[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
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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