[Federal Register Volume 64, Number 125 (Wednesday, June 30, 1999)]
[Rules and Regulations]
[Pages 35043-35049]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16545]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-300871; FRL-6084-4]
RIN 2070-AB78


Hexaconazole; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes a tolerance for residues of the 
fungicide hexaconazole, [alpha-butyl-alpha-(2,4-dichlorophenyl)-1H-
1,2,4-triazole-1-ethanol] in or on the imported raw agricultural 
commodity bananas at 0.7 parts per million (ppm). Zeneca Ag Products 
requested this tolerance under the Federal Food, Drug, and Cosmetic Act 
(FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA).

DATES: This regulation is effective June 30, 1999. Objections and 
requests for hearings must be received by EPA on or before August 30, 
1999.
ADDRESSES: Written objections and hearing requests, identified by the 
docket control number, [OPP-300871], must be submitted to: Hearing 
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St., 
SW., Washington, DC 20460. Fees accompanying objections and hearing 
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to: 
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees), 
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and 
hearing requests filed with the Hearing Clerk identified by the docket 
control number, [OPP-300871], must also be submitted to: Public 
Information and Records Integrity Branch, Information Resources and 
Services Division (7502C), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. In person, 
bring a copy of objections and hearing requests to Rm. 119, Crystal 
Mall 2 (CM #2), 1921 Jefferson Davis Hwy., Arlington, VA.
    A copy of objections and hearing requests filed with the Hearing 
Clerk may be submitted electronically by sending electronic mail (e-
mail) to: [email protected]. Copies of objections and hearing requests 
must be submitted as an ASCII file avoiding the use of special 
characters and any form of encryption. Copies of objections and hearing 
requests will also be accepted on disks in WordPerfect 5.1/6.1 file 
format or ASCII file format. All copies of objections and hearing 
requests in electronic form must be identified by the docket control 
number [OPP-300871]. No Confidential Business Information (CBI) should 
be submitted through e-mail. Electronic copies of objections and 
hearing requests on this rule may be filed online at many Federal 
Depository Libraries.

FOR FURTHER INFORMATION CONTACT: By mail: Mary L. Waller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. Office 
location, telephone number, and e-mail address: Rm. 249, CM #2, 1921 
Jefferson Davis Hwy., Arlington, VA, (703) 308-9354, 
[email protected].

SUPPLEMENTARY INFORMATION: In the Federal Register of February 24, 1999 
(64 FR 9147) (FRL-6058-9), 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 
104-170) announcing the filing of a pesticide petition (PP 0E3853) for 
tolerance by Zeneca Ag Products, 1800 Concord Pike, Wilmington, DE 
19850-5458. This notice included a summary of the petition prepared by 
Zeneca Ag Products, the registrant. There were no comments received in 
response to the notice of filing.
    The petition requested that 40 CFR 180.488 be amended by 
establishing a tolerance for residues of the fungicide hexaconazole, 
[alpha-butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-ethanol], 
in or on the imported raw agricultural commodity bananas at 0.7 ppm.

I. Background and Statutory Findings

    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 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) (FRL-5754-7).

II. 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 hexaconazole, [alpha-butyl-
alpha-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-ethanol] on the imported 
raw agricultural commodity bananas at 0.7 ppm. EPA's assessment of the 
dietary 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

[[Page 35044]]

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 
hexaconazole are discussed in this unit.
    1. Acute toxicity. Hexaconazole possesses a low order acute 
toxicity by the oral, dermal and inhalation routes of exposure 
[categories 3/4]. It is slightly to moderately irritating to the eye 
and non-irritating to the skin. Hexaconazole tested positive in animal 
studies for skin sensitization.
    2. Subchronic toxicity and chronic toxicity. Subchronic and chronic 
dietary feeding studies in mice, rats and dogs indicate that the liver 
is the primary target organ as generally seen by increased enzyme 
levels, liver cell hypertrophy, and fatty infiltration of the liver 
across species. Decreased body weight gain was also seen across 
species.
    Groups of male and female mice fed dietary doses ranging from 3.75 
milligrams (mg)/kilograms (kg)/day to 225 mg/kg/day for 29 days 
manifested group mean body weight decreases of 17% in males and 14% in 
females at the lowest observed adverse effect level (LOAEL) of 15 mg/
kg/day concurrent with hepatotoxicity. The no observed adverse effect 
level (NOAEL) was 3.75 mg/kg/day.
    Male and female rats were given dietary levels of compound in feed 
for a period of either 90 days or 2 years at doses ranging from 2.5 to 
250 mg/kg/day for 90 days or 2 years at doses ranging from 0.47 mg/kg/
day to 61 mg/kg/day. Body weight gains in the 90-day study were 
statistically significantly decreased at 250 mg/kg/day in both sexes at 
this high dose. The LOAEL of 25 mg/kg/day for both sexes was based on 
slight fatty changes in the liver of males and cortical parenchymal 
vacuolation for the adrenal gland in both sexes. The NOAEL was 2.5 mg/
kg/day.
    Dogs in a 90-day study given hexaconazole by capsule at doses of 0, 
5, 25 or 125 mg/kg/day reduced to 50 mg/kg/day with the addition of a 
new group and the termination of the original group at 125 mg/kg/day as 
a result of extreme toxicity manifested increases in alkaline 
phosphatase and serum glutamic pyruvic transaminase (SGPT) and 
decreases in cholesterol and triglycerides as well as fatty 
infiltration of the liver at the LOAEL of 25 mg/kg/day. The NOAEL was 5 
mg/kg/day. Liver organ weight increases on a relative and absolute 
basis were increased at the highest dose tested (HDT) accompanied by 
pallor and enlargement of the liver and an accumulation of lipid.
    Male and female dogs in a 12-month oral gavage study given either 
0, 2, 10 or 50 mg/kg/day of hexaconazole showed fatty infiltration of 
the liver in males and an increase in the liver weights of females at 
the LOAEL of 10 mg/kg/day. The NOAEL was 2 mg/kg/day. Albumin, total 
protein, calcium, cholesterol, and triglyceride were decreased at 50 
mg/kg/day at all time periods. Females showed an increase in SGPT and a 
decrease in plasma urea at the HDT. Alkaline phosphatase was also 
increased in both sexes at the HDT. Liver and kidney weight were 
increased at the high dose. Fatty infiltration of the liver was seen at 
the high dose in all dogs.
    3. Carcinogenicity. In a 3 dose chronic dietary/carcinogenicity rat 
feeding study, males and females received either 0, 10, 100 or 1,000 
ppm of compound in the diet. The NOAEL was 4.7 and 6.1 mg/kg/day for 
males and females respectively. The LOAEL was 47 for males and 61 mg/
kg/day females based on decreased body weight gains in females of 7% 
and fatty changes in the centrilobular region of the liver of males as 
well as increased incidence of cortical vacuolation of the adrenal 
gland and tubular atrophy of the testes in males which was considered 
to be an acceleration of natural occurring lesions. Effects at the HDT 
LOAEL were essentially an extension of the effects at the lower doses. 
There was a dose responsive positive trend in the number of benign 
Leydig cell tumors in the testes and a significant pair wise comparison 
between the HDT and the controls. These tumors were considered uncommon 
in the test strain and occurred at an accelerated rate.
    Male and female mice fed hexaconazole for a period of 2 years at 
doses ranging from 0.57 to 29.6 mg/kg/day showed body weight gain 
decreases and decreased food efficiency at the LOAEL of 23.5 mg/kg/day 
for males and 29.6 mg/kg/day for females. Increased liver weight and an 
increase in hepatocellular hypertrophy as well as an increase in 
centrilobular fatty infiltration of the liver in both sexes was also 
reported at the high dose. However, the HDT was not considered to be 
the maximum tolerated dose for the purpose of carcinogenicity testing. 
Therefore the negative finding for carcinogenicity in the mouse should 
be viewed with caution.
    4. Developmental toxicity. In a rat developmental study, pregnant 
females were gavaged with either 0, 2.5, 25, or 250 mg/kg/day of 
hexaconazole. The parental NOAEL was 25 mg/kg/day and the LOAEL was 250 
mg/kg/day based on decreased body weight gain and decreased food 
consumption. The developmental NOAEL was 2.5 mg/kg/day and the 
developmental LOAEL was 25 mg/kg/day based on delayed ossification of 
the 7th cervical transverse process and the presence of the extra 14th 
rib. At 250 mg/kg/day there was a statistically significant increase in 
late uterine deaths.
    In a rabbit developmental study, animals tested at doses of 0, 25, 
50, and 100 mg/kg/day also showed increased susceptibility to the 
effects of compound. The maternal NOAEL was 50 mg/kg/day and the LOAEL 
for maternal effects was 100 mg/kg/day based on a decreased body weight 
gain. The developmental NOAEL was 25 mg/kg/day and the developmental 
LOAEL was 50 mg/kg/day based on a decrease in mean fetal body weight.
    5. Two-generation reproduction study in rats. Animals were fed 
either 0, 1, 5, or 50 mg/kg/day of test compound. There were no 
treatment related effects on reproductive performance of either sex for 
the F0 or the F1 generations. The parental NOAEL 
was 1 mg/kg/day. The parental systemic LOAEL was determined to be 5 mg/
kg/day based on liver pathology (fatty infiltration) which was 
considered to be minimal. At 50 mg/kg/day, liver weight was increased 
accompanied with fatty changes in the liver. There was also an 
increased incidence of cytoplasmic vacuolation of the adrenal cortex in 
both sexes. The NOAEL for offspring was 5 mg/kg/day. The LOAEL for 
offspring was 50 mg/kg/day based on decreased body weight gain in pups, 
decreased litter size and decreased pup survival. Liver weights were 
increased and fatty infiltration was also observed.
    6. Mutagenicity. Hexaconazole is not considered to be a mutagen 
with the currently available data from the Gene Mutation Salmonella 
Ames Assay, Micro-nucleus Assay in Mice, In Vitro Cytogenetics Human 
Lyphocytes Cells, and the Unscheduled DNA Synthesis in Primary Rat 
Hepatocytes studies.
    7. Dermal penetration. Hexaconazole administered dermally to rats 
over a period of 21 days for 6 hours a day at dose levels of 0, 100, 
300, and 1,000 mg/kg/day induced no systemic toxicity and was not 
irritating to the skin. The LOAEL was concluded to be greater than 
1,000 mg/kg/day the HDT.
    8. EPA determined that a developmental neurotoxicity study in rats 
is not required for hexaconazole because:
    i. Hexaconazole is not structurally related to a neurotoxic agent.

[[Page 35045]]

    ii. There is no evidence in the acute, subchronic, or chronic 
studies that indicate that hexaconazole induces neurotoxic effects.
    iii. The developmental and reproductive studies do not indicate 
that the chemical is neurotoxic. Developmental effects occurred at dose 
levels that were below maternally toxic levels for both rat and rabbit 
but were not associated with neurotoxicity.
    9. General metabolism. Hexaconazole is readily absorbed and 
excreted in both urine and feces in both males and females. Metabolites 
underwent extensive glucuronidation, biliary excretion, and 
enterohepatic recirculating. Radio labeled hexaconazole concentrated in 
liver, kidney, and adrenal at 24 hours. About 94-98% of the radio 
labeled material was excreted in 7 days by both sexes with males 
excreting 77% in 3 days and females excreting 88-95% in 3 days. Males 
excreted 41% in urine and 52% in feces compared to females 64% and 29% 
in urine and feces, respectively. The majority of the metabolites were 
oxidation products of the n-butyl chain (hexaconazole acid, 5-hydroxy-
hexaconazole, 5-keto hexaconazole and an unspecified hydroxy-keto-
hexaconazole). Preferential elimination of hexaconazole was seen in the 
urine of females as 5-hydroxy-hexaconazole.

B. Toxicological Endpoints

    1. Acute toxicity. An acute reference dose (RfD) of 0.025 mg/kg/day 
was established for the subpopulation group, females 13+ only, based on 
a NOAEL of 2.5 mg/kg/day from a developmental study in the rat. Effects 
at the next higher dose level of 25 mg/kg/day were an increase in the 
delayed ossification of the 7th cervical transverse process and the 
presence of the extra 14th rib. Effects were dose responsive and 
statistically significant. These effects are presumed to occur after a 
single exposure in utero and therefore are considered to be appropriate 
for this risk assessment. The acute population adjusted dose (aPAD) is 
0.0025 mg/kg/day and includes the additional 10x FQPA safety factor. 
The FQPA Safety Factor will be applied for acute food risk assessment 
for females 13+ only because the effects occur only during in utero 
exposure and are not postnatal effects. Thus, it is not appropriate to 
apply this safety factor to the acute food risk assessment of the 
general population including infants and children. An acute dose and 
endpoint were not selected for the general population group (including 
infants and children) because there were no effects observed in oral 
toxicology studies including maternal toxicity in the developmental 
toxicity studies in rats and rabbits that are attributable to a single 
exposure dose.
    2. Short- and intermediate-term toxicity. Risk assessments for 
short- and intermediate-term toxicity are used for addressing 
residential or other similar non-dietary, non-occupational exposures. 
No short-, intermediate-, or long-term dermal or aggregate exposure 
risk assessments were performed for hexaconazole because hexaconazole 
has no registered residential uses.
    3. Chronic toxicity. EPA has established the RfD for hexaconazole 
at 0.02 mg/kg/day. This RfD is based on a 1-year oral gavage study in 
dogs. The NOAEL in this study was 2 mg/kg/day. Fatty infiltration of 
the liver and an increase in liver weights occurred at the LOAEL of 10 
mg/kg/day. An FQPA safety factor was not applied for chronic dietary 
risk assessment because:
    i. The NOAEL used in deriving the RfD was based on liver effects in 
the chronic dog study.
    ii. The developmental effects on which the FQPA factor is based 
were seen in pregnant animals of a different species (rats, and 
rabbits).
    iii. The developmental effects are considered to be ``acute'' 
effects. Therefore, the chronic population adusted dose (PAD) and the 
RfD are the same.
    4. Carcinogenicity. The EPA Cancer Peer Review Committee (CPRC) 
classified hexaconazole as a Group C (likely) carcinogen based on 
benign Leydig cell tumors in the male rats. A revised Q1* 
was calculated using the body weight 3/4 interspecies scaling factor. 
This resulted in a revised potency factor of 1.6 x 10-2 (mg/
kg/day)-1.

C. Exposures and Risks

    1. From food and feed uses. Time-limited tolerances were 
established (40 CFR 180.488) for the residues of hexaconazole, [alpha-
butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-ethanol], in or on 
the imported agricultural commodity bananas at 0.1 ppm; however, this 
tolerance expired on March 26, 1999. Risk assessments were conducted by 
EPA to assess food exposures from hexaconazole as follows:
    There are no proposed or existing residential uses for 
hexaconazole. The proposed use is limited to import bananas only. The 
aggregate exposure risk is limited to dietary exposure only. If new 
uses are added in the future, the Agency will reassess the impact of 
these uses, which may result in the necessity of residential and water 
exposure assessments.
    For all food analyses, the anticipated residue levels based on the 
field trials on banana pulp were used. The use of banana pulp residue 
levels provides a more realistic food exposure as individuals do not 
usually eat the banana peel. The residue levels of the diol metabolites 
were also included in the food exposure analysis. The diol metabolites 
are expected to be of comparable toxicity to the parent compound. EPA 
will require residue data on these metabolites for bananas, as well as 
future food uses.
    The food exposure analyses for hexaconazole is a conservative but 
more realistic estimate of food exposure with the use of the pulp 
residue values and 100% of the commodities assumed to be treated. The 
residue level value of 0.56 ppm, which was the highest residue level 
for pulp (hexaconazole-0.17 ppm + diol metabolites-0.39 ppm), was used 
in the acute dietary analysis. The residue level value of 0.11 ppm, 
which was the average from the field trials for pulp (hexaconazole-0.03 
ppm + diol metabolites-0.08 ppm), was used in the chronic dietary 
analysis.
    i. Acute exposure and risk. Acute food risk assessments are 
performed for a food-use pesticide if a toxicological study has 
indicated the possibility of an effect of concern occurring as a result 
of a 1-day or single exposure. The acute food exposure analysis for the 
population subgroup females 13+ was performed using the highest pulp 
residue level (parent + diol metabolites) and 100% crop treated. The 
FQPA Safety Factor of 10x was retained for the acute food analysis only 
for the population subgroup females 13+. The acute population adjusted 
dose (aPAD) used in the acute food analysis was 0.0025 mg/kg/day.
    ii. Chronic exposure and risk. The FQPA Safety Factor was removed 
(i.e., reduced to 1x) for chronic food exposure. Therefore, the chronic 
PAD (cPAD) and the chronic RfD are the same. For chronic food risk, 
EPA's level of concern is greater than 100% chronic PAD. All chronic 
(non-cancer) percent cPADs for all subgroups were 1%. The 
results of the chronic food exposure analysis indicate that the chronic 
food risk associated with the proposed use of hexaconazole is below the 
Agency's level of concern.
    2. From drinking water. Hexaconazole is not registered for use in 
the United States (U.S.). Therefore, no water or occupational exposure 
assessment was performed.
    3. From non-dietary exposure. The use of bananas is for import use 
only.

[[Page 35046]]

 There are currently no proposed or registered domestic or residential 
uses for this product. Therefore, no occupation exposure assessment is 
required. If domestic uses are added in the future, an occupational 
exposure assessment will have to be completed.
    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 hexaconazole 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, 
hexaconazole 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 hexaconazole 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. Aggregate Risks and Determination of Safety for U.S. Population

    1. Acute risk. The acute food exposure analysis for hexaconazole is 
a conservative but more realistic estimate of dietary exposure with the 
use of the pulp residue values. The acute food exposure analysis for 
the population subgroup females 13+ was performed using the highest 
pulp residue (parent + diol metabolite) levels and 100% crop treated 
(CT). The FQPA Safety Factor of 10x was retained for the acute dietary 
analysis only. The aPAD used in the acute dietary analysis was 0.0025 
mg/kg/day. The percent aPADs were below EPA's level of concern at the 
95th percentile of exposure for the females 13+ subgroup. The highest 
percent aPAD at the 95th percentile of exposure was 47% for the 
subgroup, females 13+ (pregnant, not nursing). Therefore, the acute 
dietary risk associated with the proposed use of hexaconazole on 
bananas is below the Agency's level of concern. The table below 
summarizes the acute food exposure.


    Summary of Acute Food Exposure and Risk for Hexaconazole at 95th
                         Percentile of Exposure
------------------------------------------------------------------------
                                                          Population
       Population Subgroup         Exposure (mg/kg/      Adjusted Dose
                                         day)                (PAD)
------------------------------------------------------------------------
Females (13+, pregnant, not       0.001181            47.2
 nursing).
Females (13+, nursing)..........  0.001136            45.4
Females (13-19 yrs., not          0.000892            35.7
 pregnant, not nursing).
Females (10+ years, not           0.001030            41.2
 pregnant, not nursing).
Females (13-50 years)...........  0.000954            38.1
------------------------------------------------------------------------


    2. Chronic risk. The chronic (non-cancer) and cancer Dietary 
Exposure Evaluation Model (DEEM) analyses used mean consumption (3-day 
average). Average pulp residues from field trials and 100% CT 
information were used. The FQPA Safety Factor was removed (equivalent 
to a factor of 1x) for chronic exposures. Therefore, the chronic PAD 
and the chronic RfD are identical. For chronic dietary risk, EPA's 
level of concern is greater than 100% cPAD. All chronic (non-cancer) 
percent PADs for all subgroups were 1%. The results of the 
chronic dietary analysis indicate that the chronic dietary risk 
associated with the existing and proposed uses of hexaconazole is below 
the Agency's level of concern (<100% PAD). The table below summarizes 
the chronic dietary exposure and includes the U.S. general population 
and other subgroups. The other subgroups included are all infant and 
children subgroups and the highest dietary exposures for the respective 
adult population subgroups (i.e., females and the other general 
population subgroup higher than U.S. population).


      Summary of Chronic (non-cancer) Dietary Exposure and Risk for
                              Hexaconazole
------------------------------------------------------------------------
                                   Exposure (mg/kg/
       Population Subgroup               day)                %RfD
------------------------------------------------------------------------
U.S. Population (the contiguous   0.000033            <1
 48 states).
Non-Hispanic other than black or  0.000050            <1
 white.
All infants (< 1 year)..........  0.000167            <1
Nursing infants (< 1 year)......  0.000077            <1
Non-nursing infants (< 1 year)..  0.000205            1.0
Children (1-6 years old)........  0.000091            <1
Children (7-12 years old).......  0.000037            <1
Females (13+/nursing)...........  0.000035            <1
------------------------------------------------------------------------

    3. Aggregate cancer risk for U.S. population. The Agency generally 
considers 1 x 10-6 as negligible risk (i.e, less than 1 in 1 
million) for cancer. The results of this analysis indicate that the 
cancer dietary risk of 5.3 x 10-7 associated with the 
proposed use of hexaconazole is below the Agency's level of concern.


 
------------------------------------------------------------------------
                                   Exposure (mg/kg/
            Subgroup                     day)            Lifetime Risk
------------------------------------------------------------------------
U.S. Population (the contiguous   0.000033            5.3 x 10-7
 48 states).
------------------------------------------------------------------------


    4. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to hexaconazole residues.

E. Aggregate Risks and Determination of Safety for Infants and Children

    1. Safety factor for infants and children -- i. In general. In 
assessing the potential for additional sensitivity of infants and 
children to residues of hexaconazole, EPA considered data from 
developmental toxicity studies in the rat and rabbit and a 2-generation 
reproduction study in the rat. The developmental toxicity studies are 
designed to evaluate adverse effects on the developing organism 
resulting from maternal pesticide exposure gestation. Reproduction 
studies provide information relating to effects from exposure to the 
pesticide on the reproductive capability of mating animals and data on 
systemic toxicity.
    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 pre- and postnatal toxicity and the 
completeness of the database unless

[[Page 35047]]

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. EPA believes that 
reliable data support using the standard uncertainty factor (usually 
100 for combined inter- and intra-species variability) and not the 
additional tenfold MOE/uncertainty factor when EPA has a complete data 
base under existing guidelines and when the severity of the effect in 
infants or children or the potency or unusual toxic properties of a 
compound do not raise concerns regarding the adequacy of the standard 
MOE/safety factor.
    ii. Developmental toxicity studies. The available data indicated 
evidence of increased susceptibility of rat and rabbit fetuses to the 
in utero exposure of hexaconazole in developmental studies. In both the 
rat and rabbit developmental toxicity studies, developmental effects 
occurred at dose levels lower than those causing maternal toxicity; in 
rats developmental toxicity was manifested as delayed ossification and 
an extra 14th rib; and in rabbits, decreased fetal weights occurred at 
doses below maternally toxic levels.
    iii. Reproductive toxicity study. In the 2-generation reproduction 
study, no increased susceptibility was observed. Effects in the 
offspring occurred only at or above treatment levels which resulted in 
evidence of parental toxicity.
    iv. Conclusion. There is a complete toxicity database for 
hexaconazole and exposure data are complete or are estimated based on 
data that reasonably accounts for potential exposures. The 10x FQPA 
safety factor will be applied only to subpopulation group females 13+ 
for the determination of acute dietary risk because the effects occur 
only during utero exposure and are not post natal effects. The FQPA 
safety factor will not be applied for chronic dietary risk assessment 
because: (a) the NOAEL used in deriving the RfD is based on liver 
effects from the chronic dog study; (b) the developmental effects on 
which the FQPA factor is based were seen in pregnant animals of a 
different species (rats and rabbits); and (c) the developmental effects 
are considered to be ``acute'' effects, and not a result of chronic 
exposure.
    2. Acute risk. A dose and endpoint were not selected for the 
general population including infants and children subpopulation group 
because their were no effects observed in the oral toxicity studies 
including maternal toxicity in the developmental toxicity studies in 
rats and rabbits that are attributable to a single exposure dose.
    3. Chronic risk. Using the exposure assumptions described in this 
unit, EPA has concluded that aggregate exposure to hexaconazole from 
food will utilize 1% of the RfD for infants and children. EPA generally 
has no concern for exposures below 100% of the RfD because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose appreciable risks to human health.
    4. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to hexaconazole 
residues.

III. Other Considerations

A. Metabolism In Plants and Animals

    The nature of the residue in plants is understood. Plant metabolism 
studies were conducted on grapes, apples, and wheat and found 
acceptable. As the nature of the residue is understood in these crops, 
no additional metabolism studies for bananas were required. The data 
indicate that the major terminal residues in plants will be parent 
hexaconazole, its diol metabolites [()-5-(2,4-
dichlorophenyl)-6-(1H-1,2,4-triazol-1-yl)hexan-2,6-diol, 
()-5-(2,4-dichlorophenyl)-5-hydroxy-6-(1H-1,2,4-triazol-1-
yl)hexanoic acid, ()-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-
triazol-1-yl)hexan-2,5-diol, and ()-2-(2,4-dichlorophenyl)-
1-(1H-1,2,4-triazol-1-yl)hexan-2,4-diol, free and conjugated] resulting 
from oxidation of the alkyl side chain of hexaconazole, and its 
triazole metabolites [1H-1,2,4-triazole, (RS)-3-(1H-1,2,4-triazol-1-yl) 
alanine (also known as triazole alanine), (1H-1,2,4-triazole-1-yl) 
acetic acid (also known as triazole acetic acid)], resulting from the 
cleavage of the triazolyl moiety of the parent compound. The 
predominant residues in apples and grapes are hexaconazole and its diol 
metabolites. The metabolism in wheat apparently differs in that while 
hexaconazole and its diol metabolites were the major terminal residues 
in straw and chaff, the major terminal residues in grain were the 
triazole degradation products. Any residues in banana flesh will result 
from extensive translocation through leaves, stalk, and skin.
    EPA determined that parent hexaconazole is the only terminal 
residue that should be included in the tolerance expression for 
bananas, which is the only food use pending at this time. The diol 
metabolites are not being included in the tolerance expression or in 
the risk assessments since they are of low toxicity and are not likely 
to be present at detectable levels in bananas.

B. Analytical Enforcement Methodology.

    The petitioner has proposed ``Agrochemical Residue Analytical 
Method 108/1 for Residues of Hexaconazole in Crops'' as the analytical 
enforcement method. Samples of homogenized whole bananas are weighed 
into a round bottom flask (fortification occurs at this step). The 
sample is extracted by refluxing with methanolic sodium hydroxide for 
1-hour. Aqueous sodium chloride is then added, and the hexaconazole is 
partitioned from the methanol/aqueous solution into dichloromethane. 
The extracts in dichloromethane are cleaned up using silica adsorption 
micro-columns. Parent hexaconazole is then determined using capillary 
column gas liquid chromatography (GLC)/nitrogen phosphorous (NP) or 
GLC/electron capture (EC). EPA concluded that Method 108/1 is adequate 
for enforcement purposes. An independent laboratory validation (ILV) of 
the method has been submitted and a satisfactory petition method 
validation (PMV) by EPA was completed.
    Adequate enforcement methodology (example - gas chromatography) is 
available to enforce the tolerance expression. The method may be 
requested from: Calvin Furlow, PRRIB, IRSD (7502C), Office of Pesticide 
Programs, Environmental Protection Agency, 401 M St., SW., Washington, 
DC 20460. Office location and telephone number: Rm 101FF, CM #2, 1921 
Jefferson Davis Hwy., Arlington, VA, (703) 305-5229.

C. Magnitude of Residues.

    A total of 18 field trials were submitted and reviewed by the 
Agency. The residue levels of hexaconazole (parent only) in whole 
unbagged bananas from all trials ranged from < 0.01 limit of 
quantitation (LOQ) to 0.64 ppm. The residue levels of hexaconazole in 
unbagged banana pulp from all field trials ranged from < 0.01 ppm (LOQ) 
to 0.17 ppm. The residue levels of the diol metabolites in whole 
unbagged bananas from all trials ranged from < 0.03 (LOQ) to 1.6 ppm. 
The residue levels of the diol metabolites in unbagged banana pulp from 
all field trials ranged from < 0.03 ppm (LOQ) to 0.39 ppm. The 
submitted data indicate that residues of hexaconazole in whole bananas 
will exceed the existing time-limited tolerance level of 0.1 ppm for 
bananas. The appropriate tolerance level is 0.7 ppm for bananas. A 
revised

[[Page 35048]]

section F was submitted amending the tolerance to 0.7 ppm for bananas.
    There are no processed commodities associated with bananas; 
therefore, no tolerances for processed commodities are required.
    There are no animal feed items associated with bananas; therefore, 
no tolerances for meat, milk, poultry, and eggs are required. For any 
future petition in which there is a potential for transfer of residues 
to animals (meat, milk, poultry, eggs, etc.), animal metabolism studies 
will be required.
    Anticipated residues were calculated from field trial data. The 
residue levels from banana pulp for parent and diol metabolites were 
used. The residue level value of 0.56 ppm, which was the highest 
residue level for pulp (hexaconazole-0.17 ppm + diol metabolites-0.39 
ppm), was used in the acute dietary analysis. The residue level value 
of 0.11 ppm, which was the average from the field trials for pulp 
(hexaconazole-0.03 ppm + diol metabolites-0.08 ppm), was used in the 
chronic dietary analysis.
    To provide for the re-evaluation of the anticipated residues, the 
Agency will require under section 408(b)(2)(E) that additional data be 
submitted within 5 years. EPA will require additional residue data on 
the diol metabolites for future food uses. If monitoring data for the 
parent need to be used in the future for dietary risk assessments, then 
diol residues may be estimated based on their ratio to parent 
hexaconazole.

D. International Residue Limits.

    There is neither a Codex proposal, nor Canadian or Mexican limits 
for residues of hexaconazole in bananas. Therefore, a compatibility 
issue is not relevant to the proposed tolerance.

IV. Conclusion

    Therefore, the tolerance is established for residues of 
hexaconazole, [alpha-butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-
triazole-1-ethanol] in the imported raw agricultural commodity bananas 
at 0.7 ppm.

V. Objections and Hearing Requests

    The new FFDCA section 408(g) provides essentially the same process 
for persons to ``object'' to a tolerance regulation as was provided in 
the old section 408 and in section 409. However, the period for filing 
objections is 60 days, rather than 30 days. EPA currently has 
procedural regulations which govern the submission of objections and 
hearing requests. These regulations will require some modification to 
reflect the new law. However, until those modifications can be made, 
EPA will continue to use those procedural regulations with appropriate 
adjustments to reflect the new law.
    Any person may, by August 30, 1999, file written objections to any 
aspect of this regulation and may also request a hearing on those 
objections. Objections and hearing requests must be filed with the 
Hearing Clerk, at the address given under the ``ADDRESSES'' section (40 
CFR 178.20). A copy of the objections and/or hearing requests filed 
with the Hearing Clerk should be submitted to the OPP docket for this 
regulation. The objections submitted must specify the provisions of the 
regulation deemed objectionable and the grounds for the objections (40 
CFR 178.25). Each objection must be accompanied by the fee prescribed 
by 40 CFR 180.33(i). EPA is authorized to waive any fee requirement 
``when in the judgement of the Administrator such a waiver or refund is 
equitable and not contrary to the purpose of this subsection.'' For 
additional information regarding tolerance objection fee waivers, 
contact James Tompkins, Registration Division (7505C), Office of 
Pesticide Programs, Environmental Protection Agency, 401 M St., SW., 
Washington, DC 20460. Office location, telephone number, and e-mail 
address: Rm. 239, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA, 
(703) 305-5697, [email protected]. Requests for waiver of tolerance 
objection fees should be sent to James Hollins, Information Resources 
and Services Division (7502C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
    If a hearing is requested, the objections must include a statement 
of the factual issues on which a hearing is requested, the requestor's 
contentions on such issues, and a summary of any evidence relied upon 
by the requestor (40 CFR 178.27). A request for a hearing will be 
granted if the Administrator determines that the material submitted 
shows the following: There is genuine and substantial issue of fact; 
there is a reasonable possibility that available evidence identified by 
the requestor would, if established, resolve one or more of such issues 
in favor of the requestor, taking into account uncontested claims or 
facts to the contrary; and resolution of the factual issues in the 
manner sought by the requestor would be adequate to justify the action 
requested (40 CFR 178.32). Information submitted in connection with an 
objection or hearing request may be claimed confidential by marking any 
part or all of that information as CBI. Information so marked will not 
be disclosed except in accordance with procedures set forth in 40 CFR 
part 2. A copy of the information that does not contain CBI must be 
submitted for inclusion in the public record. Information not marked 
confidential may be disclosed publicly by EPA without prior notice.

VI. Public Record and Electronic Submissions

    EPA has established a record for this regulation under docket 
control number [OPP-300871] (including any comments and data submitted 
electronically). A public version of this record, including printed, 
paper versions of electronic comments, which does not include any 
information claimed as CBI, is available for inspection from 8:30 a.m. 
to 4 p.m., Monday through Friday, excluding legal holidays. The public 
record is located in Rm. 119 of the Public Information and Records 
Integrity Branch, Information Resources and Services Division (7502C), 
Office of Pesticide Programs, Environmental Protection Agency, CM #2, 
1921 Jefferson Davis Hwy., Arlington, VA.
    Objections and hearing requests may be sent by e-mail directly to 
EPA at:
    [email protected]


    E-mailed objections and hearing requests must be submitted as an 
ASCII file avoiding the use of special characters and any form of 
encryption.
    The official record for this regulation, as well as the public 
version, as described in this unit will be kept in paper form. 
Accordingly, EPA will transfer any copies of objections and hearing 
requests received electronically into printed, paper form as they are 
received and will place the paper copies in the official record which 
will also include all comments submitted directly in writing. The 
official record is the paper record maintained at the Virginia address 
in ``ADDRESSES'' at the beginning of this document.

VII. Regulatory Assessment Requirements

A. Certain Acts and Executive Orders

    This final rule establishes a tolerance under section 408(d) of the 
FFDCA in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993). This final rule does not contain 
any information collections subject to OMB approval under the Paperwork 
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable 
duty or contain any

[[Page 35049]]

unfunded mandate as described under Title II of the Unfunded Mandates 
Reform Act of 1995 (UMRA) (Public Law 104-4). Nor does it require any 
special considerations as required by Executive Order 12898, entitled 
Federal Actions to Address Environmental Justice in Minority 
Populations and Low-Income Populations (59 FR 7629, February 16, 1994), 
or require OMB review in accordance with Executive Order 13045, 
entitled Protection of Children from Environmental Health Risks and 
Safety Risks (62 FR 19885, April 23, 1997).
    In addition, since tolerances and exemptions that are established 
on the basis of a petition under FFDCA section 408(d), such as the 
tolerance in this final rule, do not require the issuance of a proposed 
rule, the requirements of the Regulatory Flexibility Act (RFA) (5 
U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency previously 
assessed whether establishing tolerances, exemptions from tolerances, 
raising tolerance levels or expanding exemptions might adversely impact 
small entities and concluded, as a generic matter, that there is no 
adverse economic impact. The factual basis for the Agency's generic 
certification for tolerance actions published on May 4, 1981 (46 FR 
24950), and was provided to the Chief Counsel for Advocacy of the Small 
Business Administration.

B. Executive Order 12875

    Under Executive Order 12875, entitled Enhancing the 
Intergovernmental Partnership (58 FR 58093, October 28, 1993), EPA may 
not issue a regulation that is not required by statute and that creates 
a mandate upon a State, local or tribal government, unless the Federal 
government provides the funds necessary to pay the direct compliance 
costs incurred by those governments. If the mandate is unfunded, EPA 
must provide to OMB a description of the extent of EPA's prior 
consultation with representatives of affected State, local, and tribal 
governments, the nature of their concerns, copies of any written 
communications from the governments, and a statement supporting the 
need to issue the regulation. In addition, Executive Order 12875 
requires EPA to develop an effective process permitting elected 
officials and other representatives of State, local, and tribal 
governments ``to provide meaningful and timely input in the development 
of regulatory proposals containing significant unfunded mandates.''
    Today's rule does not create an unfunded Federal mandate on State, 
local, or tribal governments. The rule does not impose any enforceable 
duties on these entities. Accordingly, the requirements of section 1(a) 
of Executive Order 12875 do not apply to this rule.

C. Executive Order 13084

    Under Executive Order 13084, entitled Consultation and Coordination 
with Indian Tribal Governments (63 FR 27655, May 19, 1998), EPA may not 
issue a regulation that is not required by statute, that significantly 
or uniquely affects the communities of Indian tribal governments, and 
that imposes substantial direct compliance costs on those communities, 
unless the Federal government provides the funds necessary to pay the 
direct compliance costs incurred by the tribal governments. If the 
mandate is unfunded, EPA must provide OMB, in a separately identified 
section of the preamble to the rule, a description of the extent of 
EPA's prior consultation with representatives of affected tribal 
governments, a summary of the nature of their concerns, and a statement 
supporting the need to issue the regulation. In addition, Executive 
Order 13084 requires EPA to develop an effective process permitting 
elected officials and other representatives of Indian tribal 
governments ``to provide meaningful and timely input in the development 
of regulatory policies on matters that significantly or uniquely affect 
their communities.''
    Today's rule does not significantly or uniquely affect the 
communities of Indian tribal governments. This action does not involve 
or impose any requirements that affect Indian tribes. Accordingly, the 
requirements of section 3(b) of Executive Order 13084 do not apply to 
this rule.

VIII. Submission to Congress and the Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the 
Small Business Regulatory Enforcement Fairness Act of 1996, generally 
provides that before a rule may take effect, the Agency promulgating 
the rule must submit a rule report, which includes a copy of the rule, 
to each House of the Congress and the Comptroller General of the United 
States. EPA will submit a report containing this rule and other 
required information to the U.S. Senate, the U.S. House of 
Representatives and the Comptroller General of the United States prior 
to publication of the rule in the Federal Register. This rule is not a 
``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: June 10, 1999.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

    Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

    1. The authority citation for part 180 continues to read as 
follows:
    Authority: 21 U.S.C. 321(q), (346a) and 371.


    2. Sec. 180.488 is revised to read as follows:


Sec. 180.488  Hexaconazole; tolerance for residues.

    A tolerance is established for residues of the fungicide 
hexaconazole, [alpha-butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-
triazole-1-ethanol], in or on the imported raw agricultural commodity 
bananas at 0.7 parts per million (ppm). There are no U.S. registrations 
as of June 30, 1999.
[FR Doc. 99-16545 Filed 6-29-99; 8:45 am]
BILLING CODE 6560-50-F