[Federal Register Volume 64, Number 36 (Wednesday, February 24, 1999)]
[Notices]
[Pages 9147-9151]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4321]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-857; FRL-6058-9]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-857, must
be received on or before March 26, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, Crystal Mall 2 (CM #2), 1921 Jefferson Davis Highway,
Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Following the instructions under
``SUPPLEMENTARY INFORMATION.'' No confidential business information
should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment 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. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number e-mail Address
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Bipin Gandhi.................. Rm. 707A, Crystal Mall [email protected]
2 (CM #2), 1921 mail.epa.gov.
Jefferson Davis Hwy,
Arlington, VA; 703-
308-8380
Mary Waller................... Rm. 249, CM #2, 1921 [email protected]
Jefferson Davis Hwy, ail.epa.gov.
Arlington, VA; 703-
308-9354
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various raw food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports grantinig of
the
[[Page 9148]]
petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-857 (including comments and data submitted electronically as
described below). 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
official record is located at the address in ``ADDRESSES'' at the
beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (insert docket number) and
appropriate petition number. Electronic comments on this notice may be
filed online at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: February 16, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. The
petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
1. ICI Surfactants
PP 9E5063
EPA has received a pesticide petition (PP) from ICI Surfactants,
3411 Silverside Road, Wilmington, DE 19803-8340 proposing pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR 180.1001(c) and (e) to establish an exemption
from the requirement of a tolerance for polyoxyethylated sorbitol fatty
acid esters; the sorbitol solution containing up to 15% water is
reacted with 20-50 moles of ethylene oxide and aliphatic alkanoic and/
or alkenoic fatty acids C8 through C22 with minor
amounts of associated fatty acids; the resulting polyoxyethylene
sorbitol ester having a minimum molecular weight of 1,300 when used as
an inert ingredient in pesticide formulations applied to growing crops
or to raw agricultural commodities after harvest or to animals. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
Magnitude of residues. ICI Americas is petitioning that
polyoxyethylated sorbitol fatty acid esters; the sorbitol solution
containing up to 15% water is reacted with 20-50 moles of ethylene
oxide and aliphatic alkanoic and/or alkenoic fatty acids C8
through C22 with minor amounts of associated fatty acids;
the resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,000, be exempt from the requirement of a tolerance based
upon the low risk polymer criteria per 40 CFR 723.250. Therefore, an
analytical method to determine residues in raw agricultural commodities
has not been proposed. No residue chemistry data or environmental fate
data are presented in the petition as the Agency does not generally
require some or all of the listed studies to rule on the exemption from
the requirement of a tolerance for a low risk polymer inert ingredient.
B. Toxicological Profile (Low Risk Polymer Criteria)
1. Acute toxicity. In the case of certain chemical substances that
are defined as polymers, the Agency has established a set of criteria
which identify categories of polymers that present low risk. These
criteria (described in 40 CFR 723.250) identify polymers that are
relatively unreactive and stable compounds compared to other chemical
substances as well as polymers that typically are not readily absorbed.
These properties generally limit a polymer's ability to cause adverse
effects. In addition, these criteria exclude polymers about which
little is known. The Agency believes that polymers meeting these
criteria will present minimal or no risk. Polyoxyethylated sorbitol
fatty acid esters; the sorbitol solution containing up to 15% water is
reacted with 20-50 moles of ethylene oxide and aliphatic alkanoic and/
or alkenoic fatty acids C8 through C22 with minor
amounts of associated fatty acids; the resulting polyoxyethylene
sorbitol ester having a minimum molecular weight of 1,000, conform to
the definition of a polymer given in 40 CFR 723.250(b) and meet the
criteria used to identify low risk polymers under 40 CFR 723.250(e) and
is not an excluded polymer per 40 CFR 723.250(d), i.e.:
i. The polymer is not a cationic polymer, nor is it capable of
becoming a cationic polymer in the natural aquatic environment.
ii. It contain as an integral part of its composition only the
atomic elements carbon, hydrogen, and oxygen.
iii. It does not contain as an integral part of its composition,
except as impurities, any element other than those listed in 40 CFR
723.250(d)(2)(iii).
iv. It is not designed to, nor is it reasonably anticipated to
substantially degrade, decompose or depolymerize.
v. It is not manufactured or imported from monomers and/or other
reactants that are not already included on the TSCA Chemical Substance
Inventory or manufactured under an applicable TSCA section 5 exemption.
vi. It is not a water absorbing polymer with a number average
molecular weight greater than or equal to 10,000 daltons.
vii. Its minimum number-average molecular weight is greater than
1,000 and less than 10,000 daltons. It contains less than 10%
oligomeric material below molecular weight 500 and less than 25%
oligomeric material below 1,000 daltons molecular weight. Substances
with molecular weights greater than 400 are generally not readily
absorbed through the intact skin, and substances with molecular weights
greater than 1,000 are generally not absorbed through the intact
gastrointestinal (GI) tract. Chemicals not absorbed through the GI
tract are generally incapable of eliciting a toxic response.
viii. It does not contain any reactive functional groups.
ICI believes sufficient information was submitted in the petition
to assess the hazards of polyoxyethylated sorbitol fatty acid esters;
the sorbitol solution containing up to 15% water is reacted with 20-50
moles of ethylene oxide and aliphatic alkanoic and/or alkenoic fatty
acids C8 through C22 with minor amounts of
associated fatty acids; the resulting polyoxyethylene sorbitol ester
[[Page 9149]]
having a minimum molecular weight of 1,300. No toxicology data were
presented in the petition as the Agency does not generally require some
or all of the listed studies to rule on the exemption from the
requirement of a tolerance for a low risk polymer inert ingredient.
Based on this polymer conforming to the definition of a polymer and
meeting the criteria of a polymer under 40 CFR 723.250, ICI believes
there are no concerns for risks associated with toxicity.
2. Endocrine disruption. There is no evidence that polyoxyethylated
sorbitol fatty acid esters; the sorbitol solution containing up to 15%
water is reacted with 20-50 moles of ethylene oxide and aliphatic
alkanoic and/or alkenoic fatty acids C8 through
C22 with minor amounts of associated fatty acids; the
resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,000, is an endocrine disrupter. Substances with molecular
weights greater than 400 generally are not absorbed through the intact
skin, and substances with molecular weights greater than 1,000
generally are not absorbed through the intact gastrointestinal (GI)
tract. Chemicals not absorbed through the skin or GI tract generally
are incapable of eliciting a toxic response.
EPA is not requiring information on the endocrine effects of this
substance at this time; Congress has allowed 3 years after August 3,
1996, for the Agency to implement a screening program with respect to
endocrine effects.
C. Aggregate Exposure
1. Dietary exposure. Polyoxyethylated sorbitol fatty acid esters
may come in contact with food when used as inert ingredients in
pesticide formulations applied to growing crops only per 40 CFR
180.1001(d). Such use typically involves low application rates for the
inert where potential residues of inert ingredients are indirectly
controlled through tolerances established for the active ingredient.
Polyoxyethylated sorbitol esters with a molecular weight greater than
1,000 daltons are not readily absorbed through the intact
gastrointestinal tract and are considered incapable of eliciting a
toxic response.
2. Non-dietary exposure. Typical uses of polyoxyethylated sorbitol
fatty acid esters are in the synthetic fiber manufacturing industry as
emulsifiers for oils used in lubricants at low end product use rates.
In these uses the primary exposures is dermal, however, and
polyoxyethylated sorbitol esters with a molecular weight significantly
greater than 400 are not readily absorbed through the intact skin and
are considered incapable of eliciting a toxic response.
D. Cumulative Effects
There is data to support a conclusion of negligible cumulative risk
from polyoxyethylated sorbitol fatty acid esters; the sorbitol solution
containing up to 15% water is reacted with 20-50 moles of ethylene
oxide and aliphatic alkanoic and/or alkenoic fatty acids C8
through C22 with minor amounts of associated fatty acids;
the resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,300. Polymers with molecular weights greater than 400
generally are not absorbed through the intact skin, and substances with
molecular weights greater than 1,000 generally are not absorbed through
the intact gastrointestinal (GI) tract. Chemicals not absorbed through
the skin or GI tract generally are incapable of eliciting a toxic
response. Therefore, there is no reasonable expectation of increased
risk due to cumulative exposure. Based on this polymer conforming to
the definition of a polymer and meeting the criteria of a polymer under
40 CFR 723.250, ICI believes there are no concerns for risks associated
with cumulative effects.
E. Safety Determination
1. U.S. population. ICI believes sufficient information was
submitted in the petition to assess the hazards of polyoxyethylated
sorbitol fatty acid esters; the sorbitol solution containing up to 15%
water is reacted with 20-50 moles of ethylene oxide and aliphatic
alkanoic and/or alkenoic fatty acids C8 through
C22 with minor amounts of associated fatty acids; the
resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,000. Based on this polymer conforming to the definition of
a polymer and meeting the criteria of a polymer under 40 CFR 723.250,
ICI believes there are no concerns for risks associated with any
potential exposure to adults. There are no known additional pathways of
exposure (non-occupational, drinking water, etc.) where there would be
additional risk.
2. Infants and children. ICI believes sufficient information was
submitted in the petition to assess the hazards of polyoxyethylated
sorbitol fatty acid esters; the sorbitol solution containing up to 15%
water is reacted with 20-50 moles of ethylene oxide and aliphatic
alkanoic and/or alkenoic fatty acids C8 through
C22 with minor amounts of associated fatty acids; the
resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,000. Based on this polymer conforming to the definition of
a polymer and meeting the criteria of a polymer under 40 CFR 723.250,
ICI believes there are no concerns for risks associated with any
potential exposure to infants and children. There are no known
additional pathways of exposure (non-occupational, drinking water,
etc.) where infants and children would be at additional risk.
F. International Tolerances
We are not aware of any country requiring a tolerance for
polyoxyethylated sorbitol fatty acid esters; the sorbitol solution
containing up to 15% water is reacted with 20-50 moles of ethylene
oxide and aliphatic alkanoic and/or alkenoic fatty acids C8
through C22 with minor amounts of associated fatty acids;
the resulting polyoxyethylene sorbitol ester having a minimum molecular
weight of 1,000. Nor have there been any CODEX Maximum Residue Levels
(MRL's) established for any food crops at this time. (Bipin Gandhi)
2. Zeneca Ag Products
PP 0E3853
EPA has received a pesticide petition (PP 0E3853) from Zeneca Ag
Products, 1800 Concord Pike, Wilmington, DE 19850-5458, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a
tolerance for residues of hexaconazole in or on the imported raw
agricultural commodity bananas at 0.7 parts per million (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue in plants is
adequately understood. Plant metabolism studies have been conducted in
apples, grapes, and wheat. The predominant residues in each of these
studies are hexaconazole and its diol metabolites. EPA has determined
that only the parent, hexaconzole, should appear in the tolerance
expression, but that the diol metabolites are to be included in the
risk assessment.
2. Analytical method. Analytical method SOPRAM 108/3 was used to
[[Page 9150]]
determine residues (parent) of hexaconazole in or on bananas. This
method is proposed as the regulatory enforcement method. The method
uses gas liquid chromatography for identification and quantification of
hexaconazole. Results are confirmed by mass spectroscopy. The method
has been independently validated.
3. Magnitude of residues. Twenty-six separate residue trials on
bananas have been conducted and submitted to the EPA. Six of these
trials were conducted on unbagged bananas per EPAs request and the
remaining 20 trials were conducted on bagged bananas. The trials on
unbagged bananas were conducted in Mexico (3), Costa Rica (2), and
Guatemala (1). The trials on bagged bananas were conducted in Mexico
(4), Guatemala (4), Colombia (3), Equador (3), Costa Rica (1), Panama
(2), and Honduras (3). The results of these trials show that residues
of hexaconazole in the raw agricultural commodity bananas will not
exceed the proposed tolerance of 0.7 ppm. There are no livestock feed
stuffs derived from bananas and therefore no secondary residues are
expected in animal products.
B. Toxicological Profile
1. Acute toxicity. Acute toxicity data are not required for an
import tolerance; however hexaconazole has been shown to have low acute
toxicity with an acute oral LD50 of 2,189 mg/kg in female
rats and 6,071 mg/kg in male rats, a dermal LD50 of > 2,000
mg/kg in rats, and an inhalation LC50 of > 5.91 mg/L.
Hexaconazole is a non-irritant to rabbit skin and mild eye irritant in
the rabbit. It is a skin sensitizer in guinea pigs.
2. Genotoxicty. A battery of in vitro and in vivo mutagenicity
studies (5) have been conducted on hexaconazole. These studies included
an Ames assay, a mouse lymphoma assay, an in vitro cytogenetics assay
in human lymphocytes, an assay for unscheduled DNA synthesis in rat
hepatocytes, and a mouse micronucleus test. The results of these tests
were all negative indicating that hexaconazole is not genotoxic.
3. Reproductive and developmental toxicity. Developmental toxicity
studies have been conducted in rats and rabbits. Pregnant Wistar rats
were treated from day 7-16 of gestation with 0, 2.5, 25, or 250 mg/kg
hexaconazole. Administration of 250 mg/kg was associated with maternal
toxicity which consisted of reduced body weight gain and food
consumption. Also at this dosage level, increased post-implantation
loss and reduced fetal weights were seen when compared to the control
group. There was no evidence of a teratogenic effect. Developmental
toxicity at 250 mg/kg consisted of an increased incidence of extra
14th ribs, unossified calcanea, and partially ossified
5th sternebrae, and mean manus and pes scores. The incidence
of extra 14th ribs was statistically increased at 25 mg/kg
on a fetal, but not litter, basis. At 25 mg/kg, the incidence of extra
14th ribs was increased compared to the control group, but
not statistically by either fetal or litter incidence. The no observed
adversed effect level (NOAEL) for maternal toxicity was 25 mg/kg and
the NOAEL for developmental toxicity was 2.5 mg/kg.
The developmental toxicity of hexaconazole was determined in two
New Zealand rabbit studies. In the first study, dose levels of 0, 2.5,
12.5, or 50 mg/kg were administered to pregnant rabbits on days 7-19 of
gestation. The NOAEL for maternal and developmental toxicity in this
study was 50 mg/kg (the highest dosage level tested). Therefore, a
second study was conducted using dose levels of 0, 25, 50, and 100 mg//
kg. In the repeat study, reduced maternal body weight gain was observed
at 100 mg/kg and reduced fetal weights at 50 and 100 mg/kg. The NOAEL
for maternal toxicity was 50 mg/kg and the NOAEL for fetotoxicity was
25 mg/kg.
In a 2-generation reproduction study, dose levels of 0, 20, 100, or
1,000 ppm (equivalent to 0, 1, 5, and 50 mg/kg/day) were administered
in the diet to Wistar rats. Liver pathology was seen in both parental
animals and in the pups at 100 and 1,000 ppm. Reduced pup weight was
seen at 1,000 ppm in the F1 generation from postnatal day 5
onwards. There was a slight effect on pup survival at 1,000 ppm in the
F2b generation. The systemic NOAEL was 20 ppm and the
reproductive NOAEL was 100 ppm.
4. Subchronic toxicity. Subchronic toxicity studies have been
conducted in rats and dogs. Male and female Wistar rats were fed diets
containing 0, 50, 500, or 5,000 ppm hexaconzole for a period of 90
days. Findings included decreased body weight gain (500 and 5,000 ppm),
fatty changes and liver hypertrophy (500 and 5,000 ppm), and adrenal
cortical vacuolation (50, 500, and 5,000 ppm). A clear NOAEL was not
determined in this study.
Beagle dogs were orally administered 0, 5, 25, or 125 mg/kg/day
hexaconazole in gelatin capsules for 90 days. At 25 and 125 mg/kg/day,
increased alkaline phosphatase activity, increased liver weight, and
increased lipid accumulation in liver parenchymal cells were seen. The
NOAEL was 5 mg/kg/day.
5. Chronic toxicity. Chronic toxicity studies have been conducted
in rats, mice, and dogs. In a 2-year feeding study in Alpk:APfSD rats,
hexaconazole was tested at dose levels of 0, 10, 100, and 1,000 ppm
(equivalent to 0, 0.47, 4.7, and 47 mg/kg/day in males and 0, 0.61,
6.1, and 61 mg/kg/day in females). At 1,000 ppm and to a lesser extent
at 100 ppm, increased hepatocyte hypertrophy and reduced body weight
gain were observed. The NOAEL in this study was determined to be 10
ppm, equivalent to 0.47 mg/kg/day in males and 0.61 mg/kg/day in
females. An increased incidence of Leydig cell tumors was seen in male
rats at 1,000 ppm.
The oncogenic potential of hexaconazole was assessed in C57/BL/
10JfCD-1/Alpk mice. Dosage levels were 0, 5, 40, and 200 ppm
administered in the diet for a period of 2 years. At 200 ppm, decreased
body weight gain (10%) in males was observed. Food utilization was
decreased in male and female mice at this dosage level. Fatty changes
were seen in the livers of treated mice at 200 ppm. Hexaconazole was
not considered oncogenic to mice. The NOAEL was determined to be 40 ppm
which is equivalent to 4.7 mg/kg/day in male mice and 5.9 mg/kg/day in
female mice.
Beagle dogs were orally administered 0, 2, 10, or 50 mg/kg/day
hexaconazole daily in capsules for 1 year. At 10 and 50 mg/kg/day,
increased alkaline phosphatase activity, increased liver weight, and
increased fatty changes in the liver were observed. The NOAEL was 2 mg/
kg/day.
6. Animal metabolism. In the rat, 14C-hexaconazole is
readily absorbed, extensively metabolized, and readily excreted. The
major route of metabolism involves oxidation of the n-butyl chain. In
male rats the majority of the radioactivity is excreted in the feces
and in female rats in the urine. The sex difference in the proportions
of hexaconazole excreted in urine and feces is due to quantitative
differences in biliary elimination of hexaconazole metabolites.
7. Metabolite toxicology. The EPA metabolism committee considered
that only the parent hexaconazole should be included in the tolerance
expression. The diol metabolites of hexaconazole, however, were to be
considered in risk assessments. The Committee further considered that
the diol metabolites were toxicologically similar to hexaconazole and
therefore, testing of hexaconazole metabolites was not considered
necessary.
8. Endocrine disruption. Results of developmental and reproductive
studies on hexaconazole did not provide any
[[Page 9151]]
indication that hexaconazole disrupted endocrine function. In a 2-year
rat chronic toxicity study, an increased incidence of benign Leydig
cell tumors was seen at the highest dose level tested (1,000 ppm). Also
in this study a slightly increased incidence of adrenal cortical
vacuolation was seen in male rats; however, the toxicologic
significance of this finding is not known because the spontaneous
incidence in untreated male rats was very high. Zeneca has conducted
studies to determine the mechanism of induction of the Leydig cell
tumors in isolated rat and human Leydig cells.
Hexaconazole inhibits steroid production in both cell types through
inhibition of C17-20 lyase, a cytochrome P450-dependent
enzyme, leading to a decrease in testosterone production. Zeneca
postulates that the decrease in testosterone production leads to a
direct effect on the Leydig cell resulting in a compensatory
hyperplasia and eventually to tumors.
C. Aggregate Exposure
1. Dietary exposure. -- i. Chronic. For purposes of assessing the
potential dietary exposure from bananas at the tolerance level, Zeneca
has calculated the anticipated residue concentration (ARC) for the U.S.
population and various subgroups, including infants and children. In
performing this assessment, Zeneca used conservative assumptions,
including assuming that 100% of bananas imported into the U.S. would be
treated with hexaconazole. Actual residue data from the trials listed
in section 1.3 above were used in the assessment. Residue levels, which
included levels of hexaconazole plus its diol metabolites, from whole
bananas were averaged. Most of the residue values obtained were below
the level of quantification of the analytical method. In these cases 1/
2 of the quantified level was used. Therefore, the safety
determinations outlined in section E. below represent conservative
estimates of potential exposure of the U.S. population and various
subgroups to residues of hexaconazole on bananas.
ii. Acute. EPA does require acute dietary assessments for import
tolerances and therefore, an acute dietary assessment was not
conducted. However, results of residue trials indicate that levels of
hexaconazole and its metabolites are not expected to reach the
tolerance level.
2. Food. Aggregate exposure to residues of hexaconazole on food
products is not expected. There are no registrations for food uses of
hexaconazole within the U.S.; there is an import tolerance on bananas
only. Therefore, the only food source of hexaconazole residues to the
U.S. population is bananas.
3. Drinking water. No drinking water exposure is expected because
there are no U.S. registrations for hexaconazole uses. The only
existing U. S. tolerance is an import tolerance on bananas.
4. Non-dietary exposure. There are no registered uses of
hexaconazole within the U.S. and therefore no non-dietary exposure to
hexaconazole or its metabolites is expected.
D. Cumulative Effects
Although other triazole fungicides are registered for uses in the
U.S., Zeneca has no information to indicate that the toxic effects of
these fungicides (primarily liver toxicity) would be cumulative with
those of hexaconazole in the U.S. population.
E. Safety Determination
1. U.S. population. --i. Cancer. EPA has classified hexaconazole as
a Group C (Possible Human) carcinogen with a Q1* of 0.023
(mg/kg/day)-1. This classification was based on a
statistically significant increase in benign Leydig cell tumors in male
rats fed hexaconazole in the diet at a level of 1,000 ppm for 2 years.
In addition, this tumor type is an uncommon tumor in the strain of rat
used in this study and the tumors occurred at an accelerated rate. The
classification was also supported by a marginal increase in mouse liver
tumors and the structural similarity of hexaconazole to other triazole
fungicides that are mouse liver carcinogens.
Using the conservative assumptions outlined in section C.1, an
assessment of the potential cancer risk, based on a Q1* of
0.023 (mg/kg/day)-1, from dietary consumption of
hexaconazole (bananas) resulted in an exposure of 0.00025 mg/kg/day and
a lifetime risk to the U.S. population of 5.7 x 10-7. EPA
considers a lifetime cancer risk of one in a million to be acceptable.
ii. Threshold effects. Prior to the enactment of FQPA, EPA
calculated a reference dose (RfD) for hexaconazole of 0.02 mg/kg/day
based on the NOAEL from a 1-year dog study of 2 mg/kg/day and an
uncertainty factor of 100. In calculating the dietary risk of
hexaconazole to the U.S. population, Zeneca added an additional
uncertainty factor of 3 (to be protective of infants and children; see
section E.2 below) which gives a RfD of 0.007 mg/kg/day. Zeneca
considered adding an additional uncertainty factor of 10; however, it
did not believe that the effects seen at non-maternally toxic doses in
the rat and rabbit developmental toxicity studies were of a serious
enough concern to warrant an additional factor of 10.
Using the conservative assumptions outline in section C.1 and a RfD
of 0.007 mg/kgday, an assessment of the dietary risk to the U.S.
population resulted in an ARC of 0.00011 mg/kg/day or 0.4% of the RfD.
2. Infants and children. When assessing the potential for extra
sensitivity of infants and children to hexaconazole, Zeneca considered
the results of developmental (rat and rabbit) and reproductive (rat)
toxicity studies. The developmental toxicity NOAELs in the rat and
rabbit teratology studies were lower than the NOAELs for maternal
toxicity. The NOAEL (2.5 mg/kg/day) for developmental toxicity in rat
study was based on an increased incidence of extra 14th ribs
at doses of 25 mg/kg/day and higher. The NOAEL in the rabbit
developmental toxicity study was 25 mg/kg/day based on decreased fetal
body weight at doses of 50 mg/kg/day and higher. The results of a rat
2-generation reproduction study did not provide any evidence of an
increased sensitivity of the offspring to hexaconazole-induced
toxicity, including to the liver. As noted in section E.1.b above, when
calculating the RfD Zeneca added an additional safety factor of 3 to
account for the slightly increased sensitivity of the developing fetus
to the effects of hexaconazole. The NOAEL (2.0 mg/kg/day) for effects
(liver toxicity) attributed to hexaconazole in the dog is close to the
NOAEL for effects of hexaconazole on rat fetuses and lower than the
NOAEL for rabbit fetuses. Therefore the dietary risk assessment for
infants and children was performed using a RfD of 0.007 mg/kg/day.
Using the conservative assumptions outline in section C.1 and a RfD
of 0.007 mg/kg/day, an assessment of the dietary risk to non-nursing
infants (the most sensitive population subgroup) resulted in ARC of
0.00011 mg/kg/day or 1.6% of the RfD.
F. International Tolerances.
Codex Alimentarius Commission (Codex) Maximum Residue Levels (MRLs)
for hexaconazole have been established on apples (0.1 ppm), bananas
(0.1 ppm), coffee beans (0.05 ppm), grapes (0.1 ppm), wheat (0.1 ppm),
and wheat straw and dry fodder (0.5 ppm). (Mary Waller)
[FR Doc. 99-4321 Filed 2-23-99; 8:45 am]
BILLING CODE 6560-50-F
