[Federal Register Volume 65, Number 120 (Wednesday, June 21, 2000)]
[Notices]
[Pages 38535-38543]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-15161]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-945; FRL-6558-9]


Notice of Filing a Pesticide Petition To Establish a Tolerance 
for Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by docket control number PF-945, must be 
received on or before July 21, 2000.

ADDRESSES: Comments may be submitted by mail, electronically, or in 
person. Please follow the detailed instructions for each method as 
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION.'' To ensure 
proper receipt by EPA, it is imperative that you identify docket 
control number PF-945 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Shaja R. Brothers, 
Registration Division (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, Ariel Rios Bldg., 1200 Pennsylvania 
Ave., NW., Washington, DC 20460; telephone number: (703) 308-3194; e-
mail address: <a href="/cdn-cgi/l/email-protection#4c2e3e233824293e3f623f242d262d0c293c2d622b233a"><span class="__cf_email__" data-cfemail="fd9f8f928995988f8ed38e959c979cbd988d9cd39a928b">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural 
producer, food manufacturer or pesticide manufacturer. Potentially 
affected categories and entities may include, but are not limited to:

 
------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS codes         potentially
                                                       affected entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed under ``FOR FURTHER INFORMATION 
CONTACT.''

B. How Can I Get Additional Information, Including Copies of this 
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, and certain other related documents that might be available 
electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
To access this document, on the Home Page select ``Laws and 
Regulations'' and then look up the entry for this document under the 
``Federal Register--Environmental Documents.'' You can also go directly 
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for 
this action under docket control number PF-945. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
a.m. to 4 p.m.,

[[Page 38536]]

Monday through Friday, excluding legal holidays. The PIRIB telephone 
number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-945 in the subject line on the 
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: ``<a href="/cdn-cgi/l/email-protection#84ebf4f4a9e0ebe7efe1f0c4e1f4e5aae3ebf2"><span class="__cf_email__" data-cfemail="d4bba4a4f9b0bbb7bfb1a094b1a4b5fab3bba2">[email protected]</span></a>,'' or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-945. Electronic comments may 
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to 
be CBI. You may claim information that you submit to EPA in response to 
this document as CBI by marking any part or all of that information as 
CBI. Information so marked will not be disclosed except in accordance 
with procedures set forth in 40 CFR part 2. In addition to one complete 
version of the comment that includes any information claimed as CBI, a 
copy of the comment that does not contain the information claimed as 
CBI must be submitted for inclusion in the public version of the 
official record. Information not marked confidential will be included 
in the public version of the official record without prior notice. If 
you have any questions about CBI or the procedures for claiming CBI, 
please consult the person identified under ``FOR FURTHER INFORMATION 
CONTACT.''

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this 
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
control number assigned to this action in the subject line on the first 
page of your response. You may also provide the name, date, and Federal 
Register citation.

II. What Action is the Agency Taking?

    EPA has received pesticide petitions as follows proposing the 
establishment and/or amendment of regulations for residues of certain 
pesticide chemicals in or on various food commodities under section 408 
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that these petitions contain data or information 
regarding the elements set forth in section 408(d)(2); however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data support granting of the petitions. Additional data 
may be needed before EPA rules on the petitions.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: June 2, 2000.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    The petitioner summaries of the pesticide petitions are printed 
below as required by section 408(d)(3) of the FFDCA. The summaries of 
the petitions were prepared by the petitioner and represents the view 
of the petitioner. The petition summaries announce 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.

I. Interregional Research Project Number 4

9E6026

    EPA has received pesticide petition 9E6026 from the Interregional 
Research Project Number 4 (IR-4), New Jersey Agricultural Experiment 
Station, Rutgers University, New Brunswick, New Jersey 08903, 
proposing, pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of paraquat in or on the raw 
agricultural commodity (RAC) endive at 0.05 parts per million (ppm). 
EPA has determined that the petition contains data or information 
regarding the elements set forth in section 408(d)(2) of the FFDCA; 
however, EPA has not fully evaluated the sufficiency of the submitted 
data at this time or whether the data support granting of the petition. 
Additional data may be needed before EPA rules on the petition. This 
notice includes a summary of the petition prepared by Zeneca Ag 
Products, the registrant, 1800 Concord Pike. P.O. Box 15458, 
Wilmington, DE 19850-5458.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues in 
plants is adequately understood based on studies depicting the 
metabolism of paraquat in carrots and lettuce following pre-emergence 
treatments and in potatoes and soybeans following desiccant treatment. 
The residue of concern in plants is the parent chemical, paraquat.
    2. Analytical method. An adequate analytical method (spectrometric 
method) has been accepted and published in the Pesticide Analytical 
Manual (PAM Vol. II) for the enforcement of tolerances in plant 
commodities.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies conducted with the 45.6% 
paraquat dichloride technical concentrate give the following results: 
oral lethal dose (LD)<INF>50</INF> in the rat of 344 milligrams/
kilograms (mg/kg) males and 283 mg/kg females Category II; dermal 
LD<INF>50</INF> in the rat of >2,000 mg/kg for

[[Page 38537]]

males and females (Category III); the primary eye irritation study 
showed corneal involvement with clearing within 17-days (Category II); 
and dermal irritation of slight erythema and edema at 72 hours 
(Category IV). Paraquat is not a dermal sensitizer. Acute inhalation 
studies conducted pursuant to EPA guideline with aerosolized sprays 
result in lethal concentration (LC)<INF>50</INF> of 0.6 to 1.4 
<greek-m>g paraquat cation/L (Category I). However, since paraquat 
dichloride has no measurable vapor pressure; and hydraulic spray 
droplets are too large to be respirable, inhalation exposure is not a 
concern in practice.
    2. Genotoxicity. Paraquat dichloride was not mutagenic in the Ames 
test using Salmonella typhinurium strains TA1535, TA1538, TA98, and 
TA100; the chromosomal aberrations in the bone marrow test system; or 
in the dominant lethal mutagenicity study with CD-1 mice. Additionally, 
paraquat dichloride was negative for unscheduled DNA synthesis in rat 
hepatocyctes in vitro and in vivo. Paraquat was weakly positive in the 
mouse lymphoma cell assay only in the presence of metabolic activation. 
Paraquat dichloride was weakly positive in mammalian cells 
(lymphocytes) and positive in the sister chromatid exchange (SCE) assay 
in chinese hamster lung fibroblasts. Paraquat is non-mutagenic.
    3. Reproductive and developmental toxicity. A 3-generation 
reproduction study in rats fed diets containing 0, 25, 75, and 150 ppm 
(0, 1.25, 3.75, or 7.5 mg of paraquat cation/kg/day, respectively) 
showed no effect on body weight gain, food consumption and utilization, 
fertility and length of gestation of the F0, F1, and F2 parents at any 
dose. The no observed adverse effect level (NOAEL) and lowest observed 
adverse effect level (LOAEL) for systemic toxicity are 25 ppm (1.25 mg/
kg/day) and 75 ppm (3.75 mg/kg/day), respectively, expressed as 
paraquat cation, based on high mortality due to lung damage. The NOAEL 
for reproductive toxicity is <gr-thn-eq>150 ppm 7.5 mg/kg/day; highest 
dose tested (HDT) expressed as paraquat cation, as there were no 
reproductive effects observed.
    Two developmental toxicity studies were conducted in rats given 
gavage doses of 0, 1, 5, or 10 mg/kg/day and 0, 1, 3, or 8 mg/kg/day, 
respectively, expressed as paraquat cation. In the first study, the 
NOAEL for maternal toxicity was 1 mg/kg/day based on clinical signs of 
toxicity and decreased body weight gain at 5 mg/kg/day (the LOAEL). The 
NOAEL for developmental toxicity was set at 5 mg/kg/day based on 
delayed ossification of the forelimb and hindlimb digits. In the second 
study, the maternal and developmental NOAEL is 8 mg/kg/day HDT as there 
were no effects observed at any dose level. Based on both studies, the 
overall NOAEL for maternal and developmental toxicity is at least 3 mg/
kg/day.
    Two developmental toxicity studies were conducted in mice given 
gavage doses of 0, 1, 5, or 10 mg/kg/day and 0, 7.5, 15, or 25 mg/kg/
day paraquat ion, respectively. In the first study the NOAEL and LOAEL 
for maternal toxicity are 5 mg/kg/day and 10 mg/kg/day, respectively, 
based on reductions in body weight gain and death (range-finding 
study). The NOAEL and LOAEL for developmental toxicity are 5 mg/kg/day 
and 10 mg/kg/day, respectively based on an increased number of litters 
and fetuses with partial ossification of the 4th sternebra at 10 mg/kg/
day HDT. Both the maternal and developmental NOAELs are at 15 mg/kg/day 
in the second study. The maternal LOAEL of 25 mg paraquat cation/kg/day 
is based on death, decreases in body weight and body weight gain, and 
other clinical signs. The developmental LOAEL of 25 mg/kg/day is based 
on decreases in mean fetal weights, retarded ossification and other 
skeletal effects. According to the registrant, Paraquat dichloride is 
not a developmental toxin and the developmental/maternal NOAEL should 
be based on the second study and is 15 mg/kg/day.
    4. Subchronic toxicity. A 90-day feeding study was conducted in 
dogs fed doses of 0, 7, 20, 60, or 120 ppm with a NOAEL of 20 ppm based 
on lung effects such as alveolitis and alveolar collapse seen at the 
LOAEL of 60 ppm. In a 21-day inhalation toxicity study, rats were 
exposed to respirable aerosols of paraquat at doses of 0, 0.01, 0.1, 
0.5, or 1.0 <greek-m>g/L with a NOAEL of 0.01 <greek-m>g/L and a LOAEL 
of 0.10 <greek-m>g/L based on histopathological changes to the 
epithelium of the larynx and nasal discharge.
    5. Chronic toxicity. A 12-month feeding study was conducted in dogs 
fed dose levels of 0, 15, 30, or 50 ppm, expressed as paraquat cation. 
These levels corresponded to 0, 0.45, 0.93, or 1.51 mg of paraquat 
cation/kg/day, respectively, in male dogs or 0, 0.48, 1.00, or 1.58 mg 
of paraquat cation/kg/day, respectively for female dogs. There was a 
dose-related increase in the severity and extent of chronic pneumonitis 
in the mid-dose and high-dose male and female dogs. This effect was 
also noted in the low-dose male group, but was minimal when compared 
with the male controls. The systemic NOAEL is 15 ppm (0.45 mg/kg/day 
for males and 0.48 mg/kg/day for females, expressed as parquet cation). 
The systemic LOAEL is 30 ppm (0.93 mg/kg/day for males and 1.00 mg/kg/
day for females, expressed as paraquat cation).
    In a 2-year chronic feeding/carcinogenicity study, rats were fed 
doses of paraquat dichloride at 0, 25, 75, or 150 ppm which correspond 
to 0, 1.25, 3.75, or 7.5 mg of paraquat cation/kg/day. Paraquat 
enhanced the development of ocular lesions in all of the treated 
groups. The predominant lesions detected opthalmoscopically were 
lenticular opacities and cataracts. At test week 103, dose-related 
statistically significant (P0.001) increases in the incidence of ocular 
lesions were observed only in the mid-dose and high-dose male and 
female groups. Based on these findings, the NOAEL (approximate) and the 
LOAEL for systemic toxicity, for both sexes, are 25 ppm (1.25 mg/kg/
day) and 75 ppm (3.75 mg/kg/day), respectively.
    In another 2-year chronic feeding/carcinogenicity study, rats were 
dosed at 0, 6, 30, 100, or 300 ppm, expressed as paraquat dichloride 
(nominal concentrations), equivalent to 0, 0.25, 1.26, 4.15, or 12.25 
mg/kg/day, respectively (males) and 0, 0.30, 1.5, 5.12, or 15.29 mg/kg/
day respectively (females), expressed as paraquat dichloride. The 
incidence of ocular changes were low and not caused by paraquat in this 
study. The systemic NOAEL is 100 ppm of paraquat dichloride (4.15 and 
5.12 mg/kg/day, for males and females, respectively); or 3.0 mg/kg/day 
(males) and 3.7 mg/kg/day (females), expressed as paraquat cation. The 
systemic LOAEL is 300 ppm of paraquat dichloride (12.25 and 15.29 mg/
kg/day, for males and females, respectively); or 9.0 mg/kg/day (males) 
and 11.2 mg/kg/day (females), expressed as paraquat cation.
    A chronic feeding/carcinogenicity study was conducted in rats fed 
dose levels of 0, 25, 75, or 150 ppm, expressed as paraquat cation 
(nominal concentrations). These doses corresponded to 0, 1.25, 3.75, or 
7.5 mg paraquat cation/kg/day, respectively. There was uncertain 
evidence of carcinogenicity (squamous cell carcinomas in the head 
region; ears, nasal cavity, oral cavity and skin) in males at 7.5 mg/
kg/day HDT with a systemic NOAEL of 1.25 mg/kg/day. Upon submission of 
additional data to EPA, the incidence of pulmonary adenomas and 
carcinomas was well within historical ranges and it was determined that 
paraquat was not carcinogenic in the lungs and head region of the rat.
    In another chronic feeding/carcinogenicity study, rats were fed 
dose levels of 0, 6, 30, 100, or 300 ppm,

[[Page 38538]]

expressed as paraquat dichloride. There were no carcinogenic findings 
in this study at the HDT. In a 2-year chronic feeding/concinogenicity 
study, SPF Swiss derived mice were fed paraquat dichloride at dose 
levels of 0, 12.5, 37.5, or 100/125 ppm, expressed as paraquat cation. 
These rates correspond to 0, 1.87, 5.62, and 15 mg/kg/day as cation. 
Because no toxic signs appeared after 35 weeks of dosing, the 100 ppm 
level was increased to 125 ppm at week 36. There were no carcinogenic 
effects observed in this study. The systemic NOAEL for both sexes is 
12.5 ppm (1.87 mg/kg/day) and the systemic LOAEL is 37.5 ppm (5.6 mg/
kg/day), each expressed as paraquat cation based on renal tubular 
degeneration in males and weight loss and decreased food intake in 
females.
    Paraquat is classified Category E for carcinogenicity (no evidence 
of carcinogenicity in animal studies).
    6. Animal metabolism. The qualitative nature of the residue in 
animals is adequately understood based on the combined studies 
conducted with ruminants (goats and cows), swine, and poultry. The 
residue of concern in eggs, milk, and poultry, and livestock tissues is 
the parent, paraquat.

C. Aggregate Exposure

    In examining aggregate exposure, FQPA directs EPA to take into 
account available information concerning exposures from the pesticide 
residue in food and all other exposures for which there is reliable 
information. These other sources of exposure include drinking water, 
and non-occupational exposures, e.g., to pesticides used in and around 
the home. For estimating acute and chronic risks the Agency considers 
aggregate exposures from the diet and from drinking water. Exposures 
from uses in and around the home that may be short term, intermediate, 
or other durations may also be aggregated as appropriate for specific 
chemicals.
    1. Dietary exposure. For purposes of assessing the potential 
dietary exposure under the proposed tolerance, Zeneca has estimated 
aggregate exposure based on the tolerance levels of 0.05 ppm, 0.3 ppm, 
0.05 ppm, and 0.05 ppm in or on globe artichokes, dry peas, persimmons, 
endive and from all other established tolerances. Percent crop treated 
was also incorporated into the assessment to derive an upper bound 
anticipated residue contribution (ARC). The registrant has concluded 
that there are no acute endpoints of concern for paraquat, and an acute 
aggregate assessment is not required. The chronic population adjusted 
dose (cPAD) for chronic dietary assessments is 0.0045 mg/kg/day, based 
on a NOAEL of 0.45 mg/kg/day from a 1-year dog study and the addition 
of a standard uncertainty factor of 100.
    i. Food.-- a. Chronic dietary assessment. A chronic dietary 
exposure analysis was performed using current and reassessed tolerance 
level residues, contributions from the proposed tolerance for use on 
globe artichoke, dry peas, persimmons, endive, and current percent crop 
treated information to estimate the ARC for the general population and 
22 subgroups. The tolerance in globe artichoke resulted in an ARC of 
0.0000001 mg/kg/day (0.002% of the cPAD) for the general population. 
The resulting ARC for the general U.S. population from all established 
uses is 0.000367 mg/kg/day (8.2% of the cPAD). For children ages 1 to 
6, the most highly exposed subgroup, the resulting ARC is 0.001077 mg/
kg/day (23.9% of the cPAD).
    b. Acute dietary assessment. The registrant has determined that 
current data on paraquat shows no acute dietary endpoint of concern. 
Therefore, an acute dietary risk assessment was not conducted for 
paraquat.
    ii. Drinking water. The registration eligibility document (RED) for 
paraquat has stated the following:
    Paraquat is not expected to be a contaminant of groundwater. 
Paraquat dichloride binds strongly to soil clay particles and it did 
not leach from the surface in terrestrial field dissipation studies. 
There were, however, detections of paraquat in drinking water wells 
from two states cited in the pesticides in groundwater data base 
(1991). These detections are not considered to be representative of 
normal paraquat use. Therefore, paraquat is not expected to be a 
groundwater contaminant or concern based on normal use patterns.
    Due to its persistent nature, paraquat could potentially be found 
in surface water systems associated with soil particles carried by 
erosion, however, paraquat is immobile in most soils, and at very high 
application rates (50-1000X), there was no desorption of paraquat from 
soils. Based on paraquat's normal use patterns and unique environmental 
fate characteristics, exposures to paraquat in drinking water are not 
expected to be obtained from surface water sources. Therefore, the only 
exposures considered in aggregate risk assessment for paraquat is 
chronic dietary.
    2. Non-dietary exposure. Paraquat dichloride has no residential or 
other non-occupational uses that might result in non-occupational, non-
dietary exposure for the general population. Paraquat products are 
restricted use, for use by certified applicators only, which means the 
general public cannot buy or use paraquat products.

D. Cumulative Effects

    In assessing the potential risk from cumulative effects of paraquat 
and other chemical substances, the Agency has considered structural 
similarities that exist between paraquat and other bipyridylium 
compounds such as diquat dibromide. Examination of the toxicology data 
bases of paraquat and diquat dibromide, indicates that the two 
compounds have clearly different target organs. Based on available 
data, the registrant does not believe that the toxic effects produced 
by paraquat would be cumulative with those of diquat dibromide.

E. Safety Determination

    1. U.S. population. Based on the paraquat RED, the only exposure 
route of concern for paraquat is chronic dietary. Using the 
conservation assumptions presented earlier, EPA has established a cPAD 
of 0.0045 mg/kg/day. This was based on the NOAEL for the 1-year dog 
study of 0.45 mg/kg/day and employed a 100-fold uncertainty factor. 
Results of this aggregate exposure assessment, which includes EPA's 
reassessment of tolerances for existing crops and the tolerance for use 
on globe artichokes, dry peas, persimmons, and endive utilize 8.2% of 
the cPAD. Generally, exposures below 100% of the cPAD are of no concern 
because it represents the level at or below which daily aggregate 
dietary exposure over a lifetime will not pose appreciable risk to 
human health. Thus, the registrant has concluded that there is 
reasonable certainty that no harm will result from aggregate exposures 
to paraquat residues.
    2. Infants and children. Zeneca has determined that the established 
tolerances for paraquat, with amendments and changes as specified in 
this notice, meet the safety standards under the FQPA amendments to 
section 408(b)(2)(C) for infants and children. The safety determination 
for infants and children considers the factors noted above for the 
general population, but also takes into account the possibility of 
increased dietary exposure due to specific consumption patterns of 
infants and children, as well as the possibility of increased 
susceptibility to the toxic effects of paraquat residues in this 
population subgroup.
    In determining whether or not infants and children are particularly 
susceptible to toxic effects from paraquat residues, Zeneca considered 
the completeness of the data base for developmental and

[[Page 38539]]

reproductive effects, the nature and severity of the effects observed, 
and other information.
    Based on the current data requirements, paraquat has a complete 
data base for developmental and reproductive toxicity. In the 
developmental studies, effects were seen (delayed ossification in the 
forelimb and hindlimb digits) in the fetuses only at the same or higher 
dose levels than effects in the mother. In the reproduction study, no 
effects on reproductive performance were seen. Also because the NOAELs 
from the developmental and reproduction studies were equal to or 
greater than the NOAEL used for establishing the cPAD, the registrant 
concluded that it is unlikely that there is additional risk concern for 
immature or developing organisms. Finally, there is no epidemiological 
information suggesting special sensitivity of infants and children to 
paraquat. Therefore, the registrant found that an additional safety 
factor for infants and children is not warranted for paraquat.
    Zeneca estimates that paraquat residues in the diet of non-nursing 
infants (less than 1 year) account for 17.6% of the cPAD and 23.9% of 
the cPAD for children aged 1 to 6 years. Further, residues in drinking 
water are not expected. Therefore, Zeneca has determined that there is 
reasonable certainty that dietary exposure to paraquat will not cause 
harm to infants and children.

F. International Tolerances

    There is no approved CODEX maximum residue level (MRL) established 
for residues of paraquat on endive.

II. Interregional Research Project Number 4

0E6090

    EPA has received a pesticide petition 0E6090 from the Interregional 
Research Project Number 4 (IR-4); Rutgers University, New Brunswick, 
NJ, 08903-0231 proposing, pursuant to section 408(d) of the Federal 
Food , Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 
CFR part 180 by establishing a tolerance for residues of Fosetyl-Al in 
or on the raw agricultural commodity (RAC) cranberries at 0.5 parts per 
million (ppm). EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data support granting of the 
petition. Additional data may be needed before EPA rules on the 
petition. This notice includes a summary of the petition prepared by 
Aventis CropScience the registrant, P.O. Box 12014, 2 T.W. Alexander 
Drive, Research Triangle Park, NC, 27709.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of fosetyl-Al in plants is 
adequately understood. Adequate data on the nature of the residues in 
plants, including identification of major metabolites and degradates of 
fosetyl-Al, are available. Radiolabeled studies on the uptake, 
translocation and metabolism in plants show that the chemical proceeds 
through hydrolytic cleavage of the ethyl ester. The major residues are 
fosetyl-Al, phosphorus acid, and ethanol. The tolerances are 
established for the parent only, that is fosetyl-Al.
    2. Analytical method. Adequate methods are available for 
enforcement purposes. There are two analytical methods acceptable for 
determining residues of fosetyl-Al in plants: a gas chromatography 
method is available for enforcement of tolerance in pineapple and is 
listed as method I in pesticide analytical manual (PAM), Vol. II; a gas 
chromatography/phosphorus specific flame photometric detector (FPD-P) 
method (Aventis CropScience method no. 163) for citrus has undergone a 
successful method tryout on oranges and has been sent to the Food and 
Drug Adminstration (FDA) for inclusion in PAM as method II.
    3. Magnitude of residues. Field trials were conducted in EPA 
regions 1 (MA), 2 (NJ), 5 (WI), and 12 (OR). All field trial sites 
consisted of 1 untreated control plot and 1 treated plot. Each treated 
plot received four foliar spray applications of fosetyl-Al at a rate of 
4.0 lb active ingredient per acre (ai/A) # 5% each, for a total of 
approximately 16 lb ai/A. The first application was made at 
approximately 93 days prior to harvest and subsequent applications were 
made at approximately 30-day intervals. Samples were collected at 3 or 
4 days after the last application in all trials. Fosetyl-Al residues in 
treated samples ranged from <0.05 ppm to 0.35 ppm. Data from this study 
support the proposed tolerance of 0.5 ppm.

B. Toxicological Profile

    1. Acute toxicity. A complete battery of acute toxicity studies for 
fosetyl-Al technical has been conducted. The lethal dose 
LD<INF>50</INF> from the acute oral rat is 5.4 g/kg and the 
LD<INF>50</INF> from an acute dermal rabbit study is >2 g/kg. The 
LC<INF>50</INF> for a rat inhalation study is >1.73 mg/L. The acute 
oral rat and primary dermal irritation studies indicate category IV 
toxicity. A guinea pig dermal sensitization study shows fosetyl-Al is 
not a skin sensitizer. The primary eye irritation study in rabbits 
shows fosetyl-Al to be an eye irritant with Category I toxicity.
    2. Genotoxicity. Fosetyl-Al is neither mutagenic nor genotoxic. The 
genetic toxicity potential of fosetyl-Al was assessed in several 
assays. Eight mutagenicity tests performed with fosetyl-Al were 
negative. The tests included two Ames assays with S. typhimurium, two 
phase induction assays using E. coli, two micronucleus studies in mice, 
one DNA repair assay using E. coli and one mutation assay in 
Saccharomyces cereviseae.
    3. Reproductive and developmental toxicity. Fosetyl-Al is not a 
reproductive toxicant and shows no evidence of estrogenic or androgenic 
related effects.
    i. In a 3-generation reproduction study, fosetyl-Al was 
administered to rats at dietary levels of 0, 6,000, 12,000, or 24,000 
ppm. No adverse effects on reproductive performance or pup survival 
were observed in any dose group. The lowest observed adverse effect 
level (LOAEL) was established at 12,000 ppm based on effects on animal 
weights and urinary tract changes. The no observed adverse effect level 
(NOAEL) for all effects was 6,000 ppm.
    ii. A developmental study in rats dosed via oral gavage at 500, 
1,000 or, 4,000 mg/kg/day showed a developmental NOAEL of 1,000 mg/kg. 
At 4,000 mg/kg, there was maternal toxicity, as evidenced by effects on 
animal weights, maternal deaths, increased resorptions and delayed 
fetal ossification.
    iii. A rabbit developmental study showed no toxic effects at oral 
doses up to 500 mg/kg. Effects of fosetyl-Al on fetal development were 
observed only in the rat at a dose producing severe maternal toxicity. 
In the absence of maternal toxicity, no adverse effects on fetal 
development were observed, i.e. at 1,000 mg/kg/day in rats or at 500 
mg/kg/day in rabbits.
    4. Subchronic toxicity. In subchronic studies, no significant 
toxicity was observed even at doses exceeding the limit of 1,000 mg/kg/
day.
    i. A 21-day dermal study in rabbits showed mild to moderate skin 
irritation and a NOAEL of 1.5 g/kg/day.
    ii. A 90-day feeding study in rats showed a NOAEL of >5,000 ppm; 
the LOAEL was 25,000 ppm with extramedullary hematopoiesis in the 
spleen.
    iii. A 90-day dog feeding study showed a NOAEL of 10,000 ppm and a

[[Page 38540]]

LOAEL at 50,000 ppm, at which the test animals had a lower serum 
potassium level than untreated animal.
    5. Chronic toxicity. Chronic toxicity studies have been conducted 
in dogs and rats:
    i. Dog. Fosetyl-Al was fed to dogs for 2-years at concentrations of 
0, 10,000, 20,000, and 40,000 ppm. The NOAEL was 10,000 ppm, equivalent 
to 250 mg/kg/day. The LOAEL was 20,000 ppm based on a slight 
degenerative effect on the testes. These testicular changes, as well as 
a few scattered clinical changes, were seen in the high dose dogs. No 
effects were observed in the urinary tract.
    ii. Rat. Fosetyl-Al was administered via admixture in the diet to 
CD rats at target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for 
approximately 2-years. Based on these levels, respective doses were 
100, 400 and 2,000/1,500 mg/kg/day. After 2-weeks at 40,000 ppm, this 
dietary level was reduced to 30,000 ppm due to the occurrence of red 
coloration of the urine and a decrease in body weight gain. Although 
these findings were no longer apparent after week 2, analytical 
verification of dietary levels revealed that the highest dietary level 
ranged from approximately 38,000 to 61,000 ppm during the first 32-
weeks of the study. No significant differences in body weight or food 
consumption were noted at 2,000 or 8,000 ppm. No biologically 
significant differences were observed in ophthalmoscopy, hematology, 
clinical chemistry, or urinalysis for treated and control animals. 
Calculi in the urinary bladder were observed for several male and 
female rats in the high dose group. Non-neoplastic findings consisted 
of epithelial hyperplasia and inflammation in the urinary bladders of 
males at 30,000/40,000 ppm. Increased incidences of hydronephrosis, 
inflammation, and epithelial hyperplasia in the kidney were also 
observed in males from the high dose group. Females from the same group 
exhibited increased incidences of epithelial hyperplasia in the urinary 
bladder and hydronephrosis in the kidney. The NOAEL in the chronic rat 
study was 8,000 ppm (400 mg/kg/day).
    The lowest NOAEL for chronic effects of fosetyl-Al is 10,000 ppm 
(250 mg/kg/day) based on the dog study. This NOAEL is based on minor 
changes at 20,000 ppm. In the rat, calculi in the urinary bladder and 
related histopathological changes in the bladder and kidneys of males 
and females were observed at 30,000/40,000 ppm.
    6. Carcinogenicity. Long-term feeding studies were conducted with 
technical grade fosetyl-Al in mice and rats and with monosodium 
phosphite, the primary urinary metabolite of fosetyl-Al, in rats. These 
studies, in addition to a mechanistic study in rats, are described 
below:
    i. Rat. Fosetyl-Al was administered via admixture in the diet to CD 
rats at target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for 
approximately 2-years. After 2-weeks at 40,000 ppm, this dietary level 
was reduced to 30,000 ppm due to the occurrence of red coloration of 
the urine and a decrease in body weight gain. Although these findings 
were no longer apparent after Week 2, analytical verification of 
dietary levels revealed that the highest dietary level ranged from 
approximately 38,000 to 61,000 ppm during the first 32-weeks of the 
study. Calculi in the urinary bladder were observed for several male 
and female rats at 30,000/40,000 ppm. Microscopic examination revealed 
transitional cell carcinomas and papillomas in the urinary bladders of 
high dose males. In addition, a statistically significant increase in 
adrenal pheochromocytomas (benign and malignant combined) was observed 
in males at 8,000 and 30,000/40,000 ppm. The adrenal slides were 
independently reread by two consulting pathologists who found no 
significant dose-related increases in the incidence of 
pheochromocytomas or hyperplasia. The NOAEL for fosetyl-Al in the 
chronic rat study was 8,000 ppm. A subsequent mechanistic study in rats 
conducted with dietary levels of 8,000, 30,000 and 50,000 ppm 
demonstrated that the massive doses of 30,000 and 50,000 ppm fosetyl-Al 
alter calcium/phosphorous homeostasis resulting in severe acute renal 
injury, similar to that observed in the chronic rat study, and the 
formation of calculi in kidneys, ureters, and bladder. Under conditions 
of chronic exposure, these effects could lead to the formation of 
bladder tumors as seen in the chronic rat study. At 8,000 ppm, no 
evidence of renal injury was observed, a result consistent with the 
absence of bladder tumors. Thus, the bladder tumors induced by fosetyl-
Al were the result of acute renal injury followed by a chronic toxic 
reaction rather than a true carcinogenic effect.
    A carcinogenicity study in rats was conducted with monosodium 
phosphite administered via dietary mixture at levels of 2,000, 8,000, 
and 32,000 ppm. No evidence of carcinogenicity was observed in this 
study.
    ii. Mouse. A 2-year feeding/carcinogenicity study was conducted in 
mice fed diets containing fosetyl-Al at 0, 2,500, 10,000, or 20,000/
30,000 ppm. The 20,000 ppm dose was increased to 30,000 ppm during week 
19 of the study. The NOAEL for all effects was 20,000/30,000 ppm 
(3,000/4,500 mg/kg/day). There were no carcinogenic effects observed 
under the conditions of this study.
    7. Animal metabolism. Rat metabolism studies showed that most of 
the radiolabel rapidly appeared in exhaled carbon dioxide. There was 
also some radiolabel excreted in the urine as phosphite, along with a 
smaller amount as the unchanged parent compound. It appears that 
fosetyl-Al is essentially completely absorbed after ingestion and 
extensively hydrolyzed to carbon dioxide which is exhaled. The 
phosphite is excreted in the urine without further oxidation to 
phosphate. Aluminum does not appear to be absorbed to a significant 
extent from the gastrointestinal trac.
    8. Metabolite toxicology. There are no metabolites of toxicological 
concern. The tolerances are established for the parent only, that is 
fosetyl-Al.
    9. Endocrine disruption. No evidence of estrogenic or androgenic 
effects were noted in any study with fosetyl-Al. No adverse effects on 
mating or fertility indices and gestation, live birth, or weaning 
indices were noted in a 3-generation rat reproduction study at doses 
well above EPA's limit of 1,000 mg/kg/day. Therefore, Aventis 
CropScience concludes that fosetyl-Al does not have any effect on the 
endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. EPA has established the chronic reference dose 
(RfD) for fosetyl-Al at 2.5 mg/kg/day. This RfD is based on a NOAEL of 
250 mg/kg/day from a 2-year feeding study in dogs and the use of a 100 
fold safety factor to account for inter-species and intra-species 
differences. No appropriate endpoint attributable to a single dose 
exposure was identified in oral toxicity studies. Therefore, an acute 
RfD was not established and there is no expectation of acute risk. 
Since no dermal or systemic toxicity was seen at the limit dose 
following repeated dermal applications in the 21-day toxicity study 
using rats, no endpoint value was calculated for short-and 
intermediate-term exposure and risk. The Agency has concluded that 
fosetyl-Al is unlikely to pose a carcinogenic hazard to humans. 
Therefore, a cancer exposure and risk assessment is not appropriate.
    i. Food. For all currently registered uses of fosetyl-Al, chronic 
food exposure for various subgroups of the U.S. population was 
estimated by EPA through the use of the dietary exposure evaluation 
model (DEEM) software. The DEEM analysis evaluated the individual

[[Page 38541]]

food consumption as reported by respondents in the U. S. Department of 
Agricultural (USDA) 1989-1991 nationwide continuing surveys of food 
intake by individuals. As the risk estimate was low for even the most 
highly exposed subpopulation, no anticipated residues were used. In the 
surveys, 100% crop treated and tolerance level residues were assumed 
for all crops. The calculated potential exposure for the U.S. 
population is 0.077 mg/kg/day resulting in utilization of 3% of the 
chronic population adjusted dose (cPAD). Potential exposure for the 
most highly exposed group, children (1-6 years), is 0.157 mg/kg/day and 
corresponds to 6% of the chronic cPAD. Aventis CropScience anticipates 
that the incremental exposure resulting from the proposed use on 
cranberries will be minimal and that dietary exposure for the proposed 
tolerance in addition to all existing tolerances for fosetyl-Al will be 
well below the Agency's level of concern.
    ii. Drinking water. There is no established maximum contaminant 
level (MCL) or health advisory level for fosetyl-Al. The potential for 
ground water and/or surface water contamination by fosetyl-Al and its 
degradates is expected to be very low, in most cases, due to the rapid 
degradation of the compound in soil to non-toxic degradates under both 
aerobic and anaerobic conditions. Under aerobic laboratory conditions, 
the half-life of fosetyl-Al is between 1 and 1.5 hours in loamy sand, 
silt loam and clay loam and 20 minutes in sandy loam soil. The 
degradation proceeds through the hydrolysis of the ethyl ester bond, 
resulting in the formation of phosphorous acid and ethanol. The ethanol 
is further degraded into carbon dioxide. Based on the short half-life 
of fosetyl-Al and the known fate of phosphates under anaerobic 
conditions, EPA determined that an anaerobic soil metabolism study was 
not necessary. An anaerobic aquatic soil metabolism study was 
conducted. When anaerobic conditions were established by flooding soil, 
the half-life was 40 hours with silty clay loam and 14 hours with sandy 
loam soil. Aventis CropScience expects that potential fosetyl-Al 
residues in drinking water are not a significant contribution to 
aggregate exposure.
    2. Non-dietary exposure. Fosetyl-Al is currently registered for 
residential use on turf and ornamental plants. Chronic exposure is not 
expected for residential uses. There is also no expectation of acute 
risk. No appropriate endpoint attributable to a single dose exposure 
was identified in oral toxicity studies and consequently, an acute RfD 
cannot be calculated. No endpoint value is calculable for short-term 
and intermediate-term exposure and a risk analysis cannot be performed 
since no dermal or systemic toxicity was seen at the limit dose 
following repeated dermal applications in the 21-day toxicity study 
using rats. The Agency has previously concluded that fosetyl-Al is 
unlikely to pose a carcinogenic hazard to humans. Therefore, a cancer 
exposure and risk assessment is not appropriate. Thus, Aventis 
CropScience concludes that the ornamental and turf uses do not add 
significantly to the aggregate exposure for fosetyl-Al.

D. Cumulative Effects

    Effects associated with fosetyl-Al are unlikely to be cumulative 
with any other compound. The formation of calculi and bladder tumors in 
rats are the only significant toxicological effects observed with 
fosetyl-Al. These effects were observed in the rat only at a dose 
which, not only exceeds estimated human exposure by several orders of 
magnitude, but is in excess of EPA's dose limit for carcinogenicity 
studies. Therefore, an aggregate assessment based on common mechanisms 
of toxicity is not appropriate as exposure to humans will be well below 
the levels producing calculi and bladder tumors in rats. Further, 
considering the rapid elimination of fosetyl-Al in the rat metabolism 
study, any effects associated with fosetyl-Al are unlikely to be 
cumulative with any other compound. Based on these reasons, only the 
potential risks of fosetyl-Al are considered in the exposure 
assessment.

E. Safety Determination

    1. U.S. population. Chronic risk estimates associated with exposure 
to fosetyl-Al in food and water are expected to be well below the 
Agency's level of concern. The DEEM chronic exposure analysis 
previously performed by the Agency for all currently registered food 
uses showed that the U.S. general population, 3% of the cPAD is 
occupied by dietary (food) exposure. For the most highly exposed 
subgroup, children 1-6 years old, 6% of the cPAD is occupied by dietary 
(food) exposure. The contribution of fosetyl-Al residues in surface and 
ground water to chronic aggregate exposure is expected to be minimal. 
The incremental exposure resulting from the proposed use on cranberries 
is also expected to be negligible. Therefore, Aventis CropScience 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to fosetyl-Al residues.
    2. Infants and children. No indication of increased susceptibility 
of rat or rabbit fetuses to in utero and/or postnatal exposure was 
noted in the developmental and reproductive toxicity studies. The 
Agency has previously determined that no additional safety factor to 
protect infants and children is necessary for this product.
    Using the conservative assumptions described in the exposure 
section above (unit II.C.), aggregate exposure to fosetyl-Al from 
currently registered food uses will utilize up to 6% of the cPAD for 
infants and children. The incremental exposure to fosetyl-Al resulting 
from the proposed use on cranberries is expected to be minimal and even 
when considered in addition to the potential for exposure to residues 
in drinking water and from non-dietary, non-occupational exposure, the 
aggregate exposure to fosetyl-Al is not expected to exceed 100% of the 
cPAD. Aventis CropScience concludes that there is a reasonable 
certainty that no harm will result to infants and children from 
aggregate exposure to fosetyl-Al residues.

F. International Tolerances

    There are presently no Codex alimentarius commission maximum 
residue levels established for residues of fosetyl-Al.

III. Interregional Research Project Number 4

8E5012

    EPA has received a pesticide petition 8E5012 from the Interregional 
Research Project Number 4 (IR-4), New Jersey Agricultural Experiment 
Station, P.O. Box 231 Rutgers University, New Brunswick, NJ 08903 
proposing, pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of cyprodinil in or on the raw 
agricultural commodities dry bulb onion, green onion, and strawberries 
at 0.6, 4.0, and 5.0 parts per million (ppm).

A. Residue Chemistry

    1. Plant metabolism. Novartis believes the metabolism of cyprodinil 
has been well characterized in plants. The metabolism profile supports 
the use of an analytical enforcement method that accounts for only 
parent cyprodinil.
    2. Analytical method. Analytical method AG-631A is a practical 
analytical method involving extraction, filtration, and solid phase 
cleanup of samples with analysis by high performance liquid 
chromotography

[[Page 38542]]

(HPLC) and ultra-violet ray (UV). The limits of quantitation (LOQ) for 
various commodities are as follows: fruit, grain, juice-0.02 ppm; 
forage, fodder, straw-0.05 ppm; and grapes-0.01 ppm.
    3. Magnitude of residues. This petition is supported by field 
trials conducted on representative members of the bulb vegetable crop 
grouping and strawberries. All samples were analyzed by residue method 
AG-631A to determine the residues of cyprodinil. In bulb vegetables, 
the maximum residue found on representative commodities were 3.9 ppm 
and 2.7 ppm, for green onion and bulb onion, respectively. The maximum 
residue found in strawberries was 3.3 ppm. A tolerance of 5.0 ppm for 
strawberries has been proposed.

B. Toxicological Profile

    Cyprodinil appears to pose relatively little human toxicity risk 
due to low use rate, low risk to groundwater, low dietary risk and low 
worker exposure. The risk from acute dietary exposure to cyprodinil is 
considered to be very low. The mammalian toxicity studies that have 
been conducted to support the tolerances of cyprodinil are listed 
below.
    1. Acute toxicity. The following are results from the acute 
toxicity tests conducted on the technical material:
    i. A rat acute oral study for cyprodinil with a LD<INF>50</INF> of 
2,796 milligrams/kilograms(mg/kg).
    ii. A rat acute dermal study for cyprodinil with a LD<INF>50</INF> 
> 2,000 mg/kg.
    iii. A rat inhalation study for cyprodinil with a LC<INF>50</INF> > 
1.2 mg/liter air.
    iv. A primary eye irritation study in rabbits showing cyprodinil as 
minimally irritating.
    v. A primary dermal irritation study in rabbits showing cyprodinil 
as slightly irritating.
    vi. A skin sensitization study in guinea pigs showing cyprodinil as 
a weak sensitizer.
    2. Genotoxicity. The following are results from the genotoxicity 
test:
    i. In vitro gene mutation test. Ames assay-negative; chinese 
hamster V79 cell test-negative; rat hepatocyte DNA repair test-
negative.
    ii. In vitro chromosome test. Chinese hamster ovary cell 
cytogenetic test-negative.
    iii. In vivo mutagenicity test. Mouse bone marrow test-negative.
    3. Reproductive and developmental toxicity. Cyprodinil is not a 
reproductive or developmental hazard, as is demonstrated by the results 
of the following studies:
    i. Rat oral developmental. An oral developmental study in the rat 
with a maternal no observed adverse effect level (NOAEL) of 200 mg/kg 
based on reductions in body weight gain and food consumption and a 
fetal NOAEL of 200 mg/kg based on decreased pup weight and delayed 
skeletal growth at 1,000 mg/kg.
    ii. Rabbit oral developmental study. An oral developmental study in 
the rabbit with a maternal NOAEL of 150 mg/kg based on reduction in 
body weight gain and a fetal NOAEL of 400 mg/kg based on the absence of 
any fetal effects.
    iii. Rat 2-generation reproduction study. A 2-generation 
reproduction study in the rat with a systemic NOAEL of 100 ppm and a 
fetal NOAEL of 1,000 ppm (100 mg/kg). A slight decrease in pup weight 
at birth and subsequent body weight gain during the lactation phase was 
observed only at the maternally toxic dose of 4,000 ppm without any 
effects on reproduction and fertility.
    4. Subchronic toxicity. These tests are summarized below:
    i. A 28-day dermal study in the rat with a NOAEL of 5 mg/kg based 
on clinical signs.
    ii. A 90-day feeding study in the dog with a NOAEL of 1,500 ppm 
(37.5 mg/kg) based on reduced food intake and body weight.
    iii. A 90-day feeding study in the mouse with a NOAEL of 500 ppm 
(75 mg/kg) based on liver histologic changes.
    iv. A 90-day feeding study in the rat with a NOAEL of 50 ppm (5 mg/
kg) based on hematologic and histologic findings.
    5. Chronic toxicity. The reference dose (RfD) for cyprodinil is 
0.0375 mg/kg/day. This value is based on the systemic NOAEL of 3.75 mg/
kg/day in the rat chronic feeding study with a 100-fold safety factor 
to account for interspecies extrapolation and intraspecies variability.
    i. A 12-month feeding study in the dog with a NOAEL of 2,500 ppm 
(62.5 mg/kg) based on liver histologic changes.
    ii. An 18-month carcinogenicity feeding study in the mouse with a 
NOAEL of 2,000 ppm (300 mg/kg). The maximum tolerated dose (MTD) was 
5,000 ppm based on reduction in body weight gain and no evidence of 
carcinogenicity was seen.
    iii. A 24-month chronic feeding/carcinogenicity study in the rat 
with a NOAEL of 75 ppm (3.75 mg/kg) based on hematologic and histologic 
findings. The MTD was 2,000 ppm based on liver histopathology and no 
evidence of carcinogenicity was seen.
    6. Animal metabolism. Ruminant metabolism shows extensive 
degradation following a pathway that is similar to plants. 
Extrapolating from goat studies, none of the metabolites, including 
parent compound, will be near the normal minimum range for detection by 
analytical methods (0.01 to 0.05 ppm). Therefore, parent residues will 
be proposed as an adequate marker for total residues of cyprodinil in 
animals. The analysis also demonstrates that livestock tolerances are 
not required in conjunction with this petition.
    7. Endocrine disruption. Cyprodinil does not belong to a class of 
chemicals known or suspected of having adverse effects on the endocrine 
system. Developmental toxicity studies in rats and rabbits and a 
reproduction study in rats gave no indication that cyprodinil might 
have any effects on endocrine function related to development and 
reproduction. The chronic studies also showed no evidence of a long-
term effect related to the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. For the purposes of assessing the 
potential dietary exposure under the proposed tolerances, Novartis has 
estimated aggregate exposure from the previously established tolerances 
for the raw agricultural commodities: almond nutmeat at 0.02 (ppm), 
almond hulls at 0.05 ppm, grapes at 2.0 ppm, raisins at 3.0 ppm, pome 
fruit crops at 0.1 ppm, wet apple pomace at 0.15 ppm, and stone fruit 
crops at 2.0 ppm; and the requested tolerances of strawberries at 5.0 
ppm, dry bulb onion at 0.6 ppm, and green onion at 4.0 ppm. The tier 1 
chronic cyprodinil assessment displayed below used tolerance values 
listed in 40 CFR 180.532 for all commodities; 100% market share was 
assumed for all crops. Results of the cyprodinil assessment are 
displayed below as a percentage of the chronic RfD.

------------------------------------------------------------------------
                Population                           Chronic RfD
------------------------------------------------------------------------
U.S. Population...........................  11.5%
All infants ( 1 year).....................  24.6%
Nursing infants ( 1 year).................  10.7%
Non-nursing infants ( 1 year).............  28.6%
Children (1-6 years)......................  31.1%
Children (7-12 years).....................  13.5%
------------------------------------------------------------------------

    ii. Drinking water. The potential for exposure to cyprodinil 
through drinking water (surface or ground water) is slight due to the 
minimal level of this chemical anticipated to reach these

[[Page 38543]]

bodies of water. This expectation is based on the rapid degradation of 
cyprodinil and the recommended low use rates that will further restrict 
the amount of chemical available for leaching or run-off.
    2. Non-dietary exposure. Novartis believes that the potential for 
non-occupational exposure to the general public is unlikely except for 
potential residues in food crops discussed above. The proposed uses for 
cyprodinil are for agricultural crops and the product is not used 
residentially in or around the home.

D. Cumulative Effects

    Consideration of a common mechanism of toxicity is not appropriate 
at this time since there is no information to indicate that toxic 
effects produced by cyprodinil would be cumulative with those of any 
other chemicals. Consequently, only the potential exposure to 
cyprodinil is considered in this risk assessment.

E. Safety Determination

    1. U.S. population. For the U.S. population (48 contiguous states) 
chronic exposure was 11% of the RfD. EPA usually 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. Novartis concludes that 
there is a reasonable certainty that no harm will result from aggregate 
exposure to cyprodinil.
    2. Infants and children. Maximum expected chronic exposure to 
cyprodinil in the diets of the most sensitive sub-populations, for non-
nursing infants (1-year old) and 31.1% of the RfD for childern (1-6 
years old) was calculated to be 28.6% of the RfD.

F. International Tolerances

    Codex maximum residue levels (MRLs) have not been established for 
residues.
[FR Doc. 00-15161 Filed 6-20-00; 8:45 am]
BILLING CODE 6560-50-F


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