[Federal Register Volume 62, Number 242 (Wednesday, December 17, 1997)]
[Notices]
[Pages 66077-66083]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-32935]


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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: <a href="/cdn-cgi/l/email-protection#9bf4ebebb691fff4f8f0feefdbfeebfaf6faf2f7b5feebfab5fcf4ed">opp-
<span class="__cf_email__" data-cfemail="791d161a121c0d391c091814181015571c0918571e160f">[email protected]</span></a>. 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:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="deaab1b3aeb5b7b0adf0b4bfb3bbad9ebb">[email protected]</a>   Arlington, VA  
                                 pamail.epa.gov.                        
Elizabeth Haeberer............  Rm. 207, CM #2, 703-    Do.             
                                 308-2891, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#c3aba2a6a1a6b1a6b1eda6afaab9a2a1a6b7ab83a6b3c9a2aea2aaafeda6b3a2eda4acb5"><span class="__cf_email__" data-cfemail="86eee7e3e4e3f4e3f4a8e3eaeffce7e4e3f2eec6e3f6">[email protected]</span>
amail.epa.gov</a>.                         
------------------------------------------------------------------------

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:
    <a href="/cdn-cgi/l/email-protection#2f405f5f024b404c444a5b6f4a5f4e424e4643014a5f4e01484059"><span class="__cf_email__" data-cfemail="adc2dddd80c9c2cec6c8d9edc8ddccc0ccc4c183c8ddcc83cac2db">[email protected]</span></a>

    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 LD<INF>50</INF> values for 
imidacloprid technical ranged from 424 - 475 milligrams/kilogram/
bodyweight (mg/kg/bwt) in the rat. The acute dermal LD<INF>50</INF> was 
greater than 5,000 mg/kg in rats. The 4-hour rat inhalation 
LC<INF>50</INF> was >69 mg/m<SUP>3</SUP> 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/
cm<SUP>2</SUP> and for 5-year-old children from 5.1 - 33.5 g/
cm<SUP>2</SUP>. This compares with the average imidacloprid 
transferable residue level of 0.080 g/cm<SUP>2</SUP> 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  10<SUP>7</SUP> and 2.4  x  10<SUP>8</SUP>, 
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/m<SUP>3</SUP>, 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 (LD<INF>50</INF>s 1,480 and 1,670 for female 
and male rats, respectively) and eye irritation (mild effects; 
reversible within 4-days). Dermal toxicity (LD<INF>50</INF> > 5,000 mg/
kg; rabbit), inhalation toxicity (LC<INF>50</INF> > 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 F<INF>2B</INF> 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. <SUP>14</SUP>C-phenyl and 
<SUP>14</SUP>C-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

[[Page 66082]]

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


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