[Federal Register Volume 62, Number 209 (Wednesday, October 29, 1997)]
[Notices]
[Pages 56173-56180]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-28640]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-771; FRL-5749-7]
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-771, must
be received on or before November 28, 1997.
[[Page 56174]]
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: docket@epamail.epa.gov. 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: By mail: Sidney C. Jackson,
Registration Division (7505C), Office of Pesticide Programs, 401 M St.,
SW., Washington, DC 20460. Office location and telephone number, Rm.
274, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA., 703-
305-7610, e-mail: jackson.sidney@epamail.epa.gov.
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-771] (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:
opp-docket@epamail.epa.gov
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 6.1 or ASCII file format.
All comments and data in electronic form must be identified by the
docket number [PF-771] and appropriate petition number. Electronic
comments on this notice may be filed online at many Federal Depository
Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: October 22, 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. IR-4 Project
PP 2E4044 and 3E4164
EPA has received pesticide petitions (PP 2E4044 and 3E4164) from
the Interregional Research Project number 4 (IR-4), 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 tolerances for
residues of Triadimefon, 1-(4-Chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-
triazol-1-yl)-2-butanone, and its metablolites containing chlorophenoxy
and triazole moieties expressed as the fungicide in or on the raw
agricultural commodities artichoke, globe at 0.6 parts per million
(ppm) and pome fruits group (Crop Group 11) at 0.2 ppm. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition. This notice includes a
summary of each petition prepared by the Bayer Corporation(Bayer), the
registrant.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue in plants and
animals is adequately understood. The residue of concern is triadimefon
and its triazole and chlorophenoxy metabolites. Triadimefon is rapidly
absorbed by plants and translocated systemically in the young growing
tissue.
2. Analytical method. Adequate analytical methods are available for
analysis of triadimefon and its triazole and chlorophenoxy metabolites
in or on artichokes. These methods are available in PAM II as Method I.
3. Magnitude of residues. Three separate residue trials have been
conducted on globe artichokes and submitted to the EPA. The EPA has
determined that these data show that residues of triadimefon and its
metabolites containing chlorophenoxy and triazole moieties (expressed
as the fungicide) in the raw agricultural commodity artichokes, globe
will not exceed the proposed tolerance of 0.6 ppm.
For pome fruits and as part of the reregistration requirements for
triadimefon, Bayer has submitted nine trials on apples and six trials
on pears to the EPA. EPA's Chemistry Branch Tolerance Support has
concluded that these data are adequate to support the requested crop
group tolerance for triadimefon and its metabolites containing
chlorophenoxy and triazole moieties expressed as the fungicide in or on
pome fruit at 0.2 ppm.
There are no livestock feed stuffs from globe artichokes and pome
fruits, therefore, secondary residues in meat, milk, poultry and eggs
are not expected.
B. Toxicological Profile
1. Acute toxicity. A rat acute oral study resulted in a lethal dose
(LD50) of 568 61 milligrams (mg)/kilogram (kg)
[[Page 56175]]
for males and 363 41 mg/kg for females. In a rabbit acute
dermal study a LD50 of >2,000 mg/kg was determined. A rat
acute inhalation study produced a lethal concentration
(LC50) of >3.570 mg/liter(l). A primary eye irritation study
in the rabbit showed practically no irritation. A primary dermal
irritation study showed practically no irritation and a primary dermal
sensitization study indicated that triadimefon is a skin sensitizer.
2. Genotoxicity. Triadimefon has been found to be negative in the
Ames reverse mutation test and in the Structural Chromosome Aberration
Test.
3. Reproductive and developmental toxicity. A rat developmental
toxicity study showed a maternal systemic no-observed-effect level
(NOEL) of 30 mg/kg/day and the lowest-observed-effect level (LOEL) 90
mg/kg/day. The NOEL for developmental toxicity was 30 mg/kg/day and the
LOEL was 90 mg/kg/day.
In the developmental toxicity study in rabbits, the maternal
systemic NOEL was 50 mg/kg/day and the LOEL 120 mg/kg/day. The NOEL for
developmental toxicity was 20 mg/kg/day and the LOEL was 50 mg/kg/day.
Effects seen at the developmental lowest effect level(LEL) in the
rabbit study were irregular spinous process and ossification of various
bones.
A 3-generation rat reproduction study showed decreases in maternal
body weight gain, fertility, and in litter size, pups survival during
the lactation phase, and pups weights. The maternal NOEL was 300 ppm
and the reproductive NOEL was 50 ppm.
A 2-generation rat reproductive study showed reductions in litter
size, pups viability, birth and lactational weights. The reproductive
NOEL was 50 ppm.
4. Subchronic toxicity. A 3-month feeding study in the rat produced
a NOEL of 2,000 ppm based on decreased body weight gain and food
consumption attributed to palatability. A rat 30-day feeding study
showed a NOEL of 10 mg/kg. A 13-week dog-feeding study resulted in a
NOEL of 2,400 ppm based on decreased body weight gain and food
consumption due to palatability. Test results also showed a decreased
hematocrit, RBC count, hemoglobin volume and microsomal induction. A
28-day rabbit dermal study produced a NOEL >250 mg/kg and a 21-day
inhalation study in rats showed a NOEL of 78.7 mg/cubic
meters(m3)/6 hrs. per day/ 15 exposures.
5. Chronic toxicity. A 2-year rat chronic feeding study defined a
NOEL for systemic effect as 300 ppm (males = 16.4 mg/kg/day; females =
22.5 mg/kg/day). The systemic LOEL was 1,800 ppm (males = 114.0 mg/kg/
day; females = 199.0 mg/kg/day) based on neoplastic and systemic
effects. A dog feeding study showed only minimal toxic effects decrease
in body weight, increase in liver weight and in hepatic N-demethylase
activity, and an increase in serum alkaline phosphatase activity. The
NOEL was established at 100 ppm. A mouse oncogenicity study showed
hepatocellular adenomas in both sexes of NMRI mice. The NOEL was
established for males at 50 ppm. No NOEL was reached for females. A
mouse carcinogenicity study using CF1-W74 mice was negative for
carcinogenicity.
6. Animal metabolism. In a general rat metabolism study triadimefon
was initially converted by reduction of its carbonyl group. This
conversion was more rapid in males. The major metabolites were the acid
and alcohol of triadimefon. In males radioactivity was found mainly in
feces, whereas, in females, radioactivity was equally distributed
between urine and feces. No radioactivity was recovered in the expired
air. Peak tissue levels were found in 2 to 4 hours and were highest in
fat, liver and kidney.
7. Endocrine effects. No special studies investigating potential
estrogenic or endocrine effects of triadimefon have been conducted.
However, the standard battery of required studies has been completed.
These studies include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following repeated or long-term exposure. No adverse
effects were noted in any of the studies with either triadimefon or its
metabolites.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure from food under the proposed tolerances, the EPA
estimates exposure based on the Theoretical Maximum Residue
Contribution (TMRC). The TMRC is obtained by using a model which
multiplies the tolerance level residue for each commodity by
consumption data which estimates the amount of each commodity and
products derived from the commodities that are eaten by the U.S.
population and various population subgroups. The model uses a reference
dose (RfD) which the EPA has determined to be 0.04 milligrams(mg)/
kilogram(kg)/day. This RfD is based on a 2-year dog feeding study with
a NOEL of 11.4 mg/kg/day and an uncertainty factor of 300. An
uncertainty factor of 300 was applied to account for inter-species
extrapolation (10), intra-species variability (10), and the lack of an
adequate reproduction study (3). Decreased food intake, depression in
weight gain, and significantly (p >0.05) increased alkaline phosphatase
activity in both sexes were the effects observed at the lowest effect
level (LEL). This assessment assumes 100% of all commodities will
contain triadimefon residues, and those residues would be at the level
of the tolerance for estimating potential human exposure.
2. Food. Using assumptions discussed above, it was determined that
the TMRC for existing tolerances plus the proposed uses on globe
artichokes and pome fruits. For globe artichokes, the TMRC is
equivalent to 17% of the RfD for the US general population (48 states)
and 74% of the RfD for the highest population subgroup (non-nursing
infants >1 year old).
For pome fruits, the TMRC for triadimefon derived from the
previously established tolerances plus the proposed 0.2 ppm tolerance
for this crop group (pome fruit) would be 0.003782 mg/kg body
weight(bwt)/day (9.5% of the RfD) for the U.S. population 48 states and
0.009549 mg/kg bwt/day (23.9% of the RfD) for the most highly exposed
population subgroup, children (1-6 year old). Therefore, Bayer
concludes that dietary exposure from the existing and proposed uses
will not exceed the reference dose for any subpopulation including
infants and children.
For globe artichoke, the estimated acute dietary exposure is based
on a maternal NOEL of 10 mg/kg/day. The calculated Margin of Exposure
(MOE) for the general US population is 100 (at the 99th percentile);
for infants (>1 year old) 100 (at the 95th percentile); for children
(1-6 year old) 200 (at the 96th percentile); and for both females (13+
years) and males (13+ years) 333 (at the 99th percentile). These values
are all at or above the MOE level EPA considers to provide an adequate
safety margin (100).
3. Drinking water. Available data show that triadimefon and its
metabolites are mobile and persistent and have the potential to leach
into groundwater. There is no established Maximum Concentration Level
for residues of triadimefon in drinking water. No drinking water health
advisory levels have been issued for triadimefon or its metabolite
triadimefon. The ``Pesticides in Groundwater Database'' (EPA 734-12-92-
001, September 1992) indicated that triadimefon was monitored for in 14
wells in California from 1984 to 1989. There were no detectable
residues (limit of detection was not stated).
Previous experience with more persistent and mobile pesticides for
[[Page 56176]]
which there have been available data to perform quantitative risk
assessments have demonstrated that drinking water exposure is typically
a small percentage of the total exposure when compared to the total
dietary exposure. This observation holds even for pesticides detected
in wells and drinking water at levels nearing or exceeding established
maximum residue levels (MCL's). Best scientific judgement from
available data suggests that the potential exposure from residues of
triadimefon in drinking water, added to the current dietary exposure,
will not result in an exposure which exceeds the RfD.
4. Non-dietary exposure. Triadimefon is currently registered for
use on turf and ornamentals. Studies were conducted by Bayer designed
to measure the upper bound acute exposure potential of adults and
children from contact with triadimefon treated turf. The population
considered to have the greatest potential exposure from contact with
pesticide treated turf soon after pesticides are applied are young
children. The estimated safe residue levels for triadimefon on treated
turf for 10-year old children ranged from 1.3 - 6.4 micro
gram(g)/centimeter(cm)2 and for 5-year old children
from 1.1 - 5.6 g/cm2. This compares with the
average triadimefon transferable residue level of 1.0 g/
cm2 present immediately after the sprays have dried. Bayer
concludes from these studies that children can safely contact
triadimefon-treated turf as soon after application as the spray has
dried.
D. Cumulative Effects
At this time, the Agency has not made a determination that
triadimefon and other substances that may have a common mode of
toxicity would have cumulative effects. For purposes of this tolerance,
only the potential risks of triadimefon in its aggregate exposure are
being considered.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above
under aggregate exposure and based on the toxicity data, Bayer
concludes that aggregate dietary exposure to triadimefon from the
previously established tolerances plus the proposed use on globe
artichoke will utilize 17% of the RfD for the U.S. population (48
states) and 74% of the RfD for the most highly exposed population
subgroup (non-nursing infants >1 year old). In comparison, pome fruit
will vitilize 9.5% and 23.9% of the RfD for the same U.S. population
and for children (1-6 yrs), respectively. There is generally no concern
for exposures below 100 percent 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. Bayer concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to triadimefon.
Bayer estimated acute dietary exposure using the maternal NOEL of
10 mg/kg/day and determined that the calculated MOE for each population
group is at or above the MOE level EPA considers to provide an adequate
safety margin.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of triadimefon, the
data from developmental studies in both rat and rabbit and a 2-
generation reproduction study in the rat were considered. The
developmental toxicity studies evaluate any potential adverse effects
on the developing animal resulting from pesticide exposure of the
mother during prenatal development. The reproduction study evaluates
any effects from exposure to the pesticide on the reproductive
capability of mating animals through 2-generations, as well as any
observed systemic toxicity.
Results of a rat and rabbit developmental toxicity studies and a 2-
generation and 3-generation rat reproduction studies conducted with
triadimefon have been reviewed. Maternal and developmental toxicity
NOELs of 30 mg/kg/day were determined in the rat developmental toxicity
studies. In the rabbit developmental toxicity study, the maternal NOEL
was 50 mg/kg body weight(bwt)/day and the developmental NOEL was 20 mg/
kg bwt/day. The rat reproduction studies were inconclusive.
FFDCA Section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal effects and the completeness of the
toxicity database. Therefore, EPA has incorporated an additional 3-fold
uncertainty factor into the calculation of the RfD because of the
absence of an acceptable reproduction study.
There is approximately a two-fold difference between the
developmental NOEL of 20 mg/kg/day from the rabbit developmental
toxicity study and the NOEL of 11.4 mg/kg/day from the 2-year dog
feeding study which was the basis of the RfD. It is further noted that
in the rabbit developmental toxicity study, the developmental NOEL of
20 mg/kg/day is lower than the maternal systemic NOEL of 50 mg/kg/day,
suggesting the possibility of increased sensitivity for the pre-natal
child.
The TMRC value for the most highly exposed infant and children
subgroup (non-nursing infants >1 year old) occupies 74% of the RfD.
However, this calculation also assumes 100% crop treated and uses
tolerance level residues for all commodities. Refinement of the dietary
risk assessment by using percent of crop treated and anticipated
residue data would likely greatly reduce the dietary exposure estimate
and result in an anticipated residue contribution (ARC) which would
occupy a percent of the RfD that is substantially lower than the
currently calculated TMRC value.
Should an additional uncertainty factor be deemed appropriate, when
considered in conjunction with a refined exposure estimate, Bayer
believes it is unlikely that the dietary risk will exceed 100 percent
of the RfD. Due to the completeness and reliability of the toxicity
data and the exposure assessment, Bayer believes there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to triadimefon residues.
Bayer estimated acute dietary exposure using the maternal NOEL of
10 mg/kg/day and determined that the calculated MOE for infants and
children population groups is at or above the MOE level EPA considers
to provide an adequate safety margin.
F. International Tolerances
There are no CODEX, Canadian, or Mexican MRLs for triadimefon
residues in/on globe artichokes. A CODEX MRL for triadimefon residues
in/on pome fruits has been established at 0.5 ppm.
2. IR-4 Project
PP 6E4652
EPA has received a pesticide petition (PP 6E4652) from the
Interregional Research Project number 4 (IR-4), 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 the
combined residues of quizalofop-p ethyl ester [ethyl (R)-(2-[4-((6-
chloroquinoxalin-2-yl) oxy)phenoxy])-propanoate), and its acid
metabolite quizalofop-p [R-(2-[4-((6-chloroquinoxalin-2-
yl)oxy)phenoxy]) propanoic acid), and the S enantiomers of both the
ester and the acid, all expressed as quizalofop-p ethyl ester in or on
the raw agricultural commodities spearmint tops and peppermint tops at
3.0 parts per million(ppm). EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully
[[Page 56177]]
evaluated the sufficiency of the submitted data at this time or whether
the data support granting of the petition. Additional data may be
needed before EPA rules on the petition. This notice includes a summary
of the petition prepared by the DuPont Agricultural Products(DuPont),
the registrant.
A. Residue Chemistry
1. Plant metabolism. The registrant has provided plant metabolism
studies for soybeans, cotton, tomatoes, potatoes, and sugar beets.
These studies have been previously reviewed in PP 3F4268. In summary,
quizalofop-p ethyl ester is metabolized by cleavage at three sites as
follows: (a) Primary pathway is hydrolysis of the ethyl ester to form
the quizalofop-p acid, then (b) cleavage of the enol ether linkage in
the acid, between the phenyl and quinoxalinyl rings, to form phenols,
and (c) cleavage of the ether linkage between the isopropanic group and
the phenyl ring to form a phenol.
The plant metabolism data show that quizalofop-p ethyl ester does
not translocate, but is rapidly hydrolyzed to the corresponding acid;
then the phenols conjugate with the plant sugars. Metabolism studies in
soybeans using the racemic mixture quizalofop ethyl ester and the
resolved D+ isomer show nearly identical pathways.
The nature of the quizalofop-p ethyl ester residue in cottonseed,
potatoes, tomatoes, soybeans, and sugar beets is adequately understood.
The residues of concern are quizalofop-p ethyl ester and its acid
metabolite, quizalofop-p, and the S enantiomers of both the ester and
the acid, all expressed as quizalofop-p ethyl ester. EPA is translating
these data to mint.
2. Analytical method. An adequately validated residue analytical
method, LAN-1, was used to gather the magnitude of the quizalofop-p,
its acid metabolite, and residue data on mint hay and mint oil. Samples
were analyzed using MS30.00, an adaptation of Analytical Method for the
Quantification of Quizalofop (IN-YE945) and Quizalofop-Ethyl (DPX-
79379) in Raw and Processed Agricultural Commodities, Protocol No. Lan-
1, Enviro-Test Laboratory. (Reference Method: Determination of DPX-
79376, DPX-79376 Acid and Conjugates as DPX-79376 as Acid in Cottonseed
and Fractions Treated with Assure (II Herbicide. DuPont Report No. AMR
1853-90).
3. Magnitude of residues. The maximum residues detected on fresh
mint foliage at the proposed labeled level of DuPont's product, Assure,
of 0.2 pounds(lbs) active ingredient(ai) acre (1x) applied 30 days
before harvest were 0.22, 0.46, and 1.0 ppm for Indiana, Oregon and
Washington, respectively. The largest residue found on fresh mint
foliage, 2.6 ppm, was detected in a Washington sample treated with 0.4
lbs. acre (2x) 29 days before harvest, twice the maximum yearly rate
allowed. At the Level of Quantitation of 0.05 ppm, there were no
detectable residues in the mint oil, either at the proposed label rate
of 0.2 lbs. ai/acre(A), or at the exaggerated rate of 0.4 lbs. ai/A,
indicating that quizalofop-p ethyl and its acid metabolite are not
concentrated during the oil distillation process.
Results of a freezer storage stability study demonstrated that the
two compounds, quizalofop-p ethyl ester and quizalofop acid, were
stable in frozen storage at -20 degrees centigrade for 592 to 593 days
in mint hay, and 597 days in oil. Field samples were stored a maximum
of 654 days.
The residues detected in this study are well below the proposed
tolerances of 3.0 ppm for the raw agricultural commodity mint. The
nature of the residues is adequately understood and an adequate
analytical method is available for enforcement purposes. Based on the
information presented above, Dupont believes the establishment of the
proposed tolerance would protect the public health and would not expose
man or the environment to unreasonable adverse effects.
B. Toxicological Profile
1. Acute toxicity. Several acute toxicology studies were conducted
and the overall results placed technical grade quizalofop ethyl in
toxicity Category III. These include the following studies in Category
III: acute oral toxicity (LD50s 1,480 and 1,670 for female
and male rats, respectively) and eye irritation (mild effects;
reversible within 4 days). Dermal toxicity (lethal dose)
LD50 >5,000 milligram(mg)/kilogram(kg); rabbit), inhalation
toxicity (lethal concentration) LC50 >5.8 mg/liter(L); rat)
and dermal irritation were classified within Category IV. Technical
quizalofop ethyl was not a dermal sensitizer.
2. Genotoxicity. Technical quizalofop ethyl was negative in the
following genotoxicity tests: bacterial gene mutation assays with E.
coli and S. typhimurium; gene mutation assays in Chinese hamster
ovary(CHO) cells ; in vitro DNA damage assays with B. subtillis and in
rat hepatocytes; and an in vitro chromosomal aberration test in CHO
cells.
3. Reproductive and developmental toxicity. Studies supporting the
registration include: A developmental toxicity study in rats
administered dosage levels of 0, 30, 100, and 300 mg/kg/day (HDT). The
maternal toxicity no-observed-effect level (NOEL) was 30 mg/kg/day and
a developmental toxicity NOEL was greater than 300 mg/kg/day (HDT). The
maternal NOEL was based on reduced food consumption and increased liver
weights.
A developmental toxicity study in rabbits administered dosage
levels of 0, 7, 20, and 60 mg/kg/day with no developmental effects
noted at 60 mg/kg/day (HDT). The maternal toxicity NOEL was 20 mg/kg/
day based on decreases in food consumption and body weight gain at 60/
mg/kg/day (HDT).
A 2-generation reproduction study in rats fed diets containing 0,
25, 100 or 400 ppm (or approximately 1, 1.25, 5, and 20 mg/kg/day,
respectively) with a developmental (systemic effects) NOEL of 1.25 mg/
kg/day for F2B weanlings based on increased liver weights and increased
incidence of eosinophilic changes in the livers at 5.0 mg/kg/day. These
liver changes were considered to be physiological or adaptive changes
to compound exposure among weanlings. When access to the mother's feed
is available, it is a common observation that young rats will begin
consuming chow prior to complete weaning at 21-days of age. Consumption
could not be quantified; therefore, the maternal consumption was
assumed as the NOEL (if normalized on a body weight basis, exposures to
the weanling rats were likely higher). The parental NOEL of 5.0 mg/kg/
day was based on decreased body weight and premating weight gain in
males at 20 mg/kg/day (HDT).
4. Subchronic toxicity. A 90-day study was conducted in rats fed
diets containing 0, 40, 128, 1,280 ppm (or approximately 0, 2, 6.4 and
64 mg/kg/day, respectively). The NOEL was 2 mg/kg/day. This was based
on increased liver weights at 6.4 mg/kg.
A 90-day feeding study in mice was conducted with diets that
contained 0, 100, 316 or 1,000 ppm (or approximately 0, 15, 47.4, and
150 mg/kg/day, respectively). The NOEL was >15 mg/kg/day Lowest Dose
Tested (LDT) based on increased liver weights and reversible
histopathological effects in the liver at the LDT. A 6-month feeding
study in dogs was conducted with diets that contained 0, 25, 100 or 400
ppm (or approximately 0, 0.625, 2.5, and 10 mg/kg/day, respectively).
The NOEL was 2.5 mg/kg/day based on increased blood urea nitrogen at 10
mg/kg/day. A 21-day dermal study was conducted in rabbits at doses of
0, 125,
[[Page 56178]]
500 or 2,000 mg/kg/day. The NOEL was 2,000 mg/kg/day (HDT).
5. Chronic toxicity. An 18-month carcinogenicity study was
conducted in CD-1 mice fed diets containing 0, 2, 10, 80 or 320 ppm (or
approximately 0, 0.3, 1.5, 12, and 48 mg/kg/day, respectively). There
were no carcinogenic effects observed under the conditions of the study
at levels up to and including 12 mg/kg/day. A marginal increase in the
incidence of hepatocellular tumors was observed at 48 mg/kg/day, the
highest dose tested (HDT) which exceeded the maximum tolerated dose
(MTD).
A 2-year chronic toxicity/carcinogenicity study was conducted in
rats fed diets containing 0, 25, 100 or 400 ppm (or 0, 0.9, 3.7, and
15.5 mg/kg/day for males and 0, 1.1, 4.6, and 18.6 mg/kg/day for
females, respectively). There were no carcinogenic effects observed
under the conditions of the study at levels up to and including 18.6
mg/kg/day (HDT). The systemic NOEL was 0.9 mg/kg/day based on altered
red cell parameters and slight/minimal centrilobuler enlargement of the
liver at 3.7 mg/kg/day.
A 1-year feeding study was conducted in dogs fed diets containing
0, 25, 100 or 400 ppm (or approximately 0, 0.625, 2.5, and 10 mg/kg/
day, respectively). The NOEL was 10 mg/kg/day (HDT).
The Carcinogenicity Peer Review Committee (CPRC) of the EPA has
evaluated the rat and mouse cancer studies on quizalofop along with
other relevant short-term toxicity studies, mutagenicity studies, and
structure activity relationships. The CPRC concluded, after three
meetings and an evaluation by the EPA Science Advisory panel, that the
classification should be a Category D (not classifiable as to human
cancer potential). No new cancer studies were required.
The first CPRC review tentatively concluded that quizalofop should
be classified as a Category B2 (probable human carcinogen). That
classification was based on liver tumors in female rats, ovarian tumors
in female mice, and liver tumors in male mice. This classification was
downgraded to a Category C (possible human carcinogen) at a second CPRC
review. The change in classification was due to a reexamination of the
liver tumors in female rats and ovarian tumors in female mice. The
first peer review had found a statistically significant positive trend
for liver carcinomas in female rats. Subsequent to this conclusion the
tumor data were reevaluated, and the revaluation showed a reduced
number of carcinomas. Although there remained a statistically
significant positive trend for carcinomas in the study, the CPRC
concluded that the carcinomas were not biologically significant given
the few carcinomas identified (one at the mid-dose and two at the high
dose). Noting that this level of carcinomas was within historical
levels, the CPRC concluded that administration of quizalofop did not
appear to be associated with the liver carcinomas.
As to the ovarian tumors in female mice, the CPRC had first
attached importance to the fact that these tumors were statistically
significant at the high dose as compared to historical control values
although statistically significant when compared to concurrent
controls. However, review of further historical control data showed
that the level of ovarian tumors in the quizalofop study was similar to
the background rate in several other studies. Given this information
and that the quizalofop study showed no hyperplasia of the ovary, no
signs of endocrine activity related to ovarian function, and no dose
response relationship, the CPRC concluded that the ovarian tumors were
probably not compound-related.
The findings of the second CPRC review were presented to EPA's
Scientific Advisory Panel (SAP). The SAP concurred with the CPRC
conclusion that the liver tumors in female rats and the ovary tumors in
female mice showed no evidence of carcinogenicity. However, the SAP
disagreed with CPRC's classification of quizalofop as a Category C
based on the liver tumors in male mice. The SAP concluded that the
mouse liver tumors did not support such a classification because the
tumors occurred at a dose above the maximum-tolerated dose (MTD) and
because they were not statistically significant if a ``p''value of less
than 0.05. The SAP believed that such greater statistical rigor was
appropriate for variable tumor endpoints such as male mouse liver
tumors.
Following the SAP review, the CPRC changed the classification for
quizalofop to Category D. The Category D classification is based on an
approximate doubling in the incidence of male mice liver tumors between
controls an the high dose. This finding was not considered strong
enough to warrant the finding of a Category C (possible human
carcinogen) since the increase was of marginal statistical
significance, occurred at a high dose which exceeded the predicted MTD,
and occurred in a study in which the concurrent control for liver
tumors was somewhat low as compared to the historical controls, while
the high dose control group was at the upper end of previous historical
control-groups.
EPA has found the evidence on the carcinogenicity of quizalofop-p
ethyl ester in animals to be equivocal and therefore concludes that
quizalofop-p ethyl ester does not induce cancer in animals within the
meaning of the Delaney clause. Important to this conclusion was the
following evidence: (a) The only statistically significant tumor
response that appears compound-related was seen at a single dose in a
single sex in a single species; (b) the response was only marginally
statistically significant; (c) the response was only significant when
benign and malignant tumors were combined; (d) the tumors were in the
male mouse liver; (e) the tumors were within historical controls; and
(f) the mutagenicity studies were negative. Although in some
circumstances a finding of animal carcinogenicity would be made despite
any one, or even several, of the six factors noted, the combination of
all of these factors here cast sufficient doubt on the reproducibility
of the response in the high dose male mouse that EPA concludes the
evidence on carcinogenicity is equivocal.
6. Animal metabolism. The metabolism of quizalofop ethyl in animals
(rat, goat and poultry) is well understood. 14C-phenyl and
14C-quinoxaline quizalofop ethyl ester metabolism studies
have been conducted in each species. There are similarities among these
species with respect to metabolism. Quizalofop ethyl is rapidly and
extensively metabolized and rapidly excreted by rats. The principal
metabolites were the quizalofop-p acid and two dechlorinated
hydroxylated forms of the acid. Tissue residues were minimal and there
was no evidence of accumulation of quizalofop ethyl or its metabolites
in the rat.
The primary pathway in ruminants is hydrolysis of the ethyl ester
to form the quizalofop-p methyl ester. In poultry, the primary
metabolic pathway is also the hydrolysis of the ethyl ester to form the
quizalofop-p acid, then the methyl esterification to form the
quizalofop methyl ester becomes a minor pathway.
The nature of the quizalofop ethyl ester residue in livestock is
adequately understood. The residues of concern are quizalofop ethyl,
quizalofop methyl, and quizalofop, all expressed as quizalofop ethyl.
7. Metabolite toxicology. There is no evidence that the metabolites
of quizalofop ethyl as identified as either the plant or animal
metabolism studies are of any toxicological significance.
[[Page 56179]]
C. Aggregate Exposure
1. Dietary exposure. An analysis of chronic dietary risk was
conducted to determine the impact of the possible addition of
peppermint and spearmint to the Assure label. A Reference Dose (RfD) of
0.009 mg/kg/day was used in the analyses. Consumption data were
available for peppermint and spearmint from previous studies.
2. Food. The first step in the analysis was to run the TAS
(Tolerance Assessment System) program using current tolerances with an
RfD of 0.009 mg/kg/day. The Theoretical Maximum Residue Concentration
(TMRC), based on the current tolerances, was 0.000288 mg/kg/day for the
U.S. population (48 states) and 0.000759 mg/kg/day for the population
subgroup with the highest estimated exposure (non-nursing infants >1
year old). For the U.S. population subgroup this represents
approximately 3.2% of the RfD while for the most exposed population
this represents approximately 8.4% of the RfD. Based on the risk
estimates arrived at in this analysis, chronic dietary risk from the
current uses of Assure is minimal.
Consumption data for peppermint and spearmint within the TAS
database are available only for the entire U.S. population (48 states)
and not for the population subgroups. For peppermint the consumption is
listed as 0.000001 gram(g)/kg body weight(bw)/day for the raw commodity
and 0.000255 for the flavoring oil. For spearmint the consumption is
0.000001 g/kg bw/day for the raw commodity and 0.000458 for the
flavoring oil. The TMRC, based on the current tolerances and the
potential peppermint and spearmint tolerances, was 0.000290 mg/kg/day
for the U.S. population (48 states). Since no consumption data were
available for population subgroups, Theoretical Maximum Residue
Concentrations did not change and the sub group with the highest
potential exposure had a TMRC of 0.000759 g/kg/day (non-nursing infants
>1 year old). When expressed as a percentage of the RfD, the U.S.
population (48 states) was approximately 3.2% and that of the
population subgroup with the highest potential exposure, i.e. infants
and children, was approximately 8.4%. These results indicate that
predicted chronic exposure after the addition of a peppermint tolerance
is well below the RfD. The lack of specific population sub-group data
for these commodities should not be a problem since both peppermint and
spearmint are not likely to be consumed in large quantities by any
population subgroup and the difference between the TMRC and the RfD is
so great.
3. Drinking water. Another potential source of dietary exposure to
pesticides is residues in drinking water. There is no established
Maximum Concentration Level (MCL) for quizalofop ethyl in water. Based
on the low use rate of quizalofop ethyl, and a use pattern that is not
widespread (since the current and proposed uses are on minor crops),
DuPont does not anticipate residues of quizalofop in drinking water and
exposure from this route is unlikely.
4. Non-dietary exposure. Quizalofop ethyl is not registered for any
use which could result in non-occupational, non-dietary exposure to the
general population.
D. Cumulative Effects
There is no evidence to indicate or suggest that quizalofop p-ethyl
has any toxic effects on mammals that would be cumulative with those of
any other chemicals.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above
and based on the most sensitive species chronic NOEL of 0.9 mg/kg and a
reference dose (RfD) of 0.009 mg/kg/day, the existing tolerances and
proposed use of quizalofop ethyl on mint are expected to utilize 3.2%
of the RfD for the general U.S. population. Generally, exposures below
100% of the RfD are of no concern because the RfD represents the level
at or below which daily aggregate dietary exposure over a lifetime will
not pose risk to human health. Thus, there is a reasonable certainty
that no harm will result from aggregate exposure to quizalofop ethyl
resulting from proposed agricultural use on peppermint and spearmint.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of quizalofop ethyl,
data were considered from developmental toxicity studies in the rat and
rabbit, and a multi-generation reproduction study in rats. There were
no developmental effects observed in the absence of maternal toxicity
in the rat and rabbit developmental studies. Minimal adaptive or
physiological effects were observed in livers of weanlings in the 2-
generation rat reproduction study described earlier. However, this
effect was only observed at a dose that far exceeds any expected human
exposure. Further, the NOEL of 0.9 mg/kg/day from the 2-year rat study
with quizalofop ethyl, which was used to calculate the RfD(discussed
above), is already lower than any of the NOELs defined in the
developmental and reproductive toxicity studies with quizalofop ethyl.
Using the exposure assumptions described above and based on the
most sensitive species chronic NOEL of 0.9 mg/kg and a reference dose
(RfD) of 0.009 mg/kg/day, the existing tolerances and proposed use of
quizalofop ethyl on mint are expected to utilize 8.4% of the RfD for
infants and children. Infants and children have a low potential for
quizalofop ethyl exposure because of both the low levels of mint in the
diet (mint is a low dietary intake crop used primarily as an oil for
flavoring, and is diluted to a ratio of 1:250 or greater in the
finished food product), and the absence of detectable residues in mint
oil. The toxicology profile of quizalofop ethyl demonstrates low
mammalian toxicity. Because there was no evidence that offspring were
uniquely susceptible to the toxic effects of quizalofop ethyl, an
additional 10-fold uncertainty factor should not be required to protect
infants and children. Therefore, the registrant believes that the RfD
of 0.009 mg/kg/day, which utilizes a 100-fold safety factor, is
appropriate to assure a reasonable certainty of no harm to infants and
children from aggregate exposure to quizalofop ethyl.
F. International Tolerances
Since there are no Mexican, Canadian, or Codex MRLs/tolerances,
compatibility is not a problem at this time.
3. IR-4 Project
PP 6E4658
EPA has received a pesticide petition ( PP 6E4658 ) from the
Interregional Research Project Number 4 (IR-4), 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 to establish an exemption from the
requirements of a tolerance for copper-ethylenediamine complex (Komeen)
in or on the raw agricultural commodity (RAC) potatoes. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition. This notice includes a
summary of the petition prepared by the Griffin Corporation (Griffin),
the registrant.
[[Page 56180]]
A. Residue Chemistry
1. Analytical method. A practical analytical method for copper-
ethylenediamine complex is not required for crop use since it is
expected that no residues will occur in RACs.
2. Magnitude of residues. Residues are not expected in the RAC
(potatoes) since the potato tubers are underground and only the vines
which are above ground are treated.
B. Toxicological Profile
The Agency does not require subchronic, chronic, reproductive or
developmental toxicity studies for the copper salts.
Copper-ethylenediamine(Komeen) is slightly to moderately toxic upon
acute oral, dermal and inhalation exposure, slightly irritating to the
skin and moderately irritating to the eye.
Acute toxicity. The acute oral lethal dose LD50 (95%
confidence limits) for Komeen was 498 milligram(mg)/kilogram(kg) (349-
710 mg/kg).
The acute dermal LD50 for Komeen was determined to be
>2,000 mg/kg.
The acute inhalation lethal concentration LC50 (95%
confidence limits) for Komeen was 0.81 mg/liter(l) (0.26-1.37 mg/l).
Komeen was shown to be moderately irritating to the eye with all
signs of ocular irritation cleared within 10 days of treatment.
C. Aggregate Exposure
1. Dietary (food) exposure. Based on the proposed used pattern of
potato vine desiccation, no copper residues are expected to occur on
potatoes and the dietary exposure would be negligible by comparison to
the normal daily intake of copper. A single day's diet may contain 10
mg or more of copper. The daily recommended allowance of copper for
adults nutritional needs is 2 mg.
2. Drinking water. Copper is ubiquitous in the environment and
found in natural water. In 1991, the USEPA established a maximum
contamination level (MCL) for copper in drinking water of 1.3 mg/l. No
impact on copper levels found naturally in water would occur as a
result of potato vine desiccant use for this product.
3. Non-dietary exposure. Copper is registered for use as an aquatic
herbicide for outdoor residential sites. Any contributions to aggregate
exposure from this use would not be expected to be significant.
4. Potential for endocrine effects. Since copper is required for
homeostasis, low copper dietary exposures would not be expected result
in any adverse endocrine effects.
D. Cumulative Effects
Griffin believes that no cumulative adverse effects are expected
from long-term exposure to copper salts. No other elements are expected
to produce cumulative toxicity with copper.
E. Safety Determination
Copper compounds such as copper sulfate pentahydrate are considered
as Generally Recognized as Safe (GRAS) by the Food and Drug
Administration and as such are exempt from the requirement of a
tolerance when used as aquatic herbicides (40 CFR 180.1021). Copper
compounds are also exempt from the requirement of a tolerance when
applied to growing crops when used as a plant fungicide in accordance
with good agricultural practices (40 CFR 180.1001(b)(1). Copper-
ethylenediamine complex is registered as an aquatic herbicide under the
trade name, Komeen.
1. U.S. population. Copper is a component of the human diet and an
essential element. Use of copper-ethylenediamine complex is not
expected to increase the amount of copper in the diet as a result of
potato vine desiccation.
2. Infants and children. Infants and children also require copper
in their diets and Griffin believes that no special sensitivity for
this population subgroup would be expected as a result of the proposed
use.
F. International Tolerances
No international tolerances have been established for copper-
ethylenediamine complex.
[FR Doc. 97-28640 Filed 10-28-97; 8:45 am]
BILLING CODE 6560-50-F
