[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: 
<a href="/cdn-cgi/l/email-protection#b1c6d0ddddd4c39fdcd0c3c8f1d4c1d0dcd0d8dd9fd4c1d09fd6dec7"><span class="__cf_email__" data-cfemail="0e796f62626b7c20636f7c774e6b7e6f636f6762206b7e6f20696178">[email protected]</span></a>.

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:
    <a href="/cdn-cgi/l/email-protection#4d223d3d6029222e2628390d283d2c202c242163283d2c632a223b"><span class="__cf_email__" data-cfemail="721d02025f161d11191706321702131f131b1e5c1702135c151d04">[email protected]</span></a>


    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 LD<INF>50</INF> of 
pyrimethanil was 4.15 g/kg in males and 5.97 g/kg in females. The acute 
rat dermal LD<INF>50</INF> was <gr-thn-eq> 5.0 g/kg in both sexes. The 
4-hour rat inhalation LC<INF>50</INF> 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 LD<INF>50</INF> for rats is 6,750 mg/kg. 
The acute dermal LD<INF>50</INF> for rabbits > 2,000 mg/kg and for rats 
> 5,000 mg/kg. Acute inhalation LC<INF>50</INF> 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 LD<INF>50</INF> in mice and rats is 
>5,000 mg/kg. The acute dermal LD<INF>50</INF> in rats is >5,000 mg/kg. 
Mancozeb was not significantly toxic to rats after a 4-hour inhalation 
exposure, with an LD<INF>50</INF> 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 LD<INF>50</INF> is 4,000 mg/kg/day 
and the rat acute oral LD<INF>50</INF> 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 B<INF>2</INF> oncogen with a Q* of 0.06 (mg/
kg/day)<SUP>-1</SUP>. Maneb and mancozeb are also classified as 
B<INF>2</INF> 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<SUP>-9</SUP> (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<SUP>-9</SUP> 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<SUP>-3</SUP>, 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<SUP>-9</SUP> and 2.6 
x10<SUP>-8</SUP>, respectively, adjusted for a revised Q* of 0.06 (mg/
kg/day)<SUP>-1</SUP>. [57 FR 7521 March 2, 1992] With addition of the 
greens uses, the risks to these subgroups is still less than 
1x10<SUP>-7</SUP>.
    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<SUP>-9</SUP>; Non-nursing infants < 1 yr (1 yr 
lifetime corrected) -- 1.4 x 10<SUP>-11</SUP>; Children 1-6 years (6 yr 
lifetime corrected) -- 4.0 x 10<SUP>-10</SUP>; Children 7-12 years (6 
yr lifetime corrected) -- 2.6 x 10<SUP>-10</SUP>. The incremental 
oncogenic risk for infants and children is well below the 
1x10<SUP>-6</SUP> FQPA standard of ``reasonable certainty of no harm.'' 
Non-nursing infants at 10<SUP>-11</SUP> are five orders of magnitude 
below this standard. Even the highest children's group (1-6 years old) 
at 10<SUP>-10</SUP> 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


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