[Federal Register Volume 64, Number 198 (Thursday, October 14, 1999)]
[Notices]
[Pages 55714-55721]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-26861]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-893; FRL-6382-7]
Notice of Filing Pesticide Petitions to Establish a Tolerance for
Certain Pesticide Chemicals in or on Food
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 docket control number PF-893, must be
received on or before November 15, 1999.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION'' section. To
ensure proper receipt by EPA, it is imperative that you identify docket
control number PF-893 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/telephone
Product Manager number/e-mail address Address Petition number(s)
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Sidney Jackson.................... Rm. 272, CM #2, 703-305-7610, 1921 Jefferson Davis PP 9E6035
e-mail: Hwy, Arlington, VA
[email protected]
v.
Mary L. Waller.................... Rm. 249, CM #2, 703-308-9354, Do. PP 9F5066, 9F6023,
e-mail: 7E4830
waller.mary@epamail.epa.gov.
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SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed in the ``FOR FURTHER INFORMATION
CONTACT'' section.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
[[Page 55715]]
2. In person. The Agency has established an official record for
this action under docket control number PF-893. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-893 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs, Environmental Protection Agency,
401 M St., SW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
E-mail to: opp-docket@epa.gov,'' or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-893. Electronic comments may
also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI 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. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified in the ``FOR FURTHER INFORMATION
CONTACT'' section.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you
used that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
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 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 granting of the petition. Additional data
may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: October 4, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
The petitioner summaries of the pesticide petitions are printed
below as required by section 408(d)(3) of the FFDCA. The summaries of
the petitions were prepared by the petitioners and represent the views
of the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. 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. Interregional Research Project Number 4 (IR-4)
PP 9E6035
EPA has received a pesticide petition [9E6035] from the IR-4 New
Jersey Agricultural Experiment Station, P.O. Box 231, Rutgers
University, New Brunswick, NJ 08903 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 tolerances for
residues of the insecticide, spinosad (Factor A and Factor D): Factor A
is 2-[(6-deoxy-2,3,4-tri-O-methyl-alpha-L-manno-pyranosyl)oxy]-13-[5-
(dimethylamino)-tetrahydro-6-methyl-2 H-pyran-2-yl]oxy]-9-ethyl-
2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,6b-tetradecahydro-14-methyl-1 H-as-
Indaceno [3,2-d]oxacyclododecin-7,15-dione. Factor D is 2-[(6-deoxy-
2,3,4-tri-O-methyl-alpha-L-manno-pyranosyl)oxy]-13-[[5-(dimethylamino)-
tetrahydri-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-
2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimethyl-
1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dione in or on the raw
agricultural
[[Page 55716]]
commodities (RACs) barley, buckwheat, oats, and rye (grains) at 0.02
parts per million (ppm); pearl millet, proso millet, and grain Amaranth
(grains) at 1 ppm; teosinte and popcorn (grains); grass, forage, fodder
and hay (crop group 17); and animal feed, nongrass (crop group 18) at
0.02 ppm; turnip greens at 10 ppm; cilantro, and watercress at 8 ppm;
tropical fruits (sugar apple, cherimoya, atemoya, custard apple, ilama,
soursop, biriba, lychee, longan, spanish lime, rambutan, pulasan,
papaya, star apple, black sapote, mango, sapodilla, canistel, mamey
sapote, avocado, guava, feijoa, jaboticaba, wax jambu, starfruit,
passion fruit, acerola, and white sapote) at 0.3 ppm; ti palm at 10
ppm. Additionally, IR-4 requested a tolerance for spinosad on pistachio
at 0.02 ppm under conditional registration. Spinosad is manufactured by
Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268.
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 support granting of the petition.
Additional data may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of spinosad in plants (apples,
cabbage, cotton, tomato, and turnip) and animals (goats and poultry) is
adequately understood for the purposes of these tolerances. A
rotational crop study showed no carryover of measurable spinosad
related residues in representative test crops.
2. Analytical method. There is a practical method (immunoassay) for
detecting (0.005 ppm) and measuring (0.01 ppm) levels of spinosad in or
on food with a limit of detection (LOD) that allows monitoring of food
with residues at or above the level set for these tolerances. The
method has had a successful method tryout in EPA's laboratories.
3. Magnitude of residues. No additional residue data are being
submitted in support of the proposed residue tolerances. Previously
submitted cereal grain crops residue data in support of a pending
tolerance petition (PP 8F5002) are to be used for barley, buckwheat,
oats, and rye (wheat residue studies); pearl millet, proso millet, and
grain Amaranth (sorghum residue studies); and popcorn and teosinte
(field corn residue studies). In the same petition, there is a pending
tolerance of 1 ppm for forage, fodder, hay, and straw of cereal grains
(crop group 16). Previously submitted residue data in support of the
established residue tolerance on Brassica (cole) leafy vegetables,
greens subgroup are to be used for turnip greens and ti palm.
Previously submitted residue data in support of the established residue
tolerance on leafy vegetables (except Brassica) are to be used for
cilantro and watercress. Previously submitted residue data in support
of almond are used for pistachio. Previously submitted residue data in
support of established residue tolerances on citrus fruits and apples
and a pending residue tolerance (PP 8F5002) on stone fruits are to be
used for tropical fruits. The use pattern (low application rate and
spot treatment nature) associated with the forage crops (crop groups 17
and 18) indicates that no residue data are needed to establish a limit
of quantitation (LOQ) tolerance.
As a condition for registration of spinosad on pistachios, the
Agency requires IR-4 to fulfill the guideline requirements of a total
of five completed field rials on representative commodities for Crop
Group 14, almonds and pecans.
B. Toxicological Profile
1. Acute toxicity--Spinosad has low acute toxicity. The rat oral
lethal dose (LD50) is 3,738 milligrams/kilograms (mg/kg) for
males and > 5,000 mg/kg for females, whereas the mouse oral
LD50 is > 5,000 mg/kg. The rabbit dermal LD50 is
> 5,000 mg/kg and the rat inhalation lethal concentration
(LC50) is > 5.18 milligrams/liter (mg/L) air. In addition,
spinosad is not a skin sensitizer in guinea pigs and does not produce
significant dermal or ocular irritation in rabbits. End use
formulations of spinosad that are water-based suspension concentrates
have similar low acute toxicity profiles.
2. Genotoxicity. Short-term assays for genotoxicity consisting of a
bacterial reverse mutation assay (Ames test), an in vitro assay for
cytogenetic damage using the Chinese hamster ovary cells, an in vitro
mammalian gene mutation assay using mouse lymphoma cells, an in vitro
assay for DNA damage and repair in rat hepatocytes, and an in vivo
cytogenetic assay in the mouse bone marrow (micronucleus test) have
been conducted with spinosad. These studies show that spinosad does not
elicit a genotoxic response.
3. Reproductive and developmental toxicity. Spinosad caused
decreased body weight (bwt) in maternal rats given 200 mg/kg/day by
gavage, the highest dose tested (HDT). This was not accompanied by
either embryo toxicity, fetal toxicity, or teratogenicity. The no
observed adverse effect levels (NOAELs) for maternal toxicity and fetal
toxicity in rats were 50 and 200 mg/kg/day, respectively. A teratology
study in rabbits showed that spinosad caused decreased bwt gain and a
few abortions in maternal rabbits given 50 mg/kg/day, the HDT. Maternal
toxicity was not accompanied by either embryo toxicity, fetal toxicity,
or teratogenicity. The NOAELs for maternal and fetal toxicity in
rabbits were 10 and 50 mg/kg/day, respectively. In a 2-generation
reproduction study in rats, parental toxicity was observed in both
males and females given 100 mg/kg/day, the HDT. Perinatal effects
(decreased litter size and pup weight) at 100 mg/kg/day were attributed
to maternal toxicity. The NOAEL for maternal and pup effects was 10 mg/
kg/day.
4. Subchronic toxicity. Spinosad was evaluated in 13-week dietary
studies and showed NOAELs of 4.89 and 5.38 mg/kg/day, respectively in
male and female dogs; 6 and 8 mg/kg/day, respectively in male and
female mice; and 33.9 and 38.8 mg/kg/day, respectively in male and
female rats. No dermal irritation or systemic toxicity occurred in a
21-day repeated dose dermal toxicity study in rabbits given 1,000 mg/
kg/day.
5. Chronic toxicity. Based on chronic testing with spinosad in the
dog and the rat, the EPA has set a chronic population adjusted dose
(cPAD) of 0.027 mg/kg/day for spinosad. The cPAD has incorporated a
100-fold uncertainty factor to the NOAELs found in the chronic dog
study to account for interspecies and intraspecies variation. cPAD is
equivalent to the reference dose (RfD) divided by the Food Quality
Protection Act (FQPA) safety factor (SF). For spinosad, EPA has
determined that the additional 10x SF to account for enhanced
sensitivity of infants and children be reduced to 1x, i.e., removed.
Thus, the cPAD of 0.027 mg/kg/day is equivalent to the chronic RfD. The
NOAELs shown in the dog chronic study were 2.68 and 2.72 mg/kg/day,
respectively for male and female dogs. The NOAELs (systemic) shown in
the rat chronic/carcinogenicity/neurotoxicity studies were 9.5 and 12.0
mg/kg/day, respectively for male and female rats. Using the Guidelines
for Carcinogen Risk Assessment published September 24, 1986 (51 FR
33992), it is proposed that spinosad be classified as Group E for
carcinogenicity (no evidence of carcinogenicity) based on the results
of carcinogenicity studies in two species. There was no evidence of
carcinogenicity in an 18-month mouse feeding study and a 24-month rat
feeding study at all dosages tested. The
[[Page 55717]]
NOAELs shown in the mouse carcinogenicity study were 11.4 and 13.8 mg/
kg/day, respectively for male and female mice. A maximum tolerated dose
was achieved at the top dosage level tested in both of these studies
based on excessive mortality. Thus, the petitioner believes that the
doses tested are adequate for identifying a cancer risk and that a
cancer risk assessment is not needed.
6. Animal metabolism. There were no major differences in the
bioavailability, routes or rates of excretion, or metabolism of
spinosyn A and spinosyn D following oral administration in rats. Urine
and fecal excretions were almost completed in 48 hours post-dosing. In
addition, the routes and rates of excretion were not affected by
repeated administration.
7. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent material (spinosyn A and spinosyn D).
Thus, there is no need to address metabolite toxicity.
8. Endocrine disruption. There is no evidence to suggest that
spinosad has an effect on any endocrine system.
C Aggregate Exposure
1. Dietary exposure--i. Food. For purposes of assessing the
potential dietary exposure from use of spinosad on the RACs listed in
this notice as well as from other existing and pending spinosad crop
uses, a conservative estimate of aggregate exposure is determined by
basing the Theoretical Maximum Residue Contribution (TMRC) on the
proposed tolerance level for spinosad and assuming that 100% of these
proposed new crops and other pending and existing (registered for use)
crops grown in the United States were treated with spinosad. The TMRC
is obtained by multiplying the tolerance residue levels by the
consumption data which estimates the amount of crops and related
foodstuffs consumed by various population subgroups. The use of a
tolerance level and existing and pending spinosad crop uses, a
conservative estimate of aggregate exposure is determined by basing the
TMRC on the proposed tolerance level for spinosad and assuming that
100% of these proposed new crops and other pending and existing
(registered for use) crops grown in the United States were treated with
spinosad. The TMRC is obtained by multiplying the tolerance residue
levels by the consumption data which estimates the amount of crops and
related foodstuffs consumed by various population subgroups. The use of
a tolerance level and 100% of crop treated clearly results in an
overestimate of human exposure and a safety determination for the use
of spinosad on crops cited in this summary that is based on a
conservative exposure assessment.
ii. Drinking water. Another potential source of dietary exposure to
pesticides is residues in drinking water. Based on the available
environmental studies conducted with spinosad wherein its properties
show little or no mobility in soil, there is no anticipated exposure to
residues of spinosad in drinking water. In addition, there is no
established maximum concentration level for residues of spinosad in
drinking water.
2. Non-dietary exposure. Spinosad is currently registered for use
on a number of crops including cotton, fruits, and vegetables in the
agriculture environment. Spinosad is also currently registered for
outdoor use on turf and ornamentals at low rates of application (0.04
to 0.54 pounds of active ingredient per acre (lbs a.i./ per acre) and
indoor use for drywood termite control (extremely low application rates
used with no occupant exposure expected). Thus, the potential for non-
dietary exposure to the general population is considered negligible.
D. Cumulative Effects
The potential for cumulative effects of spinosad and other
substances that have a common mechanism of toxicity is also considered.
In terms of insect control, spinosad causes excitation of the insect
nervous system, leading to involuntary muscle contractions, prostration
with tremors, and finally paralysis. These effects are consistent with
the activation of nicotinic acetylcholine receptors by a mechanism that
is clearly novel and unique among known insecticidal compounds.
Spinosad also has effects on the gamma aminobatopic acid (GABA)
receptor function that may contribute further to its insecticidal
activity. Based on results found in tests with various mammalian
species, spinosad appears to have a mechanism of toxicity like that of
many amphophilic cationic compounds. There is no reliable information
to indicate that toxic effects produced by spinosad would be cumulative
with those of any other pesticide chemical. Thus it is appropriate to
consider only the potential risks of spinosad in an aggregate exposure
assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions and
the cPAD, the aggregate exposure to spinosad use on other pending and
existing crop uses will utilize 25.5% of the cPAD for the U.S.
population. A more realistic estimate of dietary exposure and risk
relative to a chronic toxicity endpoint is obtained if average
anticipated residue values from field trials are used. Inserting the
average residue values in place of tolerance residue levels produces a
more realistic, but still conservative risk assessment. Based on
average anticipated residue levels in a dietary risk analysis, the use
of spinosad on other pending and existing crop uses will utilize 4.1%
of the cPAD for the U.S. population. EPA generally has no concern for
exposures below 100% of the cPAD because the cPAD represents the level
at or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. The new crop uses proposed
in this notice are minor uses. The petitioner expects these uses to
contribute only a negligible impact to the cPAD, and also believes that
there is reasonable certainty that no harm will result from aggregate
exposure to spinosad residues on existing and all pending crop uses
including the ones listed in this notice.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of spinosad, data from
developmental toxicity studies in rats and rabbits and a 2-generation
reproduction study in the rat are considered. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure during prenatal
development. Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability
and potential systemic toxicity of mating animals and on various
parameters associated with the well-being of pups.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for prenatal and postnatal toxicity and the completeness of the
data base. Based on the current toxicological data requirements, the
data base for spinosad relative to prenatal and postnatal effects for
children is complete. Further, for spinosad, the NOAELs in the dog
chronic feeding study which were used to calculate the cPAD (0.027 mg/
kg/day) are already lower than the NOAELs from the developmental
studies in rats and rabbits by a factor of more than 10-fold.
Concerning the reproduction study in rats, the pup effects shown at
the HDT were attributed to maternal toxicity. Therefore, the petitioner
concludes that an additional uncertainty factor is not needed and that
the cPAD at 0.027 mg/
[[Page 55718]]
kg/day is appropriate for assessing risk to infants and children.
In addition, EPA has determined that the 10x factor to account for
enhanced sensitivity of infants and children is not needed for spinosad
because: (i) The data provided no indication of increased
susceptibility of rats or rabbits to in utero and/or postnatal exposure
to spinosad. In the prenatal developmental toxicity studies in rats and
rabbits and 2-generation reproduction in rats, effects in the offspring
were observed only at or below treatment levels which resulted in
evidence of parental toxicity, (ii) no neurotoxic signs have been
observed in any of the standard required studies conducted, and (iii)
the toxicology data base is complete and there are no data gaps.
Using the conservative exposure assumptions previously described as
tolerance level residues, the percent cPAD utilized by the aggregate
exposure to residues of spinosad on other pending and existing crop
uses is 51.2% for children 1 to 6 years old, the most sensitive
population subgroup. If average or anticipated residues are used in the
dietary risk analysis, the use of spinosad on these crops will utilize
9.4% of the cPAD for children 1 to 6 years old. The new crop uses
proposed in this notice are minor ones and are expected to contribute
only a negligible impact to the cPAD. Thus, based on the completeness
and reliability of the toxicity data and the conservative exposure
assessment, the petitioner concludes that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to spinosad residues on the above proposed uses
including other pending and existing crop uses.
F. International Tolerances
There are no Codex maximum residue levels established for residues
of spinosad on barley, buckwheat, oats, rye, pearl millet, proso
millet, grain Amaranth, teosinte, popcorn, turnip greens, cilantro,
watercress, tropical fruit, ti palm, grass forage, fodder, and hay
(crop group 17), and nongrass animal feeds (crop group 18) or any other
food or feed crop.
2. Sipcam Agro USA, Inc.
PP 9F5066, 9F6023, and 7E4830
EPA has received three pesticide petitions [9F5066, 9F6023, and
7E4830] from Sipcam Agro USA, Inc., 70 Mansell Court, Suite 230,
Rosewell, GA 30076 proposing, pursuant to section 408(d) of the FFDCA,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing tolerances
for residues of 1-2(2,4-dichlorophenyl)-3-(1,1,2,2-
tetrafluoroethoxy)propyl-1H-1,2,4-triazole (Tetraconazole) in or on the
RAC of beets, sugar at 0.01 ppm; beets, sugar, roots at 0.1 ppm; beets,
sugar, tops at 7.0 ppm; beets, sugar, pulp, dried at 0.3 ppm; and
beets, sugar, molasses at 0.3 ppm (9F5066), peanuts meat (hulls
removed) at 0.03 ppm, peanuts meal at 0.03 ppm, and peanuts oil at 0.1
ppm (9F6023), and imported bananas at 0.2 ppm (7E4830) and in animal
commodities of milk at 0.02 ppm; cattle, meat at 0.01 ppm; cattle meat
byproducts at 2.0 ppm and cattle fat at 0.1 ppm (9F5066). EPA has
determined that the petitions contain 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 of tetraconazole in
plants was studied extensively in wheat, grapes and sugar beets. The
principal compounds found in all three plant species were unchanged
tetraconazole and the degradation product triazole. Evidence was found
for more extensive metabolism in plant tissues to form bound residues
that were incorporated into the structural matrices (cellulose and
lignin) surrounding plant cells.
2. Analytical method. An analytical residue method utilizing gas
chromatography with electron capture detection is available for
enforcement purposes, which has been validated among all banana, sugar
beet, and peanut raw and processed matrices, as well as for milk, meat,
and meat byproduct matrices. This method is described within the
magnitude of residue studies provided to EPA in support of the
petitions for tolerances pertaining to bananas, sugar beets, and peanut
matrices.
3. Magnitude of residues--i. Banana. Residue data from a study
conducted with tetraconazole applied in the field to banana plants at
12 locations in the field throughout Latin America to support
establishment of a tolerance of 0.2 ppm (unbagged, whole fruit basis)
for residues of tetraconazole on bananas. The magnitude of residues on
the edible pulp portion of the fruit grown under typical banana
cultivation practices was less than 0.02 ppm, which is the maximum
anticipated residue to be used for dietary exposure risk assessment.
ii. Sugar beets. Residue data from a study conducted with
tetraconazole applied to sugar beets in the field at 11 locations in
the United States in the manner proposed for registration, and a
further study among the products of sugar beet processing, support the
establishment of tolerances for residues of tetraconazole on sugar beet
roots at a level of 0.1 ppm, on sugar beet tops at 7 ppm, in sugar beet
pulp (dried) and in (sugar beet) molasses at 0.3 ppm, and in refined
(sugar beet) sugar at 0.01 ppm. A magnitude of residue study conducted
with lactating dairy cows fed tetraconazole for a duration of 28 days,
followed by terminal sacrifice and analysis of tissues, supports the
establishment of tolerances for residues of tetraconazole in milk at
0.02 ppm, in cattle meat at 0.01 ppm, in cattle meat byproducts at 2
ppm, and in cattle fat at 0.1 ppm.
iii. Peanuts. Residue data from a study conducted with
tetraconazole applied to peanuts in the field at 12 locations in the
United States in the manner proposed for registration, and a further
study among the products of peanut processing, support the
establishment of tolerances for residues of tetraconazole on peanuts
(nutmeats) at a level of 0.03 ppm, and in processed peanut meal and oil
at 0.03 ppm and 0.1 ppm, respectively.
B. Toxicological Profile
1. Acute toxicity. Acute toxicity studies with technical grade
tetraconazole include: an acute oral dose study in the rat which
demonstrated an average (both sexes) LD50 level of 1,140 mg/
kg bwt; an acute dermal dose toxicity study on the rat which indicated
an LD50 > 2,000 mg/kg; a 4-hour inhalation study in the rat
which found the LD50 to be greater than 3.66 mg/L of air
(MMAD 1.1 microns); a primary eye irritation study with rabbit,
indicating that tetraconazole may be a slight eye irritant; a primary
dermal irritation study in rabbit showing tetraconazole to be non-
irritating; and a dermal sensitization study on guinea pig which
demonstrated that tetraconazole was not a skin sensitizer.
2. Genotoxicty. The mutagenic potential of tetraconazole has been
evaluated in five studies including: a reverse gene mutation assay in
Salmonella typhimurium cells; a cell mutation assay in mouse lymphoma
L5178Y cells in vitro, with and without metabolic activation; a
chromosomal aberration assay in Chinese hamster ovary cells in vitro,
with and without metabolic activation; a mouse bone marrow micronucleus
assay in vivo; and an unscheduled DNA synthesis assay in
[[Page 55719]]
HeLa epithelioid cells. All studies were negative for genotoxicity and/
or mutagenic potential.
3. Reproductive and developmental toxicity. A developmental
toxicity study with rats given oral gavage doses of 5, 22.5, and 100
mg/kg/day from days 6 through 15 of gestation resulted in a NOAEL for
maternal toxicity of 5 mg/kg/day based upon bwt reduction, reduced food
intake and post-dose salivation at the two higher doses, as compared
with zero-dose controls. The developmental NOAEL was 22.5 mg/kg/day.
Among the highest dose group there was evidence of minimal increase in
the incidence of supernumerary ribs among the fetuses.
A developmental toxicity study in rabbits given oral gavage doses
of 7.5, 15, and 30 mg/kg/day on days 6 through 18 of gestation resulted
in a maternal NOAEL of 15 mg/kg/day. Effects observed in the dams in
the high-dose group were decreased bwt gain and reduced food
consumption as compared with zero-dose controls. There were no
developmental effects observed in this study.
A 2-generation reproduction study in rats fed diets containing 10,
70, and 490 ppm resulted in a reproductive NOAEL of 10 ppm (0.6 mg/kg/
day) based upon toxicity to the dam, slightly retarded growth rate in
offspring at the higher two doses, and slightly increased liver weights
in offspring at the highest dose, as compared with zero-dose controls.
4. Subchronic toxicity. A 90-day oral subchronic toxicity study was
conducted with technical grade tetraconazole in rats at 10, 60, and 360
ppm in the diet. Treatment related increased liver weights and
centrilobular hepatocyte enlargement were observed at the two highest
dose levels. The NOAEL was 10 ppm (0.8 mg/kg/day), by comparison with
data from the zero-dose control group.
A 90-day oral subchronic toxicity study was conducted in mice with
dietary concentrations of technical grade tetraconazole at 5, 25, 125,
and 625 ppm. The two highest dosages resulted in liver enlargement,
accentuated lobular markings and liver pallor. Microscopic tissue
alterations related to tetraconazole were liver enlargement at the
three highest doses and single cell necrosis/degeneration and/or areas
of necrosis at the two highest doses. The NOAEL was 5 ppm (1 mg/kg/
day).
5. Chronic toxicity. A 12-month chronic oral toxicity study in
Beagle dogs was conducted with technical tetraconazole at dose levels
of 0.7, 2.8, and 5.6 mg/kg/day (22.5, 90, and 360 ppm dietary
concentrations, respectively). At the highest dose, liver and kidney
weights and cholesterol levels were elevated, and liver injury occurred
based upon increased levels of GPT, -GT and OCT. The no effect
level was 0.7 mg/kg/day, as compared with zero-dose control animals.
A chronic (full-lifetime) feeding/carcinogenicity study was
conducted with Crl:CD(SD)BR rats fed tetraconazole at dietary levels of
10, 80, 640, and 1,280 ppm for 104 weeks in males and 10, 80, and 640
ppm for 104 weeks in females. In the liver, changes such as hepatocyte
enlargement and increased incidence of eosinophilic hepatocytes, seen
at doses of 80, 640, or 1,280 ppm were associated with hepatic enzyme
induction.
The class of compounds (triazoles) to which tetraconazole belongs
is known to induce liver microsomal enzymes. The follicular cell
hypertrophy and cystic follicular hyperplasia of the thyroid seen in
male rats at 1,280 ppm are also likely to be linked to the hepatic
changes. Compounds such as phenobarbital are also known to induce
thyroid changes in rats due to increased hepatic clearance of thyroxin,
mediated by hepatic enzyme induction.
A special mechanistic study was conducted in order to more fully
determine the potential role of microsomal enzyme induction by
tetraconazole administered in the diet upon the histopathologic
findings in rat. Dietary administration of tetraconazole to rats for 4
weeks resulted in the induction of cytochrome P450, including those of
the CYP2B and 3A subfamilies, and of UDP-glucuronyl transferase.
Chronic dietary administration of tetraconazole to rats did not
induce a carcinogenic response. No increase in tumors was noted at the
high dose groups among males or females. The liver was the target
organ. There was a marginal increase in benign liver cell tumors among
male rats fed 640 ppm but these were not statistically significant and
not dose-related, and the benign tumors did not progress to malignant
liver cell tumors. There were some changes in the liver at 80 ppm,
whereas 10 ppm (approximately 0.6 mg/kg/day) was observed to be the
NOAEL.
The incidence of foci or areas of basophilic hepatocytes was
greater in male rats given 10, 80, or 640 ppm than in zero-dose
controls. This is a common spontaneous age-related change which showed
no dose relationship in this study and is considered unlikely to be of
toxicological importance.
A chronic feeding/carcinogenicity study was conducted with
tetraconazole in Crl:CD-l (ICR)BR mice at dietary levels of 10, 90,
800, and 1,250 ppm for 80 weeks. Treatment-related non-neoplastic
changes were also seen at 1,250 ppm in the lungs, kidneys, testes,
epididymides, ovaries and bone, particularly the cranium; a compression
of the brain was noted in a number of mice reflecting the extent of
cranial bone changes and an increased thymic involution was seen in
male mice that died on test. The 1,250 ppm dietary level for
tetraconazole, because of the substantial bwt gain changes and
increased mortality (more in males), appeared to be above the maximum
tolerated dose (MTD). At 800 ppm, there were increases in non
neoplastic changes in lungs, kidneys, testes, epididymides, ovaries and
bone. In addition, there was substantial reduction in weight gain as
compared with zero-dose control animals, but the mortality rate was
unaffected. Eight hundred ppm appeared to be a reasonable estimate of
the MTD for mouse.
At 90 ppm, non-neoplastic changes were detected in bone and the
epididymides in addition to liver changes. No treatment-related
findings were seen in mice treated at 10 ppm (approximately 1.5 mg/kg/
day), and this dose level was defined as the NOAEL.
In this same study, an increased incidence of benign liver cell
tumors was observed in males and females fed 800 ppm, and an increased
incidence of benign and malignant liver cell tumors in males and
females given 1,250 ppm. These tumors were associated with increased
signs of hepatotoxicity including hepatocyte vacuolation and fat
deposition at 90, 800, and 1,250 ppm; granulomatous inflammation,
pigmented macrophages, bile duct hyperplasia and pericholangitis in
mice given 800 and 1,250 ppm. In addition, there was evidence of
treatment-related hepatocellular enlargement and increased numbers of
altered foci of eosinophilic and basophilic hepatocytes in both sexes
given 800 and 1,250 ppm; eosinophilic hepatocytes were noted in male
(only) mice receiving 90 ppm.
Tetraconazole is a triazole, and this class of compounds is known
to induce liver microsomal enzymes. A special mechanistic study was
conducted in order to more fully determine the potential role of
microsomal enzyme induction by tetraconazole administered in the diet
upon the formation of tumors in mouse. Dietary administration of
tetraconazole to mice for 4 weeks results in the induction of
cytochrome P450-related activities, as well as the concentrations of
microsomal protein and cytochrome P450, and of the phase II activity,
and p-nitrophenol UDP-
[[Page 55720]]
glucuronyl transferase activity. The effects of tetraconazole on the
cytochrome P450-dependent MFO system were somewhat different from those
of phenobarbital. Many of these enzymes have not been as well-
characterized in mice compared to rats. However, the phase II enzyme
activity increases were similar to those of phenobarbital. It is
concluded from these studies that prolonged induction of liver
microsomal enzymes and/or production of sustained liver injury can lead
to the formation of liver tumors in mice.
6. Animal metabolism. Four metabolism studies (rat and goat
triazole- and phenyl-labeled) were conducted in animals with
14C labeled tetraconazole. In the rat the initial metabolism
proceeded through cleavage of the tetrafluoroethyl ether moiety,
followed by a 2-step oxidation to tetraconazole-acid. In the goat the
initial oxidation step formed tetraconazole-difluoroacetic acid,
followed by ether cleavage to tetraconazole-alcohol, then further
oxidation to tetraconazole-acid. In both the rat and the goat, the
tetraconazole-acid functional group was enzymatically displaced, and
the resulting thioether was oxidized to tetraconazole-acid-methyl-
sulfoxide. An alternative pathway for tetraconazole-alcohol degradation
was to form either glucuronide derivatives of tetraconazole-alcohol, or
enzymatic triazole displacement to form dichlorophenyl-acetyl-cysteine.
The nature of the residue in the goat is adequately understood for the
purpose of regulating dietary exposure to residues. The liver retained
the highest radioactivity, and muscle contained the lowest
radioactivity. Tetraconazole was found to be the major residue in the
liver and fat, and triazole was the major residue in milk, muscle and
kidney.
7. Endocrine disruption. Based upon the findings from all of the
full-lifetime and chronic toxicology studies, teratogenicity,
mutagenicity and multi-generational reproductive studies conducted with
tetraconazole, it is concluded that there were no indications of any
potential to cause disruption or modification of endocrine function
among any of the four animal species that have been studied (rat,
mouse, rabbit and dog). Among the studies conducted with these four
species there were no behavioral, reproductive or teratogenic effects,
or histopathological changes in endocrine sensitive tissues such as the
uterus, ovaries, mammary glands, or the testes.
C. Aggregate Exposure
1. Dietary exposure. Tolerances have been proposed to accompany
uses proposed for tetraconazole products on bananas, sugar beets and
peanuts. Tolerance-level residues may be utilized to conduct dietary
exposure risk assessments, except that for bananas, the anticipated
residue would be only 10% of the tolerance level because more than 90%
of the residue on a whole-fruit basis remained on the peel.
Drinking water. A drinking water exposure assessment was performed
for surface water with the screening model generic expected
environmental concentration (GENEEC), using the input parameters
represented by the environmental fate data obtained for tetraconazole
in guideline-compliant studies. The model SCI-GROW was utilized to
perform a ground water exposure assessment. The combined predicted
levels of exposure in drinking water from surface and ground water,
without any mitigation by means of filtration or other treatments
typically applied to human drinking water, were 0.32 micrograms/kg/day
for the highest-exposure age cohort nursing and non-nursing infants (>
1 year), or 5.3% of the chronic reference dose (RfD). The level of
exposure to infants through drinking water, coupled with the maximum
dietary exposure for non-nursing infants, thereby resulted in a maximum
combined potential exposure of 0.90 micrograms/kg/day, or 15.1% of the
RfD.
2. Non-dietary exposure. Tetraconazole products are not yet
registered for any uses in the United States, however there is a
pending registration for usage on turf grass which would permit
applications to golf courses, commercial turf grass and sod farms.
Tetraconazole products will be labeled so as to prohibit applications
on residential turf grass. Tetraconazole products are not intended for
registration or utilization in any setting which would contribute to
human exposure in households or residential vicinities.
D. Cumulative Effects
Tetraconazole is a member of a class of compounds with structures
containing 1,2,4-triazole substituents. Data are not yet available to
determine whether tetraconazole has a common mechanism of toxicity in
mammalian systems with other substances, or how to include this
pesticide in a cumulative risk assessment.
E. Safety Determination
1. U.S. population. The lowest dietary NOAEL for tetraconazole in
chronic or subchronic studies, expressed in terms of bwt dose on a
daily basis, was confirmed in two studies to be 0.6 mg/kg/day. These
two studies were the chronic/oncogenicity (full-lifetime) study in rat,
and the 2-generation reproduction study in rat. Therefore the chronic
RfD to be used for human exposure risk assessment should be 0.006 mg/
kg/day by incorporation of both a 10-fold interspecies safety factor
and a 10-fold intraspecies safety factor. A chronic dietary exposure
analysis dietary risk evaluation system (DRES) was conducted for
tetraconazole, conservatively assuming tolerance-level residues in/on
bananas, sugar beets, and peanuts, including all secondary processed
commodity tolerances associated with these crops plus milk, meat and
meat byproducts. The maximum potential dietary exposure of
tetraconazole to the U.S. population was calculated to be 0.223
micrograms/kg/day, or 4.5% of the chronic RfD.
For acute effects, the lowest NOAEL for tetraconazole was observed
for maternal effects in the rat developmental study at 5 mg/kg/day,
wherein decreased maternal bwt and food consumption were observed at
the lowest observed adverse levels (LOAELs) of 22.5 mg/kg/day;
therefore, the acute RfD for human exposure risk assessments is 0.05
mg/kg/day. An acute dietary exposure analysis was performed, focusing
upon females aged 13 to 50 years, based upon the acute RfD. The dietary
exposure model EXPedite predicted a maximum (99.9th percentile)
potential dietary exposure level of 1.06 micrograms/kg/day for females
of childbearing age, which represents 2.1% of the acute RfD.
2. Infants and children. There is a complete data base for
tetraconazole which includes prenatal and postnatal developmental and
reproduction toxicity data. In a 2-generation reproduction study with
rats, all reproductive parameters investigated showed no treatment-
related effects except slightly retarded growth rate and slightly
increased liver weight at weaning in the offspring at the highest dose
of 35.8 mg/kg/day. The NOAEL for reproductive effects in offspring was
4.8 mg/kg/day, which was 12 times higher than the NOAEL for toxicity
effects in the dams. Thus the available evidence suggests that
mammalian offspring would be less sensitive to potential toxicological
effects from tetraconazole than would adults.
In the developmental toxicity (teratology) study conducted in the
rat, tetraconazole did not cause any developmental effects in fetuses
at 22.5 mg/kg/day even when maternal toxicity
[[Page 55721]]
was observed. In the rabbit a dose level of 30 mg/kg/day caused
maternal toxicity, but there were no developmental effects.
The extensive data base that is available for tetraconazole
contains no indication that tetraconazole would represent any unusual
or disproportionate hazard to infants or children. Therefore there is
no need to impose additional safety factors above the 10x interspecific
uncertainty factor, coupled with the 10x intraspecific uncertainty
factor, for conducting risk assessments pertaining to infants or
children.
A chronic DRES was conducted for tetraconazole, conservatively
assuming tolerance-level residues in/on bananas, sugar beets, and
peanuts, including all secondary processed commodity tolerances
associated with these crops plus milk, meat, and meat byproducts. The
highest potential dietary exposures to non-nursing infants less than l-
year old and children 1 to 6 years old were 0.552 micrograms/kg/day and
0.527 micrograms/kg/day, or 11% and 10.5% of the chronic RfD,
respectively. These were the two age cohorts which represented the
highest proportionate utilization of the chronic reference dose.
F. International Tolerances
There are no established Codex, Canadian, or Mexican tolerances
(MRLs) established for tetraconazole. No MRLs for tetraconazole have
been established under the EU uniform code for pesticide registrations.
The following MRLs (expressed in ppm) have been established for
tetraconazole residues on sugarbeet roots; Belgium, France, Portugal,
Spain (0.05); Hungary (0.1); and Italy (0.2). In addition to sugar
beets, the following MRLs (in ppm) for tetraconazole have also been
established in the following countries for several RACs; apples, and/or
pome fruits (Israel, Spain 0.2, France 0.3, Italy, Portugal, Poland
0.5); grapes (Israel, Jordan, France, Portugal, Spain 0.2, Italy 0.5);
stone fruits (Italy, Spain 0.2); cucumbers (Italy, Poland, Egypt,
Jordan 0.2); melons (Egypt, Jordan, Italy 0.05, Israel 0.2); peaches
and/or stone fruits (Italy, Spain 0.2); wheat grain (Morocco, Belgium,
France, Hungary, Poland, Italy, Portugal, United Kingdom 0.05); oat
grain (United Kingdom 0.1); barley grain (Italy 0.1, United Kingdom
0.2); tomatoes (Egypt, Israel, Jordan 0.2); and mango (Israel 0.2).
[FR Doc. 99-26861 Filed 10-13-99; 8:45 am]
BILLING CODE 6560-50-F
