[Federal Register Volume 62, Number 232 (Wednesday, December 3, 1997)]
[Notices]
[Pages 63942-63951]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-31542]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-780; FRL-5756-1]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-780, must 
be received on or before January 2, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. Follow the instructions under ``SUPPLEMENTARY 
INFORMATION.'' No confidential business information should be submitted 
through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

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

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                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-            Davis Hwy,     
                                 mail:miller.joanne@ep   Arlington, VA  
                                 amail.epa.gov.                         
James Tompkins (PM 25)........  Rm. 239, CM #2, 703-    1921 Jefferson  
                                 305-5697, e-mail:       Davis Hwy,     
                                 tompkins.james@epamai   Arlington, VA. 
                                 l.epa.gov.                             
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-780] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number (insert docket number) and appropriate 
petition number. Electronic comments on notice may be filed online at 
many Federal Depository Libraries.

List of Subjects

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

    Dated: November 21, 1997

Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim 
without editing them in any way. The petition summary announces the 
availability of a description of the analytical methods available to 
EPA for the detection and measurement of the pesticide chemical 
residues or an explanation of why no such method is needed.

1. Valent U.S.A. Corporation

PP 7F4873

    EPA has received a pesticide petition (PP 7F4873) from Valent 
U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek, CA 94596. 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of clethodim in or on the raw 
agricultural commodities tuberous and corm vegetables (crop subgroup 1-
C) at 1.0 parts per million (ppm), potato flakes/granules at 2.0 ppm, 
sunflower seed at 5.0 ppm, sunflower meal at 10.0 ppm, canola seed at 
0.5 ppm, and canola meal at 1.5 ppm. The crop subgroup 1-C tolerance 
should replace the 0.5 ppm tolerance that already exists for clethodim 
in/or potato tubers which was based on data from Canada. The

[[Page 63943]]

proposed analytical method for these commodities is EPA-RM-26D-3, a 
high-performance liquid chromatography (HPLC) method. 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. Clethodim is used for postemergent control of 
grasses in a wide variety of crops including cotton, soybeans, sugar 
beets, onions, tomatoes, etc. Plant metabolism studies have been 
performed in carrots, soybeans, and cotton. Studies were performed with 
clethodim radiolabeled in the ring structure and in the side chain to 
follow both parts of the molecule.
    The major metabolic pathway in plants is initial sulfoxidation to 
form clethodim sulfoxide followed by further sulfoxidation to form 
clethodim sulfone; elimination of the chloroallyloxy side chain to give 
the imine sulfoxide and sulfone; and hydroxylation to form the 5-OH 
sulfoxide and 5-OH sulfone. Clethodim sulfoxide and clethodim sulfone 
conjugates were also detected as major or minor metabolites, depending 
on plant species and subfractions. Once cleaved from clethodim, the 
chloroallyloxy moiety udergoes extensive metabolism to eliminate the 
chlorine atom and incorporate the three-carbon moieties into natural 
plant components.
    Based on these metabolism studies, the residues of concern in crops 
are clethodim and its metabolites containing the cyclohexene moiety, 
and their sulfoxides and sulfones.
    2. Analytical method. Adequate analytical methodology is available 
for detecting and measuring levels of clethodim and its metabolites in 
crops. For most commodities, the primary enforcement method is EPA-RM-
26D-3, an HPLC method capable of distinguishing clethodim from the 
structurally related herbicide sethoxydim. However, for milk natural 
interferences prevent adequate quantitation of clethodim moieties and 
the common-moiety method (RM-26B-2) is the primary enforcement method 
with EPA-RM-26D-3 as the secondary method if needed to determine 
whether residues are clethodim or sethoxydim. Both of these methods 
have successfully undergone petition method validations at EPA.
    3. Magnitude of residues. Clethodim is the active ingredient in 
SELECT 2 EC Herbicide (EPA Reg. No. 59639-3) and SELECT Herbicide (also 
known as PRISM and ENVOY Herbicides, EPA Reg. No. 59639-78). Tolerances 
have been established for residues in cotton, soybean, sugar beet, 
onion (dry bulb), and animal commodities, and tolerances are expected 
soon for alfalfa, peanut, dry bean, and tomato commodities. A summary 
of available field residue data for the pending tolerances on tuberous 
and corm vegetables (crop subgroup 1-C), sunflower, and canola 
commodities is presented below.
    In 17 field trials, potatoes were treated with two post-emergent 
applications of 0.25 lb. a.i./A each, approximately 14-days apart, and 
harvested approximately 30 days after the last application. Trials were 
performed in EPA Regions 1, 2, 3, 5, 9, 10, and 11. Residues for potato 
tuber samples ranged from < 0.1 ppm to 0.80 ppm total clethodim. The 
highest average field trial (HAFT) residue was 0.775 ppm. The average 
residue value for all trials, excluding samples less than the limit of 
detection, was 0.42 ppm. Two processing studies were also performed for 
potatoes. Residues were found to concentrate in flakes, but not wet 
peel or chips. The average concentration factor for flakes was 2.4. 
Since potato is the only representative crop for crop subgroup 1-C per 
40 CFR 180.41, these data support time-limited tolerances of 1.0 ppm in 
tuberous and corm vegetables (crop subgroup 1-C) and 2.0 ppm in flakes/
granules.
    In 8 field trials, sunflowers were treated with two post-emergent 
applications of 0.25 lb. a.i./A each. Sunflower seeds were harvested 56 
to 72 days after the last application. Trials were performed in EPA 
Regions 5, 7, and 8. Residues for sunflower seed samples ranged from 
0.46 ppm to 4.4 ppm total clethodim. The highest average field trial 
(HAFT) residue was 4.2 ppm. The average residue level was 1.6 ppm. A 
processing study was also performed for sunflowers. Residues were found 
to concentrate in meal, but not in refined oil. The concentration 
factor for meal was 2.1. These data support tolerances of 5.0 ppm in 
sunflower seed and 10.0 ppm in sunflower meal.
    In 18 field trials, canola or rape was treated with one post-
emergent application of 0.11 to 0.32 lb. a.i./A and harvested 
approximately 70 to 98 days after the application. Most of the trials 
were performed in Canada in growing regions adjacent to the U.S. areas 
where canola is grown. These data were used to support a maximum 
residue level in Canada and are being cited in order to harmonize 
maximum residue levels between the U.S. and Canada and remove the 
existing trade barrier. Residues in canola seed samples ranged from < 
0.05 ppm to 0.54 ppm. The highest average field trial (HAFT) residue 
was 0.505 ppm. The average residue value for all trials, including 
samples less than the limit of detection at one-half the limit, was 
0.162 ppm. A processing study was also performed for canola and 
residues were found to concentrate in meal, but not in crude oil. Since 
the highest residues were the result of application rates higher than 
those proposed for the U.S., these data support tolerances of 0.5 ppm 
in canola seed and 1.5 ppm in canola oil.

B. Toxicological Profile

    1. Acute toxicity. Clethodim Technical is slightly toxic to animals 
following acute oral (Toxicity Category III), dermal (Toxicity Category 
IV), or inhalation exposure (Toxicity Category IV under current 
guideline interpretation). Clethodim is a moderate eye irritant 
(Category III), a severe skin irritant (Category II), and does not 
cause skin sensitization in the modified Buehler test in guinea pigs. 
In addition, an acute oral no-observed effect level (NOEL) has been 
determined in rats to be 300 milligrams/kilograms (mg/kg). Since this 
NOEL is significantly higher than the lowest chronic NOEL of 1 mg/kg/
day, chronic exposures are expected to be of the most concern and this 
summary will focus on repeated exposures.
    2. Genotoxicty. Clethodim Technical did not induce gene mutation in 
microbial in vitro assays. A weak response in an in vitro assay for 
chromosome aberrations was not confirmed when clethodim was tested in 
an in vivo cytogenetics assay up to the maximally tolerated dose level, 
nor was the response observed in vitro using technical material of a 
higher purity. No evidence of unscheduled DNA synthesis was seen 
following in vivo exposure up to a dose level near the LD50 
(1.5 g/kg). This evidence indicates that clethodim does not present a 
genetic hazard to intact animal systems.
    3. Reproductive and developmental toxicity. No reproductive 
toxicity was observed with Clethodim Technical at feeding levels up to 
2,500 ppm. Developmental toxicity was observed in two rodent species, 
but only at maternally toxic dose levels. In rats, the developmental 
NOEL was 300 mg/kg/day while the maternal toxicity NOEL was only 150 
mg/kg/day. In rabbits, the developmental NOEL was >300 mg/kg/day and 
the maternal NOEL was only 25 mg/kg/day. Valent therefore does not

[[Page 63944]]

consider clethodim to be a reproductive or developmental hazard. These 
studies also indicate that clethodim does not adversely affect 
endocrine function.
    4. Subchronic toxicity. High doses of Clethodim Technical cause 
decreased body weights, increased liver size (increased weight and cell 
hypertrophy), and anemia (decreased erythrocyte counts, hemoglobin, or 
hematocrit) in rats and dogs. No observable effect levels have been 
determined to be 100 mg/kg/day for a 4-week dermal study in rats, 200 
to 1,000 ppm for 4- or 5-week feeding studies in rats or mice, 500 ppm 
in a 13-week feeding study in rats, and 25 mg/kg/day in a 90-day oral 
study in dogs.
    5. Chronic toxicity and oncogenicity. In chronic studies conducted 
in rats, mice, and dogs, compound-related effects noted at high doses 
included decreased body weight, increased liver size (liver weight and 
hypertrophy), and anemia (decreased hemoglobin, hematocrit, and 
erythrocyte count). Bone marrow hyperplasia was observed in dogs at the 
highest dose tested. No treatment-related increases in incidence of 
neoplasms were observed in any study. Chronic NOELs were 200 ppm for an 
18-month feeding study in mice and 500 ppm for a 24-month study in 
rats. The lowest NOEL is from the 1-year oral dog study and is 1 mg/kg/
day clethodim technical. Based on this study and a 100-fold safety 
factor, the reference dose (RfD) for clethodim was determined to be 
0.01 mg/kg/day. Valent believes that clethodim is not carcinogenic. 
These studies also indicate that clethodim does not adversely affect 
endocrine function.
    6. Animal metabolism. The in vivo metabolism of clethodim in rats 
was tested at a high dose (468 mg/kg), low dose (4.4 mg/kg), and a low 
dose (4.8 mg/kg) following 14-days of treatment with Clethodim 
Technical. A single oral dose of [14C]-clethodim was given to each rat 
and expired carbon dioxide and excreta were collected over the next 2- 
and 7-days, respectively, to determine radiolabel recovery. Several 
organs and tissues, and the remaining carcass, were collected after 
sacrifice to determine radiolabel recovery. In all treatment groups, 
nearly all of the radiolabel was eliminated in the urine (87-93%), 
feces (9-17%), and carbon dioxide (0.5-1%) and less than 1% of the dose 
was recovered in the organs and tissues after 7- days.
    Elimination was rapid as most of the recovered dose was eliminated 
within 48 hours. The low dose groups eliminated clethodim slightly 
faster than the high dose group, and repeated exposure to clethodim 
prior to radiolabel dosing did not affect the rate of elimination or 
distribution of recovered radiolabel. There were no apparent sex 
differences with respect to elimination or distribution of metabolites.
    The primary excretory metabolites were identified as clethodim 
sulfoxide (48-63%), clethodim S-methyl sulfoxide (6-12%), clethodim 
imine sulfoxide (7-10%), and clethodim 5-hydroxy sulfoxide (3-5%). 
Minor metabolites included clethodim oxazole sulfoxide (2-3%), 
clethodim trione sulfoxide (1%), clethodim (1%), clethodim 5-hydroxy 
sulfone (0.3-1%), clethodim sulfone (0.1-1%), aromatic sulfone (0.2-
0.7%), and S-methyl sulfone (0-0.4%).
    7. Dermal penetration. The dermal penetration of SELECT 2 EC 
Herbicide, the end-use product, was tested on unabraded, shaved skin of 
rats. Single doses of approximately 0.05, 0.5, and 5.0 mg of 
radiolabeled (14C-clethodim) SELECT 2 EC Herbicide, were applied 
topically to 10 cm2 sites on the dorsal trunk. After 2, 10, 
or 24 hours, urine, feces, volatiles, scrubbings of the skin, skin at 
treatment site, blood, several tissues, and the carcass were collected 
and counted for radioactivity. Clethodim was found to be slowly 
absorbed through the skin in a time-dependent manner. The percent of 
dose absorbed increased with length of exposure and decreased with 
increasing dose. 10-hour absorption rates ranged from 7.5% to 30.0%. 
Most of the absorbed material was found in the urine and carcass, and 
most of the unabsorbed material was found in the skin scrubbings 
indicating that material was still on the skin surface.
    8. Metabolite toxicology. 2 metabolites of clethodim, clethodim 
imine sulfone (RE-47719) and clethodim 5-hydroxy sulfone (RE-51228), 
have been tested in toxicity screening studies to evaluate the 
potential impact of these metabolites on the toxicity of clethodim. In 
general, these metabolites were found to be less toxic than Clethodim 
Technical for acute and oral toxicity studies; reproduction and 
teratology screening studies; and several mutagenicity studies.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Clethodim is approved for use in the 
production of commercial agricultural crops including cotton, soybeans, 
sugar beets, and onions (dry bulb). Approval is expected soon for 
several additional crops. Dietary exposures are expected to represent 
the major route of exposure to the public. Since chronic exposures are 
of more concern than acute exposures for clethodim, this summary will 
focus primarily on chronic issues. Chronic dietary assessments for 
clethodim have been conducted by the registrant for all currently 
approved crops, all pending crops, and the crops proposed in this 
petition (tuberous and corm vegetables, sunflower, and canola).
    In Valent's assessment, anticipated residues were used for all crop 
and animal commodities. Anticipated residue levels were the mean levels 
found in crop field trial data after treatment with the maximum 
recommended rate and harvested at minimum allowable intervals. These 
values are, therefore, slightly conservative. An assessment was 
performed assuming 100% of crop treated (still conservative) as well as 
assuming a more realistic percent of crop treated based on market 
survey data for existing uses or market projections for proposed uses. 
Adjusting for percent of crop treated is justified because most of 
treated commodities are combined in central locations and broadly 
distributed to the public; none of the clethodim tolerances or uses are 
limited to specific regions in the U.S.; and the primary concern is 
with chronic dietary exposure which minimizes the variance of single 
serving residues. The results of these assessments are summarized below 
in the Safety Determination section and indicate that chronic dietary 
exposures for existing and proposed uses of clethodim are well below 
the reference dose in either case.
    ii. Drinking water. Since clethodim is applied outdoors to growing 
agricultural crops, the potential exists for clethodim or its 
metabolites to leach into groundwater. Drinking water, therefore, 
represents a potential route of exposure for clethodim and should be 
considered in an aggregate exposure assessment.
    Based on available studies used in EPA's assessment of 
environmental risk for clethodim (memo from E. Brinson Conerly dated 
June 26, 1990), clethodim itself was classified as mobile in soil, but 
very non-persistent, representing a minimal groundwater concern. 
Metabolites of clethodim were also classified as mobile, but are 
slightly more persistent (half-lives up to 30-days versus up to 3-days 
for parent). Regarding clethodim metabolites, the Agency concluded that 
the ``potential for groundwater contamination may be somewhat higher 
than for clethodim but would still be expected to be relatively low in 
most cases due to their moderately low persistence''.
    There is no established Maximum Concentration Level for residues of 
clethodim in drinking water under the Safe Drinking Water Act.

[[Page 63945]]

    Based on this information, Valent believes that clethodim appears 
to represent an insignificant risk for exposure through drinking water.
    2. Non-dietary exposure. Clethodim is currently approved for the 
commercial production of agricultural crops including soybeans, cotton, 
sugar beets, onions, and ornamental plants as well as for use on non-
crop areas. The new uses proposed in this notice of filing are all 
agricultural crops. While there is a potential for clethodim to be used 
in non-crop areas (e.g. around parks and rights-of-way) where the 
public does spend some time, the likelihood of significant exposure is 
very small. First, this grass herbicide cannot be sprayed on lawns 
where the public does spend significant amounts of time, but instead 
must be used where there is no crop or around ornamental plants that 
are tolerant to the chemical. The public does not spend significant 
amounts of time in these areas. And second, clethodim is not persistent 
in the environment so the potential for public exposure is short term. 
Therefore, Valent believes that the potential for non-occupational 
exposure to the general public, other than through the diet or drinking 
water, is insignificant.

D. Cumulative Effects

    There is one other pesticide compound registered in the United 
States, sethoxydim, which is structurally related to clethodim and has 
similar effects on animals. Sethoxydim is approved for use on a variety 
of agricultural crops, in non-crop areas, and around the home. This 
chemical should be considered in an aggregate exposure assessment along 
with clethodim. Dietary exposure is expected to represent the major 
route of exposure for sethoxydim as well as for clethodim.
    The reference dose for sethoxydim is 0.09 mg/kg/day based on the 1-
year dog feeding study NOEL and a 100-fold safety factor. This in on 
the same order of magnitude as clethodim, 0.01 mg/kg/day, which is also 
based on a 1-year dog study and a 100-fold safety factor.
    A discussion of the cumulative effects from clethodim and 
sethoxydim exposures is presented below in the Safety Determination 
section.

E. Safety Determination

    1. U.S. population. Using the dietary exposure assessment 
procedures described above for clethodim, chronic dietary exposures 
resulting from existing and proposed uses of clethodim were compared to 
the reference dose (RfD) of clethodim. In Valent's conservative 
assessment (using anticipated residues and assuming 100% treated for 
all crops), exposure for the U.S. population would occupy 13.6% of the 
RfD and non-nursing infants (< 1-year) are most highly exposed with 
total exposure occupying 32.3% of the RfD. Exposure to children 1 to 6 
years old would occupy 27.1% of the RfD. In Valent's realistic analysis 
(using anticipated residues and estimated percent of crop treated for 
all crops), exposure for the U.S. population would occupy only 0.6% of 
the RfD and non-nursing infants are still the highest and would be at 
only 1.6% of the RfD.
    For sethoxydim, recent EPA dietary assessments have been performed 
in conjunction with the extension of several time-limited tolerances. 
In a Final Rule published in the Federal Register of April 11, 1997 (62 
FR 17735) (FRL-5598-7), EPA estimated that exposure to all existing 
tolerances for sethoxydim would occupy 36% of the sethoxydim RfD for 
the U.S. population and 72% of the RfD for the most exposed 
subpopulation of children aged 1- to 6-years. The assumptions used were 
conservative and the final rule stated that ``actual risks using more 
realistic assumptions would likely result in significantly lower risk 
estimates.''
    Since clethodim and sethoxydim have similar toxicological effects 
in mammals, the contributions to the individual reference doses may 
need to be considered in an aggregate exposure assessment. The EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate exposure 
over a lifetime will not pose appreciable risks to human health. 
Directly summing the results of the conservative sethoxydim and the 
conservative clethodim contributions to RfD would be approaching 100%. 
However, reliable information is not available to indicate that 
directly summing the percent of RfD for these two chemicals is the most 
appropriate thing to do. Since using realistic assumptions for 
clethodim, including adjustment for percent of crop treated, result in 
large decreases in dietary risk (about 20-fold) Valent expects that the 
sethoxydim risk estimates would also be reduced significantly. 
Therefore, Valent believes that the cumulative chronic dietary risk of 
sethoxydim and clethodim is likely to be well below the 100% level for 
all population subgroups.
    Regarding drinking water exposures, sethoxydim is similar to 
clethodim representing a minimal risk for leaching into groundwater due 
to its rapid degradation in the environment. There is no established 
Maximum Concentration Level for residues of sethoxydim in drinking 
water under the Safe Drinking Water Act.
    Regarding non-occupational exposures, sethoxydim is registered for 
use in non-crop areas and around the home and may have some potential 
for exposure to the general public. However, as discussed for 
clethodim, sethoxydim cannot be applied to grass where public contact 
is expected and sethoxydim is not persistent in the environment. Valent 
therefore expects that non-occupational exposures to the public be 
minimal for sethoxydim.
    In summary, dietary exposure for clethodim and sethoxydim are each 
expected to occupy less than 10% of their RfD's when anticipated 
residue levels and percent of crop treated values are considered. 
Exposures through the drinking water or other non-occupational routes 
are expected by Valent to be minimal. Collectively, Valent believes 
that the aggregate risks associated with the uses of these two 
chemicals is small and demonstrates a reasonable certainty of no harm 
to the public.
    2. Infants and children. As discussed above, dietary exposure for 
clethodim and sethoxydim is greatest for children ages 1-6-years or 
non-nursing infants less than 1-year old. However, using a realistic 
approach to estimating exposures, exposures are expected to be below 
10% of the RfD for each chemical even for infants and children. The 
databases for clethodim and sethoxydim are complete relative to current 
pre- and post-natal toxicity testing requirements including 
developmental toxicity studies in two species and multi-generation 
reproduction studies in rats. Reproduction and developmental effects 
have been found in toxicology studies for clethodim and sethoxydim, but 
the effects were seen at levels that were also maternally toxic. This 
indicates that developing animals are not more sensitive than adults. 
FQPA requires an additional safety factor of up to 10 for chemicals 
which represent special risks to infants or children. Clethodim and 
sethoxydim do not meet the criterion for application of an additional 
safety factor for infants and children. Valent believes that this 
demonstrates a reasonable certainty of no harm to children and infants 
from the proposed uses of clethodim.

F. International Tolerances

    Although some have been proposed, there are no Mexican or Codex 
tolerances or maximum residue limits established for clethodim on 
potatoes, sunflower, or canola commodities. In

[[Page 63946]]

Canada, there are maximum residue limits established for potato tubers 
at 0.5 ppm and canola oil at 0.1 ppm. The use rates proposed for the 
use on tuberous and corm vegetables (crop subgroup 1-C) may exceed the 
0.5 ppm level in tubers so a higher level is necessary. In Canada, 
canola oil is the only canola commodity considered for a residue limit 
since this is the commodity consumed by humans. In the U.S., a 
tolerance is not being proposed for the processed commodity canola oil 
since concentration did not occur in the processing study. 
Consequently, residue in oil up to 0.5 ppm would be allowed in the U.S. 
However, the residue data indicate that residues in oil are not 
expected to exceed 0.1 ppm and Valent does not believe this would 
represent a barrier against exporting U.S.-treated canola oil into 
Canada.

2. Zeneca Ag Products

PP 6F4609

    EPA has received a pesticide petition (PP 6F4609) from Zeneca Ag 
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, DE 19850. 
proposing pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of diquat dibromide in or on the 
raw agricultural commodity dried shelled pea and bean (except soybean) 
subgroup (seed) at 0.80 ppm. The proposed analytical method is a 
spectrophotometric method measuring absorption following derivitisation 
of the diquat with alkaline sodium dithionite. EPA has determined that 
the petition contains data or information regarding the elements set 
forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of diquat in plants is 
adequately understood. The residue of concern in plants is diquat per 
se. No further plant metabolism data are necessary for this proposed 
use.
    2. Analytical method. The method of analysis is a spectrophotometic 
method measuring absorption following derivitisation of the diquat with 
alkaline sodium dithinoite.
    3. Magnitude of residues. Dry Pea - Six residue field trials were 
conducted during 1994 in California, Idaho, Oregon, Texas, and 
Washington. The seed samples were analyzed for the active ingredient 
diquat. Diquat residues in dry pea seed ranged from 0.05 to 0.56 ppm.
    Lentil - Five residue field trials were conducted during 1994 in 
Idaho, North Dakota, and Washington. The seed samples were analyzed for 
the active ingredient diquat. Diquat residues in lentil seed ranged 
from < 0.05 to 0.54 ppm.
     Dry Bean - Eight residue field trials were conducted during 1994 
in California, Colorado, Idaho, Michigan, Minnesota, North Dakota, 
Nebraska, and New York. The bean seed were analyzed for the active 
ingredient diquat. Diquat residues were less than the limit of 
quantitation (<0.05 ppm) in all the bean seed samples.

B. Toxicological Profile

    1. Acute toxicity. In studies using laboratory animals, diquat 
dibromide has been shown generally to be of moderate toxicity. It can 
cause slight to severe eye irritation and has been placed in Toxicity 
Category II for acute dermal eye irritation effects. It is slightly 
acutely toxic by the oral and inhalation routes and has been placed in 
Toxicity Category III for these effects. Diquat dibromide causes slight 
dermal irritation and has been placed in Toxicity Category IV for this 
effect. It is not a skin sensitizer.
    2. Genotoxicty. Diquat dibromide was negative for mutagenicity in 
the following test: 1 gene mutation (Ames), 2 structural chromosome 
aberration (mouse micronucleus and dominant lethal in mice) and 1 other 
genotoxic effects (unscheduled DNA synthesis in rat hepatocytes in 
vitro). Diquat was positive in 1 gene mutation test (mouse lymphoma 
cell assay) and in 1 chromosome aberration test (human blood 
lymphocytes, depending on the concentration of diquat dibromide and the 
presence or absence of the metabolic activation system). EPA has 
concluded that Diquat does not appear to present a mutagenicity concern 
in (in vivo) studies and for heritable risk considerations based on 
available information.
    3. Reproductive and developmental toxicity. In a rat 
multigeneration study, diquat was fed at dose levels equivalent to 0, 
16, 80 or 400/240 ppm of diquat cation. There was evidence of toxicity 
in both adults and offspring at 400/240 ppm diquat. A low incidence of 
toxicity was seen at 80 ppm in the adult rats only. Based on the 
findings, the NOEL and LOEL for systemic toxicity are 16 ppm (0.8 mg/
kg/day) and 80 ppm (4 mg/kg/day), respectively, expressed as diquat 
cation. The NOEL and LOEL for reproductive toxicity are 80 ppm (4 mg/
kg/day) and 400/240 ppm (20/12 mg/kg/day) respectively, expressed as 
diquat cation.
    In a developmental toxicity study in rabbits, diquat dibromide was 
administered by gavage at dose levels of 0, 1, 3, or 10 mg/kg/day. 
There was no evidence to suggest that diquat was teratogenic to the 
rabbit at any dose level tested. Based on the findings, the NOEL and 
LOEL for maternal toxicity are 1 mg/kg/day and 3 mg/kg/day, 
respectively, expressed as diquat cation. The developmental toxicity 
NOEL and LOEL are, respectively, 3 mg/kg/day and 10 mg/kg/day, 
expressed as diquat cation.
    In a developmental toxicity study in the rat, diquat dibromide was 
administered by oral gauge dose levels of 0, 4, 12 or 40 mg/kg/day. 
Diquat was not a rat teratogen at any of the dose levels tested. 
Maternal toxicity and foetotoxicity were in evidence at 40 mg/kg/day 
with mild and transient maternal toxicity persisting to the lowest dose 
level tested (4 mg/kg/day). The developmental toxicity NOEL and LOEL 
are, respectively, 12 mg/kg/day and 40 mg/kg/day expressed as diquat 
cation.
    4. Subchronic toxicity. A supplemental subchronic dermal toxicity 
study using rabbits exposed to technical diquat dibromide at doses of 
0, 20, 40, 80, or 160 mg/kg/day with a toxicological NOEL and LOEL for 
systemic toxicity, for both sexes, of 20 mg/kg/day and 40 mg/kg/day, 
respectively.
    A repeated dermal toxicity study using rats exposed to technical 
diquat dibromide at doses of 0, 5, 20, 40 or 80 mg/kg of body weight/
day with a toxicological NOEL and LOEL for systemic toxicity, for both 
sexes, of 5 mg/kg/day and 20 mg/kg/day, respectively.
    An inhalation study using rats resulted in increase in lung weight, 
lung/body weight and lung/brain weight, lung lesions, and mottling and 
reddening of the lungs in females; however, all effects except the 
latter were reversible. A second inhalation study using rats showed no 
effects on any of the parameters examined at a dose of 0.1 g/
l. Based on both studies the NOEL and LOEL on inhalation exposure are 
0.1g/L and 0.49 g/L, respectively.
    5. Chronic toxicity.-- i. 2-Year rat study. - A chronic feeding 
carcinogenicity study was conducted on rats which were fed diets 
containing 0, 5, 15, 75 or 375 ppm of diquat cation. The systemic NOEL 
for both sexes was 15 ppm (0.58 mg/kg/day for males and

[[Page 63947]]

0.72 mg/kg/day for females, expressed as diquat cation); and the 
systemic LOEL was 75 ppm (2.91 mg/kg/day for males and 3.64 mg/kg/day 
for females, expressed as diquat cation).
    ii. 1-Year dog study. - A chronic dog study was conducted on 
beagles which were fed diets containing 0, 0.5, 2.5, or 12.5 mg/kg/day, 
expressed as diquat cation. The systemic NOEL for both sexes was 0.5 
mg/kg/day and systemic LOEL was 2.5 mg/kg/day.
    iii. 2-Year mice study. - A chronic feeding/carcinogenicity study 
was conducted on mice which were fed diets containing 0,30,100 or 300 
ppm, expressed as diquat cation. The systemic NOEL for both sexes was 
30 ppm. The systemic LOEL was 100 ppm. Zeneca believes that diquat was 
not carcinogenic in this study.
    The carcinogenic potential of diquat dibromide was evaluated by the 
Health Effects Division Reference Dose (RfD)/Peer Review Committee on 
March 31, 1994. The Committee classified diquat dibromide into Group E 
(evidence of noncarcinogenicity for humans, based on a lack of evidence 
of carcinogenicity in acceptable studies with two animal species, rat 
and mouse.
    6. Animal metabolism. The reregistration requirements for animal 
metabolism are fulfilled. The qualitative nature of the residue in 
animals is adequately understood based on acceptable poultry, ruminant, 
and fish metabolism studies. There are no animal feed items associated 
with this proposed use. The diquat metabolism and magnitude of residue 
in animals is not germane to this petition.
    7. Metabolite toxicology. The qualitative nature of the residue in 
plants is adequately understood based on an acceptable potato 
metabolism study and rat bioavailabilty study. The terminal residue of 
concern in plants is diquat per se. The qualitative nature of the 
residue in animals is adequately understood.

C. Aggregate Exposure

    Diquat is a non-selective, contact herbicide with both food and 
non-food uses. As such, aggregate non-occupational exposure would 
include exposures resulting from consumption of potential residues in 
food and water, as well as from residue exposure resulting from non-
crop use around trees, shrubs, lawns, walks, driveways, etc. Thus, the 
possible human exposure from food, drinking water and residential uses 
has been assessed below.
    1. Dietary exposure-- i. Food. Acute dietary - The EPA did not 
identify an acute toxicity endpoint of concern for diquat in the 
Reregistration Eligibility Decision (RED) document, and determined that 
an acute dietary risk assessment is not required for this chemical.
    ii. Chronic dietary. For purposes of assessing the potential 
chronic dietary exposure, Zeneca has estimated the aggregate exposure 
based on Theoretical Maximum Residue Contribution (TMRC) for all 
existing tolerances and the proposed tolerances of diquat on dry beans 
and dry peas at 0.8 ppm. The TMRC is obtained by multiplying the 
tolerance level residues (existing and proposed) by the consumption 
data which estimates the amount of those food products eaten by various 
population subgroups. Exposure of humans to residues could also result 
if such residues are transferred to meat, milk, poultry or eggs. The 
following assumptions were used in conducting this exposure assessment: 
100% of the crops were treated, the RAC residues would be at the level 
of the tolerance, and certain processed food residues would be at 
anticipated (average) levels based on processing studies. In addition, 
residues of diquat in tap water at the Maximum Contaminant Level (MCL) 
of 0.02 ppm was included in the dietary assessment. These conservative 
assumptions result in a ``worst-case'' risk assessment and a 
significant overestimate of actual human exposure. An assessment was 
also performed using Anticipated Residues Contributions (ARC) derived 
from field trial data for sorghum, soybeans, potatoes, dry beans and 
peas. The ARC assessment also included percent crop treated data as 
cited in the July 1995 Diquat RED, as well as market projections for 
dry beans and peas. The resulting TMRC for the US population is 
0.002946 mg/kg body weight/day (58.9% of the RfD). For this same group, 
the Anticipated Residue Contribution (ARC) is 0.000711 mg/kg body 
weight/day (14.2% RfD). For children ages 1 to 6 and non-nursing 
infants the TMRC was 0.004571 mg/kg body-weight/day (91.4% RfD) and 
0.003620 mg/kg body-weight/day (72.4% RfD), respectively. For these 
same groups the ARC was 0.001513 mg/kg body-weight/day (30.3% RfD) for 
children ages 1 to 6, and 0.002795 mg/kg body-weight/day (55.9% RfD) 
for non-nursing infants. None of the subgroups assessed exceeded 100% 
of the RfD.
    iii. Drinking water. In examining aggregate exposure, FQPA directs 
EPA to consider available information concerning exposures from the 
pesticide residue in food and all other non-occupational exposures. The 
primary non-food sources of exposure the Agency looks at, include 
drinking water (whether from groundwater or surface water), is exposure 
through pesticide use in gardens, lawns, etc (residential uses).
    The lifetime health advisory and maximum contaminant level (MCL) 
set by EPA for diquat are the same and given as 0.02 parts per million 
(ppm) as required under the Drinking Water Regulations under the Safe 
Drinking Water Act. Drinking water which meets the EPA standard is 
associated with little to no risk and should be considered safe. 
Inclusion of MCL level residues of diquat in water in the dietary 
assessment demonstrated a safe exposure level to all subgroups in the 
US population. The Agency no longer establishes tolerances for residues 
in potable water; the tolerance for diquat dibromide has been replaced 
with a designated maximum contaminant level goal (MCLG) of 0.02 ppm for 
residues of diquat in potable water.
    The primary route of environmental dissipation of diquat is strong 
adsorption to soil particles. Diquat does not hydrolyse or photodegrade 
and is resistant to microbial degradation under aerobic and anaerobic 
conditions. There were no major degradates isolated from any of the 
environmental fate studies. When used as an aquatic herbicide, diquat 
is removed from the water column by adsorption to soil sediments, 
aquatic vegetation, and organic matter. Adsorbed diquat is persistent 
and immobile, and is not expected to be a ground-water contaminant. The 
environmental fate data base for diquat is complete for reregistration 
of diquat dibromide.
    2. Non-dietary exposure. As a non-selective, contact herbicide, 
homeowner use of diquat will consist primarily of spot spraying of 
weeds around trees, shrubs, walks, driveways, flower beds, fence lines, 
etc. The potential for exposure following application as a spot 
treatment in residential gardens, driveway edges, patios, etc. is low 
due to the limited frequency and duration of exposure. The exposures 
which would result from the use of diquat are determined to be of an 
intermittent nature. Any exposures to diquat would result from dermal 
exposure. These exposures are not expected to pose any acute toxicity 
concerns. Based on the US EPA National Home and Garden Pesticide Use 
Survey (RTI/5100/17-01F, March 1992), the average homeowner is expected 
to use non-selective herbicides only about four times a year. Thus, 
these exposure have not been factored into a chronic exposure 
assessment. Also, diquat has extremely low skin permeation, is not 
volatile, presenting

[[Page 63948]]

no inhalation risk, and has rapid and strong binding characteristics to 
leaf surfaces and soil. The Agency concludes that non-occupational and 
non-dietary exposure to diquat will not be significant and has not been 
aggregated with dietary exposures in estimating chronic risk.

D. Cumulative Effects

    The only other compound in the bipyridilium chemical family is 
paraquat dichloride. Since diquat dibromide and paraquat dichloride 
have different toxicological endpoints and therefore do not have a 
common mode of action, there is no need for an assessment of cumulative 
effects.

E. Safety Determination

    1. U.S. population. The proposed uses utilize 58.9% of the RfD for 
the general U.S. population, based on the assumptions of 100% crop 
treated, MCL level residues in tap water and all residues at tolerance 
levels; 72.4% of the RfD for non-nursing infants under 1-year old, 
19.6% of the RfD for nursing infants under 1-year old; 91.4% of the RfD 
for children 1-6 years old; and 71.5% of the RfD for children 7-12 
years old. An additional risk assessment for residential uses is 
unnecessary because there is no evidence for toxicological concern via 
the dermal or inhalation routes of exposure. Given diquat's strong 
binding characteristics, exposure via drinking water is highly 
unlikely. Zeneca concludes that there is reasonable certainty that no 
harm will occur from aggregate exposure to diquat.
    2. Infants and children. FFCDA section 408 provides that EPA shall 
apply an additional ten fold margin of exposure for infants and 
children in the case of threshold effects to account for pre- and post-
natal toxicity and the completeness of the database unless EPA 
determines that a different margin of exposure will be safe for infants 
and children. EPA believes that reliable data support using the 
standard margin of exposure (usually 100 x for combined inter- and 
intra-species variability) and not the additional tenfold margin of 
exposure when EPA has a complete data base under existing guidelines 
and when the severity of the potential effect in infants and children 
or the potency or unusual toxic properties of a compound do not raise 
concerns regarding the adequacy of the standard margin of exposure.
    Risk to infants and children was determined by the use of a rat 
multigeneration reproduction study and developmental toxicity studies 
in rabbits and rats. The reproduction study provides information on 
potential effects from exposure on the reproductive capability of 
mating parents and on systemic toxicity. The developmental studies 
provide information on the potential for adverse effects from exposure 
on the developing organism during prenatal development.
    The toxicological data base for evaluating pre- and post-natal 
toxicity for diquat is considered to be complete. In the rat 
reproduction study, systemic toxicity to the mating parents was 
observed at 4 and 20/12 mg diquat cation/kg body weight/day, and 
reproductive effects in the form of decreased pups per litter and 
decreased body weight gain were seen at 20/12 mg/kg/day. Given that the 
effects seen in the pups and litters were at doses that clearly 
affected the parents at this dose level and below, diquat is considered 
not to affect reproductive performance without significantly 
compromising the health of the parental animals.
    Developmental effects in the rat and rabbit studies, including 
decreased body weights, kidney and liver effects, and delayed 
ossification, were only observed at the highest doses tested and are 
considered to be related to the significant maternal toxicity exhibited 
at these dose levels. There was no evidence in these studies that 
diquat caused teratogenic effects.
    Furthermore, the RfD is currently based on effects seen at 0.5 mg/
kg/day in the dog. Effects seen at maternally toxic doses in the rat 
developmental study were 80 times higher, and in the rabbit study were 
20 times higher than the level on which the RfD is based. Thus, Zeneca 
does not believe the effects seen in these studies are of such a 
concern to require an additional safety factor. Accordingly, Zeneca 
concludes that the RfD has an adequate margin of protection for infants 
and children and there is reasonable certainty that no harm will occur 
to infants and children from aggregate exposure to diquat.

F. International Tolerances

    Codex lists diquat cation in dry beans and peas at 0.2 ppm. Diquat 
is listed in Canada in beans and peas at 0.1 ppm. There are no Mexican 
maximum residue limits for diquat on dry beans or peas.

3. E.I. DuPont de Nemours and Co., Inc.

PP 7F4849

    EPA has received a pesticide petition (PP 7F4849) from E.I. DuPont 
de Nemours and Co., Inc. (DuPont), Barley Mill Plaza, P.O. Box 80083, 
Wilmington, DE 19880-0038. proposing pursuant to section 408(d) of the 
Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 
part 180 by establishing a tolerance for residues of for azafenidin, 2-
[2,4-dichloro-5-(2-propynyloxy) phenyl]-5,6,7,8-tetrahydro-1,2,4-
triazolo [4,3-a] pyridin-3(2H)-1 in or on the raw agricultural 
commodities of the crop grouping of citrus, grapes, sugarcane and 
sugarcane molasses. The proposed analytical method involves 
homogenization, filtration, partition and cleanup with analysis by gas 
chromatography using mass selective detection. EPA has determined that 
the petition contains data or information regarding the elements set 
forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues of 
azafenidin in citrus, grapes and sugarcane is adequately understood for 
the purposes of registration. Metabolic pathways in grapefruit, grapes 
and sugarcane are similar, consisting of rapid O-dealkylation and 
production of hydroxyl derivatives, with subsequent formation of 
glucuronide and sulfate.
    2. Analytical method. The proposed analytical method involves 
homogenization, filtration, partition and cleanup with analysis by gas 
chromatography using mass selective detection.
    3. Magnitude of residues. DuPont proposes establishing tolerances 
for residues azafenidin, 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-
5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-1 (Milestone*) in 
or on the agricultural commodities of the crop grouping of citrus at 
0.1 ppm, grapes at 0.02 ppm, sugarcane at 0.02 ppm and sugarcane 
molasses at 0.1 ppm .

B. Toxicological Profile

    1. Acute toxicity. Technical azafenidin has been placed in acute 
toxicology category III based on overall results from several studies. 
Results from the following studies indicate toxicology category III: 
acute dermal toxicity (LD50 > 2,000kg; rabbits) and eye 
irritation (effects reversible within 72 hours; rabbits). Acute oral 
toxicity (LD50 > 5,000 mg/kg; rats), acute inhalation 
toxicity (LC50 > 5.4 mg/L, rats) and skin irritation (slight 
effects resolved within 48 hours; rabbits) results were assigned 
toxicology category IV. Technical azafenidin is not a dermal 
sensitizer.
    An acute neurotoxicity study was conducted in rats administered

[[Page 63949]]

azafenidin via gavage at 0, 100, 300 or 900 mg/kg. Azafenidin was not 
neurotoxic at any dose. The systemic NOEL was 100 mg/kg for males and 
females based on reduced food consumption and body weights at 300 mg/kg 
and above.
    2. Genotoxicty. Technical azafenidin was negative for genotoxicity 
in a battery of in vitro and in vivo tests. These tests included the 
following: mutagenicity in bacterial (Ames test) and mammalian (CHO/
HGPRT assay) cells; in vitro cytogenetics (chromosomal aberration in 
human lymphocytes); in vivo cytogenetics (bone marrow micronucleus 
assay in mice); and unscheduled DNA synthesis in rat primary 
hepatocytes.
    3. Reproductive and developmental toxicity. A 2-generation 
reproduction study was conducted in rats with dietary technical 
azafenidin concentrations of 0, 5, 30, 180 or 1,080 ppm. The NOEL was 
30 ppm (1.7 to 2.8 mg/kg/day for P1 and 
F1 males and females and their offspring). This 
was based on the following effects at 180 ppm (10.1 to 17.8 mg/kg/day 
for P1 and F1 males and 
females and/or their offspring): slight reductions in mean body weights 
for F1 males and females; reductions in mean 
gestation body weight gain and implantation efficiency; slightly 
increased gestation lengths; decreased offspring survival, body weights 
and other indices of offspring health; and increased incidence of 
diarrhea among F1 parental males.
     A developmental study was conducted in rats administered technical 
azafenidin by gavage at 0, 3, 8, 16 or 24 mg/kg/day. Azafenidin was not 
teratogenic. The NOEL was 16 mg/kg/day based on the following 
observations at 24 mg/kg/day: reduced maternal body weight, increased 
resorptions, reductions in litter size and fetal weights and increased 
sternebral variations. The maternal effects consisted of transient body 
weight reductions; however, the nature of these effects suggested that 
fetal resorptions contributed to these weight reductions.
    A developmental study was conducted in rabbits administered 
technical azafenidin by gavage at 0, 12, 36, 100 or 300 mg/kg/day. 
Azafenidin was not teratogenic. The NOELs for maternal and offspring 
toxicity were 12 and 100 mg/kg/day, respectively. The maternal NOEL was 
based on reduced body weight at 36 and 100 mg/kg/day and mortality at 
higher doses. Excessive maternal toxicity at 300 mg/kg/day precluded a 
Crop field trial residue data from citrus, grape and sugarcane studies 
show that the proposed tolerances on these commodities will not be 
exceeded when Milestone* is used as directed. Assessment of 
developmental effects at this level. However, the developmental NOEL 
was considered to be 100 mg/kg/day since there were no indications of 
fetal toxicity up to and including this dose level.
    4. Subchronic toxicity. A 90-day study in mice was conducted at 
dietary concentrations of 0, 50, 300, 900 or 1,500 ppm. The NOEL was 
300 ppm (47.2 and 65.8 mg/kg/day for male and female mice, 
respectively). This was based on reduced body weight gain in males and 
microcytic and hypochromic anemia in males and females at 900 ppm (or 
144 and 192 mg/kg/day for males and females, respectively).
    Technical azafenidin was administered in the diets of rats at 0, 
50, 300, 900 or 1,500 ppm for 90 days. The NOEL was 300 ppm (24.2 and 
28.2 mg/kg/day for male and female rats, respectively). This was based 
on methemoglobinemia and microcytic and hypochromic anemia in males and 
females at 900 ppm (or 71.9 and 83.8 mg/kg/day for male and female 
rats, respectively).
    Dogs were administered technical azafenidin in their diets at 0, 
10, 60, 120 or 240 ppm for 90-days. The NOEL was 10 ppm (0.34 and 0.33 
mg/kg/day for males and females, respectively). This was based on 
enlarged hepatocytes and increased serum alkaline phosphatase and 
alanine aminotransferase activities at 60 ppm (2.02 and 2.13 mg/kg/day 
for male and female dogs, respectively).
    A 90-day subchronic neurotoxicity study was conducted in rats at 0, 
50, 750 or 1,500 ppm. There were no neurological effects observed in 
this study. The NOEL for systemic toxicity was 50 ppm (3.0 mg/kg/day) 
and 750 ppm (54.5 mg/kg/day) for male and female rats, respectively. 
These were based on reduced food consumption and body weights and 
increased incidences of clinical signs of toxicity at the higher doses.
    A 28-day dermal study was conducted in rats at 0, 80, 400 or 1,000 
mg/kg/day. There was no dermal irritation or systemic toxicity among 
males or females at the highest dose tested. The NOEL was > 1,000 mg/
kg/day.
    5. Chronic toxicity. An 18-month mouse study was conducted with 
dietary concentrations of 0, 10, 30, 300 or 900 ppm technical 
azafenidin. This product was not oncogenic in mice. The systemic NOEL 
was 300 ppm (39.8 and 54.1 mg/kg/day for males and females, 
respectively). This was based on hepatotoxicity among males and reduced 
body weights and food efficiency among females at 900 ppm (or 122 and 
163 mg/kg/day for males and females, respectively).
    A 2-year chronic toxicity/oncogenicity study was conducted in rats 
fed diets that contained 0, 5, 15, 30, 300 or 900 ppm technical 
azafenidin. This product was not oncogenic in rats. The systemic NOEL 
was 300 ppm (12.1 and 16.4 mg/kg/day males and females, respectively). 
The NOEL was defined by microcytic, hypochromic and hemolytic anemia 
and mortality at 900 (or 35.2 and 50.2 mg/kg/day for male and female 
rats, respectively).
    Technical azafenidin was administered for 1-year to dogs at dietary 
concentrations of 0, 5, 10, 120 and 360 ppm. The NOEL was 10 ppm (0.30 
mg/kg/day for males and females). This was based on observations of 
altered hepatocyte morphology, hydropic degeneration and elevated 
alanine aminotransferase and alkaline phosphatase at 30 ppm (0.86 and 
0.87 mg/kg/day for male and female dogs, respectively) and above.
    6. Animal metabolism. The metabolism of azafenidin in animals (rat 
and goat) is adequately understood and is similar among the species 
evaluated. Azafenidin was readily absorbed following oral 
administration, extensively metabolized and rapidly eliminated in the 
urine and feces. The terminal elimination half-life in plasma was 40 
hours in rats. Less than 1% of the administered dose was present in rat 
tissues at 120 hours. There were no volatile metabolites of azafenidin. 
The major metabolic pathways in the rat and goat consisted of rapid O-
dealkylation and production of hydroxyl derivatives, subsequent 
formation of glucuronide and sulfate conjugates and elimination of 
these conjugates in feces and urine. There was no evidence of 
accumulation of azafenidin or its metabolites in the tissues of either 
species or in the goat's milk.
    7. Metabolite toxicology. There is no evidence that the metabolites 
of azafenidin identified in animal or plant metabolism studies are of 
any toxicological significance. The existing metabolism studies 
indicate that the metabolites formed are unlikely to accumulate in 
humans or in animals that may be exposed to these residues in the diet. 
The fact that no quantifiable residues were found in edible portions of 
treated crops further indicates that exposures to and accumulation of 
metabolites are unlikely.

C. Aggregate Exposure

    1. Food--i.  Acute dietary exposure. Since there were no acute 
affects appropriate for assessment of the general population, the NOEL 
of 16 mg/

[[Page 63950]]

kg/day from the rat developmental toxicity study was used to assess 
acute dietary risk for females 13-years of age and older. Exposures 
were estimated using the DEEM computer software (version 5.03b, Novigen 
Sciences, Inc, 1997). The proposed azafenidin tolerances for the raw 
agricultural commodities and processed fractions that were used in the 
calculations included: grapes, 0.02 ppm; citrus, 0.1 ppm; and sugarcane 
- 0.02 ppm for cane sugar and 0.1 ppm for molasses. The following 
exposures indicate margins of exposure > 11,000 at the 95th percentile 
and provides a reasonable certainty that no harm to the individual or 
the developing child will occur under these conservative exposure 
assumptions (i.e., all labeled crops are treated, residues are present 
at the proposed tolerances and there is no reduction of residues prior 
to consumption of these food commodities).

------------------------------------------------------------------------
                                    Exposure - 95th                     
         Subpopulations           Percentile (mg/kg/         MOEa       
                                         day)                           
------------------------------------------------------------------------
13+/Pregnant; Not Nursing.......  0.000868            86,800            
13+/Nursing.....................  0.001384            11,561            
13 - 19/ Not Pregnant; Not        0.001119            14,561            
 Nursing.                                                               
20+/Not Pregnant; Not Nursing...  0.000832            0.19,231          
13 - 50 Years...................  0.000938            17,056            
------------------------------------------------------------------------
a MOE - Margin of Exposure = NOEL from rat developmental study (16 mg/kg/
  day) divided by the 95th percentile exposure.                         

    ii.Chronic dietary exposure. A Reference Dose (RfD) of 0.003 mg/kg/
day has been proposed based on the NOEL from the most sensitive chronic 
study (NOEL of 0.3 mg/kg/day from the 1-year dog study) and applying a 
100-fold uncertainty factor. General and subpopulation exposures were 
estimated using the DEEM computer software (version 5.03b, Novigen 
Sciences, Inc, 1997). The following proposed azafenidin tolerances for 
the raw agricultural commodities and processed fractions were used in 
the calculations: grapes, 0.02 ppm; citrus, 0.1 ppm; and sugarcane - 
0.02 ppm for cane sugar and 0.1 ppm for molasses. Exposure assessments 
assumed 100% of the crops were treated with azafenidin, that residues 
were present at the tolerance level and that no residues were removed 
prior to consumption of treated crops. These assessments indicated 
adequate margins of exposure for all subpopulations and that only 21% 
or less of the RfD was utilized by any group. For example, the TMRCs 
were 0.000237 mg/kg/day (7.9% RfD) for the general population and 
0.000619 mg/kg/day (20.6% RfD) for the subpopulation with the highest 
potential exposure, children ages 1 through 6 years.
    2. Drinking water. Other potential dietary sources of exposure of 
the general population to pesticides are residues in drinking water. 
There is no Maximum Contaminant Level established for residues of 
azafendidin. The petitioner is reporting to the Environmental Fate and 
Groundwater Branch of EPA (EFGWB) the interim results of a prospective 
groundwater monitoring study conducted at a highly vulnerable site. 
Based on the preliminary results of this study the petitioner does not 
anticipate residues of azafenidin in drinking water and exposure from 
this route is unlikely. However, given that less than 21% of the RfD is 
attained by the TMRC for the population subgroup with the highest 
theoretical dietary exposure (children 1-6 years of age), there is 
ample allowance for safe exposure to azafenidin via drinking water 
should it ever be detected.
    3. Non-dietary exposure. Azafenidin is proposed for use in weed 
control in selective non-food crop situations including certain 
temperate woody crops, and in non-crop situations including industrial 
sites and unimproved turf areas. Azafenidin is not be used in on 
residential temperate woody plantings, or on lawns, walkways, 
driveways, tennis courts, golf courses, athletic fields, commercial sod 
operations, or other high maintenance fine turf grass areas, or similar 
areas. Any non-occupational exposure to azafenidin is likely to be 
negligible.

C. Cumulative Effects

    The herbicidal activity of azafenidin is due to its inhibition of 
an enzyme involved with synthesis of the porphyrin precursors of 
chlorophyll, protoporphyrinogen oxidase. Mammals utilize this enzyme in 
the synthesis of heme. Although there are other herbicides that also 
inhibit this enzyme, there is no reliable information that would 
indicate or suggest that azafenidin has any toxic effects on mammals 
that would be cumulative with those of any other chemicals. In addition 
there is no valid methodology for combining the risks of adverse 
effects of overexposures to these compounds.

D. Safety Determination

    1. U.S. population. Based on the completeness and reliability of 
this azafenidin toxicology database and using the conservative 
aggregate exposure assumptions presented earlier, it has been concluded 
that azafenidin products may be used with a reasonable certainty of no 
harm relative to exposures from food and drinking water. A chronic RfD 
of 0.003 mg/kg/day has been proposed from the NOEL of the most 
sensitive chronic dietary study and the use of a 100-fold uncertainty 
factor. The TMRC determined for proposed tolerances in citrus, grapes 
and sugar cane utilized only 7.9% of the RfD (an exposure of 0.000237 
mg/kg/day). Although there was no data to accurately assess potential 
exposures through drinking water, the small fraction of the RfD 
utilized for food by the general and subpopulations indicate that is 
unlikely that aggregate exposures will exceed acceptable limits. In 
addition, the use patterns and physical chemical properties of 
azafenidin suggest that the potential for significant concentrations in 
drinking water are remote. It has been concluded that the aggregate 
exposure for the proposed tolerances on citrus, grapes and sugar cane 
provide a reasonable certainty of no harm to the general population. 
Because of effects observed in the rat developmental toxicology study, 
an acute safety determination based on margins of exposure was 
calculated from the NOEL of 16 mg/kg/day. The subpopulation potentially 
at risk was considered to be females 13-years of age and older. 
However, based on the MOEs presented previously of >11,000 at the 95th 
exposure percentile, it was concluded that these potential dietary 
exposures represented a reasonable certainty of no harm for this group. 
An MOE of 100 or greater is generally considered protective.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of azafenidin, data 
from the previously discussed developmental and multigeneration 
reproductive toxicity studies were considered. Developmental studies 
are designed to evaluate adverse effects on the developing organism 
resulting from pesticide exposure during pre-natal development. 
Reproduction studies provide information relating to reproductive and 
other effects on adults and offspring from pre-natal and post-natal 
exposures to the pesticide. The rat reproduction and developmental 
studies indicated developmental effects in this species at exposures 
that produced minimal maternal effects. A clear dose-response and 
developmental NOEL has been defined for these effects. FFDCA section

[[Page 63951]]

408 provides that EPA may apply an additional uncertainty 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. The 
additional uncertainty factor may increase the MOE from the usual 100- 
up to 1,000-fold. Based on current toxicological data requirements, the 
database for azafenidin relative to pre- and post-natal effects for 
children is complete. In addition, the NOEL of 0.3 mg/kg/day in the 1-
year dog study and upon which the RfD is based is much lower than the 
NOELs defined in the reproduction and developmental toxicology studies. 
Conservative assumptions utilized to estimate aggregate dietary 
exposures of infants and children to azafenidin (0.000619 mg/kg/day) 
demonstrated that only 20.6% of the RfD was utilized for the proposed 
tolerances. Based on these exposure estimates and the fact that MOEs in 
excess of 1,000-fold exist relative to the NOELs in the rat 
reproduction study (NOEL = 1.7 mg/kg/day and MOE = 2,746) and the rat 
developmental toxicity study (NOEL = 16 mg/kg/day and MOE = 25,848), 
the extra 10-fold uncertainty factor is not warranted for these groups. 
Therefore, it may be concluded that there is reasonable certainty that 
no harm will result to infants and children from aggregate exposures to 
azafenidin].

E. International Tolerances

    There are no established Canadian, Mexican or Codex MRLs for 
azafenidin. Compatibility is not a problem.
[FR Doc. 97-31542 Filed 12-2-97; 8:45 am]
BILLING CODE 6560-50-F