[Federal Register Volume 63, Number 72 (Wednesday, April 15, 1998)]
[Notices]
[Pages 18411-18420]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-9395]



[[Page 18411]]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-801; FRL-5781-9]


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-801, must 
be received on or before May 15, 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. 119FF, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
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:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Sidney Jackson (PM 5).........  Rm. 268, CM #2, 703-    1921 Jefferson  
                                 305-7610, e-            Davis Hwy,     
                                 mail:jackson.sidney@e   Arlington, VA  
                                 pamail.epa.gov.                        
Bipin Gandhi (PM 5)...........  Rm. 4W53, CS #2, 703-   Do.             
                                 308-8380, e-mail:                      
                                 gandhi.bipin@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 support 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-801] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number FRL-5781-9 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: April 1, 1998

    James Jones,

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. Interregional Research Project

 PP 2E4101

    EPA has received a pesticide petition (PP 2E4101) 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 
residues of the insecticide cyfluthrin, [cyano[4-fluoro-3-
phenoxyphenyl]-methyl-3-[2,2- dicloroethenyl]-2,2-
dimethylcyclopropanecarboxylate] in or on the raw agricultural 
commodity dried hops at 20.0 parts per million (ppm) and to remove the 
established tolerance for fresh hops at 4.0 ppm. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the Federal Food Drug and Cosmetic 
Act (FFDCA); however, EPA has not fully evaluated the sufficiency of 
the submitted data at this time or whether the data supports granting 
of the proposed tolerance. Additional data may be needed before EPA 
rules on the petition. This notice includes a summary of the petition 
prepared by Bayer Corporations (Bayer), the registrant.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of cyfluthrin in plants is 
adequately understood. Studies have been conducted to delineate the 
metabolism of radiolabeled cyfluthrin in various crops all showing 
similar results. The residue of concern is cyfluthrin.

[[Page 18412]]

    2. Analytical method. Adequate analytical methodology (gas liquid 
chromatography with an electron capture detector) is available for 
enforcement purposes. The methodology was successfully validated by 
EPA's Beltsville laboratory in support of tolerances on cottonseed. The 
enforcement methodology has been submitted to the Food and Drug 
Administration for publication in the Pesticide Analytical Manual Vol. 
II (PAM II). Because of the long lead time for publication of the 
method in PAM II, the analytical methodology is being made available in 
the interim to anyone interested in pesticide enforcement when 
requested from Calvin Furlow, Public Response and Program Resource 
Branch, Field Operations Division (7502C), Office of Pesticide 
Programs, U.S. Environmental Protection Agency, 401 M St., SW., 
Washington, DC 20460. Office location and telephone number: Rm. 119FF, 
CM #2, 1921 Jefferson-Davis Hwy., Arlington, VA 22202, (703) 305-5232.
    The established tolerances for residues of cyfluthrin in/on eggs, 
milks, fat, meat and meat by-products of cattle, goats, hogs, horses, 
sheep and poultry are adequate to cover secondary residues resulting 
from the proposed use as delineated in 40 CFR 180.6(a)(2).
    3. Magnitude of residues. Import tolerances for cyfluthrin are 
presently established on fresh hops at 4.0 ppm and on dried hops at 
20.0 ppm. IR-4 has conducted field trials in Washington, Oregon and 
Idaho in order to support expansion of the tolerances to include the 
domestic production of hops in the United States.
    The residue data submitted to the EPA by IR-4 consist of three 
trials, one each in Washington, Oregon and Idaho. In each trial, hops 
were planted in three plots, two treated and one untreated. Cyfluthrin 
(Baythroid 2) was applied by foliar (ground) application at a rate of 
0.05 pounds(lb) active ingredient(ai)/acre(A) to one plot and 0.1 lb 
ai/A to another. Five separate applications were made with an interval 
of 7-days between the last application and harvest.
    Residues of cyfluthrin were detected in all treated samples from 
each trial and no interferences were detected in samples from control 
plots. The residue data are consistent for each trial. Cyfluthrin 
applied at 0.05 lb ai/A was detected from 0.44 to 0.78 ppm on fresh 
hops and from 1.83 to 2.36 ppm on dried hops. At 0.10 lb ai/A, residues 
were detected at 1.10 to 2.70 ppm on fresh hops and 3.76 to 7.57 ppm on 
dried hops.

B. Toxicological Profile

    The data base for cyfluthrin is essentially complete. Data lacking 
but desirable are an acute neurotoxicity study in rats and a 90-day 
neurotoxicity study in rats. Although these data are lacking, Bayer 
believes the available toxicity data are sufficient to support the 
proposed tolerance and these missing data will not significantly change 
its risk assessment. Bayer has committed to submit the acute 
neurotoxicity study and the 90-day neurotoxicity study.
    1. Acute toxicity. Results of acute toxicity tests show an acute 
oral lethal dose (LD50) grater than or equal to 16.2 
milligram (mg)/ kilogram (kg), a dermal (LD50) >5,000 mg/kg, 
inhalation lethal concentration (LC50 greater than or equal 
to 0.468 mg/liter(L), primary eye irritation and primary dermal 
irritation show toxicity categories III and IV, respectively. Dermal 
sensitization tests conducted show that cyfluthrin is not a dermal 
sensitizer.
    2. Genotoxicty. Mutagenicity tests were conducted, including 
several gene mutation assays (reverse mutation and recombination assays 
in bacteria and a Chinese hamster ovary(CHO)/HGPRT assay); a structural 
chromosome aberration assay (CHO/sister chromatid exchange assay); and 
an unscheduled DNA synthesis assay in rat hepatocytes. All tests were 
negative for genotoxicity.
    3. Reproductive and developmental toxicity. An oral developmental 
toxicity study in rats with a maternal and fetal no-observed effect 
level (NOEL) of 10 mg/kg/day (highest dose tested). An oral 
developmental toxicity study in rabbits with a maternal NOEL of 20 mg/
kg/day and a maternal lowest effect level (LEL) of 60 mg/kg/day, based 
on decreased body weight gain and decreased food consumption during the 
dosing period. A fetal NOEL of 20 mg/kg/day and a fetal LEL of 60 mg/
kg/day were also observed in this study. The LEL was based on increased 
resorptions and increased postimplantation loss.
    A developmental toxicity study in rats by the inhalation route of 
administration with a maternal NOEL of 0.0011 mg/l and a LEL of 0.0047 
mg/l, based on reduced mobility, dyspnea, piloerection, ungroomed coats 
and eye irritation. The fetal NOEL is 0.00059 mg/l and the fetal LEL is 
0.0011 mg/l, based on sternal anomalies and increased incidence of 
runts. A second developmental toxicity study in rats by the inhalation 
route of administration has been submitted to the Agency. A 3-
generation reproduction study in rats with a systemic NOEL of 2.5 mg/
kg/day and a systemic LEL of 7.5 mg/kg/day due to decreased parent and 
pup body weights. The reproductive NOEL and LEL are 7.5 mg/kg/day and 
22.5 mg/kg/day respectively.
    4. Subchronic toxicity. In a 28-day oral toxicity study in rats, 
cyfluthrin demonstrated a NOEL of 20 mg/kg/day. The lowest-observed-
effect level (LOEL) was 80 (40) mg/kg/day in both sexes based on 
clinical signs of nerve toxicity, decreases in body weight gain, and 
changes in liver and adrenal weights. The high dose was 80 mg/kg/day 
during the first and third weeks and 40 mg/kg/day during the second and 
fourth weeks.
    In a six month dog feeding study established a NOEL at 5 mg/kg/day 
for male and females. The LOEL for this study was 15 mg/kg/day for both 
sexes, based on neurological effects (hindlimb abnormalities) and 
gastrointestinal disturbances.
    A 21-day repeated dose dermal toxicity study, male and female rats 
were treated with cyfluthrin by dermal occlusion at target doses of 0, 
100, 340, or 1,000 mg/kg/day for 6 hours/day (average actual dose 
levels were 0, 113, 376 or 1,077 mg/kg/day). No mortality was observed, 
and there were no treatment-related effects on body weight, 
ophthalmology, organ weights, clinical biochemistry, or hematology. The 
LOEL for dermal effects was 376 mg/kg/day for male and female Sprague-
Dawley rats based on gross and histological skin lesions. The NOEL for 
dermal effects was 113 mg/kg/day. The LOEL for systemic effects was 
1,077 mg/kg/day based on decreased food consumption, red nasal 
discharge and urine staining. The NOEL for systemic effects was 376 mg/
kg/day.
    5. Chronic toxicity. A 12-month chronic feeding study in dogs with 
a NOEL of 4 mg/kg/day. The LEL for this study is established at 16 mg/
kg/day, based on slight ataxia, increased vomiting, diarrhea and 
decreased body weight.
    A 24-month chronic feeding/carcinogenicity study in rats showed a 
NOEL of 2.5 mg/kg/day and LEL of 6.2 mg/kg/day, based on decreased body 
weights in males, decreased food consumption in males, and inflammatory 
foci in the kidneys in females.
    6. Carcinogenicity. A 24-month carcinogenicity study in mice was 
conducted. There were no carcinogenic effects observed under the 
conditions of the study.
    A 24-month chronic feeding/carcinogenicity study in rats was 
conducted. There were no carcinogenic effects observed under the 
conditions of the study.

[[Page 18413]]

    Cyfluthrin has been classified as a Group E chemical (evidence of 
non-carcinogenicity for humans) by the Agency. The classification was 
based on a lack of convincing evidence of carcinogenicity in adequate 
studies with two animal species, rat and mouse.
    7. Animal metabolism. A metabolism study in rats showed that 
cyfluthrin is rapidly absorbed and excreted, mostly as conjugated 
metabolites in the urine, within 48 hours. An enterohepatic circulation 
was observed.
    8. Ednocrine effects. No special studies investigating potential 
estrogenic or endocrine effects of cyfluthrin 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. According to 
Bayer no endocrine effects were noted in any of the studies.

C. Aggregate Exposure

    1. Dietary exposure. In examining aggregate exposure, FFDCA section 
408 requires that EPA take into account available and reliable 
information concerning exposure from the pesticide residue in the food 
in question, residues in other foods for which there are tolerances, 
residues in ground water or surface water that is consumed as drinking 
water, and other non-occupational exposures through pesticide use in 
gardens, lawns, or buildings (residential and other indoor uses). 
Dietary exposure to residues of a pesticide in a food commodity are 
estimated by multiplying the average daily consumption of the food 
forms of that commodity by the tolerance level or the anticipated 
pesticide residue level. The Theoretical Maximum Residue Contribution 
(TMRC) is an estimate of the level of residues consumed daily if each 
food item contained pesticide residues equal to the tolerance. In 
evaluating food exposures, EPA takes into account varying consumption 
patterns of major identifiable subgroups of consumers, including 
infants and children. The TMRC is a ``worst case'' estimate since it is 
based on the assumptions that food contains pesticide residues at the 
tolerance level and that 100% of the crop is treated by pesticides that 
have established tolerances. If the TMRC exceeds the Reference Dose 
(RfD) or poses a lifetime cancer risk that is greater than 
approximately one in a million, EPA attempts to derive a more accurate 
exposure estimate for the pesticide by evaluating additional types of 
information (anticipated residue data and/or percent of crop treated 
data) which show, generally, that pesticide residues in most foods when 
they are eaten are well below established tolerances.
    2. Food. Under a petition to establish tolerances for cyfluthrin in 
or on citrus (PP 4F4313 and FAP 4H5687, the EPA has recently performed 
a chronic dietary exposure/risk assessment for cyfluthrin using a RfD 
of 0.025 mg/kg body weight(bwt)/day, based on a NOEL of 50 ppm (2.5 mg/
kg bwt/day) and an uncertainty factor of 100. The NOEL was determined 
in a 2-year rat feeding study. The endpoint effects of concern were 
decreased body weights in males and inflammation of the kidneys in 
females at the LEL of 6.2 mg/kg/day. This dietary exposure/risk 
assessment estimated the current dietary exposure for the U.S. 
population resulting from established tolerances, including the current 
4 ppm tolerance on fresh hops, is 0.002907 mg/kg/bwt day. This 
represents 11.6% of the RfD. The exposure to children (1-6 years old), 
the subgroup population exposed to the highest risk was 0.00662 mg/kg/
bwt/day or 26.4% of the RfD. The current action will increase the 
exposure to 0.003266 mg/kg/bwt day or 13% of the RfD for the U.S. 
population and 0.006622 mg/kg/bwt day or 26.4% or the RfD for children 
(1-6 years old). Generally speaking, EPA has no cause for concern if 
the total dietary exposure from residues for uses for which there are 
published and proposed tolerances is less than the RfD. Therefore, 
Bayer concludes that the chronic dietary risk of cyfluthrin, as 
estimated by the dietary risk assessment, does not appear to be of 
concern.
    3. Drinking water. Cyfluthrin is immobile in soil, therefore, will 
not leach into ground water. Additionally, due to the insolubility and 
lipophilic nature of cyfluthrin, any residues in surface water will 
rapidly and tightly bind to soil particles and remain with sediment, 
therefore, Bayer does not anticipate dietary exposures to cyfluthrin 
from drinking water.
    4. Non-dietary exposure. Non-occupational exposure to cyfluthrin 
may occur as a result of inhalation or contact from indoor residential, 
indoor commercial, and outdoor residential uses. Reliable data to 
determine aggregate exposures from these sources are currently not 
available. However, determinations of worst case exposure from 
inhalation in indoor settings (continuous exposure at saturation vapor 
concentration) indicated that adequate margins of safety existed even 
under these conditions. Since this evaluation greatly overestimated 
exposure, the contribution to aggregate exposure from inhalation in 
normal uses would be expected to be negligible. Estimations of outdoor 
residential exposure have been required for cyfluthrin in a data call-
in issued in 1995. These data are being generated by the Outdoor 
Residential Exposure Task Force (ORETF). However, available data show 
that the acute dermal toxicity of cyfluthrin is very low, with the 
LD50 being greater than 5,000 mg/kg, the highest dose 
tested. Sub-acute (21-day) dermal toxicity data showed only localized 
(skin) effects at higher level exposures (1,000 mg/kg/day and 340 mg/
kg/day). Other than skin effects at these high exposure levels, no 
effects were observed at any exposure levels, the highest level tested 
being 1,000 mg/kg/day. The use rate for cyfluthrin on residential turf 
is 1 g (1,000 mg) active ingredient per 1,000 square feet which would 
indicate that potential exposures would be well below levels tested. In 
addition, the localized skin effects seen at the prolonged higher 
exposures in animal tests have not been reported for non-occupational 
exposures to cyfluthrin in currently accepted uses, indicating that 
exposures are below the threshold of any observable effects. Indoor 
uses are limited to areas with little or no contact, so exposures would 
be expected to be even less. Thus, the dermal route of exposure does 
not appear to be significant and the contribution to aggregate exposure 
from dermal contact would be expected to be negligible.

D. Cumulative Effects

    In consideration of potential cumulative effects of cyfluthrin and 
other substances that have a common mechanism of toxicity, Bayer 
concludes that there are currently no available data or other reliable 
information indicating that any toxic effects produced by cyfluthrin 
would be cumulative with those of other chemical compounds; thus only 
the potential risks of cyfluthrin have been considered in this 
assessment of its aggregate exposure.

E. 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 
cyfluthrin from all current uses as well as the proposed tolerance will 
utilize little more than 13% of the RfD for the U.S. population. EPA 
generally has no concerns for exposures below 100% of

[[Page 18414]]

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 
cyfluthrin residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of cyfluthrin, the data 
from developmental studies in both rat and rabbit and a 2-generation 
reproduction study in the rat can be 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.
    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 cyfluthrin relative to pre- and post-natal 
effects is complete. The NOELs observed in the developmental and 
reproduction study are equivalent or higher than the NOEL from the 2-
year rat feeding study, used with a 100 fold uncertainty factor to 
establish the reference dose. Therefore, Bayer believes that an 
additional uncertainty factor is not warranted and that the RfD at 
0.025 mg/kg/day is appropriate for assessing aggregate risk to infants 
and children.
    Using the conservative exposure assumptions described above, 
cyfluthrin residues resulting from established tolerances, including a 
tolerance of 20 ppm on dry hops, would utilize 26.4% of the RfD for 
children (1-6 years old), the subgroup population exposed to the 
highest risk. Generally, EPA has no cause for concern if the exposure 
is less than 100% of the RfD. Therefore, based on the completeness and 
the reliability of the toxicity data and the conservative exposure 
assessment, Bayer concludes that there is a reasonable certainty that 
no harm will result to infants and children from aggregate exposure to 
the residues of cyfluthrin, including all anticipated dietary exposure 
and all other non-occupational exposures.

F. International Tolerances

    A Codex maximum residue levels (MRLs) or 20 ppm has been 
established for residues of cyfluthrin on dried hops.

2. Interregional Research Project

PP Nos. 6E3404, 6E4685, 1E3966, 9E3697, and 5E4580

    EPA has received pesticide petitions (PP Nos. 6E3404, 
6E4685,1E3966, 9E3697, and 5E4580) from the Interregional Research 
Project Number 4 (IR-4), proposing pursuant to section 408(d) of the 
Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 
amend 40 CFR part 180 tolerances for residues of esfenvalerate, (S)-
cyano-(3-phenoxyphenyl)methyl (S)-4-chloro-alpha-(1-methylethyl) 
benzeneacetate in or on the raw agricultural commodities mustard greens 
at 5 ppm (PP 6E3404), kiwifruit at 0.5 ppm (PP 6E4685), globe artichoke 
at 1.0 ppm (PP 1E3966), cranberry at 0.2 ppm (PP 9E3697), and kohlrabi 
at 2.0 ppm (PP 5E4580). EPA has determined that these petitions contain 
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 submitted data at this time or whether these data 
support granting the proposed tolerances. Additional data may be needed 
before EPA rules on the petitions. This notice contains a summary of 
the petitions submitted by DuPont Agricultural Products, the 
registrant.

A. Residue Chemistry

    1. Plant metabolism. The metabolism and chemical nature of residues 
of fenvalerate in plants and animals are adequately understood. The 
fate of fenvalerate has been extensively studied using radioactive 
tracers in plant and animal metabolism/nature of the residue studies. 
These studies have demonstrated that the parent compound is the only 
residue of toxicological significance. EPA has concluded that the 
qualitative nature of the residue is the same for both fenvalerate and 
esfenvalerate.
    2. Analytical method. There is a practical analytical method 
utilizing electron-capture gas chromatography with nitrogen phosphorous 
detection available for enforcement with a limit of detection that 
allows monitoring food with residues at or above tolerance levels. The 
limit of detection for updated method is the same as that of the 
current PAM II, which is 0.01 ppm.
    3. Magnitude of residues. Fenvalerate is a racemic mixture of four 
isomers (about 25% each). Technical Asana (the S,S-isomer enriched 
formulation, esfenvalerate), has been the only fenvalerate formulation 
sold in the U.S. for agricultural use. Since the S,S-isomer is the 
insecticidally active isomer, the use rate for Asana is 4 
times lower than that for Pydrin. A petition is pending (PP 
4F4329), to convert tolerances (still to be expressed as the sum of all 
isomers) based on the use rates for Asana. Bridging residue 
studies have shown Asana residues to be 3-4 times lower than 
Pydrin residues.

B. Toxicological Profile

    1. Acute toxicity. A battery of acute toxicity studies places 
technical esfenvalerate in Toxicity Category II for acute oral toxicity 
(rat lethal dose LD50 87.2 mg/kg, Category III for acute 
dermal (rabbit LD50 >2,000 mg/kg) and primary eye irritation 
(mild irritation in rabbits), and Category IV for primary skin 
irritation (minimal skin irritation in rabbits that reversed within 72 
hours after treatment). Acute inhalation on technical grade active 
ingredient (a.i.) was waived due to negligible vapor pressure. A dermal 
sensitization test on esfenvalerate in guinea pigs showed no 
sensitization.
    2. Genotoxicity. Esfenvalerate was not mutagenic in reverse 
mutation assays in S. typhimurium and E. coli and did not induce 
mutations Chinese hamster V79 cells or chromosome aberrations in 
Chinese hamster ovary cells. Esfenvalerate did not induce micronuclei 
in bone marrow of mice given up to 150 mg/kg intra peritoneally. 
Esfenvalerate did not induce unscheduled deoxyribonucleic acid (DNA) 
synthesis in HeLa cells. Other genetic toxicology studies submitted on 
racemic fenvalerate indicate that the mixture containing equal parts of 
the four stereoisomers is not mutagenic in bacteria. The racemic 
mixture was also negative in a mouse host mediated assay and in a mouse 
dominant lethal assay.
    3. Reproductive and developmental toxicity. Esfenvalerate was 
administered to pregnant female rats by gavage in a pilot developmental 
study at doses of 0, 1, 2, 3, 4, 5, and 20 mg/kg/day and a main study 
at 0, 2.5, 5, 10, and 20 mg/kg/day. Maternal clinical signs (abnormal 
gait and mobility) were observed at 2.5 mg/kg/day and above. A maternal 
NOEL of 2 mg/kg/day was established for the pilot study. The 
developmental NOEL was >20 mg/kg/day.
    Esfenvalerate was administered by gavage to pregnant female rabbits 
in a pilot developmental study at doses of 0, 2, 3, 4, 4.5, 5, and 20 
mg/kg/day and a main study at doses of 0, 3, 10, and 20 mg/kg/day. 
Maternal clinical signs (excessive grooming) were observed at 3 mg/kg/
day and above. A maternal NOEL of 2 mg/kg/day was established on the

[[Page 18415]]

pilot study. The developmental NOEL was > 20 mg/kg/day.
    A 2-generation feeding study with esfenvalerate was conducted in 
the rat at dietary levels of 0,75, 100, and 300 ppm. Skin lesions and 
minimal (non biologically significant) parental body weight effects 
occurred at 75 ppm. The NOEL for reproductive toxicity was 75 ppm (4.2-
7.5 mg/kg/day) based on decreased pup weights at 100 ppm.
    4. Subchronic toxicity. Two 90-day feeding studies with 
esfenvalerate were conducted in rats - one at 50, 150, 300, and 500 ppm 
esfenvalerate, and a second at 0, 75, 100, 125, and 300 ppm to provide 
additional dose levels. The NOEL was 125 ppm (6.3 mg/kg/day) based on 
clinical signs (jerky leg movements) observed at 150 ppm (7.5 mg/kg/
day) and above.
    A 90-day feeding study in mice was conducted at 0, 50, 150, and 500 
ppm esfenvalerate with a NOEL of 150 ppm (30.5 mg/kg) based on clinical 
signs of toxicity at 500 ppm (106 mg/kg).
    A 3-month subchronic study in dogs was satisfied by a 1-year oral 
study in dogs, in which the NOEL was 200 ppm (5 mg/kg/day).
    A 21-day dermal study in rabbits with fenvalerate conducted at 100, 
300, and 1,000 mg/kg/day with a no-observed-adverse effect level 
(NOAEL) of 1,000 mg/kg/day.
    5. Chronic toxicity. In a 1-year study, dogs were fed 0, 25, 50, or 
200 ppm esfenvalerate with no treatment related effects at any dietary 
level. The NOEL was established at 200 ppm (5 mg/kg/day). An effect 
level for dietary administration of esfenvalerate for dogs of 300 ppm 
had been established earlier in a three week pilot study used to select 
dose levels for the chronic dog study.
    One chronic study with esfenvalerate and three chronic studies with 
fenvalerate have been conducted in mice.
    In an 18-month study, mice were fed 0, 35, 150, or 350 ppm 
esfenvalerate. Mice fed 350 ppm were sacrificed within the first 2 
months of the study after excessive self-trauma related to skin 
stimulation and data collected were not used in the evaluation of the 
oncogenic potential of esfenvalerate. The NOEL was 35 ppm (4.29 and 
5.75 mg/kg/day for males and females, respectively) based on lower body 
weight and body weight gain at 150 ppm. Esfenvalerate did not produce 
carcinogenicity.
    In a 2-year feeding study, mice were administered 0, 10, 50, 250 or 
1,250 ppm fenvalerate in the diet. The NOEL was 10 ppm (1.5 mg/kg/day) 
based on granulomatous changes (related to fenvalerate only, not 
esfenvalerate) at 50 ppm (7.5 mg/kg/day). Fenvalerate did not produce 
carcinogenicity.
    In an 18-month feeding study, mice were fed 0, 100, 300, 1,000, or 
3,000 ppm fenvalerate in the diet. The NOEL is 100 ppm (15.0 mg/kg/day) 
based on fenvalerate-related microgranulomatous changes at 300 ppm (45 
mg/kg/day). No compound related carcinogenicity occurred.
    Mice were fed 0, 10, 30, 100, or 300 ppm fenvalerate for 20-months. 
The NOEL was 30 ppm (3.5 mg/kg/day) based on red blood cell effects and 
granulomatous changes at 100 ppm (15 mg/kg/day). Fenvalerate was not 
carcinogenic at any concentration.
    In a 2-year study, rats were fed 1, 5, 25, or 250 ppm fenvalerate. 
A 1,000 ppm group was added in a supplemental study to establish an 
effect level. The NOEL was 250 ppm (12.5 mg/kg/day). At 1,000 ppm (50 
mg/kg/day), hind limb weakness, lower body weight, and higher organ-to-
body weight ratios were observed. Fenvalerate was not carcinogenic at 
any concentration. (A conclusion that fenvalerate is associated with 
the production of spindle cell sarcomas at 1,000 ppm was retracted by 
EPA).
    EPA has classified esfenvalerate in Group E - evidence of non-
carcinogenicity for humans.
    6. Animal metabolism. In animal studies, after oral dosing with 
radioactive fenvalerate, the majority of the administered radioactivity 
was eliminated in the initial 24-hours. The metabolic pathway involved 
cleavage of the ester linkage followed by hydroxylation, oxidation, and 
conjugation of the acid and alcohol moieties.
    7. Metabolite toxicology. The parent molecule is the only moiety of 
toxicological significance appropriate for regulation in plant and 
animal commodities.

C. Aggregate Exposure

    1. Dietary exposure. Tolerances have been established for the 
residues of fenvalerate/esfenvalerate, in or on a variety of 
agricultural commodities. In addition, pending tolerance petitions 
exist for use of esfenvalerate on sugar beets, sorghum, head lettuce, 
celery, pistachios, and a number of other minor use commodities. For 
purposes of assessing dietary exposure, chronic and acute dietary 
assessments have been conducted using all existing and pending 
tolerances for esfenvalerate. EPA recently (August 2, 1997) reviewed 
the existing toxicology data base for esfenvalerate and selected the 
following toxicological endpoints. For acute toxicity, EPA established 
a NOEL of 2.0 mg/kg/day from rat and rabbit developmental studies based 
on maternal clinical signs at higher concentrations. An MOE of 100 was 
required. For chronic toxicity. EPA established the Reference Dose 
(RfD) for esfenvalerate at 0.02 mg/kg/day. This RfD was also based on a 
NOEL of 2.0 mg/kg/day in the rat developmental study with an 
uncertainty factor of 100. Esfenvalerate is classified as a Group E 
carcinogen - no evidence of carcinogenicity in either rats or mice. 
Therefore, a carcinogenicity risk analysis for humans is not required.
    2. Food. A chronic dietary exposure assessment was conducted using 
Novigen's DEEM (Dietary Exposure Estimate Model). Anticipated residues 
and adjustment for percent crop treated were used in the chronic 
dietary risk assessment. The percentages of the RfD utilized by the 
most sensitive sub-population, children 1-6 years, was 4.6% based on a 
daily dietary exposure of 0.000911 mg/kg/day. Chronic exposure for the 
overall US population was 1.9% of the RfD based on a dietary exposure 
of 0.000376 mg/kg/day. This assessment has been approved by EPA and 
included pending tolerances (including mustard greens, kiwifruit, globe 
artichoke, cranberry, and kohlrabi) and all food tolerances for 
incidental residues from use in food handling establishments. EPA has 
no concern for exposures below 100% of the RfD because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose appreciable risks to human health.
    Potential acute exposures from food commodities were estimated 
using a Tier 3 (Monte Carlo) Analysis and appropriate processing 
factors for processed food and distribution analysis. This analysis 
used field trial data to estimate exposure and federal and market 
survey information to derive the percent of crop treated. These data 
are considered reliable and used the upper end estimate of percent crop 
treated in order to not underestimate any significant subpopulation. 
Regional consumption information was taken into account. The MOEs for 
the most sensitive sub-population (children 1-6 years) were 202 and 103 
at the 99th, and 99.9th percentile of exposure, 
respectively, based on daily exposures of 0.009908 and 0.019445 mg/kg/
day. The MOEs for the general population are 355 and 171 at the 
99th and 99.9th percentile of exposure, 
respectively, based on daily exposure estimates of 0.005635 and 
0.011717 mg/kg/day. The EPA has stated there is no cause for concern if 
total acute exposure

[[Page 18416]]

calculated for the 99.9th percentile yields an MOE of 100 or larger. 
This acute dietary exposure estimate is considered conservative and EPA 
considered the MOEs adequate in a recent final rule published in the 
Federal Register at 62 FR 63019 (November 26, 1997) (FRL-5781-1).
    3. Drinking water. Esfenvalerate is immobile in soil and will not 
leach into groundwater. Due to the insolubility and lipophilic nature 
of esfenvalerate, any residues in surface water will rapidly and 
tightly bind to soil particles and remain with sediment, therefore not 
contributing to potential dietary exposure from drinking water.
    A screening evaluation of leaching potential of a typical 
pyrethroid was conducted using EPA's Pesticide Root Zone Model (PRZM). 
Based on this screening assessment, the potential concentrations of a 
pyrethroid in ground water at depths of 1 and 2 meters are essentially 
zero (much less than 0.001 parts per billion (ppb).
    Surface water concentrations for pyrethroids were estimated using 
PRZM3 and Exposure Analysis Modeling System (EXAMS) using Standard EPA 
cotton runoff and Mississippi pond scenarios. The maximum concentration 
predicted in the simulated pond was 0.052 ppb. Concentrations in actual 
drinking water would be much lower than the levels predicted in the 
hypothetical, small, stagnant farm pond model since drinking water 
derived from surface water would be treated before consumption.
    Chronic drinking water exposure was estimated to be 0.000001 mg/kg/
day for both the U.S. general population and for non-nursing infants. 
Less than 0.1% of the RfD was occupied by both population groups.
    Using these values, the contribution of water to the acute dietary 
risk estimate was estimated for the U.S. population to be 0.000019 mg/
kg/day at the 99th percentile and 0.000039 mg/kg/day at the 
99.9th percentile resulting in MOEs of 105,874 and 51,757, 
respectively. For the most sensitive subpopulation, non-nursing infants 
less than 1-year old, the exposure is 0.000050 mg/kg/day and 0.000074 
mg/kg/day at the 99th and 99.9th percentile, 
respectively, resulting in MOEs of 39,652, and 27,042, respectively.
    Therefore, DuPont believes that there is reasonable certainty of no 
harm from drinking water.
    4. Non-dietary exposure. Esfenvalerate is registered for non-crop 
uses including spray treatments in and around commercial and 
residential areas, treatments for control of ectoparasites on pets, 
home care products including foggers, pressurized sprays, crack and 
crevice treatments, lawn and garden sprays, and pet and pet bedding 
sprays. For the non-agricultural products, the very low amounts of 
active ingredient they contain, combined with the low vapor pressure 
(1.5 x 10-9 mm Mercury at 25 deg. C.) and low dermal 
penetration, would result in minimal inhalation and dermal exposure.
    To assess risk from (nonfood) short and intermediate term exposure, 
EPA has recently selected a toxicological endpoint of 2.0 mg/kg/day, 
the NOEL from the rat and rabbit developmental studies. For dermal 
penetration/absorption, EPA selected 25% dermal absorption based on the 
weight-of-evidence available for structurally related pyrethroids. For 
inhalation exposure, EPA used the oral NOEL of 2.0 mg/kg/day and 
assumed 100% absorption by inhalation.
    Individual non-dietary risk exposure analyses were conducted using 
a flea infestation scenario that included pet spray, carpet and room 
treatment, and lawn care, respectively. The total potential short- and 
intermediate-tern aggregate non-dietary exposure including lawn, 
carpet, and pet uses are: 0.000023 mg/kg/day for adults, 0.00129 mg/kg/
day for children 1-6 years and 0.00138 mg/kg/day for infants less than 
1-year old.
    EPA concluded in the final rule published in the Federal Register 
at 62 FR 63019 (November 26, 1997) that the potential non-dietary 
exposure for esfenvalerate are associated with substantial margins of 
safety.
    5. Aggregate exposure dietary and non dietary. EPA has concluded 
that aggregate chronic exposure to esfenvalerate from food and drinking 
water will utilize 1.9% of the RfD for the U.S. population based on a 
dietary exposure of 0.000377 mg/kg/day. The major identifiable subgroup 
with the highest aggregate exposure are children 1-6 years old. EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health.
    The acute aggregate risk assessment takes into account exposure 
from food and drinking water. The potential acute exposure from food 
and drinking water to the overall U.S. population provides an acute 
dietary exposure of 0.011756 mg/kg/day with an MOE of 170. This acute 
dietary exposure estimate is considered conservative, using anticipated 
residue values and percent crop-treated data in conjunction with Monte 
Carlo analysis.
    Short- and intermediate-term aggregate exposure takes into account 
chronic dietary food and water (considered to be a background exposure 
level) plus indoor and outdoor residential exposure. The potential 
short- and intermediate-term aggregate risk for the U.S. population is 
an exposure of 0.0082 mg/kg/day with an MOE of 244.
    It is important to acknowledge that these MOEs are likely to 
significantly underestimate the actual MOEs due to a variety of 
conservative assumptions and biases inherent in the exposure assessment 
methods used for their derivation. Therefore, it can be concluded that 
the potential non-dietary and dietary aggregate exposures for 
esfenvalerate are associated with a substantial degree of safety. EPA 
has previously determined in the final rule published in the Federal 
Register at 62 FR 63019 (November 26, 1997) that there was reasonable 
certainty that no harm will result from aggregate exposure to 
esfenvalerate residues. Head lettuce was included in that risk 
assessment.

D. Cumulative Effects

    Section 408 (b) (2) (D) (v) requires that, when considering whether 
to establish, modify, or revoke a tolerance, the Agency consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity''. In a recent final rule on esfenvalerate 
published in the Federal Register at 62 FR 63019 (November 26, 1997) 
EPA concluded, available information in this context might include not 
only toxicity, chemistry, and exposure data, but also scientific 
policies and methodologies for understanding common mechanisms of 
toxicity and conducting cumulative risk assessments. For most 
pesticides, although the Agency has some information in its files that 
may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way. EPA has begun a pilot process to study this issue 
further through the examination of particular classes of pesticides. 
The Agency hopes that the results of this pilot process will increase 
the Agency's scientific understanding of this question such that EPA 
will be able to develop and apply scientific principles for better

[[Page 18417]]

determining which chemicals have a common mechanism of toxicity and 
evaluating the cumulative effects of such chemicals. The Agency 
anticipates, however, that even as its understanding of the science of 
common mechanisms increases, decisions on specific classes of chemicals 
will be heavily dependent on chemical specific data, much of which may 
not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides as to which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed). Although esfenvalerate is 
similar to other members of the synthetic pyrethroid class of 
insecticides, EPA does not have, at this time, available data to 
determine whether esfenvalerate has a common method of toxicity with 
other substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
esfenvalerate does not appear to produce a toxic metabolite produced by 
other substances. For the purposes of this tolerance action, therefore, 
EPA has not assumed that esfenvalerate has a common mechanism of 
toxicity with other substances.

E. Safety Determination

    1. U.S. population. A chronic dietary exposure assessment using 
anticipated residues, monitoring information, and percent crop treated 
indicated the percentage of the RfD utilized by the General Population 
to be 1.9%. There is generally no concern for exposures below 100% of 
the RfD because the RfD represents the level at or below which daily 
aggregate dietary exposure over a lifetime will not pose appreciable 
risks to human health.
    For acute exposure, a MOE of greater than 100 is considered an 
adequate MOE. A Tier 3 acute dietary exposure assessment found the 
General Population to have MOE's of 355 and 171 at the 99th 
and 99.9th percentile of exposure, respectively. These 
values were generated using actual field trial residues and market 
share data for percentage of crop treated. These results depict an 
accurate exposure pattern at an exaggerated daily dietary exposure 
rate.
    Short- and intermediate-term aggregate exposure risk from chronic 
dietary food and water plus indoor and outdoor residential exposure for 
the U.S. population is an exposure of 0.0082 mg/kg/day with an MOE of 
244.
    Therefore, there is a reasonable certainty that no harm will result 
from chronic dietary, acute dietary, non-dietary, or aggregate exposure 
to esfenvalerate residues.
    2. Infants and children. FFDCA section 408 provides that EPA shall 
apply an additional tenfold margin of safety for infants and children 
unless EPA determines that a different margin of safety will be safe 
for infants and children. EPA has stated that reliable data support 
using the standard MOE and uncertainty factor (100 for combined inter- 
and intra-species variability) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing 
guidelines and when the severity of the effect in infants or children 
or the potency or unusual toxic properties of a compound do not raise 
concerns regarding the adequacy of the standard MOE/safety factor. In a 
recent final rule published in the Federal Register at 62 FR 63019 
(November 26 1997), EPA concluded that reliable data support use of the 
standard 100-fold uncertainty factor for esfenvalerate, and that an 
additional uncertainty factor is not needed to protect the safety of 
infants and children. This decision was based on, no evidence of 
developmental toxicity at a doses up to 20 mg/kg/day (ten times the 
maternal NOEL) in prenatal developmental toxicity studies in both rats 
and rabbits; offspring toxicity only at dietary levels which were also 
found to be toxic to parental animals in the 2-generation reproduction 
study; and no evidence of additional sensitivity to young rats or 
rabbits following pre- or postnatal exposure to esfenvalerate.
    A chronic dietary exposure assessment found the percentages of the 
RfD utilized by the most sensitive sub-population to be 4.6% for 
children 1-6 years based on a dietary exposure of 0.000912 mg/kg/day. 
The % RfD for nursing and non-nursing infants was 1.1% and 2.7%, 
respectively. The Agency has no cause for concern if RfD are below 
100%.
    The most sensitive sub-population, children 1-6 years, had acute 
dietary MOEs of 202 and 103 at the 99th and 
99.9th percentile of exposure, respectively. Nursing infants 
had MOEs of 195 and 146 at the 99th and 99.9th 
percentile of exposure, respectively. Non-nursing infants had MOEs of 
304 and 158 at the 99th and 99.9th percentile of 
exposure, respectively. The Agency has no cause for concern if total 
acute exposure calculated for the 99.9th percentile yields a MOE of 100 
or larger.
    EPA has recently concluded that the potential short- or 
intermediate-term aggregate exposure of esfenvalerate from chronic 
dietary food and water plus indoor and outdoor residential exposure to 
children (1-6 years old) is 0.0113 mg/kg/day with an MOE of 177. For 
infants (less than 1-year old) the exposure is 0.0098 mg/kg/day with an 
MOE of 204. Thus, there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to esfenvalerate 
residues published in the Federal Register at 62 FR 63019 (November 26, 
1997) (FRL-5754-6).

F. International Tolerances

    Codex maximum residue levels (MRL's) have been established for 
residues of fenvalerate on a number of crops that also have U.S. 
tolerances. There are some minimal differences between the section 408 
tolerances and certain Codex MRL values for specific commodities. These 
differences could be caused by differences in methods to establish 
tolerances, calculate animal feed, dietary exposure, and as a result of 
different agricultural practices. Therefore, some harmonization of 
these maximum residue levels may be required.

3. Novartis Crop Protection, Inc.

PP 7E4920

    EPA has received a pesticide petition (PP 7E4920) from Novartis 
Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419, 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 inert 
tolerances for residues of cloqiontocet-mexyl (acteic acid, [5-chloro-
8-quinolinyl)oxy]-,1-methylhexylester; CGA-185072) in or on the raw 
agricultural commodities wheat grain at 0.02 ppm and wheat straw at 
0.05 ppm. The proposed analytical method involves homogenization, 
filtration, partition, and cleanup with analysis by high performance 
liquid chromotography 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

[[Page 18418]]

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 CGA-185072 in wheat has been 
investigated. Total residues in all crop samples are low. Metabolism 
involves primarily rapid hydrolysis of the parent to the resulting acid 
followed by conjugation.
    2. Analytical method. Novartis has submitted practical analytical 
methods for the determination of CGA-185072 and its major plant 
metabolite CGA-153433 in wheat raw agricultural commodities (RACs). 
CGA-185072 is extracted from crops with acetonitrile, cleaned up by 
solvent partition and solid phase extraction and determined by column 
switching HPLC with UV detection. CGA-153433 is extracted from crops 
with an acetone-buffer (pH=3) solution, cleaned up by solvent partition 
and solid phase extraction, and determined by HPLC with UV detection. 
The limits of quantification (LOQ) for the methods are 0.02 ppm for 
CGA-185072 in forage and grain, 0.05 ppm for CGA-185072 in straw, and 
0.05 ppm for CGA-153433 in forage, straw and grain.
    3. Magnitude of residues. Twelve residue trials were conducted from 
1989-1992 in the major spring wheat growing areas of Manitoba, Alberta 
and Saskatchewan, which share compatible crop zones with the major 
spring wheat growing areas of the U.S. (MT, ND, SD, MN). Nine trials 
were conducted in 1989-91 with a tank mix of CGA-184927 (a.i.) and the 
CGA-185072 safener as separate EC formulations and three trials in 1992 
were conducted with CGA-184927 and the CGA-185072 safener as a pre-pack 
EC formulation. All trials had a single post-emergence application of 
CGA-185072 at a rate of 20 g a.i./Ha. At PHIs of 55-97 days, no 
detectable residues of CGA-185072 or its metabolite CGA-153433 were 
found in mature grain or straw from these trials. Separate decline 
studies (3) on green forage showed no detectable residues of CGA-185072 
or CGA-153433 at 3 days after application. Freezer storage stability 
studies indicated reasonable stability of both analytes for a period of 
one year, with CGA-185072 declining to 83% in grain and 67% in straw 
after two years, while CGA-153433 was stable for at least two years.

B. Toxicological Profile

    1. Acute toxicity. The acute oral and dermal LD50 values 
for cloquintocet-mexyl are greater than 2,000 mg/kg for rats of both 
sexes, respectively. Its acute inhalation LC50 in the rat is 
greater than 0.94 mg/liter , the highest attainable concentration. 
Cloquintocet-mexyl is slightly irritating to the eyes, minimally 
irritating to the skin of rabbits, but was found to be sensitizing to 
the skin of the guinea pig. This technical would carry the EPA signal 
word ``Caution''.
    2. Genotoxicty. The mutagenic potential of cloquintocet-mexyl was 
investigated in six independent studies covering different end points 
in eukaryotes and prokaryotes in vivo and in vitro. These tests 
included: Ames reverse mutation with Salmonella typhimurium and Chinese 
hamster V79 cells; chromosomal aberrations using human lymphocytes and 
the mouse micronucleus test; and DNA repair using rat hepatocytes and 
human fibroblasts. Cloquintocet-mexyl was found to be negative in all 
these tests and, therefore, is considered devoid of any genotoxic 
potential at the levels of specific genes, chromosomes or DNA primary 
structure.
    3. Reproductive and developmental toxicity. Dietary administration 
of cloquintocet-mexyl over two generations at levels as high as 10,000 
ppm did not affect mating performance, fertility, or litter sizes, but 
a slightly reduced body weight development of adults and pups was noted 
at this level. The target organ was kidney in adults and pups. The 
treatment had no effect on reproductive organs. The developmental and 
reproductive NOEL was 5,000 ppm, corresponding to a mean daily intake 
of 350 mg/kg cloquintocet-mexyl.
    In a developmental toxicity study in rats, the highest dose level 
of 400 mg/kg resulted in reduced body weight gain of the dams and signs 
of retarded fetal development. No teratogenic activity of the test 
article was detected. The NOEL for dams and fetuses was 100 mg/kg/day.
    In a developmental toxicity study in rabbits, mortality was 
observed in dams at dose levels of 300 mg/kg. No teratogenic effects 
were noted. Fetuses showed signs of slightly retarded development. The 
NOEL for both dams and fetuses was 60 mg/kg/day.
    4. Subchronic toxicity. In a 90-day study, rats fed 6,000 ppm 
exhibited reduced body weight gain and one male died with acute 
nephritis and inflamed urinary bladder. Reduced liver and kidney 
weights were observed in males fed 1,000 and 6,000 and in females fed 
6,000 ppm. Target organs were identified to be kidney and urinary 
bladder. The NOEL was 150 ppm (9.66 mg/kg in males and 10.2 mg/kg in 
females).
    In a 90-day study in beagle dogs, a level of 40,000 ppm resulted in 
deterioration of general condition so that the feeding level was 
reduced in a stepwise fashion to 15,000 ppm. Anemia was noted at 15,000 
ppm and the feeding level of 1,000 ppm. The NOEL of 100 ppm was 
equivalent to a mean daily intake of 2.9 mg/kg in males and females.
    5. Chronic toxicity. In a 12-month feeding study in dogs, 15,000 
ppm resulted in inappetence and body weight loss. As a result, this 
feeding level was adjusted to 10,000 ppm after 2-weeks. Animals fed 
this level exhibited anemia and an elevation in blood urea levels. The 
kidney was considered the target organ. The NOEL of 1,500 ppm was 
equivalent to a mean daily intake of 43.2 mg/kg in males and 44.8 mg/kg 
in females.
    Lifetime dietary administration of cloquintocet-mexyl to mice 
resulted in reduced body weights in both sexes at 5,000 ppm. Overall 
body weight gain was reduced by 17% to 22% in males and females, 
respectively, indicating the MTD was achieved or exceeded. 
Histopathological examination revealed chronic inflammation of the 
urinary bladder. There was no indication of any tumorigenic response 
due to treatment. The NOEL of 1,000 ppm was equivalent to a mean daily 
dose of 111 mg/kg in males and 102 mg/kg in females.
    A top feeding level of 2,000 ppm was selected, based on the 90-day 
study, for the lifetime feeding study in the rat. This feeding level 
was well-accepted, but produced hyperplasia of the thymus in males and 
hyperplasia of the thyroid in females. There was no increase in tumors 
of any type and the total number of tumor- bearing animals showed no 
dose-related trends. The NOEL of 100 ppm was equivalent to a mean daily 
dose of 3.77 mg/kg in males and 4.33 mg/kg in females.
    6. Animal metabolism. In rats, approximately 50% of an oral dose of 
cloquintocet-mexyl was rapidly absorbed through the gastrointestinal 
tract and excreted via urine and bile. The administered dose was 
excreted independent of sex and was essentially complete within 48 
hours. 95% of the excreted dose was associated with one metabolite, an 
acid residue of cloquintocet-mexyl, CGA-153433. Simultaneous 
administration of the cloquintocet-mexyl and clodinafop-propargyl did 
not alter the rate of excretion of cloquintocet-mexyl or its metabolite 
pattern.
    7. Metabolite toxicology. At the present time there is no evidence 
which affords an association of the toxicities noted with the highest 
feeding levels of cloquintocet-mexyl with its primary metabolite, CGA-
153433.

[[Page 18419]]

    8. Endocrine disruption. A special study was conducted to 
investigate a histological finding of hyperplasia of thyroid gland 
epithelium noted in the female rat in the standard lifetime combined 
chronic toxicity and carcinogenicity study. This study was a 28-day 
oral gavage study with a 28-day recovery period at dose levels as high 
as 400 mg/kg/day or approximately 4,000 ppm. No effect was noted on the 
level of thyroid hormones at any of the treatment levels. Although 
thyroid hyperplasia and an accompanying increase in pituitary 
basophilic cells were noted at the end of 28-days, these effects were 
reversible in the recovery period.

C. Aggregate Exposure

    1. Dietary exposure. Cloquintocet-mexyl is intended to be used as a 
safener for the post emergence herbicide, clodinafop-propargyl, used in 
wheat. The use rate is very low (formulated at a 1:4 ratio of safener 
to active ingredient). Results from plant metabolism and residue 
studies show that residues of the safener cloquintocet-mexyl or its 
metabolites are below the detection limit in wheat grains and other 
wheat byproducts including green wheat used for forage. Tolerances in 
wheat and wheat products are being proposed at the detection limit of 
0.02 ppm (LOQ) for the parent active ingredient in wheat grain and 0.05 
ppm (LOQ) in wheat straw. For cloquintocet, similar tolerances will be 
proposed in wheat grain (0.02 ppm) and wheat straw (0.05 ppm).
    i. Chronic. The RfD of 0.0377 mg/kg/day was derived from the male 
NOEL of 3.77 mg/kg/day. Based on the assumption that 100% of all wheat 
used for human consumption would contain residues of cloquintocet-mexyl 
and anticipated residues would be at the level of \1/2\ the LOQ, the 
potential dietary exposure was calculated using the TAS 
exposure program based on the food survey from the year of 1977-1978. 
Calculations were made for anticipated residues using \1/2\ the LOQ or 
0.01 ppm. Calculated on the basis of the assumptions above, the chronic 
dietary exposure of the U.S. population to cloquintocet-mexyl would 
correspond to 0.000014 mg/kg/day or 0.04% of its RfD. MOE against NOEL 
in the most sensitive species is 269,286-fold.
    Using the same conservative exposure assumptions, the percent of 
the RfD that will be utilized is 0.01% for nursing infants less than 1-
year old, 0.03% for non-nursing infants, 0.08% for children 1-6 years 
old and 0.06% for children 7-12 years old. It is concluded that there 
is a reasonable certainty that no harm will result to infants and 
children from exposure to residues of cloquintocet-mexyl.
    ii. Acute. Using the same computer software package used for the 
calculation of chronic dietary exposure, the acute dietary exposure was 
calculated for the general population and several sub-populations 
including children and women of child bearing age. The USDA Food 
Consumption Survey of 1989-1992 was used, however, instead of the 1977-
1978 survey used for the chronic assessment. MOEs were calculated 
against the NOEL of 2.9 mg/kg found in a 90-day dietary toxicity study 
in dogs, which is the lowest NOEL observed in a short term or 
reproductive toxicity study. NOELs from reproductive or developmental 
toxicity studies were significantly higher and there was no evidence 
that cloquintocet-mexyl has any potency to affect these endpoints.
    The exposure model predicted that 99.9% of the general population 
will be exposed to less than 0.000104 mg/kg cloquintocet-mexyl per day, 
which corresponds to a MOE of almost 27,944 when compared to the NOEL 
of 2.9 mg/kg. Children 1-6 years constitute the sub-population with the 
highest predicted exposure. Predicted acute exposure for this subgroup 
is less than 0.000134 mg/kg/day, corresponding to a MOE of at least 
21,721 for 99.9% of the individuals.
    2. Drinking water. Other potential sources of exposure of the 
general population to residues of pesticides are residues in drinking 
water. Results of studies have shown that cloquintocet-mexyl or its 
degradation products do not have any leaching potential. Accordingly, 
there is no risk of groundwater contamination with cloquintocet-mexyl 
or its metabolites. Thus, aggregate risk of exposure to cloquintocet-
mexyl does not include drinking water. Cloquintocet-mexyl is not 
intended for uses other than the agricultural use on wheat. Thus, there 
is no potential for non-occupational exposure.
    The Maximum Contaminant Level Goal (MCLG) calculated for 
cloquintocet-mexyl according to EPA's procedure leads to an exposure 
value substantially above levels that are likely to be found in the 
environment under proposed conditions of use.
    MCLG = RfD x 20% x 70 kg/2 L
    MCLG = 0.0377 mg/kg x 0.2 x 70 kg/2 L
    MCLG = 0.264 ppm = 264 ppb
    3. Non-dietary exposure. Exposure to cloquintocet-mexyl for the 
mixer/loader/ground boom/aerial applicator was calculated using the 
Pesticide Handlers Exposure Database (PHED). It was assumed that the 
product would be applied 10-days per year by ground boom application to 
a maximum of 300 acres per day by the grower, 450 acres per day by the 
commercial groundboom applicator, and 741 acres per day for the aerial 
applicator at a maximum use rate of 28 grams active ingredient (7 grams 
of cloquintocet-mexyl) per acre. For purposes of this assessment, it 
was assumed that an applicator would be wearing a long-sleeved shirt 
and long pants and the mixer/loader would, in addition, wear gloves. 
Daily doses were calculated for a 70 kg person assuming 100% dermal 
penetration.
    The results indicate that large margins of safety exist for the 
proposed experimental use of cloquintocet-mexyl. The use pattern of 
cloquintocet indicates that the NOEL(1,000 mg/kg/day) from the 28-day 
rat dermal study is appropriate for comparison to mixer/loader-
applicator exposure. The chronic NOEL of 3.77 mg/kg/day from the 2-year 
feeding study in rats is used to examine longer term exposure.
    For short-term exposure, MOEs for cloquintocet ranged from 2.4E+05 
for commercial open mixer-loader to 2.5E+06 for commercial groundboom 
enclosed-cab applicator. For chronic exposure, MOEs ranged from 3.2E+04 
for commercial open mixer-loader to 3.5E+05 for commercial groundboom 
enclosed-cab applicator. Aerial application of cloquintocet results in 
short-term MOEs of 1.4E+05 for the mixer-loader and 2.5E+05 for pilots. 
Chronic MOEs are 2.0E+04 for the mixer-loader and 3.4E+04 for the 
pilot. Based on this assessment, occupational exposure to cloquintocet-
mexyl results in acceptable MOEs.
    In reality, the proposed label for the end use product containing 
the active ingredient plus cloquintocet-mexyl will require more 
restrictive personal protective equipment for applicators and other 
handlers, resulting in additional margins of safety.

D. Cumulative Effects

    Novartis has considered the potential for a cumulative exposure 
assessment for effects of cloquintocet-mexyl and other substances with 
the same mechanism of toxicity. It is concluded that such a 
determination would be inappropriate at this time because of the unique 
role of cloquintocet-mexyl as a product specific safener.

E. Safety Determination

    1. U.S. population. Using the same conservative exposure 
assumptions as described for chronic and acute dietary exposure, 
aggregrate exposure of the

[[Page 18420]]

U.S. population to cloquintocet-mexyl would correspond to 0.000014 mg/
kg/day or 0.04% of its RfD. The chronic MOE against the NOEL in the 
most sensitive species is 269,286-fold. EPA generally has no concern 
for exposures below 100% of the RfD because the RfD represents the 
level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risks to human health. Therefore, it 
is concluded that there is a reasonable certainty that no harm will 
result from aggregate exposure to residues of cloquintocet-mexyl.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of cloquintocet-mexyl, 
data from developmental toxicity studies in the rat and rabbit and a 2- 
generation reproduction study in the rat have been considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from chemical exposure during 
prenatal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to a chemical on 
the reproductive capability of mating animals and data on systemic 
toxicity.
    The highest dose level of 400 mg/kg/day in a developmental toxicity 
study in rats resulted in reduced body weight gain of the dams and 
signs of retarded fetal development. No teratogenic activity due to the 
test article was detected. The NOEL for dams and fetuses was 100 mg/kg/
day. Although mortality was observed in rabbit dams at the dose level 
of 300 mg/kg/day, no teratogenic effects were noted. The NOEL for both 
dams and fetuses was 60 mg/kg/day.
    Dietary administration of cloquintocet-mexyl over 2-generations at 
levels as high as 10,000 ppm did not affect mating performance, 
fertility, or litter sizes in rats, but a slightly reduced body weight 
development of adults and pups was noted at this level. The target 
organ was kidney in adults and pups. The treatment had no effect on 
reproductive organs. The developmental and reproductive NOEL was 5,000 
ppm, corresponding to a mean daily intake of 350 mg/kg cloquintocet-
mexyl.
    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 toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete. Further, for cloquintocet-mexyl, the NOEL of 3.77 mg/kg/day 
from the combined chronic/oncogenicity study in rats, which was used to 
calculate the RfD, is already lower than the NOEL's of 100 and 60 mg/
kg/day for the rat and rabbit developmental toxicity studies, 
respectively. Further, the developmental and reproductive NOEL of 350 
mg/kg/day from the cloquintocet-mexyl reproduction study is nearly 100 
times greater than the NOEL for the combined chronic/oncogenicity rat 
study. These data would indicate there is no additional sensitivity of 
infants and children to cloquintocet-mexyl. Therefore, it is concluded 
that an additional uncertainty factor is not warranted to protect the 
health of infants and children from the use of cloquintocet-mexyl.
    Using the conservative exposure assumptions described above, it is 
concluded that the percentage of the RfD that will utilized by 
aggregate exposure to residues of cloquintocet-mexyl for its proposed 
use as a safener for clodinafop-propargyl on wheat is 0.01% for nursing 
infants less than 1-year old, 0.03% for non-nursing infants, 0.08% for 
children 1-6 years old and 0.06% for children 7-12 years old. 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative nature of the exposure assessment, it is 
concluded that there is a reasonable certainty that no harm will result 
to infants and children from exposure to residues of cloquintocet-
mexyl.

F. International Tolerances

    Cloquintocet-mexyl is used as a safener for the herbicide, 
clodinafop-propargyl. There are no Codex Alimentarius Commission 
(CODEX) maximum residue levels (MRLs) established for residues of 
cloquintocet-mexyl in or on raw
[FR Doc. 98-9395 Filed 4-14-98; 8:45 am]
BILLING CODE 6560-50-F