[Federal Register Volume 66, Number 53 (Monday, March 19, 2001)]
[Notices]
[Pages 15459-15468]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-6731]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-999; FRL-6766-8]


Notice of Filing Pesticide Petitions to Establish a Tolerance for 
Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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

DATES: Comments, identified by docket control number PF-999, must be 
received on or before April 18, 2001.

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-999 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

[[Page 15460]]



 
------------------------------------------------------------------------
                               Office location/
       Product Manager         telephone number/    Petition(s) number
                                e-mail address
------------------------------------------------------------------------
Shaja Brothers                 Registration           PP 0E6183, 0E6083,
                                Division                          0E6175
                                (7505C), Office
                                of Pesticide
                                Programs,
                                Environmental
                                Protection
                                Agency, Ariel
                                Rios Bldg.,
                                1200
                                Pennsylvania
                                Ave.,
                                NW.,Washington,
                                DC 20460;
                                telephone
                                number: (703)
                                308-3194; and e-
                                mail address:
                                [email protected]
                                ..
Joseph Tavano                  Registration                    PP 0F6220
                                Division
                                (7505C), Office
                                of Pesticide
                                Programs,
                                Environmental
                                Protection
                                Agency, Ariel
                                Rios Bldg.,
                                1200
                                Pennsylvania
                                Ave.,
                                NW.,Washington,
                                DC 20460;
                                telephone
                                number: (703)
                                305-6411; and e-
                                mail address:
                                [email protected]..
------------------------------------------------------------------------


SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

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

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

    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed 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-999. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-999 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: [email protected], 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-999. 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

[[Page 15461]]

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

II. What Action is the Agency Taking?

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

List of Subjects

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

    Dated: February 23, 2001.
 Peter Caulkins,
 Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required bysection 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. Valent U.S.A. Corporation

0F6220

    EPA has received a pesticide petition (OF6220) from Valent U.S.A. 
Corporation, 1333 North California Street, Suite 600, Walnut Creek, CA 
945968025 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 pyriproxyfen, 2-[1-
methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine in or on the raw 
agricultural commodity stone fruit at 1.0 parts per million (ppm). EPA 
has determined that the petition contains data or information regarding 
the elements set forth in section 408(d)(2) of the FFDCA; however, EPA 
has not fully evaluated the sufficiency of the submitted data at this 
time or whether the data supports granting of the petition. Additional 
data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. Metabolism of \14\C-pyriproxyfen labelled in 
the phenoxyphenyl ring and in the pyridyl ring has been studied in 
cotton, apples, tomatoes, lactating goats, and laying hens (and rats). 
The major metabolic pathways in plants is aryl hydroxylation and 
cleavage of the ether linkage, followed by further metabolism into more 
polar products by further oxidation and/or conjugation reactions. 
However, the bulk of the radiochemical residue on RAC samples remained 
as parent. Comparing metabolites detected and quantified from cotton, 
apple, tomato, goat and hen (and rat) shows that there are no 
significant aglycones in plants which are not also present in the 
excreta or tissues of animals. The residue of concern is best defined 
as the parent, pyriproxyfen. Ruminant and poultry metabolism studies 
demonstrated that transfer of administered 14C-residues to 
tissues was low. Total 14C-residues in goat milk, muscle and 
tissues accounted for less than 2% of the administered dose, and were 
less than 1 ppm in all cases. In poultry, total 14C-residues 
in eggs, muscle and tissues accounted for about 2.7% of the 
administered dose, and were less than 1 ppm in all cases except for 
gizzard.
     2.  Analytical method. Practical analytical methods for detecting 
and measuring residue levels of pyriproxyfen (and relevant metabolites) 
have been developed and validated in/on all appropriate agricultural 
commodities, respective processing fractions, milk, animal tissues, and 
environmental samples. The extraction methodology has been validated 
using aged radiochemical residue samples from metabolism studies. The 
methods have been validated in cottonseed, apples, soil, and oranges at 
independent laboratories. EPA has successfully validated the analytical 
method for analysis of cottonseed raw agricultural commodity. The limit 
of detection of pyriproxyfen in the methods is 0.01 ppm which will 
allow monitoring of food with residues at the levels proposed for the 
tolerances.
    3. Magnitude of residues--stone fruit. Seven field trials in 
cherries were conducted in 1998 through 1999. Similarly, 10 field 
trials were conducted for peaches, and 7 field trials were conducted 
for plums. The proposed use pattern for the three stone fruit crops is 
identical. The analytical data show that the average measured residue 
in/on cherry samples was 0.33 ppm (n = 14, n-1 = 
0.20 ppm) pyriproxyfen. Similarly, the analytical data show that the 
average measured residue in/on peach samples was 0.16 ppm (n = 20, 
n-1 = 0.06 ppm), and in/on plum samples was 0.06 
ppm (n = 14,  n-1 = 0.06 ppm), of pyriproxyfen. A 
processing study in prunes demonstrated that pyriproxyfen concentrated 
in prunes (2.9-fold). The highest average residue (HAR) from field 
trials was 0.20 ppm. All these data support proposed tolerances for 
pyriproxyfen in/on stone fruit crop group at 1.0 ppm and no processed 
commodity tolerance is necessary.
     i.  Secondary residues. Using proposed tolerances to calculate the 
maximum feed exposure to fed animals, and using the very low potential 
for residue transfer documented in the milk cow feeding residue study, 
finite, detectable secondary residues in animal tissues, milk, and eggs 
are not expected. Therefore, tolerances are not proposed for these 
commodities.
     ii.  Rotational crops. The results of a confined rotational crops 
accumulation study indicate that no rotational crop planting 
restrictions or rotational crop tolerances are required.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of technical grade 
pyriproxyfen is low by all routes. The compound is classified as 
Category III for acute dermal and inhalation toxicity, and Category IV 
for acute oral toxicity, and skin/eye irritation. Pyriproxyfen is not a 
skin sensitizing agent.
    2. Genotoxicty. Pyriproxyfen does not present a genetic hazard. 
Pyriproxyfen was negative in the following tests for mutagenicity: Ames 
assay with and

[[Page 15462]]

without S9, in vitro unscheduled DNA synthesis in HeLa S3 cells, in 
vitro gene mutation in V79 Chinese hamster cells, and in vitro 
chromosomal aberration with and without S9 in Chinese hamster ovary 
cells.
    3. Reproductive and developmental toxicity. Pyriproxyfen is not a 
developmental or reproductive toxicant. Developmental toxicity studies 
have been performed in rats and rabbits, and multigenerational effects 
on reproduction were tested in rats. These studies have been reviewed 
and found to be acceptable to the Agency.
     In the developmental toxicity study conducted with rats, technical 
pyriproxyfen was administered by gavage at levels of 0, 100, 300, and 
1,000 milligrams/kilogram of body weight/day (mg/kg bw/day) during 
gestation days 7-17. Maternal toxicity (mortality, decreased body 
weight gain and food consumption, and clinical signs of toxicity) was 
observed at doses of 300 mg/kg bw/day and greater. The maternal NOAEL 
was 100 mg/kg bw/day. A transient increase in skeletal variations was 
observed in rat fetuses from females exposed to 300 mg/kg bw/day and 
greater. These effects were not present in animals examined at the end 
of the postnatal period, therefore, the NOAEL for prenatal 
developmental toxicity was 100 mg/kg bw/day. An increased incidence of 
visceral and skeletal variations was observed postnatally at 1,000 mg/
kg bw/day. The NOAEL for postnatal developmental toxicity was 300 mg/kg 
bw/day.
     In the developmental toxicity study conducted with rabbits, 
technical pyriproxyfen was administered by gavage at levels of 0, 100, 
300, and 1,000 mg/kg bw/day during gestation days 6-18. Maternal 
toxicity (clinical signs of toxicity including one death, decreased 
body weight gain and food consumption, and abortions or premature 
deliveries) was observed at oral doses of 300 mg/kg bw/day or higher. 
The maternal NOAEL was 100 mg/kg bw/day. No developmental effects were 
observed in the rabbit fetuses. The NOAEL for developmental toxicity in 
rabbits was 1,000 mg/kg bw/day.
     In the rat reproduction study, pyriproxyfen was administered in 
the diet at levels of 0, 200, 1,000, and 5,000 ppm through 2 
generations of rats. Adult systemic toxicity (reduced body weights, 
liver and kidney histopathology, and increased liver weight) was 
produced at the 5,000 ppm dose (453 mg/kg bw/day in males, 498 mg/kg 
bw/day in females) during the pre-mating period. The systemic NOAEL was 
1,000 ppm (87 mg/kg bw/day in males, 96 mg/kg bw/day in females). No 
effects on reproduction were produced at 5,000 ppm, the highest dose 
tested.
    4. Subchronic toxicity. Subchronic oral toxicity studies conducted 
with pyriproxyfen technical in the rat, mouse and dog indicate a low 
level of toxicity. Effects observed at high dose levels consisted 
primarily of decreased body weight gain; increased liver weights; 
histopathological changes in the liver and kidney; decreased red blood 
cell counts, hemoglobin and hematocrit; altered blood chemistry 
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in 
survival rates. The NOAELs from these studies were 400 ppm (23.5 mg/kg 
bw/day for males, 27.7 mg/kg bw/day for females) in rats, 1,000 ppm 
(149.4 mg/kg bw/day for males, 196.5 mg/kg bw/day for females) in mice, 
and 100 mg/kg bw/day in dogs.
     In a 4-week inhalation study of pyriproxyfen technical in rats, 
decreased body weight and increased water consumption were observed at 
1,000 mg/m3. The NOAEL in this study was 482 mg/
m3.
     A 21-day dermal toxicity study in rats with pyriproxyfen technical 
did not produce any signs of dermal or systemic toxicity at 1,000 mg/kg 
bw/day, the highest dose tested (HDT). In a 21-day dermal study 
conducted with KNACK. Insect Growth Regulator the test 
material produced a NOAEL of 1,000 mg/kg bw/day (HDT) for systemic 
effects, and a NOAEL for skin irritation of 100 mg/kg bw/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in 
chronic studies with dogs, rats and mice. EPA has established a 
reference dose (RfD) for pyriproxyfen of 0.35 mg/kg bw/day, based on 
the NOAEL in female rats from the 2-year chronic/oncogenicity study. 
Effects cited by EPA in the Reference Dose Tracking Report include 
negative trend in mean red blood cell volume, increased hepatocyte 
cytoplasm and cytoplasm: nucleus ratios, and decreased sinusoidal 
spaces.
     Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen have 
shown that repeated high dose exposures produced changes in the liver, 
kidney and red blood cells, but did not produce cancer in test animals. 
No oncogenic response was observed in a rat 2-year chronic feeding/
oncogenicity study or in a 78 week study on mice. The oncogenicity 
classification of pyriproxyfen is ``E'' (no evidence of carcinogenicity 
for humans).
     Pyriproxyfen technical was administered to dogs in capsules at 
doses of 0, 30, 100, 300 and 1,000 mg/kg bw/day for 1-year. Dogs 
exposed to dose levels of 300 mg/kg bw/day or higher showed overt 
clinical signs of toxicity, elevated levels of blood enzymes and liver 
damage. The NOAEL in this study was 100 mg/kg bw/day.
     Pyriproxyfen technical was administered to mice at doses of 0, 
120, 600 and 3,000 ppm in diet for 78 weeks. The NOAEL for systemic 
effects in this study was 600 ppm (84 mg/kg bw/day in males, 109.5 mg/
kg bw/day in females), and a LOAEL of 3,000 ppm (420 mg/kg bw/day in 
males, 547 mg/kg bw/day in females) was established based on an 
increase in kidney lesions.
     In a 2-year study in rats, pyriproxyfen technical was administered 
in the diet at levels of 0, 120, 600, and 3,000 ppm. The NOAEL for 
systemic effects in this study was 600 ppm (27.31 mg/kg bw/day in 
males, 35.1 mg/kg bw/day in females). A LOAEL of 3,000 ppm (138 mg/kg 
bw/day in males, 182.7 mg/kg bw/day in females) was established based 
on a depression in body weight gain in females.
    6. Animal metabolism. The absorption, tissue distribution, 
metabolism and excretion of 14C-labeled pyriproxyfen were 
studied in rats after single oral doses of 2 or 1,000 mg/kg bw 
(phenoxyphenyl and pyridyl label), and after a single oral dose of 2 
mg/kg bw (phenoxyphenyl label only) following 14 daily oral doses at 2 
mg/kg bw of unlabelled material. For all dose groups, most (88-96%) of 
the administered radiolabel was excreted in the urine and feces within 
2 days after radiolabeled test material dosing, and 92-98% of the 
administered dose was excreted within 7 days. Seven days after dosing, 
tissue residues were generally low, accounting for no more than 0.3% of 
the dosed \14\C. Radiocarbon concentrations in fat were higher than in 
other tissues analyzed. Recovery in tissues over time indicates that 
the potential for bioaccumulation is minimal. There were no significant 
sex or dose-related differences in excretion or metabolism.
    7. Metabolite toxicology. Metabolism studies of pyriproxyfen in 
rats, goats and hens, as well as the fish bioaccumulation study 
demonstrate that the parent is very rapidly metabolized and eliminated. 
In the rat, most (88-96%) of the administered radiolabel was excreted 
in the urine and feces within 2 days of dosing, and 92-98% of the 
administered dose was excreted within 7 days. Tissue residues were low 
7 days after dosing, accounting for no more than 0.3% of the dosed 
\14\C. Because parent and metabolites are not retained in the body, the 
potential for acute toxicity from in situ, formed metabolites is low. 
The potential for chronic toxicity is adequately tested by chronic 
exposure

[[Page 15463]]

to the parent at the MTD and consequent chronic exposure to the 
internally formed metabolites.
     Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, PYPAC, 2-OH-pyridine and 
2,5-diOH-pyridine, have been tested for mutagenicity (Ames) and acute 
oral toxicity to mice. All seven metabolites were tested in the Ames 
assay with and without S9 at doses up to 5,000 micro-grams per plate or 
up to the growth inhibitory dose. The metabolites did not induce any 
significant increases in revertant colonies in any of the test strains. 
Positive control chemicals showed marked increases in revertant 
colonies. The acute toxicity to mice of 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to 
markedly differ from pyriproxyfen, with all metabolites having acute 
oral LD50 values greater than 2,000 mg/kg bw. The two 
pyridines, 2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral 
LD50 values of 124 (male) and 166 (female) mg/kg bw, and 
1,105 (male) and 1,000 (female) mg/kg bw, respectively.
    8. Endocrine disruption. Pyriproxyfen is specifically designed to 
be an insect growth regulator and is known to produce juvenoid effects 
on arthropod development. However, this mechanism-of-action in target 
insects and other arthropods has no relevance to any mammalian 
endocrine system. While specific tests, uniquely designed to evaluate 
the potential effects of pyriproxyfen on mammalian endocrine systems 
have not been conducted, the toxicology of pyriproxyfen has been 
extensively evaluated in acute, sub-chronic, chronic, developmental, 
and reproductive toxicology studies including detailed histopathology 
of numerous tissues. The results of these studies show no evidence of 
any endocrine-mediated effects and no pathology of the endocrine 
organs. Consequently, it is concluded that pyriproxyfen does not 
possess estrogenic or endocrine disrupting properties applicable to 
mammals.

C. Aggregate Exposure

    1. Dietary exposure. An evaluation of chronic dietary exposure to 
include drinking water has been performed for the U.S. population and 
various sub-populations including infants and children. Because no 
acute dietary endpoint was determined, the Agency concludes that there 
is a reasonable certainty of no harm from acute exposure from drinking 
water.
    i. Food. a. Chronic dietary exposure to pyriproxyfen residues was 
calculated for the U.S. population and 26 population subgroups assuming 
tolerance level residues and 100% of the crop treated. The results from 
several representative subgroups are listed in the table below. Chronic 
dietary exposure was at or below 0.705% of the reference dose, with 
stone fruit commodities contributing the most to chronic exposure. 
Generally speaking, the Agency has no cause for concern if total 
residue contribution for published and proposed tolerances is less than 
100% of the RfD.

Tier I Calculated Chronic Dietary Exposures to the Total U.S. Population
      and Selected Sub-Populations to Pyriproxyfen Residues in Food
------------------------------------------------------------------------
                                              Exposure (mg/   Percent of
            Population Subgroup                kg bw/day)        RfD
------------------------------------------------------------------------
Total U.S. Population (all seasons)                0.000535        0.153
Females (13+/Nursing)                              0.000597        0.171
Females (20+ years, not preg. or nursing)          0.000415        0.119
Children (1-6 Years)                               0.001381        0.395
All Infants (<1 Year Old)                          0.002156        0.616
Non-Nursing Infants (<1 Year Old)                  0.002467        0.705
Nursing Infants (<1 Year Old)                      0.001096        0.313
------------------------------------------------------------------------

     b. Acute dietary risk assessments are performed for a food use 
pesticide if a toxicological study has indicated the possibility of an 
effect of concern occurring as the result of a one day or single 
exposure. No acute dietary endpoint and dose was identified in the 
toxicology database for pyriproxyfen, therefore the Agency has 
concluded that there is a reasonable certainty of no harm from acute 
dietary exposure.
    ii. Drinking water. Since pyriproxyfen is applied outdoors to 
growing agricultural crops, the potential exists for pyriproxyfen or 
its metabolites to reach ground or surface water that may be used for 
drinking water. Because of the physical properties of pyriproxyfen, it 
is unlikely that pyriproxyfen or its metabolites can leach to potable 
groundwater. To quantify potential exposure from drinking water, 
surface water concentrations for pyriproxyfen were estimated using 
GENEEC 1.3. The average 56-day concentration predicted in the simulated 
pond water was 0.16 ppb. Using standard assumptions about body weight 
and water consumption, the chronic exposure to pyriproxyfen from this 
drinking water would be 4.57 x 10-\6\ and 1.6 x 
10-\5\ mg/kg bw/day for adults and children, respectively; 
0.0046 percent of the RfD (0.35 mg/Kg/day) for children. Based on this 
worse case analysis, the contribution of water to the dietary risk is 
negligible.
    2. Non-dietary exposure. Pyriproxyfen is the active ingredient in 
numerous registered products for household use -- primarily for indoor, 
non-food applications by consumers. The consumer uses of pyriproxyfen 
typically do not involve chronic exposure. Instead, consumers are 
exposed intermittently to a particular product (e.g., pet care pump 
spray) containing pyriproxyfen. Since pyriproxyfen has a relatively 
short elimination half-life, cumulative toxicological effects resulting 
from bioaccumulation are not plausible following short-term, 
intermittent exposures. Further, pyriproxyfen is short-lived in the 
environment and this indoor domestic use of pyriproxyfen provides only 
relatively short-term reservoirs. Thus, consumer use of these products 
results in acute- and short-term intermittent exposures.
     No acute dermal, or inhalation dose or endpoint was identified in 
the toxicity data for pyriproxyfen. Similarly, doses and endpoints were 
not identified for short- and intermediate-term dermal or inhalation 
exposure to pyriproxyfen. The Agency has concluded that there are 
reasonable certainties of no harm from acute-, short-term, and 
intermediate-term dermal and inhalation occupational and residential 
exposures due to the lack of significant toxicological effects 
observed. Thus, no detailed exposure and risk analyses for non-dietary 
exposures to pyriproxyfen are necessary.

[[Page 15464]]

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that the Agency must consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' Available information in this context 
include not only toxicity, chemistry, and exposure data, but also 
scientific policies and methodologies for understanding common 
mechanisms of toxicity and conducting cumulative risk assessments. For 
most pesticides, although the Agency has some information in its files 
that may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way.
     There are no other pesticidal compounds that are structurally 
related to pyriproxyfen and have similar effects on animals. In 
consideration of potential cumulative effects of pyriproxyfen and other 
substances that may have a common mechanism of toxicity, there are 
currently no available data or other reliable information indicating 
that any toxic effects produced by pyriproxyfen would be cumulative 
with those of other chemical compounds. Thus, only the potential risks 
of pyriproxyfen have been considered in this assessment of aggregate 
exposure and effects.
     Valent will submit information for EPA to consider concerning 
potential cumulative effects of pyriproxyfen consistent with the 
schedule established by EPA at 62 FR 42020 (Aug. 4, 1997) (FRL-5734-6) 
and other subsequent EPA publications pursuant to the Food Quality 
Protection Act.

E. Safety Determination

    1. U.S. population--i. chronic dietary exposure and risk --adult 
sub-populations. Using the Tier I dietary exposure assessment 
procedures described above for pyriproxyfen, calculated chronic dietary 
exposure resulting from residue exposure from existing and proposed 
uses of pyriproxyfen is minimal. The estimated chronic dietary exposure 
from food for the overall U.S. population and many non-child/infant 
subgroups is from 0.000338 to 0.000652 mg/kg bw/day, 0.097 to 0.186% of 
the RfD. Addition of the small but worse case potential chronic 
exposure from drinking water (calculated above) increases exposure by 
only 4.57 x 10-\6\ mg/kg bw/day and does not change the 
maximum occupancy of the RfD significatly. Generally, the Agency has no 
cause for concern if total residue contribution is less than 100% of 
the RfD. It can be concluded that there is a reasonable certainty that 
no harm will result to the overall U.S. Population and many non-child/
infant subgroups from aggregate, chronic exposure to pyriproxyfen 
residues.
    ii. Acute dietary exposure and risk-- adult sub-populations. An 
acute dietary dose and endpoint was not identified. Thus, the risk from 
acute aggregate exposure is considered to be negligible.
    iii. Non-dietary exposure and aggregate risk--adult sub-
populations. Acute-, short-term, and intermediate-term dermal and 
inhalation risk assessments for residential exposure are not required 
due to the lack of significant toxicological effects observed.
    2. Infants and children --i. safety factor for infants and 
children. In assessing the potential for additional sensitivity of 
infants and children to residues of pyriproxyfen, FFDCA section 408 
provides that EPA shall apply an additional margin of safety, up to 10-
fold, for added protection for infants and children in the case of 
threshold effects unless EPA determines that a different margin of 
safety will be safe for infants and children.
     The toxicological database for evaluating pre- and post-natal 
toxicity for pyriproxyfen is complete with respect to current data 
requirements. There are no special pre- or post-natal toxicity concerns 
for infants and children, based on the results of the rat and rabbit 
developmental toxicity studies or the 2-generation reproductive 
toxicity study in rats. Valent concludes that reliable data support use 
of the standard 100-fold uncertainty factor and that an additional 
uncertainty factor is not needed for pyriproxyfen to be further 
protective of infants and children.
    ii. Chronic dietary exposure and risk-- infants and children. Using 
the conservative Tier I exposure assumptions described above, the 
percentage of the RfD that will be utilized by chronic dietary (food 
only) exposure to residues of pyriproxyfen ranges from 0.000714 mg/kg 
bw/day for children (7-12 years old), up to 0.002467 mg/kg bw/day for 
non-nursing infants (<1 year old), 0.204 to 0.705% of the RfD, 
respectively. Adding the worse case potential incremental exposure to 
infants and children from pyriproxyfen in drinking water (1.6 x 
10-\5\ mg/kg bw/day) does not materially increase the 
aggregate, chronic dietary exposure and only increases the occupancy of 
the RfD by 0.0046% to 0.710% for non-nursing infants (<1 year old). 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 can be concluded that there is a reasonable certainty that 
no harm will result to infants and children from aggregate, chronic 
exposure to pyriproxyfen residues.
    iii. Acute dietary exposure and risk -- infants and children. An 
acute dietary dose and endpoint was not identified. Thus, the risk from 
acute aggregate exposure is considered to be negligible.
    iv. Non-dietary exposure and aggregate risk -- infants and 
children. Acute-, short-term, and intermediate-term dermal and 
inhalation risk assessments for residential exposure are not required 
due to the lack of significant toxicological effects observed.

F. International Tolerances

     There are no presently existing Codex MRLs for pyriproxyfen.

2. Interregional Research Project Number 4 (IR-4)

0E6083 and 0E6175

    EPA has received pesticide petitions (0E6083 and 0E6175) from the 
Interregional Research Project Number 4 (IR-4), Technology Centre of 
New Jersey, 681 U.S. Highway #1 South, North Brunswick, New Jersey 
08902-3390 proposing, pursuant to section 408(d) of the Federal Food, 
Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 
180 by establishing tolerances for the combined residues of the 
herbicide, pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-2,6-
dinitrobenzenamine, and its 3,5-dinitrobenzyl alcohol metabolite (CL 
202347) in or on the following raw agricultural commodities: tree nuts 
(crop group 14) and pistachio at 0.1 parts per million (ppm), almond 
hull at 0.4 ppm, and fruiting vegetable (crop group 8) at 0.1 ppm. EPA 
has determined that the petitions contain data or information regarding 
the elements set forth in section 408(d)(2) of the FFDCA; however, EPA 
has not fully evaluated the sufficiency of the submitted data at this 
time or whether the data support granting of the petitions. Additional 
data may be needed before EPA rules on the petitions. This notice 
includes a summary of the petitions prepared by American Cyanamid 
Company, One Campus Drive, Parsippany, NJ 07054.

[[Page 15465]]

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues of 
pendimethalin in plants is understood based on adequate studies 
conducted with 14C pendimethalin on various crops. 
Pendimethalin and its 3,5-dinitrobenzyl alcohol metabolite (CL202347) 
are the residues of concern.
    2. Analytical method. Section 408 (b)(3) of the amended FFDCA 
requires EPA to determine that there is a practical method for 
detecting and measuring levels of the pesticide chemical residue in or 
on food and that the tolerance be set at a level at or above the limit 
of detection of the designated method. Gas Chromatography (GC) 
analytical methods, M691 and M692, are proposed as the enforcement 
method in tree nuts and pistachio as well as fruiting vegetables, for 
the residues of pendimethalin and the alcohol metabolite (CL 202347), 
respectively. Both methods have a limit of quantitation (LOQ) of 0.05 
ppm for pendimethalin and the alcohol metabolite.

B. Toxicological Profile

    1. Acute toxicity. The acute oral lethal dose (LD50) 
values for pendimethalin technical ranged from 1,050 to 1,250 
milligrams/kilogram(mg/kg) body weight (bw) in the rat. The acute 
dermal LD50 was greater than 5,000 mg/kg in rabbits. The 4-
hour rat inhalation lethal concentration (LC50) was >320 mg/
cubic meter (m\3\) air (aerosol). Pendimethalin was not irritating to 
rabbit skin or eyes. Pendimethalin did not cause skin sensitization in 
guinea pigs.
    2. Genotoxicity. Extensive mutagenicity studies conducted to 
investigate point and gene mutations, DNA damage and chromosomal 
aberration, both using in vitro and in vivo test systems show 
pendimethalin to be non-genotoxic.
    3. Reproductive and developmental toxicity. A 2-generation rat 
reproduction study gave a no observed adverse effect level (NOAEL) of 
2,500 ppm (172 and 216 mg/kg bw/day in males and females, respectively) 
for reproductive toxicity and a lowest observed adverse effect level 
(LOAEL) of 5,000 ppm (346 and 436 mg/kg bw/day in males and females, 
respectively). Rat and rabbit developmental toxicity studies were 
negative at doses up to 500 mg/kg/bw and 60 mg/kg bw/day, respectively.
    4. Subchronic toxicity. Ninty-day feeding studies were conducted in 
rats and dogs. The NOAELs for these tests were 500 ppm (50 mg/kg bw/
day) and 62.5 mg/kg bw/day for the rat and dog studies, respectively.
    5. Chronic toxicity. The reference dose (RfD) of 0.1 mg/kg/day was 
established based on a combination of three studies in male rats:
    i. A 56-day oral thyroid function study,
    ii. A 92-day thyroid function study; and
    iii. A 14-day intrathyroidal metabolism study.
The NOAEL was established at 10 mg/kg/day. The LOAEL of 31 mg/kg/day 
was based on thyroid hormonal changes and histologic thyroid changes. 
An Uncertainty Factor (UF) of 100 was applied to account for both 
interspecies and intraspecies variability.
    6. Carcinogenicity. Pendimethalin has been classified as a Group C, 
``possible human carcinogen'', chemical by EPA, based on a 
statistically significant increased trend and pairwise comparison 
between the high dose group and controls for thyroid follicular cell 
adenomas in male and female rats. EPA recommends using the RfD approach 
for quantification of human risk. Therefore, the RfD is deemed 
protective of all chronic human health effects, including cancer.
    7. Animal metabolism. Although not relevant to this petition, 
adequate goat and poultry metabolism studies are available for 
pendimethalin. The Agency has determined that there is no reasonable 
expectation of finite pendimethalin residues of concern in animal 
commodities as a result of use on multiple crops and no tolerances for 
pendimethalin residues of concern in livestock commodities are needed.
    8. Endocrine disruption. It is known that pendimethalin affects the 
pituitary thyroid axis. However, as the RfD (0.10 mg/kg/day) is based 
on the reversible, non-adverse hormonal and histologic thyroid changes 
observed in the subchronic studies, these effects are already taken 
into consideration in the characterization of potential risks to 
humans.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Tolerances have been established (40 
CFR 180.361) for the combined residues of pendimethalin and its 3,5-
dinitrobenzyl alcohol metabolite (CL 202347), in or on a variety of raw 
agricultural commodities at levels ranging from 0.05 ppm in rice grain 
to 0.1 ppm in corn, peanuts, soybeans and other commodities. Based on 
conservative assumptions of tolerance level residues and 100% crop 
treatment with pendimethalin, the EPA's Dietary Risk Elimination System 
(DRES) estimates chronic dietary exposure to pendimethalin from all 
currently registered uses to be only 0.00042 mg/kg/day (< 1% RfD) for 
the overall U.S. population. The estimated most highly exposed DRES 
subgroup for pendimethalin is non-nursing infants at a level of 0.00140 
mg/kg/day (<2% RfD). Thus, American Cyanamid Company believes that the 
additional dietary burdens (0.000002 mg/kg/day, 0.002% RfD for the 
general U.S. population), that will result from the proposed tolerances 
of pendimethalin in tree nuts and pistachio will be insignificant. 
Also, American Cyanamid Company believes that the additional dietary 
burdens (0.000217 mg/kg/day, 0.2% RfD for the general U.S. population 
and (0.000085 mg/kg/day, 0.1% RfD for non-nursing infants), that will 
result from the proposed tolerances of pendimethalin in fruiting 
vegetables will be insignificant.
    ii. Drinking water. Pendimethalin has low water solubility and a 
strong absorption to soil, which makes it essentially immobile in all 
soil types. Thus, there is no concern for the potential for 
pendimethalin to runoff to surface water or leach to ground water. No 
Maximum Concentration Level and no Health Advisory Level has been 
established for residues of pendimethalin in drinking water. The Agency 
has conducted a pendimethalin drinking water exposure analysis for a 10 
kg child and determined that a chronic exposure from a worse-case 
dietary intake of 0.0018 mg/kg/day would utilize < 2% of the RfD. Thus, 
American Cyanamid Company believes that contributions to the dietary 
burden from residues of pendimethalin in water would be 
inconsequential.
    2. Non-dietary exposure. Pendimethalin is currently registered for 
use on the following residential and non-food sites: Ornamental lawns, 
grasses, ground covers, turf, and ornamental plantings. The Agency has 
stated that it does not consider that these types of outdoor 
residential uses constitute a chronic residential exposure scenario. 
Although there may be short- and intermediate-term non-occupational 
exposure scenarios, American Cyanamid Company has concluded that the 
margins of exposure for residential applicators exposure (MOE 833) and 
residential post-application exposures to children (MOE 111) are more 
than adequate.

D. Cumulative Effects

    The Agency has not yet published guidelines to determine whether 
pendimethalin has a common mechanism of toxicity with other substances 
or how to include this pesticide in a cumulative risk assessment. 
Unlike other pesticides for

[[Page 15466]]

which EPA has followed a cumulative risk approach based on a common 
mechanism of toxicity, pendimethalin does not appear to produce a toxic 
metabolite produced by other substances. For the purposes of this 
tolerance action, therefore, it is assumed that pendimethalin does not 
have a common mechanism of toxicity with other substances.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and based on the completeness and reliability of the 
toxicity data, American Cyanamid Company concludes that the total 
aggregate exposure to pendimethalin from food will utilize less than 1% 
of the RfD for the overall 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. Despite the 
potential for exposure to pendimethalin in drinking water and from non-
dietary, non-occupational exposures, American Cyanamid Company does not 
expect the aggregate exposure to exceed 100% of the RfD. The additional 
dietary burden for the general U.S. population that will result from 
the proposed tolerances of pendimethalin in tree nuts and pistachio 
will be only 0.000002 mg/kg/day, 0.002% RfD. Also, the additional 
dietary burden for the general U.S. population that will result from 
the proposed tolerances of pendimethalin in fruiting vegetables will be 
only 0.000217 mg/kg/day, 0.2% RfD. Thus, American Cyanamid Company 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to pendimethalin residues as a result of the 
establishment of the proposed tolerances in tree nuts and pistachio and 
the establishment of the proposed tolerances in fruiting vegetables.
    2. Infants and children. The major identifiable subgroup with the 
highest aggregate exposure is non-nursing infants less than 1 year old. 
In assessing the potential for additional sensitivity of infants and 
children to residues of pendimethalin, the data from developmental 
toxicity studies in the rat and rabbit and a 2-generation reproduction 
study in the rat have been considered. 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. The pre- 
and post-natal toxicology database for pendimethalin is complete with 
respect to current toxicological data requirements. The database does 
not indicate a potential for increased sensitivity from pre- and post-
natal exposure. No developmental toxicity was observed in either the 
rat or rabbit developmental toxicity studies, nor was there any 
evidence in the 2-generation toxicity study that there was 
developmental or reproductive toxicity at dose levels below those in 
which parental toxicity was observed. For rabbits, the developmental 
toxicity NOAEL was > 60 mg/kg/day, at the highest dose tested (HDT). 
The maternal NOAEL was > 60 mg/kg/day, based upon mortality observed at 
125 mg/kg/day in a pilot study. For rats, there were no maternal or 
developmental effects at any dose level and the NOAELs were > 500 mg/
kg/day, the HDT. In the 2-generation reproductive toxicity study in 
rats, the reproductive NOAEL was 172 mg/kg/day. The reproductive LOAEL 
of 346 mg/kg/day was based on decreased pup weight, which occurred in 
the presence of parental (systemic) toxicity at 346 mg/kg/day.
    FFDCA section 408 provides that EPA may apply an additional 10-fold 
margin of safety 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 current toxicological data 
requirements, the toxicology database for pendimethalin is complete.
    Furthermore, for pendimethalin, the reproductive NOAEL of 172 mg/
kg/day is 17-fold higher than the NOAEL of 10 mg/kg/day used for the 
RfD. Additionally, the reproductive LOAEL occurred in the presence of 
parental (systemic) toxicity and there was no evidence of developmental 
toxicity in either the rat or the rabbit studies. Therefore, American 
Cyanamid Company believes that these proposed tolerances do not 
represent any unacceptable pre- or post-natal risk to infants and 
children.
    Using the conservative exposure assumptions described above, EPA 
has previously concluded that aggregate exposure to pendimethalin from 
food will utilize less than 2% of the RfD for infants and children. The 
additional dietary burden for non-nursing infants, (<1 year old) that 
will result from the proposed tolerances of pendimethalin in tree nuts 
and pistachio will be zero. The additional dietary burden for non-
nursing infants, (<1 year old) that will result from the proposed 
tolerances of pendimethalin in fruiting vegetables will be only 
0.000085 mg/kg/day, 0.1% of the RfD. 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. Despite the potential for 
exposure to pendimethalin in drinking water and from non-dietary, non-
occupational exposure, American Cyanamid Company does not expect the 
aggregate exposure to exceed 100% of the RfD. Thus, American Cyanamid 
Company concludes that there is a reasonable certainty that no harm 
will result to infants and children from aggregate exposure to 
pendimethalin residues.

F. International Tolerances

    There are no CODEX, Canadian or Mexican International Maximum 
Residue Levels (MRLs) established for residues of pendimethalin in tree 
nuts and pistachio, almond hull or in fruiting vegetables at this time.

3. Interregional Research Project Number 4 (IR)

0E6183

    EPA has received a pesticide petition (0E6183) 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 the 
herbicide carfentrazone-ethyl (ethyl--2-dichloro-5-[4-
(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-
fluorobenzene-propanoate)and the metabolite carfentrazone-ethyl 
chloropropionic acid (, 2-dichloro-5-[-4-(difluoromethyl)-4,5-
dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoic 
acid) in or on the raw agricultural commodity within the crop subgroup 
caneberry at 0.1 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 FMC Corporation, Agricultural Products Group, 
Philadelphia, PA 19103.

[[Page 15467]]

A. Residue Chemistry

    1. Plant metabolism. The metabolism of carfentrazone-ethyl in 
plants is adequately understood. The residues of concern are the 
combined residues of carfentrazone-ethyl and carfentrazone-ethyl-
chloropropionic acid.
    2.  Analytical method. There is a practical analytical method for 
detecting and measuring levels of carfentrazone and its metabolites in 
or on food with a limit of quantitation that allows monitoring of food 
with residues at or above the levels set in the tolerances. The 
analytical method for carfentrazone-ethyl involves separate analyses 
for parent and its metabolites. The parent is analyzed by gas 
chromatography/electron capture detection (GC/ECD). The metabolites are 
derivatized with boron trifluoride and acetic anhydride for analysis by 
gas chromatography/mass spectrometry detection (GC/MSD) using selective 
ion monitoring.
    3. Magnitude of residues. Carfentrazone-ethyl 40 DF was applied to 
4 caneberry trials in the appropriate EPA regions. The caneberries were 
harvested at the appropriate growth stages and subsequent analyses 
determined that the residues of carfentrazone-ethyl and its metabolites 
would not exceed the proposed tolerances of 0.1 ppm.

B. Toxicological Profile

    1. Acute toxicity. Carfentrazone-ethyl demonstrates low oral, 
dermal and inhalation toxicity. The acute oral lethal dose 
(LD50) value in the rat was greater than 5,000 mg/kg, acute 
dermal LD50 value in the rat was greater than 4,000 mg/kg, 
and the acute inhalation lethal concentration(LC50) value in 
the rat was greater than 5.09 mg/L/4h. Carfentrazone-ethyl is non-
irritating to rabbit skin and minimally irritating to rabbit eyes. It 
did not cause skin sensitization in guinea pigs. An acute neurotoxicity 
study in the rat had a systemic No Observed Adverse Effect Level 
(NOAEL) of 500 mg/kg based on clinical signs and decreased motor 
activity levels; the NOAEL for neurotoxicity was greater than 2,000 mg/
kg highest dose tested (HDT) based on the lack of neurotoxic clinical 
signs or effects on neuropathology.
    2. Genotoxicity. Carfentrazone-ethyl did not cause mutations in the 
Ames assay with or without metabolic activation. There was a positive 
response in the chromosome aberration assay without activation but a 
negative response with activation. The mouse micronucleus assay (an in 
vivo test which also measures chromosome damage), the CHO/HGPRT forward 
mutation assay and the unscheduled DNA synthesis assay were negative. 
The overwhelming weight of the evidence supports the conclusion that 
carfentrazone-ethyl is not genotoxic.
    3. Reproductive and developmental toxicity. Carfentrazone-ethyl is 
not considered to be a reproductive or a developmental toxin. In the 2-
generation reproduction study, the NOAEL for reproductive toxicity was 
greater than 4,000 ppm (greater than 323 to greater than 409 mg/kg/
day). In the developmental toxicity studies, the rat and rabbit 
maternal NOAELs were 100 mg/kg/day and 150 mg/kg/day, respectively. The 
developmental NOAEL for the rabbit was greater than 300 mg/kg/day 
(HDT), and for the rat the NOAEL was 600 mg/kg/day based on increased 
litter incidences of thickened and wavy ribs at 1,250 mg/kg/day. These 
two findings (thickened and wavy ribs) are not considered adverse 
effects of treatment but related delays in rib development which are 
generally believed to be reversible.
    4. Subchronic toxicity. Ninty-day feeding studies were conducted in 
mice, rats and dogs with carfentrazone-ethyl. The NOAEL for the mouse 
study was 4,000 ppm (571 mg/kg/day), for the rat study was 1,000 ppm 
(57.9 mg/kg/day for males; 72.4 mg/kg/day for females) and for dogs was 
150 mg/kg/day. A 90-day subchronic neurotoxicity study in the rat had a 
systemic NOAEL of 1,000 ppm (59.0 mg/kg/day for males; 70.7 mg/kg/day 
for females) based on decreases in body weights, body weight gains and 
food consumption at 10,000 ppm; the neurotoxicity NOAEL was greater 
than 20,000 ppm (1,178.3 mg/kg/day for males; 1,433.5 mg/kg/day for 
females) (HDT).
    5. Chronic toxicity. Carfentrazone-ethyl is not carcinogenic to 
rats or mice. A 2-year combined chronic toxicity/carcinogenicity study 
in the rat was negative for carcinogenicity and had a chronic toxicity 
NOAEL of 200 ppm (9 mg/kg/day) for males and 50 ppm (3 mg/kg/day) for 
females based on red fluorescent granules consistent with porphyrin 
deposits in the liver at the 500 and 200 ppm levels, respectively. An 
18 month carcinogenicity study in the mouse had a carcinogenic NOAEL 
that was greater than 7,000 ppm (>1,090 mg/kg/day for males; >1,296 mg/
kg/day for females) based on no evidence of carcinogenicity at the HDT. 
A 1-year oral toxicity study in the dog had a NOAEL of 50 mg/kg/day 
based on isolated increases in urine porphyrins in the 150 mg/kg/day 
group (this finding was not considered adverse).
    Using the Guidelines for Carcinogen Risk Assessment, carfentrazone-
ethyl should be classified as Group ``E'' for carcinogenicity -- no 
evidence of carcinogenicity -- based on the results of carcinogenicity 
studies in two species. There was no evidence of carcinogenicity in an 
18-month feeding study in mice and a 2-year feeding study in rats at 
the dosage levels tested. The doses tested are adequate for identifying 
a cancer risk. Thus, a cancer risk assessment is not necessary.
    6. Animal metabolism. The metabolism of carfentrazone-ethyl in 
animals is adequately understood. Carfentrazone-ethyl was extensively 
metabolized and readily eliminated following oral administration to 
rats, goats, and poultry via excreta. All three animals exhibited a 
similar metabolic pathway.
    7. Endocrine disruption. An evaluation of the potential effects on 
the endocrine systems of mammals has not been determined; however, no 
evidence of such effects was reported in the chronic or reproductive 
toxicology studies described above. There was no observed pathology of 
the endocrine organs in these studies. There is no evidence at this 
time that carfentrazone-ethyl causes endocrine effect.

C. Aggregate Exposure

    1. Dietary exposure--Acute. Based on the available toxicity data, 
the EPA has established an acute Reference Dose (aRfD) for 
carfentrazone-ethyl of 5 mg/kg/day. The aRfD for carfentrazone-ethyl is 
based on acute neurotoxicity study in rats with a threshold NOAEL of 
500 mg/kg/day and an uncertainty factor of 100.
    Chronic. Based on the available toxicity data, the EPA has 
established a chronic Reference Dose (cRfD) for carfentrazone-ethyl of 
0.03 mg/kg/day. The cRfD for carfentrazone-ethyl is based on a 2-year 
chronic toxicity/carcinogenicity study in rats with a threshold NOAEL 
of 3 mg/kg/day and an uncertainty factor of 100. For purposes of 
assessing the potential chronic dietary exposure, a Tier 1 dietary risk 
assessment was conducted based on the Theoretical Maximum Residue 
Contribution (TMRC) from the established and proposed tolerances for 
carfentrazone-ethyl, as follows: 0.1 ppm in or on wheat grain; 0.3 ppm 
in or on wheat hay; 0.2 ppm in or on wheat straw; 1.0 ppm in or on 
cereal grain forage (except corn and sorghum); 0.1 ppm in or on sorghum 
and corn (sweet and field) forage, 0.15 ppm in or on stover and 0.1 ppm 
in or on sweet corn, K+ CWHR (kernels plus cob with husk removed), in 
or on the soybean seed at 0.1 ppm, in or on cotton at 3.5 ppm, in

[[Page 15468]]

or on cotton gin byproducts, in or on cottonseed (undelinted) and 0.2 
ppm in/on caneberry at 0.1 ppm. (The TMRC is a ``worse case'' estimate 
of dietary exposure since it is assumed that 100% of all crops for 
which tolerances are established are treated and that pesticide 
residues are present at the tolerance levels). In conducting this 
exposure assessment, the following very conservative assumptions were 
made-100% of soybeans, cotton and cereal grains will contain 
carfentrazone-ethyl residues and those residues would be at the level 
of the tolerance which result in an overestimate of human exposure.
    i. Food. Dietary exposure from the proposed uses would account for 
0.1% or less of the aRfD in subpopulations (including infants and 
children). Dietary exposure from the proposed uses would account for 
3.2% or less of the cRfD in subpopulations (including infants and 
children).
    ii. Drinking water. Studies have indicated that carfentrazone-ethyl 
will not move into groundwater, therefore water has not been included 
in the dietary risk assessment.
    2. Non-dietary exposure. The potential for non-occupational 
exposure to the general population has not been fully assessed.

D. Cumulative Effects

    EPA is also required to consider the potential for cumulative 
effects of carfentrazone-ethyl and other substances that have a common 
mechanism of toxicity. FMC does not have information to indicate that 
toxic effects produced by carfentrazone-ethyl would be cumulative with 
those of any other chemical compounds; thus only the potential risks of 
carfentrazone-ethyl are considered in this exposure assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described and based on the completeness and reliability of the toxicity 
data, the aggregate exposure to carfentrazone-ethyl will utilize 0.06% 
of the aRfD and 1.4% of the cRfD for the U.S. population. EPA generally 
has no concern for exposures below 100% of the RfD. Therefore, based on 
the completeness and reliability of the toxicity data and the 
conservative exposure assessment, there is a reasonable certainty that 
no harm will result from aggregate exposure to residues of 
carfentrazone-ethyl, including all anticipated dietary exposure and all 
other non-occupational exposures.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of carfentrazone-ethyl, 
EPA considers data from developmental toxicity studies in the rat and 
rabbit and the 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. Reproduction studies provide information relating 
to effects on the reproductive capacity of males and females exposed to 
the pesticide. Developmental toxicity was not observed in developmental 
toxicity studies using rats and rabbits. Subsequently, there was no 
reproductive toxicity observed in the 2-generation reproduction study 
in rats as well.
    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, FMC 
concludes that the database relative to pre- and post-natal effects for 
children is complete and an additional uncertainty factor is not 
warranted. Therefore at this time, the RfD of 0.03 mg/kg/day is 
appropriate for assessing aggregate risk to infants and children.
    Using the conservative exposure assumptions described above, the 
percent of the RfD that will be utilized by aggregate exposure to 
residues of carfentrazone-ethyl for non-nursing infants (<1 year old) 
would be 0.08% of the aRfD and 3.0% of the cRfD; for children 1-6 years 
of age would be 0.08% of the aRfD and 3.2% of the cRfD, (the most 
highly exposed group). Based on the completeness and reliability of the 
toxicity data and the conservative exposure assessment, there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to the residues of carfentrazone-ethyl 
including all anticipated dietary exposure.

F. International Tolerances

    There are no Codex Alimentarius Commission (Codex) Maximum Residue 
Levels (MRLs) for carfentrazone-ethyl on any crops at this time.
[FR Doc. 01-6731 Filed 3-16-01; 8:45 am]
BILLING CODE 6560-50-S