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Notice of Filing of Pesticide Petitions
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: December 17, 1997 (Volume 62, Number 242)]
[Notices]
[Page 66077-66083]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17de97-72]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-781; FRL-5758-3]
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-781, must
be received on or before January 16, 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-
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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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James Tompkins (PM 25)........ Rm. 265, CM #2, 703- 1921 Jefferson
305-7801, e- Davis Hwy,
mail:tompkins.james@e Arlington, VA
pamail.epa.gov.
Elizabeth Haeberer............ Rm. 207, CM #2, 703- Do.
308-2891, e-mail:
haeberer.elizabeth@ep
amail.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-781]
[[Page 66078]]
(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 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number PF-781 and appropriate petition number.
Electronic comments on 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: December 4, 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. Bayer Corporation
PP 5F4480
EPA has received a pesticide petition (PP 5F4480) from Bayer
Corporation, 8400 Hawthorn Rd., P.O. Box 4913, Kansas City, MO 64120-
0013. 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 imidacloprid in or on the raw
agricultural commodity pecans at 0.05 parts per million (ppm). The
proposed analytical method involves homogenization, filtration,
partition and cleanup with analysis by high performance liquid
chromatography using UV 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 metabolism of imidacloprid in plants is
adequately understood for the purposes of these tolerances. The
residues of concern are combined residues of imidacloprid and its
metabolites containing the 6-chloro-pyridinyl moiety, all calculated as
imidacloprid.
2. Analytical method. The analytical method is a common moiety
method for imidacloprid and its metabolites containing the 6-
chloropyridinyl moiety using a permanganate oxidation, silyl
derivatization, and capillary GC-MS selective ion monitoring. This
method has successfully passed a petition method validation in EPA
labs. There is a confirmatory method specifically for imidacloprid and
several metabolites utilizing GC/MS and HPLC-UV which has been
validated by the EPA as well. Imidacloprid and its metabolites are
stable for at least 24 months in the commodities when frozen.
3. Magnitude of residues. Field studies were conducted to determine
imidacloprid residues on pecans following treatment with either a
single soil or two foliar applications. Seven field studies were
conducted using a single soil application of 0.5 lb active ingredient
per acre. 5-field studies were conducted using two foliar applications
at a rate of 0.17 lb active ingredient per acre, with a 10-day
interval. After the final foliar application or the soil application,
samples were collected at earliest harvest which ranged from 4 to 21-
days for the foliar application or 99 to 150 days for the soil
application. Maximum residues, in pecans, detected following either 2
foliar applications or 1 soil application were >0.05 ppm. Therefore, a
tolerance of 0.05 ppm of pecans is being proposed with a preharvest
interval defined as earliest harvest (shuck split). CBTS has concluded
that existing poultry meat and egg tolerances are adequate to support
the proposed new uses of imidacloprid.
B. Toxicological Profile
1. Acute toxicity. The acute oral LD50 values for
imidacloprid technical ranged from 424 - 475 milligrams/kilogram/
bodyweight (mg/kg/bwt) in the rat. The acute dermal LD50 was
greater than 5,000 mg/kg in rats. The 4-hour rat inhalation
LC50 was >69 mg/m3 air (aerosol). Imidacloprid
was not irritating to rabbit skin or eyes. Imidacloprid did not cause
skin sensitization in guinea pigs.
2. Genotoxicty. Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, both using in vitro and in vivo test systems show
imidacloprid to be non-genotoxic.
3. Reproductive and developmental toxicity. A 2-generation rat
reproduction study gave a no-observed-effect level (NOEL) of 100 ppm (8
mg/kg/bwt). Rat and rabbit developmental toxicity studies were negative
at doses up to 30 mg/kg/bwt and 24 mg/kg/bwt, respectively.
4. Subchronic toxicity. 90-day feeding studies were conducted in
rats and dogs. The NOEL's for these tests were 14 milligrams/kilogram/
bodyweight/day (mg/kg/bwt/day) (150 pm) 5 mg/kg/bwt/day (200 ppm) for
the rat and dog studies respectively.
5. Chronic toxicity. A 2-year rat feeding/carcinogenicity study was
negative for carcinogenic effects under the conditions of the study and
had a NOEL of 100 ppm (5.7 mg/kg/bwt in male and 7.6 mg/kg/bwt female)
for noncarcinogenic effects that included decreased body weight gain in
females at 300 ppm and increased thyroid lesions in males at 300 ppm
and females at 900 ppm. A 1-year dog feeding study indicated a NOEL of
1,250 ppm (41 mg/kg/bwt). A 2-year mouse carcinogenicity study that was
negative for carcinogenic effects under conditions of the study and
that had a NOEL of 1,000 ppm 208 milligrams/kilogram/day (mg/kg/day).
Imidacloprid has been classified under ``Group E'' (no evidence of
carcinogenicity) by EPA's OPP/HED's Reference Dose (RfD) Committee.
There is no cancer risk associated with exposure to this chemical. The
reference dose (RfD) based on the 2-year rat feeding/carcinogenic study
with a NOEL of 5.7 mg/kg/bwt and 100-fold uncertainty factor, is
calculated to be 0.057 mg/kg/bwt. The theoretical maximum residue
contribution (TMRC) from published uses is 0.008187 mg/kg/bwt/day
utilizing 14.4% of the RfD.
6. Animal metabolism. The metabolism of imidacloprid in animals
[[Page 66079]]
is adequately understood. The residues of concern are combined residues
of imidacloprid and its metabolites containing the 6-chloro-
pyridinylmoiety, all calculated as imidacloprid.
C. Aggregate Exposure
Imidacloprid is a broad-spectrum insecticide with excellent
systemic and contact toxicity characteristics with both food and non-
food uses. Imidacloprid is currently registered for use on various food
crops, tobacco, turf, ornamentals, buildings for termite control, and
cats and dogs for flea control.
1. Dietary exposure. The EPA has determined that the reference dose
(RfD) based on the 2-year rat feeding/carcinogenic study with a NOEL of
5.7 mg/kg/bwt and 100-fold uncertainty factor, is calculated to be
0.057 mg/kg/bwt.
2. Food. The theoretical maximum residue contribution (TMRC) from
this proposed use on Pecans as well as all published uses and pending
uses is 0.008149 mg/kg/bwt/day utilizing 14.3% of the RfD for the
general population. For the most highly exposed subgroup in the
population, children (1-6 years), the TMRC for the all uses is 0.018367
mg/kg/day. This is equal to 32.2% of the RfD. Therefore, dietary
exposure from the existing uses including the currently proposed
tolerance will not exceed the reference dose for any subpopulation
(including infants and children).
3. Drinking water. Although the various imidacloprid labels contain
a statement that this chemical demonstrates the properties associated
with chemicals detected in ground water, the Registrant is not aware of
imidacloprid being detected in any wells, ponds, lakes, streams, etc.
from its use in the U.S. In studies conducted in 1995, imidacloprid was
not detected in 17 wells on potato farms in Quebec, Canada. In
addition, ground water monitoring studies are currently underway in
California and Michigan. Therefore, contributions to the dietary burden
from residues of imidacloprid in water would be inconsequential.
4. Non-dietary exposure-- i. Residential turf. Bayer has conducted
an exposure study to address the potential exposures of adults and
children from contact with imidacloprid treated turf. The population
considered to have the greatest potential exposure from contact with
pesticide treated turf soon after pesticides are applied is young
children. Margins of safety (MOS) of 7,587 - 41,546 for 10-year-old
children and 6,859 - 45,249 for 5-year-old children were estimated by
comparing dermal exposure doses to the imidacloprid no-observable
effect level of 1,000 mg/kg/day established in a 15-day dermal toxicity
study in rabbits. The estimated safe residue levels of imidacloprid on
treated turf for 10-year-old children ranged from 5.6 - 38.2 g/
cm2 and for 5-year-old children from 5.1 - 33.5 g/
cm2. This compares with the average imidacloprid
transferable residue level of 0.080 g/cm2 present
immediately after the sprays have dried. These data indicate that
children can safely contact imidacloprid-treated turf as soon after
application as the spray has dried.
ii. Termiticide. Imidacloprid is registered as a termiticide. Due
to the nature of the treatment for termites, exposure would be limited
to that from inhalation and was evaluated by EPA's Occupational and
Residential Exposure Branch (OREB) and Bayer. Data indicate that the
Margins of Safety for the worst case exposures for adults and infants
occupying a treated building who are exposed continuously (24 hours/
day) are 8.0 x 107 and 2.4 x 108,
respectively - and exposure can thus be considered negligible.
iii. Tobacco smoke. Studies have been conducted to determine
residues in tobacco and the resulting smoke following treatment.
Residues of imidacloprid in cured tobacco following treatment were a
maximum of 31 ppm (7 ppm in fresh leaves). When this tobacco was burned
in a pyrolysis study only 2% of the initial residue was recovered in
the resulting smoke (main stream plus side stream). This would result
in an inhalation exposure to imidacloprid from smoking of approximately
0.0005 mg per cigarette. Using the measured subacute rat inhalation
NOEL of 5.5 mg/m3, it is apparent that exposure to
imidacloprid from smoking (direct and/or indirect exposure) would not
be significant.
iv. Pet treatment. Human exposure from the use of imidacloprid to
treat dogs and cats for fleas has been addressed by EPA's OREB who have
concluded that due to the fact that imidacloprid is not an inhalation
or dermal toxicant and that while dermal absorption data are not
available, imidacloprid is not considered to present a hazard via the
dermal route.
D. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data, it can be concluded that total aggregate exposure to
imidacloprid from all current uses including those currently proposed
will utilize little more than 15% of the RfD for the U.S. population.
EPA generally has no concerns 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. Thus, it can be concluded that there is a reasonable certainty
that no harm will result from aggregate exposure to imidacloprid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of imidacloprid, the
data from developmental studies in both rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure of the mother
during prenatal development . The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through two generations, as well as any observed systemic
toxicity.
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. Based on current toxicological data requirements,
the toxicology database for imidacloprid relative to pre- and post-
natal effects is complete. Further for imidacloprid, the NOEL of 5.7
mg/kg/bwt from the 2-year rat feeding/ carcinogenic study, which was
used to calculate the RfD (discussed above), is already lower than the
NOELs from the developmental studies in rats and rabbits by a factor of
4.2 to 17.5 times. Since a 100-fold uncertainty factor is already used
to calculate the RfD, it is surmised that an additional uncertainty
factor is not warranted and that the RfD at 0.057 mg/kg/bwt/day is
appropriate for assessing aggregate risk to infants and children.
Using the conservative exposure assumptions described above, it can
be concluded that the TMRC from use of imidacloprid from published and
pending uses is 0.008149 mg/kg/bwt/day utilizing 14.3% of the RfD for
the general population. For the most highly exposed subgroup in the
population, children (1-6 years), the TMRC for the published tolerances
is 0.018367 mg/kg/day. This is equal to 32.2% of the RfD. Therefore,
dietary exposure from the existing uses including the currently
proposed tolerances will not exceed the reference dose for any
subpopulation (including infants and children).
[[Page 66080]]
E. International Tolerances
No CODEX Maximum Residue Levels (MRL's) have been established for
residues of Imidacloprid on any crops at this time. (Elizabeth Haeberer)
2. E. I. Du Pont de Nemours & Company
PP 5F4545
EPA has received a pesticide petition (PP 5F4545) from E. I. Du
Pont de Nemours & Company (DuPont), P.O. Box 80038, 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 to
establish an exemption from the requirement of a tolerance for
quizalofop (2-[4-(6-chloroquinoxalin-2-yl)oxy) phenoxy]) - propanoic
acid], and quizalofop ethyl [ethyl-2- [4-(6-chloroquinoaxalin-2-yl)oxy)
phenoxy) propanoat in or on the raw agricultural commodities canola
seed and canola meal . The proposed analytical method involves
homogenization, filtration, partition and cleanup with analysis by high
performance liquid chromatography using UV 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. Quizalofop-p ethyl ester is metabolized by
cleavage at three sites as follows:
(i) Primary pathway is hydrolysis of the ethyl ester to form the
quizalofop-p acid, then (ii) Cleavage of the enol ether linkage in the
acid, between the phenyl and quinoxalinyl rings, to form phenols, and
(iii) 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 plants 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.
2. Analytical method. An adequate analytical methodology (high-
pressure liquid chromatography using either ultraviolet or fluorescence
detection) is available for enforcement purposes in Vol. II of the Food
and Drug Administration Pesticide Analytical Method (PAM II, Method I).
Adequately validated residue analytical methods, LAN-1 and LAN-3,
were used to gather the magnitude of the quizalofop-p, its acid
metabolite, phenols 1, 2, and 4, residue data on canola and canola
processed commodities.
3. Magnitude of residues. Dupont proposes establishing tolerances
for the combined residues of quizalofop (2-[4-(6-chloroquinoaxalin-2-
yl)oxy) phenoxy])-propionic acid], and quizalofop ethyl [ethyl-2- [4-
(6-chloroquinoxalin-2-yl)oxy) phenoxy) propanoat for the raw
agricultural commodities canola seed at 1.0 parts per million (ppm) and
canola meal at 1.5 ppm.
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 (LD50 > 5,000 mg/
kg; rabbit), inhalation toxicity (LC50 > 5.8 mg/L; rat) and
dermal irritation were classified within Category IV. Technical
quizalofop ethyl was not a dermal sensitizer.
2. Genotoxicty. 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 milligrams/kilogram/
day (mg/kg/day) highest dose tested (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, 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
(HDT) which exceeded the maximum tolerated
[[Page 66081]]
dose (MTD). (Please see the discussion by the EPA HED Carcinogenicity
Peer Review Committee.)
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 g/
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 HED 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 OPP 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 was 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 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: (1) The only statistically significant tumor
response that appears compound-related was seen at a single dose in a
single sex in a single species; (2) the response was only marginally
statistically significant; (3) the response was only significant when
benign and malignant tumors were combined; (4) the tumors were in the
male mouse liver; (5) the tumors were within historical controls; and
(6) 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.
C. Aggregate Exposure
1. Dietary exposure. Quizalofop ethyl is a herbicide with proposed
use on canola. The only potential for non-occupational aggregate
exposure would come from dietary intake.
An analysis of chronic dietary risk was conducted to determine the
impact of the possible addition of canola to the Assure label. A
Reference Dose (RfD) of 0.009 mg/kg/day was used in the analyses.
Consumption data for canola
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had to be estimated using various production and usage statistics.
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-
yr. 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.
Unfortunately the 1977-1979 food consumption database does not
contain any consumption data for canola oil. At the time the survey was
conducted, canola oil was not a significant part of the U.S. diet.
Since 1977 more canola oil is used in U.S. homes, although total
production and usage are still minor as compared to soybean oil.
Conservative assumptions were used to estimate canola consumption in
the U.S. The USDA's Oilseed Analysis Division indicated that an average
of 1.1 billion pounds of canola oil was used in the U.S. annually over
the past 5-years. The dietary exposures that might occur by way of
consumption of canola oil can be estimated by taking the average annual
consumption of canola oil in the U.S. (includes both domestically
produced and imported canola oils) and dividing it by the approximate
U.S. population of 266.3 million people. This gives a per-capita
consumption estimate for the general population. To calculate exposure,
this number is divided by the average number of days in a year and the
average body weight of a person (60 kg). (This weight is the same that
was used by EPA as part of their ``Food Factor'' system that predated
the current Tolerance Assessment System). This value is also supported
by taking the average weight of children between the ages of 6-months
to 19-years (36 kg) and the average weight of adults (70 kg), and
assuming that an average person lives to be 69-years old (Review Draft
of the Exposure Factors Handbook, U.S. EPA). Using these assumptions,
canola oil consumption was calculated to be 0.088 g/kg bw/day.
While this method provides a useful estimate of exposure, it is
clearly a conservative estimate for risk assessment purposes, since
this estimate assumes that all the canola oil used in the U.S. is
indeed ingested. In reality some percentage of any commodity is lost
between production and consumption. In addition, oil may be used in
cooking activities such as deep-fat frying where most of the oil is not
actually eaten but is discarded or recycled. With the understanding
that the dietary analysis will be very conservative, the consumption
data for canola used in the DRES analysis for all population subgroups
was set at 0.088 g/kg bw/day. This was done by entering a consumption
estimate of 0.088 for ``rapeseed'' for all population subgroups (there
is no agricultural commodity in TAS for canola oil).
When a tolerance for canola (1.0 ppm) was added to the current
tolerances, the TMRC was 0.000376 mg/kg/day for the U.S. population (48
states) and 0.000847 mg/kg/day for the highest population subgroup
(non-nursing infants >1-yrs. old). When expressed as a percentage of
the RfD, the U.S. population (48 states) was approximately 4.2% and the
highest population subgroup was approximately 9.4%. These results
indicate that predicted chronic exposure after the addition of a canola
tolerance is well below the RfD even with the conservative (high)
nature of the assumptions that were made in calculating consumption.
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 conservative 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 canola are expected
to utilize 4.2% 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 canola.
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 NOEL's defined in the
developmental and reproductive toxicity studies with quizalofop ethyl.
As mentioned previously, canola oil is a very minor component of
the diet, and thus had not been included as part of the 1977-79 food
survey used in EPA's DRES system. DuPont is not aware of specific food
survey data concerning consumption of canola oil by infants and
children. However, the 1977-79 food survey database does provide
consumption data for other edible oils for each of the population
subgroups, including infants and children. This data indicates that
non-nursing infants consume more soybean and coconut oil than any of
the other 22 population subgroups, specifically consuming 4.2 times
more soybean oil and 49.1 times more coconut oil than the consumption
by the general U.S. population. The data also show that children 1-6
consume more corn, cottonseed, peanut, and sunflower oil than any other
subgroup listed, to a maximum of 2 times more than the general U.S.
population. Using this data and making the most conservative assumption
to extrapolate to canola oil, we can estimate that infants and children
consume 49 times more canola oil than does the U.S. population, and
calculate an approximate daily consumption of 4.3 grams canola oil/kg
body weight. If we use the additional conservative assumptions that all
the canola oil consumed contains
[[Page 66083]]
quizalofop ethyl residues at tolerance levels of 1.0 ppm, we calculate
that the TMRC in the infants' and children's diets would be 0.000847
mg/kg/day or 9.4% of the RfD.
As indicated above, infants and children have a low potential for
quizalofop ethyl exposure because of both the low levels of canola oil
in the diet, and the absence of detectable residues in field-treated
canola. 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 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
Harmonization of Tolerances: Since there are no Mexican or Codex
MRLs/tolerances, compatibility is not a problem at this time.
Compatibility cannot be achieved with the Canadian negligible residue
type limit at 0.1 ppm at the USA use pattern, which had findings of
real residues above 0.1 ppm. (James Tompkins)
[FR Doc. 97-32935 Filed 12-16-97; 8:45 am]
BILLING CODE 6560-50-F