[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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: opp-docket@epa.gov. 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,
waller.mary@epa.gov.
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="">-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,="">tompkins.jim@epa.gov. 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:
opp-docket@epa.gov
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
