution of radioactivity 72 hours after dosing was as follows: (1) 30% (male and female) was excreted in the urine, (2) 60% (female) to 67% (male) was excreted in the feces, and (3) about 4% (male) to 10% (female) of the administered radioactivity remained in the tissues, with the highest concentration in the fat (2.3 ppm, males; 5.4 ppm, females). Significant sex differences existed for the pharmacokinetics of NA73 in these rats, with females exhibiting slower elimination rats and higher tissue residues (about double) than males. NA 73 was metabolized to a large number of metabolites that were excreted both in the urine and feces. Seven metabolites were structurally identified in addition to the parent compound in both excreta of both sexes, with the major fecal metabolite, PT18 (cis) accounting for 10% of the dosed radioactivity. The others were all minor metabolites accounting for less than 1.4%. About 20% of the dose was excreted as unchanged NA73 (97% of which was in the feces). No significant sex difference was apparent with respect to metabolite formation. 870.7600 Dermal penetration The total percent of dose absorbed averaged 2%, 1%, and 1.1% for cannulated rats (10hour sacrifice) and 0.8%, 0.2%, and 0.2% for non cannulated rats (1hour sacrifice) at the low, medium, and high dose levels, respectively. The amount of radioactivity in the blood, carcass, urine and other organs totaled <2% of the applied dose. The results of this study (2% dermal absorption) can be used for risk assessment purposes. 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 intraspecies 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.

For nondietary risk assessments (other than cancer) the UF is used to
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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 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 hexythiazox used for human risk assessment is shown in the following Table 2:
Table 2.Summary of Toxicological Dose and Endpoints for Hexythiazox for Use in Human Risk Assessment Dose used in risk FQPA SF and LOC for Study and toxicological Exposure scenario assessment, UF risk assessment effects Acute Dietary (females 1350 years of Developmental NOAEL = FQPA SF = 1X aPAD = Developmental Toxicity age) 240 mg/kg/day UF = 100 acute RfD/FQPA SF = StudyRat Acute RfD = 2.4 mg/kg/ 2.4 mg/kg/day day
Developmental LOAEL = 720 mg/kg/day based on delayed ossification Acute Dietary (general population
including infants and children)\2\
Chronic Dietary (all populations) NOAEL = 2.5 mg/kg/day FQPA SF = 1X cPAD = 1Year Toxicity Feeding UF = 100 Chronic RfD = chronic RfD/FQPA SF = StudyDog 0.025 mg/kg/day 0.025 mg/kg/day LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology ShortTerm Dermal (17 days) Oral maternal NOAEL = LOC for MOE = 100 Developmental Toxicity (Occupational/Residential) 240 mg/kg/day (dermal (Occupational) StudyRat absorption rate = 2%) LOC for MOE = 100 LOAEL = 720 mg/kg/day (Residential, includes based on decreased the FQPA SF) maternal body weight gain during gestation days 717 and decreased food consumption on gestation days 912 IntermediateTerm Dermal (1 week Oral NOAEL = 5.4 mg/kg/ LOC for MOE = 100 13Week Feeding Study several months) (Occupational/ day (dermal absorption (Occupational) Rat Residential) rate = 2%)
LOC for MOE = 100 LOAEL = 38.1 mg/kg/day (Residential, includes based on increased the FQPA SF) absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zone fasciculata LongTerm Dermal (several months Oral NOAEL = 2.5 mg/kg/ LOC for MOE = 100 1Year Feeding Study lifetime) (Occupational/Residential) day (dermal absorption (Occupational) Dog rate = 2%)
LOC for MOE = 100 LOAEL = 12.5 mg/kg/day (Residential, includes based on increased the FQPA SF) absolute and relative adrenal weights and associated adrenal histopathology ShortTerm Inhalation (17 days) Oral NOAEL = 240 mg/kg/ LOC for MOE = 100 Developmental Toxicity (Occupational/Residential) day (inhalation (Occupational) StudyRat absorption rate =
100%)
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LOC for MOE = 100 LOAEL = 720 mg/kg/day (Residential, includes based on decreased the FQPA SF) maternal body weight gain during gestation days 717 and decreased food consumption on gestation days 912 IntermediateTerm Inhalation (1 week Oral NOAEL = 5.4 mg/kg/ LOC for MOE = 100 13Week Feeding Study several months) (Occupational/ day (inhalation (Occupational) Rat Residential) absorption rate =
100%)
LOC for MOE = 100 LOAEL = 38.1 mg/kg/day (Residential, includes based on increased the FQPA SF) absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zone fasciculata LongTerm Inhalation (several months Oral NOAEL = 2.5 mg/kg/ LOC for MOE = 100 1Year Feeding Study lifetime) (Occupational/Residential) day (inhalation (Occupational) Dog absorption rate =
100%)
LOC for MOE = 100 LOAEL = 12.5 mg/kg/day (Residential, includes based on increased the FQPA SF) absolute and relative adrenal weights and associated adrenal histopathology Cancer (oral, dermal, inhalation) Category C (possible Q1* = 2.22 x 10² Increases in incidence human carcinogen) of malignant and combined benign/ malignant liver tumors in mice ¹ UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern
² A dose and endpoint attributable to a single exposure were not identified from the available oral toxicity studies, including maternal toxicity in the developmental toxicity studies. *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 180.448) for the residues of hexythiazox, in or on a variety of raw agricultural commodities. Tolerances are established on plant commodities ranging from 0.02 ppm on apples to 2.0 ppm on hops. Hexythiazox is the common name for the active ingredient in Savey Ovicide/Miticide. When formulated as the product Savey 50 WP, the product is registered for agricultural use on outdoor terrestrial food crops. When sold under an alternate brand name, Hexygon, the product is also registered for commercial nonfood use on outdoor ornamental and nursery stock. Savey 50 WP contains 50% hexythiazox by weight. For these petitions, Savey will be applied to hops, stone fruit, pome fruit, strawberry, and cotton crops at a maximum of 0.1875 pounds of active ingredient per acre (ai/Acre) (1.6 lbs ai/Acre for cotton). Savey is formulated as a wettable powder (packaged in open bags or water soluble paks) and is applied once per season or crop. Savey provides control against tetranychid mite species by direct or indirect contact with treated plant surfaces. According to label specifications the use of this product may include alternation of active classes of insecticides on succeeding generations and targeting the most susceptible life stage. Risk assessments were conducted by EPA to assess dietary exposures from hexythiazox 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) 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: For acute dietary risk assessments, the entire distribution of single day food consumption events is combined with a single residue level (deterministic analysis) to obtain a distribution of exposure in mg/kg. A conservative analysis was performed using existing and recommended tolerance level residues and 100% crop treated (CT) information for all commodities. For acute dietary risk, EPA's level of concern is >100% aPAD. The acute dietary exposure estimate for the females 1350 years old subgroup is presented in Table 3 at the 95^th percentile. The results of the acute analysis indicate that the estimated acute dietary risk associated with the existing and recommended uses of hexythiazox is below EPA's current level of concern for the females 1350 years old subgroup, as shown in the following Table 3:
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Table 3.Acute Result at 95th Percentile from DEEM Analysis Exposure (mg/kg/ Subgroup day) % aPAD Females 1350 years old 0.002617 <1

For the acute dietary analysis, existing and recommended tolerance level residues and 100% CT information were used for all commodities (conservative, Tier 1 analysis). DEEM default processing factors were used.

ii. Chronic exposure. In conducting this chronic dietary risk assessment the DEEM 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 chronic exposure assessments: For chronic dietary risk assessments, the 3day average of consumption for each subpopulation was combined with residues in commodities to determine average exposure in mg/kg/day. A refined, deterministic analysis was performed using AR levels for most crops and % CT or anticipated market share information for all crops. For chronic dietary risk, EPA's level of concern is >100% cPAD. Dietary exposure estimates for the U.S. population and other representative subgroups are presented in Table 4. The results of the chronic analysis indicate that the estimated chronic dietary risk associated with the existing and recommended uses of hexythiazox is below EPA's current level of concern for the U.S. population and all population subgroups, as shown in the following Table 4:
Table 4.Summary of Results from Chronic DEEM Analysis Subgroups Exposure (mg/kg/day) % cPAD U.S. Population 0.000011 <1 All infants (<1 year old) 0.000027 <1 Children (16 years old) 0.000028 <1 Children (712 years old) 0.000015 <1 Females (1350 years old) 0.000008 <1 Males (1319 years old) 0.000004 <1 Males (20 + years old) 0.000008 <1 Seniors (55 + years old) 0.000010 <1

For the chronic and cancer analyses, ARs from field trial data, the weighted average of %CT Quantitative Usage Analyses (QUA), and processing factors (where applicable) were used (see Table 5). DEEM default processing factors were used unless otherwise noted in the following Table 5:
Table 5.Summary of Hexythiazox ARs for Chronic and Cancer Dietary Risk Assessment Based on FieldTrial Data CT/ Recommended Tolerance Anticipated Commodity (ppm) Processing Factor AR (ppm) Market Share (%) Almond nutmeat 0.30 NA 0.046 2 Almond hulls 10 NA 2.7 2 Cherries 1.0 NA 0.20 <1 Peaches 1.0 NA 0.14 1 Nectarines 1.0 NA 0.054 2 Undelinted cottonseed 0.20 NA 0.059 1 Cottonseed meal 0.20 0.01 x 0.059 1 Refined cottonseed oil 0.20 0.13 x 0.059 1 Apples 0.50 NA 0.12 2 [[Page 58444]]
Apple juice 0.50 0.5 x\c\ 0.12 2 Wet apple pomace 0.80 2.4 x 0.12 2 Pears\b\ 0.30 NA 0.30* 3 Hops\b\ 2.0 NA 2.0* 45 Dates\b\ 0.10 NA 0.10* 45 Strawberries 3.0 NA 0.75 14 Milk 0.02 NA 0.00019 Liver\a\ 0.02 NA 0.0016 Meat byproducts (except 0.02 NA 0.00066 liver)\a\
Fat\a\ 0.02 NA 0.00021 Hog Meat 0.02 NA 1.0 x 10^9d Hog Liver 0.02 NA 4.8 x 10^8d Hog Meat byproducts (except 0.02 NA 2.0 x 10^8d liver)
Hog Fat 0.02 NA 6.3 x 10^9d *Ars were not calculated for these crops
\a\These ARs were used for meat, fat and meat byproducts of cattle, horses, goats and sheep in the chronic and cancer analyses.
\b\ARs were not calculated for commodities not included in the subject petitions. \c\DEEM default ratio kept constant for ``applejuice/cider'' and ``applejuiceconcentrate''. \d\These ARs were rounded up to 0.000001 ppm because DEEM can not accomidate more than 6 place holders.
iii. Cancer. A refined, deterministic carcinogenic risk estimate analysis was performed using AR levels for most crops and % CT or anticipated market share information for all crops. The dietary exposure estimate for the U.S. population is presented in Table 6. The result of the carcinogenicity analysis indicates that the estimated dietary risk associated with the existing and recommended uses is below the level the Agency generally considers negligible for excess lifetime cancer risk (1 x 10⁶), as shown in the following Table 6: Table 6.Summary of Results from Carcinogenic DEEM Analysis Exposure
Subgroup (mg/kg/day) Lifetime Risk U.S. Population 0.000011 2.4 x 10⁷

For the cancer analyses, ARs from field trial data, the weighted average of %CT (QUA) and processing factors (where applicable) were used (see Table 5 above). DEEM default processing factors were used unless otherwise noted in Table 5.

iv. Anticipated residue and percent crop treated information. Section 408(b)(2)(E) 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), 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) 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 percent crop treated (PCT) as required by section 408(b)(2)(F), EPA may require registrants to submit data on PCT.

The Agency used percent crop treated (PCT) information specified above. The Agency believes that the three conditions listed above have been met. With respect to Condition 1, PCT estimates are derived from Federal and private market survey data, which are reliable and have a valid basis. EPA uses a weighted average PCT for chronic dietary exposure estimates. This weighted average PCT figure is derived by averaging Statelevel data for a period of up to 10 years, and weighting
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for the more robust and recent data. A weighted average of the PCT reasonably represents a person's dietary exposure over a lifetime, and is unlikely to underestimate exposure to an individual because of the fact that pesticide use patterns (both regionally and nationally) tend to change continuously over time, such that an individual is unlikely to be exposed to more than the average PCT over a lifetime. For acute dietary exposure estimates, EPA uses an estimated maximum PCT. The exposure estimates resulting from this approach reasonably represent the highest levels to which an individual could be exposed, and are unlikely to underestimate an individual's acute dietary exposure. The Agency is reasonably certain that the percentage of the food treated is not likely to be an underestimation. 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 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 hexythiazox 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 hexythiazox 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 hexythiazox.

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, 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 %RfD or %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 hexythiazox they are further discussed in the aggregate risk sections below.

Based on the GENEEC and SCIGROW models the estimated environmental concentrations (EECs) of hexythiazox in surface water and ground water for acute exposures are estimated to be 910.32 ng/L for surface water and 1.47 ng/L for ground water. The EECs for chronic exposures are estimated to be 280.88 ng/L for surface water and 1.47 ng/L 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). Hexythiazox 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) 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 hexythiazox 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, hexythiazox 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 hexythiazox 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. Safety factor for infants and childreni. In general. FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base 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 margin of exposure (MOE) analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans.

ii. Prenatal and postnatal sensitivity. EPA has evaluated the toxicology data base of hexythiazox and reassessed the cRfD, as well as the toxicological endpoints recommended for acute dietary and occupational/residential exposure risk assessments. The Agency also addressed the potential enhanced sensitivity of infants and children from exposure to hexythiazox as required by FQPA and concluded that the pre and postnatal toxicology data base for hexythiazox is complete with respect to FQPA considerations. The results of these studies indicated no increased susceptibility of rats or rabbits to in utero and/or postnatal exposure to hexythiazox. In the developmental toxicity study in rabbits, no
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developmental effects were seen at doses up to the limit dose. In the developmental toxicity study in rats, the developmental effects (delayed ossification) occurred at the same dose level (720 mg/kg/day) as the maternal effects (decreased maternal body weight gain and decreased food consumption). In the two generation reproduction study, the effects in the offspring (decreased pup body weight during lactation and delayed hair growth and/or eye opening) were observed only at treatment levels which resulted in evidence of parental toxicity (decreased body weight gain and increased absolute and relative liver, kidney, and adrenal weights).

A developmental neurotoxicity (DNT) study is not required at this time. However, EPA has requested an evaluation to determine the relationship between the adrenal effects (increased adrenal weights and/or adrenal pathology) seen in four studies (90day feeding study in rats, chronic/carcinogenicity rat, chronic dog, and 2generation reproduction study in rats) and the need for a DNT. It appears that the effects are more endocrinerelated (not developmental) and will be addressed once the endocrine policy is in place. The possibility of the effects being endocrine related is also supported by reports of ovarian weight increases in several studies in rats. In addition, the results of the developmental toxicity studies in rats and rabbits and the 2 generation reproduction study do not support a DNT. No neuropathology or CNS malformations were seen in the developmental toxicity studies. In the 2generation reproduction study in rats, there were no findings in pups that were suggestive of changes in neurological development, although no functional assessment was performed. Additionally, there was no evidence of neurotoxicity in other studies.

iii. Conclusion. There is a complete toxicity data base for hexythiazox and exposure data are complete or are estimated based on data that reasonably accounts for potential exposures. EPA determined that the 10X safety factor to protect infants and children should be removed and reduced to 1x. The FQPA factor is removed because an additional safety factor is not needed to protect the safety of infants and children.

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 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 through drinking water e.g., allowable chronic water exposure (mg/kg/day) = cPAD (average food + residential exposure). This allowable exposure through drinking water is used to calculate a DWLOC.

A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weights. Default body weights and consumption values as used by the USEPA Office of Water are used to calculate DWLOCs: 2L/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg (child). Default body weights and drinking water consumption values vary on an individual basis. This variation will be taken into account in more refined screeninglevel and quantitative drinking water exposure assessments. Different populations will have different DWLOCs. Generally, a DWLOC is calculated for each type of risk assessment used: acute, shortterm, intermediateterm, chronic, and cancer.

When EECs for surface water and groundwater are less than the calculated DWLOCs, OPP concludes with reasonable certainty that exposures to the pesticide in drinking water (when considered along with other sources of exposure for which OPP has reliable data) would not result in unacceptable levels of aggregate human health risk at this time. Because OPP considers the aggregate risk resulting from multiple exposure pathways associated with a pesticide's uses, levels of comparison in drinking water may vary as those uses change. If new uses are added in the future, OPP will reassess the potential impacts of residues of the pesticide in drinking water as a part of the aggregate risk assessment process.

1. Acute risk. Acute aggregate risk estimates are below EPA's level of concern. A Tier 1 acute dietary exposure analysis for hexythiazox was performed using tolerance level residues and