[Federal Register Volume 62, Number 148 (Friday, August 1, 1997)]
[Notices]
[Pages 41379-41386]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20216]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-751; FRL-5732-4]
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-751, must
be received on or before September 2, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7506C), Information Resources and Services
Division, Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by 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. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Mary Waller, Acting (PM 21),
Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location and telephone number: Rm. 265, CM #2, 1921 Jefferson
Davis Highway, Arlington, VA 22202, (703) 308-9354; e-mail:
waller.mary@epamail.epa.gov.
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 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.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-751] (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 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [PF-751] and appropriate petition
number. Electronic
[[Page 41380]]
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: July 22, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
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. AgrEvo USA Company
PP 4E4384
EPA has received a pesticide petition (PP 4E4384)from AgrEvo USA
Company, Little Falls Centre One, 2711 Centerville Rd., Wilmington, DE
19808, proposing pursuant to section 408(d) of the Federal Food, Drug
and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of the fungicide (N-4,6-
dimethylpyrimidin-2-yl) aniline expressed as pyrimethanil in or on the
raw agricultural commodity (RAC) grapes at 5.0 ppm, and the processed
food, raisins at 8.0 ppm.
A. Residue Chemistry
1. Metabolism. Numerous studies have been conducted to evaluate the
absorption, distribution, metabolism and/or excretion of pyrimethanil
in rats. These studies indicate that pyrimethanil is rapidly absorbed,
metabolized and excreted primarily through the kidneys; rats given an
oral dose of 1,000 mg/kg excrete over 95% of compound related products
in urine within 6 to 8 hours, studies in other species including the
dog and mouse show similar rapid and quantitative excretion profiles.
There is no evidence of any significant accumulation in tissues on
repeat dosing in rats.
2. Analytical method. The nature of the residue in grapes is
adequately understood. The residue of concern is the parent compound
only. The proposed analytical method for determining residues of
pyrimethanil is high-pressure liquid chromatography, with a UV
detector. This method has adequate accuracy, precision and sensitivity
for this purpose. This method has been confirmed through an independent
laboratory validation.
3. Magnitude of residues. Field residue and processing studies were
submitted from trials from the various countries of proposed use
including France, Germany, Italy, South Africa, Spain and Greece. These
data demonstrate that the proposed tolerance of 5.0 ppm will be
adequate to cover the residues in grapes or wine. Processing data show
that pyrimethanil residues in wine will not exceed the tolerance in the
RAC grapes. Data from residue trials in Chile reflecting the proposed
use pattern on table grapes also demonstrate that the proposed
tolerance of 5.0 ppm is adequate to cover the residues on fresh table
grapes. Processing data on raisins indicates that there is a
concentration factor of 1.6 and a tolerance of 8.0 ppm is proposed to
cover the residues of pyrimethanil in raisins. Residues in juice were
determined to be 70% of the residues in fresh grapes; therefore, the
tolerance on fresh grapes is sufficient to cover the potential residues
of pyrimethanil in grape juice.
B. Toxicological Profile
1. Acute toxicity. The acute rat oral LD50 of
pyrimethanil was 4.15 g/kg in males and 5.97 g/kg in females. The acute
rat dermal LD50 was 5.0 g/kg in both sexes. The
4-hour rat inhalation LC50 was >1.98 mg/L in males and in
females. Pyrimethanil was not irritating to rabbit skin and slightly
irritating to the rabbit eyes. Pyrimethanil did not cause skin
sensitization in guinea pigs. Based on these data, EPA has classified
pyrimethanil as Tox Category III for inhalation and oral toxicity, and
Tox Category IV for dermal toxicity, skin and eye irritation.
2. Genotoxicty. No evidence of genotoxicity was noted in an
extensive battery of in vitro and in vivo studies. Negative studies
determined acceptable by EPA included an Ames Assay (S. typhimurium),
Gene mutation (E. coli), In vivo mouse micronucleus, in-vitro
chromosome analysis of cultured human lymphocytes and Unscheduled DNA
synthesis.
3. Reproductive and developmental toxicity. A developmental
toxicity study was conducted in rats. The NOEL s for maternal and
developmental effects were determined by the EPA to be 85 mg/kg/day for
maternal toxicity and 1,000 mg/kg/day (limit dose) for developmental
effects. There were no teratogenetic or embryotoxic effects in fetuses
at 1,000 mg/kg/day.
A developmental toxicity study in rabbits with a maternal NOEL of 7
mg/kg/day. The developmental NOEL was determined by the EPA to be 45
mg/kg/day.
A 2-generation rat reproduction study was determined by the EPA to
have a reproductive and developmental NOEL of 23.1 mg/kg/day in males
and 27.4 mg/kg/day in females.
4. Subchronic toxicity. A 90-day feeding study was conducted in
CRL:CD (SD) BR strain rats with a NOEL of 5.4 mg/kg/day.
A 90-day study was conducted in beagle dogs with a NOEL of 6 mg/kg/
day and a LOEL of 80mg/kg/day.
5. Chronic toxicity. A 12-month dog study was determined by EPA to
have a NOEL of 30 mg/kg/day.
A 2-year mouse oncogenicity study in CRL: CD-1 (ICR) BR with a NOEL
for systemic effects of 211 and 253 mg/kg/day for males and females,
respectively. At doses up to 1,600 ppm there was no evidence of
oncogenicity. The EPA concluded that the highest dose did not achieve
an MTD, however the EPA Peer Review Committee concluded that the data
were sufficient to classify the compound with respect to
carcinogenicity at this time.
A combined chronic toxicity/oncogenicity study was conducted in
CRL:CD (SD) BR strain rats with a NOEL of 17 and 22 mg/kg/day for males
and females, respectively. Findings included increased thyroid
follicular cell adenomas in male and female rats. The EPA Peer Review
Committee concluded on February 11, 1997 that there was sufficient
evidence from the data provided to conclude that the thyroid tumors
were a result of disruption of the thyroid-pituitary status.
6. Endocrine effects. There is no evidence from the data or
chemical structure that pyrimethanil causes endocrine effects other
than those already noted for the thyroid-pituitary-liver axis.
C. Aggregate Exposure
Dietary exposure. The aggregate exposure to pyrimethanil is limited
to dietary exposure only because no U.S. registrations are being
sought. A worst case estimate of the dietary exposure from the
tolerance on grapes results in a maximum theoretical exposure of 0.55%
of the reference dose for the U.S. population and a worst case
estiimate of 1.29% of the ADI for children 1-6 years old. This worst
case estimate assumes
[[Page 41381]]
that all diets contain grapes and grape products with the maximum
theoretical residue. In reality this will not be the case because in
commerce, only imported grapes and grape products have the potential
for residues. In addition, only a portion of the crop will actually be
treated and, under actual use conditions the residue will be much
smaller that the residue trials indicate. It can therefore be estimated
that the actual exposure to pyrimethanyl in the diet will be less than
0.1% of the ADI, or negligible from a dietary point of view.
D. Cumulative Effects
There is no evidence that the mechanism of toxicity of pyrimethanil
shares a common mechanism with any other pesticides. In addition, the
dietary exposure in grapes or grape products is negligible and
therefore, AgrEvo believes that even if it did share a common mechanism
with another product, pyrimethanil would not contribute in a
significant way to the overall risk.
E. Safety Determination
1. U.S. population --Reference dose. Based upon the results of the
oncogenicity studies, genotoxicity studies, structure-activity analysis
and studies on the effects of pyrimethanil on the thyroid-pituitary-
liver axis, the EPA Peer Review Committee has concluded that
pyrimethanil should be classified as a category C with respect to
carcinogenicity and that a threshold methodology (MOE) should be
considered in conducting the risk assessment. The appropriate reference
dose is .3 mg/kg/day based upon the NOEL in the chronic oral dog study
with a 100 fold safety factor. This reference dose is adequate to
protect infants and children and based upon the data there is no need
for an additional safety factor.
2. Infants and children. It is proposed that an additional 10X
safety factor is not required for pyrimethanil. The toxicology data are
complete and there is no evidence of increased sensitivity to young
animals. Therefore, a 100X safety factor should be sufficient and
protective of the health of adults, infants and children.
F. International Tolerances
At the present time there are no Mexican, Canadian or Codex maximum
residue limits for pyrimethanil in or on grapes. Therefore
compatibility is not an issue.
2. Griffin Corporation
PP 5F4582
EPA has received a pesticide petition (PP 5F4582) from Griffin
Corporation, P.O. Box 1847, 2509 Rocky Ford Road, Valdosta, GA 31603-
1847 proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of maneb, mancozeb and their
metabolite ethylenethiourea (ETU) in or on the raw agricultural
commodity walnuts at 0.05 parts per million (ppm). An adequate
analytical method is available for enforcement purposes. 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. Residue tolerances are established for maneb
and mancozeb at 40 CFR 180.110 and 40 CFR 180.176, respectively. It is
well known that the key metabolite of toxicological concern is
ethylenethiourea (ETU). Ethylenebisdithiocarbamate (EBDC), including
maneb and mancozeb are not systemic in plants; therefore, EBDC and ETU
residues that might be found on walnut nutmeats would then occur as a
surface residue transferred at the time of harvesting or shelling
operations.
2. Analytical method. An adequate analytical method is available
for enforcement purposes. The method describes gas chromatographic
procedures and appropriate limits of quantitation. In general, maneb
and mancozeb residues are measured by digesting the crop component with
acid, which converts the EBDC to carbon disulfide. The carbon disulfide
residues are measured to determine the level of EBDC residue. ETU
residues are measured by extraction from the crop and analysis by high
pressure liquid chromatography or by extraction, formation of a
derivative, and measurement of the derivative by gas chromatography.
3. Magnitude of residues. Residues of maneb and mancozeb in walnut
meat samples ranged from just below to just above the limit of
quantitation (0.01 ppm). The ETU metabolite was not detected in any
samples analyzed (limit of quantitation was 0.01 ppm).
B. Toxicological Profile
1. Acute toxicity. Maneb and mancozeb are virtually non-toxic after
administration by the oral, dermal and respiratory routes.
i. Maneb. The acute oral LD50 for rats is 6,750 mg/kg.
The acute dermal LD50 for rabbits > 2,000 mg/kg and for rats
> 5,000 mg/kg. Acute inhalation LC50 for rats > 1.30 mg/l.
Maneb is classified as a slight irritant to skin and eye irritation in
rabbits clears in 7 days. Maneb has been classified as a sensitizer in
guinea pigs.
ii. Mancozeb. The acute oral LD50 in mice and rats is
>5,000 mg/kg. The acute dermal LD50 in rats is >5,000 mg/kg.
Mancozeb was not significantly toxic to rats after a 4-hour inhalation
exposure, with an LD50 value of > 5.14 mg/L. Mancozeb is
classified as not irritating to skin on initial contact and is a
moderate eye irritant. It has been classified as not a sensitizer in
the Buehler test.
iii. ETU. The mouse acute oral LD50 is 4,000 mg/kg/day
and the rat acute oral LD50 is 545 mg/kg/day. ETU is a
moderate to weak sensitizer.
2. Genotoxicty. Regarding genotoxicity, maneb and mancozeb have
been adequately tested in a wide variety of in vitro and in vivo
mutagenicity tests. Although EPA believes maneb and mancozeb have some
genotoxic potential, and the World Health Organization (WHO) has said
the evidence for genotoxicity is equivocal, Griffin is informed that
the well-conducted scientifically valid studies demonstrate mancozeb is
not genotoxic in mammalian systems. Mancozeb is negative in the Ames
test and negative in vitro and in vivo somatic and germ cell tests. It
did not induce unscheduled DNA synthesis (UDS). These same conclusions
would be expected to apply to maneb. In fact, the FAO and WHO concluded
``that maneb is not genotoxic.''
The WHO reviewed the genotoxicity of ETU in 1993 and concluded that
ETU is not genotoxic in mammalian systems. EPA has classified ETU as
being weakly genotoxic, at most.
3. Reproductive and developmental toxicity. Maneb and mancozeb do
not produce birth defects and are not toxic to the developing fetus at
doses below those which are toxic to the mother.
i. Maneb. The 1993 FAO/WHO Toxicology Evaluations summarized two
rat studies as follows: NOAEL - 20 mg/kg/day, LOAEL - 100 mg/kg/day
(LOAEL effects being decreased maternal body weight gain and food
consumption; embryofetoxicity); NOAEL - 100 mg/kg/day, LOAEL 500
[[Page 41382]]
mg/kg/d (LOAEL effects being decreased maternal body weight gain and
food consumption, embryofetotoxicity and teratogenicity).
ii. Mancozeb. The mancozeb maternal no observable effect level
(NOEL) was established at 30-32 mg/kg/day in rats and rabbits. The
fetal NOEL is 128 mg/kg/day in rats and > 80 mg/kg/day in rabbits. The
parental no observable adverse effect level (NOAEL) was 120 ppm (7.0
mg/kg/day) in a 2-generation reproduction study in rats. Mancozeb had
no effect on reproduction, on the microscopic appearance of the
reproductive organs, or on neonatal survival or growth below adult
toxic levels in appropriate studies.
iii. ETU. In a 2-generation rat reproduction study, the ETU
parental NOEL was 2.5 ppm, or 0.11-0.43 mg/kg/day, and there were no
reproductive effects. The developmental toxicity of ETU has been
studied in six species and the results are species-specific. ETU did
not produce developmental effects in mice (NOEL-100 mg/kg/day), rabbits
(NOEL-40 mg/kg/day), guinea pigs, or cats. In hamsters, the NOEL was
100 mg/kg/day. In rats, the maternal NOEL was 50 mg/kg/day, with a
fetal NOEL of 5-15 mg/kg/day.
4. Chronic toxicity. The chronic toxicity of the EBDCs is driven by
its metabolite ETU. The primary effects are on the pituitary-thyroid-
liver axis.
i. Maneb. While the EPA Maneb Chemical Fact Sheet does not include
chronic toxicology information due to data gaps at the time of
publication, combined chronic-oncogenic long-term studies are
summarized in the 1993 FAO/WHO Toxicology Evaluations: NOAEL - 20 mg/
kg/day, LOAEL - 67 mg/kg/day (LOAEL effects: decreased body weight, T4;
increased 131I half-life, thyroid weight).
ii. Mancozeb. In a 2-year combined chronic toxicity/oncogenicity
study in the rat, the NOEL was 125 ppm (4.8 mg/kg/day) based on thyroid
effects. An increased incidence of thyroid tumors was seen at the
highest dose of 750 ppm. These effects are likely due to ETU exposure
resulting from bioconversion of mancozeb in the rat. This is consistent
with the toxicology of ETU, which is described below. In comparison
with laboratory animals, humans are expected to exhibit a lesser degree
of sensitivity to thyroid inhibitors because humans possess a
substantial reserve supply of thyroid hormone, much of it carried in
serum bound to thyroxine-binding globulin. This protein is missing in
rodents. Additionally, there is a threshold effect for thyroid tumors
and the levels of human exposure are well below those that produced
tumors in the rat study. The WHO concluded that the data support an RfD
for mancozeb of 0.05 mg/kg/day based on this study. An EBDC group ADI
of 0.03 mg/kg/day was established by the WHO in 1993.
In an 18-month mancozeb combined chronic toxicity/oncogenicity
study in the mouse, the NOEL was 1,000 ppm, or 13 mg/kg/day. No tumors
were seen in any dose in this study. In a 1-year dog feeding study, the
NOEL was 200 ppm, or 7.8 mg/kg/day.
In a 21-day mancozeb dermal toxicity study in the rat, the NOEL was
1,000 mg/kg/day, with no effects seen at the limit dose. Respiratory
administration to rats for 13 weeks decreased body weights and serum T4
levels, and induced thyroid hyperplasia. All effects were reversible
after 13 weeks of post-exposure recovery.
iii. ETU. In an 18-month mouse feeding study for ETU by the
National Toxicology Program (NTP), the NOEL was 100 ppm, or 17 mg/kg/
day. Tumors of the liver, thyroid, and pituitary were seen at 330 and
1,000 ppm. A 2-year rat feeding chronic/oncogenicity study established
a NOEL of 5 ppm, or 0.37 mg/kg/day. Tumors were seen in the thyroid and
pituitary. The WHO established an RfD of 0.004 mg/kg/day based on these
data.
5. Carcinogenicity. Prolonged ingestion of ETU at very high levels
has caused thyroid and pituitary tumors in rats and mice and an
increase in liver tumors in mice. Thyroid tumors were also formed when
mancozeb was fed to rats at high doses (750 ppm) for long periods of
time. It is generally accepted that these tumors result from ETU
formation in the rat from feeding high doses of mancozeb. Because 7.5
percent of EBDC is converted to ETU in rats, feeding 750 ppm of EBDC
can produce enough ETU to cause tumors in these animals. No
carcinogenic effects were seen from feeding maneb and mancozeb to mice.
ETU is classified as a B2 oncogen with a Q* of 0.06 (mg/
kg/day)-1. Maneb and mancozeb are also classified as
B2 oncogens because of ETU.
C. Aggregate Exposure
1. Dietary exposure. The consumer exposure to EBDC and ETU residues
was measured in a market basket survey during an EPA Special Review
which concluded in 1992. The data showed that aggregate ETU exposure
from all current uses is less than 50% of the RfD. More specifically,
Griffin residue data show no detectable residues of ETU on walnuts.
Even if low levels of residues were present, mean per capita
consumption of walnuts is negligible. USDA dietary consumption data
from 1977-78 indicates that it is 0.0048243 g/kg bw/day for the U.S.
general population. Moreover, there is no concern with identifiable
subpopulations (see infants and children consumption).
FQPA requires EPA to use ``available information'' to consider
risks to infants and children before establishing a tolerance.
Available information demonstrates that dietary exposures to infants
and children from walnuts is immaterial; furthermore, there are also no
processed food uses for walnuts.
2. Drinking water. Maneb and mancozeb have no tendency to
contaminate groundwater or drinking water because they degrade rapidly
in soil and water, have low solubility in water, and are absorbed to
soil. Although the water solubility of ETU is relatively high, ETU is
not expected to contaminate groundwater for several reasons. First, ETU
is only present in the soil as the result of degradation of the parent
EBDCs (maneb or mancozeb), and it is being degraded at the same time it
is being formed. Thus, the ETU concentration will always be low.
Second, the degradation of ETU is rapid, thus it will degrade before it
can move.
Data from laboratory studies and field dissipation studies have
been integrated in computer modeling studies to predict the movement of
maneb and mancozeb and ETU in California from EBDC applications on
tomatoes and pears (mancozeb only) using the USDA GLEAMS model, which
accounts for degradation products as well as the parent. The model
predicts that there would be no measurable residues near the bottom of
the rooting zone of tomatoes and pears, even with a heavy amount of
simulated rainfall. Therefore, the model predicts that maneb, mancozeb
and ETU will not leach into groundwater. The modeling predictions are
consistent with the fact that EBDCs and ETU degrade rapidly in soil and
with the results of actual field dissipation studies.
The most direct evidence that ETU will not contaminate groundwater
comes from an extensive review of actual groundwater samples that have
been analyzed for ETU. In EPA's own National Pesticide Survey, only one
well out of 1,295 samples had an ETU residue. There were no measurable
ETU residues in community wells, with a sensitivity of 0.0045 ppm. The
one residue was in an area where EBDC fungicides are not heavily used.
Analysis of nearly 100 additional samples in state surveys did not show
any confirmed residues of ETU, even in
[[Page 41383]]
vulnerable areas such as Florida, Maine and New York.
Specific to walnuts which are grown almost exclusively in
California, the California Environmental Protection Agency's Pesticide
Well Inventory Database reveals extensive annual sampling for maneb and
ETU during the period August 15, 1984 to September 29, 1994, but only
one ETU detect (10 years ago in 1987) at 0.725 ppb. After not finding
ETU for decade, CDPR ceased testing for EBDCs.
Additionally, maneb, mancozeb and ETU degrade rapidly in natural
water/sediment systems. Thus, ETU is not likely to be present in
drinking water from natural surface water systems.
3. Non-dietary exposure. Mancozeb is labeled for application to
residential lawns only by commercial applicators, and both maneb and
mancozeb are labelled for ornamentals and vegetables by homeowners or
professional applicators. Mancozeb products are commonly applied to
golf course greens to control a broad complex of turf diseases.
Application to golf course fairways is less common. There are no
reliable data to assess the exposure from these uses.
Any acute exposures to children would come from oral or dermal
exposure. As previously discussed, maneb and mancozeb are not orally or
dermally acutely toxic. Furthermore, golf is not played by infants or
children; therefore, no exposure to infants and children would be
expected. Thus, there is a reasonable certainty that no harm would
occur to infants or children from these uses. Regardless, there are no
non-occupational exposures associated with walnut uses.
D. Cumulative Effects
The toxicological effects from maneb and mancozeb are due to ETU.
Other EBDC fungicides, including metiram and zineb are also converted
to ETU. The EBDC fungicides have been extensively reviewed by the US-
EPA as part of a Special Review which was concluded in 1992 with
publication of the PD4 document. These fungicides were regulated
against their common metabolite, ETU, and use restrictions were enacted
as part of the conclusion of the Special Review. As a result, common
mode of action has received considerable evaluation by the Agency and
currently approved risk levels have already accommodated any potential
concerns.
E. Safety Determination
1. U.S. population. DRES analyses for the U.S. general population
show vanishingly small oncogenic risks from combined maneb and ETU
residues on walnuts (reflective of mancozeb, as well, since 100% maneb
application assumed for calculation). The Combined Oncogenic Risk for
Maneb and ETU Residues for the U.S. population 48 states subgroup is
1.7 x 10-9 (ETU Oncogenic Risk). The general U.S. population
oncogenic risk with consumption of walnuts is essentially no different
than the risk without walnut consumption. An ETU oncogenic risk of
10-9 is three orders of magnitude below the FQPA standard,
again a negligible contribution.
The RfD of ETU will not be exceeded. In concluding that EBDC
Special Review, EPA calculated that the 45 crops on the EBDC labels
occupied 47% of the RfD for the general population using a safety
factor of 3,000, resulting in an RfD of 0.00008 mg/kg/day (established
in 1988). With a new complete database, the WHO established a reference
dose of 0.004 mg/kg/day. Because the WHO evaluation used all recently
developed data, Griffin believes their number is appropriate. With this
RfD and with addition of turnips, mustard greens, and collards to the
maneb label since the Special Review ended, the dietary exposure to ETU
will utilize less than 2% of the RfD. The incremental RfD utilized for
the U.S. general population by walnut uses, a fractional
0.71x10-3, is so minute it does not change this number. The
total percent RfD utilized by all uses, including addition of walnuts,
is well below the 100% RfD level, and is not perceptibly changed by
addition of walnut uses.
The sole acute risk would be for women of childbearing age. In
concluding the EBDC special review, EPA calculated that the Margin of
Exposure (MOE) for mancozeb would be 4, 985 based on field trial data
and concluded the margin would be adequate. The MOE would be even
higher based on the consumer exposure data from the market basket
survey. Thus, there is adequate safety for this group. Because walnuts
have such a low dietary consumption, it will not add to the exposure.
Thus, there is a reasonable certainly that no harm will result from
EBDC uses generally, and walnut uses specifically.
EPA has previously determined that the dietary risk from ``all EBDC
treated crops combined'' is acceptable; this summary of exposure and
toxicological safety shows that use of maneb and mancozeb on walnuts
will not materially increase that risk. FQPA anticipates that
tolerances will be reviewed over the next decade. (See FFDCA sections
408 (b)(2)(E)(ii) and 408(q)). The Agency should issue the walnut time-
limited tolerances on maneb and mancozeb now, since this process will
provide the opportunity for the Agency to visit any broader questions
that may arise in the future as to the tolerances at issue.
2. Infants and children. As with the U.S. general population, there
is no concern with identifiable subpopulations. The consumption figures
for walnuts are: U.S. general population -- 0.0048243 g/kg bw/day; non-
nursing infants -- 0.0029131 g/kg bw/day, children 1-6 -- 0.0133432 g/
kg bw/day, and children 7-12 --- 0.0087970 g/kg bw/day. Available
information demonstrates that exposures to infants and children from
walnuts is immaterial. In addition, there are no processed food uses
for walnuts. Thus, the raw crop's dietary impact for children is de
minimis. In fact, the PD4 separate dietary analysis for children and
infants that considered far more extensive uses than walnuts found
risks no greater than those of the general population, even when
overstated by calculations using an unrealistic lifetime exposure.
Specifically, EPA calculated the dietary risk to infants and children
from the allowed 45 uses to be 3.7 x 10-9 and 2.6
x10-8, respectively, adjusted for a revised Q* of 0.06 (mg/
kg/day)-1. [57 FR 7521 March 2, 1992] With addition of the
greens uses, the risks to these subgroups is still less than
1x10-7.
DRES analyses for infants and children show vanishingly small
oncogenic risks from combined maneb and ETU residues on walnuts
(reflective of mancozeb, as well, since 100% maneb application assumed
for calculation). The Combined Oncogenic Risk for Maneb and ETU
Residues (ETU Oncogenic Risk) for the subgroups: U.S. population 48
states -- 1.7 x 10-9; Non-nursing infants < 1="" yr="" (1="" yr="" lifetime="" corrected)="" --="" 1.4="" x="">-11; Children 1-6 years (6 yr
lifetime corrected) -- 4.0 x 10-10; Children 7-12 years (6
yr lifetime corrected) -- 2.6 x 10-10. The incremental
oncogenic risk for infants and children is well below the
1x10-6 FQPA standard of ``reasonable certainty of no harm.''
Non-nursing infants at 10-11 are five orders of magnitude
below this standard. Even the highest children's group (1-6 years old)
at 10-10 is an infinitesimal four orders of magnitude lower
than the standard.
The Agency also estimated that the 45 crops allowed at the end of
the special review occupied less than 50% of the RfD of 0.00008 mg/kg/
day for infants and children. With addition of greens and use of the
WHO ETU ADI of 0.004
[[Page 41384]]
mg/kg/day, ETU utilizes less than 2% of the ADI for infants and
children.
The reproductive and developmental toxicity does not require
additional safety factors because the database for maneb, mancozeb and
ETU is complete. Furthermore, the NTP evaluated the toxicity of the ETU
in utero in rats and mice and found that there was no significant
increase in toxicity, with the exception of a slight increase in rat
thyroid tumors, which have a threshold effect. Thus, prenatal and
postnatal exposure does not lead to increased sensitivity in infants
and children, and there is no evidence that ETU would present only
unusual or disproportionate hazard to infants and children. Therefore,
there is no need to impose an additional safety factor for infants and
children.
FQPA anticipates that tolerances will be reviewed over the next
decade. (See FFDCA sections 408 (b)(2)(E)(ii) and 408(q)). This process
will provide the opportunity for the Agency to visit any broader
questions that may arise in the future as to the tolerances at issue.
F. International Tolerances
There is no Codex MRL for walnuts. Codex has established MRLs for
the dithiocarbamate group, including maneb and mancozeb, on 21 crops
and proposed MRLs on 29 additional substrates.
3. Rohm and Haas Company
PP 2E4141
EPA has received a pesticide petition (PP 2E4141) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing an import tolerance for residues of the fungicide
myclobutanil and free and bound forms of its metabolite in or on the
raw agricultural commodity bananas at 4.0 parts per million (ppm) in
the whole fruit (0.8 ppm in edible portion). An adequate analytical
method is available for enforcement purposes. 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 metabolism of myclobutanil in plants is
well understood. The chemical identities of probable plant residues
resulting from the use of myclobutanil on bananas have been elucidated.
The major metabolite is alpha-(3-hydroxybutyl)-alpha-(4-chlorophenyl)-
1H-1,2,4-triazole-1-propanenitrile. Analyses indicate that the majority
of the residue is located on the banana peel.
2. Analytical method. Myclobutanil residues, parent plus free and
bound alcohol metabolites, are measured at an analytical sensitivity of
0.01 mg/kg in most crops by extraction of samples, partitioning into an
organic solvent, clean up on silica gel, and GLC using nitrogen
specific thermionic detection. Myclobutanil residues in animal
commodities are measured in essentially the same manner with the
additional diol metabolite in milk.
3. Magnitude of residues. The residue levels found on banana peel
ranged between 1.02 and 1.62 ppm at a 200 ppm application rate and
between 1.32 and 3.77 ppm at a 400 ppm application rate. In general,
the average total residues in the edible pulp were a small percentage
(5.8 to 7.8%) of the average total residues in the peel.
B. Toxicological Profile
1. Acute toxicity. Myclobutanil is essentially non-toxic after
administration by the oral, dermal and respiratory routes. Myclobutanil
is not irritating to skin (Draize score = 0), slightly irritating to
the eyes (mean irritation score = 0), and it is not a sensitizer. The
highest EPA acute toxicity category is III based on ocular irritation.
No evidence exists regarding differential sensitivity of children and
adults to acute exposure.
2. Genotoxicity. A reverse mutation assay (Ames), point mutation in
CHO/HGPRT cells, in vitro and in vivo (mouse) cytogenetic assays,
unscheduled DNA synthesis, and a dominant-lethal study in rats were
conducted. All were negative for mutagenic effects.
3. Reproductive and developmental toxicity. In assessing the
potential for additional sensitivity of infants and children to
residues of myclobutanil, data were considered from developmental
toxicity studies in the rat and rabbit and a 2-generation reproduction
study in the rat. The developmental toxicity studies are designed to
evaluate adverse effects on the developing organism resulting from
pesticide exposure during prenatal development to one or both parents.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
From the rat developmental study, the maternal (systemic) no-
observed-effect level (NOEL) was 93.8 mg/kg/day, based on rough hair
coat, and salivation at the lowest-observed effect level (LOEL) of
312.6 mg/kg/day. The developmental (pup) NOEL was 93.8 mg/kg/day, based
on increased incidences of 14th rudimentary and 7th cervical ribs at
the LOEL of 312.6 mg/kg/day. From the rabbit developmental study, the
maternal (systemic) NOEL was 60 mg/kg/day, based on reduced weight
gain, clinical signs of toxicity and abortions at the LOEL of 200 mg/
kg/day. The developmental (pup) NOEL was 60 mg/kg/day, based on
increases in number of resorptions, decreases in litter size, and a
decrease in the viability index at the lowest effect level (LEL) of 200
mg/kg/day.
From the rat reproduction study, the maternal (systemic) NOEL was
2.5 mg/kg/day, based on increased liver weights and liver cell
hypertrophy at the LOEL of 10 mg/kg/day. The developmental (pup) NOEL
was 10 mg/kg/day, based on decreased pup body weight during lactation
at the LEL of 50 mg/kg/day. The reproductive (parental) NOEL was 10 mg/
kg/day, based on increased incidence of stillborns, and atrophy of the
testes, epididymides, and prostate at the LEL of 50 mg/kg/day.
4. Chronic toxicity. In 2-year combined chronic toxicity/
oncogenicity studies in rats and 18-month oncogenicity studies in mice,
the overall NOEL was 80 ppm (2.49 mg/kg/day) based on decreased body
weight, and liver and testicular atrophy. In a 1-year chronic toxicity
study in dogs, the NOEL was 3.83 mg/kg/day based on hepatotoxicity. The
LOEL was 14.3 mg/kg/day. The Reference Dose (RfD) of 0.025 mg/kg/day
was established by the Agency based on the chronic feeding study in
rats with a NOEL of 2.5 mg/kg/day and an uncertainty factor of 100.
There was testicular atrophy at the lowest effect level (LEL) of 9.9
mg/kg/
Twenty four-month rat and 18-month mouse chronic feeding/
carcinogenicity studies with myclobutanil produced no statistically
significant increase in the incidence of combined, benign or malignant
tumors. Worst-case estimates of dietary intake of myclobutanil in human
adults and children indicate effects on the liver will not occur, thus
there is a reasonable certainty of no harm. Using its Guidelines for
Carcinogen Risk Assessment published September 24, 1986, EPA has
classified myclobutanil as a Group E chemical (no evidence of
carcinogenicity for humans) based on the results of carcinogenicity
[[Page 41385]]
studies in two species. The doses tested were adequate for identifying
a cancer risk.
5. Animal metabolism. The metabolism of myclobutanil in animals is
adequately understood for the purposes of this tolerance.
C. Aggregate Exposure
1. Dietary exposure. Established U.S. tolerances for myclobutanil
and its metabolites are found in 40 CFR 180.443, and range from 0.02
ppm for cotton seed and eggs to 5.0 ppm for cherries (sweet and sour).
There are no livestock feed items associated with the proposed use on
bananas, so no additional livestock dietary burden will result from
this registration. Therefore, existing meat, milk and poultry
tolerances are adequate.
For the purposes of assessing the potential dietary exposure under
this petition, the estimated aggregate exposure was based on the
theoretical maximum residue contribution (TMRC) from the tolerances for
myclobutanil on all registered uses plus banana pulp, the edible
portion of whole bananas, at 0.8 ppm. The tolerance for myclobutanil on
bananas (whole fruit) is 4.0 ppm. The TMRC is obtained by multiplying
the tolerance level residues for banana pulp by the consumption data
which estimates the amount of bananas and other products eaten by
various population subgroups.
The RfD based on the 2-year rat chronic feeding study (NOEL of 2.49
mg/kg bwt/day) and using a hundred-fold uncertainty factor is
calculated to be 0.025 mg/kg bwt/day. The TMRC from previously
established tolerances and tolerances established here is 0.003286 mg/
kg bwt/day for the general population and utilizes 13.1% of the RfD.
The percentage of the RfD for the most highly exposed subgroup, non-
nursing infants (less than 1 year old) is 72.3%. The TMRC was
calculated based on the assumption that myclobutanil occurs at the
maximum legal limit in all of the dietary commodities for which
tolerances are proposed. Even with this probable large overestimate of
exposure/risk, the TMRC is well below the RfD for the population as a
whole and for each of the 22 subgroups considered.
Thus, the dietary risk from exposure to myclobutanil appears to be
minimal for the use on bananas. In conducting this exposure assessment,
very conservative assumptions (100% of bananas will contain
myclobutanil residues and those residues would be at the level of the
tolerance) were made which results in an overestimate of human
exposure. Thus, in making a safety determination for these tolerances,
this conservative exposure assessment is taken into account.
2. Drinking water. Myclobutanil will not contaminate groundwater or
drinking water because of its adsorptive properties on soil, solubility
in water, and degradation rate. Data from laboratory studies and field
dissipation studies have been used in the USDA PRZM/GLEAMS computer
model to predict the movement of myclobutanil. The model predicts that
myclobutanil will not leach into groundwater, even if heavy rainfall is
simulated. The modeling predictions are consistent with the data from
environmental studies in the laboratory and the results of actual field
dissipation studies. There are no data on passage of myclobutanil
through water treatment facilities and there are no State water
monitoring programs which target myclobutanil.
Based on the available studies used in the assessment of
environmental risk, it is not anticipated that there will be exposure
to residues of myclobutanil in drinking water. Review of terrestrial
field dissipation data indicated that myclobutanil did not leach into
groundwater in either sandy loam or coastal soil. There is no
established Maximum Concentration Level for residues of myclobutanil in
drinking water. No drinking water health advisories have been issued
for myclobutanil. The ``Pesticides in Groundwater Database'' has no
information concerning myclobutanil. Based on the available data, the
Agency does not anticipate that there will be significant exposure to
the general population from myclobutanil residues in drinking water.
Since myclobutanil is unlikely to leach into groundwater, there is no
increased risk from this source.
3. Non-dietary exposure. EPA has not provided Rohm and Haas Company
with an estimate of non-occupational exposure for myclobutanil,
however, there are no products registered in the United States for
home-owner use which contain myclobutanil. While this does not preclude
potential exposure, the market channels for home-owner products do not
contain myclobutanil. This makes the potential for non-occupational
exposure to the general population essentially nil and the contribution
from this source is not expected to be significant.
D. Cumulative Effects
EPA is aware of and has considered the potential for cumulative
effects of myclobutanil and other substances that have a common
mechanism of fungicidal activity. These are commonly designated as the
DMI fungicides. The Rohm and Haas Company, other producers, University
advisors, economic consultants, and the EPA are well aware of the
existing national IPM and resistance management programs for these
fungicides which strongly discourage the use of multiple products
either concomitantly or in succession within the same season. The
activities within these highly publicized programs and the Fungicide
Resistance Action Committee, which monitors fungal resistance on an
annual basis, support the conclusion that overlapping use of DMI
fungicides on the same crop are unlikely. In addition, Rohm and Haas
Company is not aware of any toxicological data available to EPA or to
the producers which suggest that there is a common mechanism of
mammalian or ecological toxicity among these fungicidal products.
Therefore, it is reasonable to conclude that EPA has reliable
information to indicate that toxic effects produced by myclobutanil
should not be considered to be cumulative with those of any other
chemical compounds. Thus, consideration of a common mechanism of
toxicity for these fungicidal products is not appropriate at this time.
EPA should consider only the potential risks of myclobutanil in its
aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above, based on the completeness and reliability of the
toxicity data, it was concluded that aggregate exposure to myclobutanil
will utilize 13.1% of the RfD for the U.S. population. EPA generally
has no concern for exposures below 100% of the RfD because the RfD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health. It is
therefore concluded that there is a reasonable certainty that no harm
will result from aggregate exposure to myclobutanil residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of myclobutanil, data
were considered from developmental toxicity studies in the rat and
rabbit and a 2-generation reproduction study in the rat. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the
[[Page 41386]]
reproductive capability of mating animals and data on systemic
toxicity.
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 pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, for the chemical myclobutanil, the NOEL at 2.5 mg/
kg/day from the rat study, which was used to calculate the RfD, is
already lower than the NOELs from the developmental studies in rats and
rabbits by a factor of approximately 4-fold.
The effects observed in the reproductive toxicity study suggest
that there is no unique sensitivity for infants and children.
Therefore, the data support a conclusion that an additional uncertainty
factor is not warranted and that the RfD at 0.025 mg/kg/day is
appropriate for assessing aggregate risk to infants and children.
Using the conservative exposure assumptions described above, it was
concluded that the percent of the RfD that will be utilized by
aggregate exposure to residues of myclobutanil ranges from 13.1% for
adults up to 72.3% for non-nursing infants. Therefore, based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, EPA has already published a conclusion which
indicates that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to myclobutanil
residues.
F. International Tolerances
There are Codex maximum residue levels (MRL) established for
residues of myclobutanil for apricot, cherry, peach, plum/prune
(fresh), prune (dried), grapes, apples, and pears. Rohm and Haas
company has proposed modifications to the current CXL for stone fruits
only to accommodate US GAP.
[FR Doc. 97-20216 Filed 7-31-97; 8:45 am]
BILLING CODE 6560-50-F
