[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: opp-
[email protected]. 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:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number      e-mail Address
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Bipin Gandhi..................  Rm. 707A, Crystal Mall  Bipin.Gandhi@epa
                                 2 (CM #2), 1921         mail.epa.gov.
                                 Jefferson Davis Hwy,
                                 Arlington, VA; 703-
                                 308-8380
Mary Waller...................  Rm. 249, CM #2, 1921    Waller.Mary@epam
                                 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:
    [email protected]


    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