[Federal Register Volume 63, Number 37 (Wednesday, February 25, 1998)]
[Notices]
[Pages 9519-9528]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4803]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-790; FRL-5768-4]


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-790, must 
be received on or before March 27, 1998.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Divison 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. 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. 119 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/e-        Address    
                                     mail address                       
------------------------------------------------------------------------
George LaRocca (PM 21)........  Rm. 204, CM #2, 703-    1921 Jefferson  
                                 305-6100, e-mail:       Davis Hwy,     
                                 larocca.george@epamai   Arlington, VA  
                                 l.epa.gov.                             
James A. Tompkins (PM 25).....  Rm. 239, CM #2, 703-    Do.             
                                 305-5697, e-mail:                      
                                 tompkins.james@epamai
l.epa.gov.                             
Hoyt Jamerson (PM 05).........  Rm. 268, CM #2, 703-    Do.             
                                 308-9368, e-mail:                      
                                 jamerson.hoyt@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 raw 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 grantinig of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-790 (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.

[[Page 9520]]

    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 5.1/6.1 file format or 
ASCII file format. All comments and data in electronic form must be 
identified by the docket control number (insert docket number) and 
appropriate petition number. Electronic comments on this notice may be 
filed online at many Federal Depository Libraries.
    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: February 11, 1998.

Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The 
summaries of the petitions were prepared by the petitioners. 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. DowElanco

PP 1F3935

    EPA has received a pesticide petition (PP 1F3935) from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46268-1054 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 triclopyr, (3,5,6-trichloro-2-pyridinyl)oxyacetic acid and 
its metabolites 3,5,6-trichloro-2-pyridinol (TCP) and 2-methoxy-3,5,6-
trichloropyridine (TMP) in or on the raw agricultural commodity fish at 
3.0 parts per million (ppm), and shellfish at 5.0 ppm. EPA has 
determined that the petition contains data or information regarding the 
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Analytical method. Adequate methodology is available for the 
enforcement of tolerances for triclopyr residues of concern. Gas 
chromatography methods are available for the determination of triclopyr 
residues of concern. Residues of triclopyr, 3,5,6-trichloro-2-
pyridinol, and 2-methoxy-3,5,6-trichloropyridine can be separately 
determined. The limits of quantitation are 0.01 - 0.05 ppm in fish and 
shellfish, depending on the compound being analyzed. The water method 
has a limit of quantitation of 0.1 ppb.
    2. Magnitude of residues. In field studies, triclopyr and its 
metabolites in water have half-lives of 0.5 - 15 days. Triclopyr 
residues in lake water treated at the maximum label rate were below 0.5 
ppm within 3 - 14 days. In pond water where whole ponds were treated at 
the maximum label rate, residues were below 0.5 ppm by 28 days after 
treatment. After 42 days in both lakes and ponds, residues were non-
detectable (<0.010 ppm) to 0.013 ppm.
    Residues of triclopyr and its metabolites 3,5,6-trichloro-2-
pyridinol and 2-methoxy-3,5,6-trichloropyridine reach a maximum 
concentration in fish at 3-14 days after treatment of water, and total 
residues of triclopyr and its metabolites were detectable in the edible 
flesh at a maximum level of 3.0 ppm in fish and 5.0 ppm in shellfish. 
Residues in fish and shellfish decline as residues in water dissipate.

B. Toxicological Profile

    1. Acute toxicity. The developmental no-effect level (NOEL) of 30 
milligram/kilogram/day (mg/kg/day) from a rabbit developmental study 
was recommended for the acute dietary risk assessment. At the lowest 
effect level (LEL) of 100 mg/kg/day, there were embryotoxic and 
fetotoxic effects associated with significant maternal toxicity, 
including death. Acute exposure assessment will evaluate risk to 
pregnant females age 13 and older.
    2. Short- and Intermediate-Term Toxicity. Based on the available 
data, short- and intermediate-term dermal and inhalation risk 
assessments are not required. A systemic NOEL of 1,000 mg/kg/day, the 
highest dose tested (HDT), was determined in a 21-day dermal toxicity 
study in rabbits. The LC50 from the acute inhalation study 
in rats was determined to be > 2.6 mg/L (Toxicity Category III).
    3. Chronic toxicity. The Reference Dose (RfD) for triclopyr is 0.05 
mg/kg/day. This RfD is based on a 2-generation reproductive toxicity 
study in rats with a NOEL of 5.0 mg/kg/day using an uncertainty factor 
of 100. At the next higher dose level of 25 mg/kg/day, an increased 
incidence of slight degeneration of the proximal tubules of the kidneys 
was observed in some P1 and P2 parents of both sexes. Chronic exposure 
assessment will evaluate risk using this RfD.
    4. Carcinogenicity. Environmental Protection Agency's Cancer Peer 
Review Committee (CPRC) concluded that triclopyr should be classified 
as a ``Group D chemical'' - not classifiable as to human 
carcinogenicity. A cancer risk assessment is not required.
    5. Animal metabolism. Disposition and metabolism of 14C-
triclopyr in rats demonstrated that triclopyr was well absorbed after 
oral administration. Excretion was relatively rapid with a majority of 
radioactivity eliminated in the urine by 24 hours. At the high dose of 
60 mg/kg, urinary elimination of 14C-triclopyr was decreased 
due to apparent saturation of renal elimination mechanisms. Fecal 
elimination of 14C-triclopyr was a minor route of excretion, 
as was elimination via exhaled air. Unmetabolized parent chemical 
represented >90% of urinary radioactivity, with the remainder accounted 
for by the metabolite 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), and 
possible glucuranide and/or sulfate conjugates of 3,5,6-TCP. Plasma 
elimination following intravenous administration of 14C-
triclopyr was consistent with a one-compartment model with an 
elimination half-life of 3.6 hour and zero-order kinetics from 0-12 
hours at the 60 mg/kg dose.
    6. Bioequivalency. Toxicology studies conducted with triclopyr have 
been performed using both the free acid or the triethylamine salt from 
of triclopyr. Bioequivalency of the two chemical forms of triclopyr has 
been addressed through the conduct of special studies with the 
triethylamine from of triclopyr. These studies, which included data on 
comparative disposition, plasma half-life, tissue distribution, 
hydrolytic cleavage under physiological and environmental conditions 
for triclopyr triethylamine salt were found to adequately address the 
issue of Bioequivalency. In addition, subchronic toxicity studies 
supported the pharmacokinetics data in demonstrating bioequivalence. 
Therefore, studies conducted with any one from of triclopyr can be used 
to support the toxicology database as a whole.
    7. Endocrine Effects. An evaluation of the potential effects on the 
endocrine systems of mammals has not been

[[Page 9521]]

determined; However, no evidence of such effects were reported in the 
chronic or reproductive toxicology studies described above. There was 
no observed pathology of the endocrine organs in these studies. There 
is no evidence at this time that triclopyr causes endocrine effects.

C. Aggregate Exposure

    1. Dietary exposure. The RfD for triclopyr is based upon the 2-
generation reproduction toxicity study in rats with a NOEL of 5.0 mg/
kg/day, the lowest dose tested. An uncertainty factor of 10 for 
interspecies differences in response and an uncertainty factor of 10 
for intraspecies differences in response was applied. Thus, the RfD for 
triclopyr was established at 0.05 mg/kg/day by the RfD Peer Review 
Committee on September 4, 1996.
    A chronic dietary exposure analysis was performed using tolerance 
level residues and 100 percent crop treated information to estimate the 
Theoretical Maximum Residue Contribution (TMRC) for the general 
population and 22 subgroups. Existing tolerances, including the 
proposed tolerances for fish and shellfish, result in a TMRC that 
represents 1.25% of the RfD for the U.S. general population. The 
highest subgroup, Non-Nursing Infants (<1 year old) occupies 2.65% of 
the RfD. The chronic analysis for triclopyr is a worse case estimate of 
dietary exposure with all residues at tolerance level and 100 percent 
of the commodities assumed to be treated with triclopyr. Based on the 
risk estimates calculated in this analysis, the chronic dietary risk 
from the uses currently registered is not of concern.
    Since the toxicological endpoint to which exposure is being 
compared in the acute dietary risk analysis is a developmental NOEL (30 
mg/kg/day), females (13+ years) are the sub population of particular 
interest. The Margin of Exposure (MOE) is a measure of how close the 
high end exposure comes to the NOEL (the highest dose at which no 
effects were observed in the laboratory test), and is calculated as the 
ratio of the NOEL to the exposure (NOEL/exposure = MOE.) Generally, 
acute dietary margins of exposure greater than 100 tend to cause no 
dietary concern. The high end MOE value of 1,639 is above the 
acceptable level and demonstrates no acute dietary concern.
    An acute dietary exposure analysis was performed using tolerance 
level residues and 100 percent crop treated to estimate the high end 
exposure for the general population and females (13+, pregnant, non-
nursing). The high end exposure was assumed to be the upper 0.5% of 
consumers, that is, the 99.5 percentile. The resulting exposure 
estimates and margins of exposure are as follows:


                                                                                                                
----------------------------------------------------------------------------------------------------------------
                Population Subgroup                        Exposure (mg/kg BW/day)                 MOE          
----------------------------------------------------------------------------------------------------------------
U.S. Population                                                                 0.01359                     2208
Females                                                                         0.01831                     1639
----------------------------------------------------------------------------------------------------------------


    These high end MOE values are above the acceptable level and 
demonstrate no acute dietary concerns.
    2. Drinking water. The use of triclopyr as described on the label 
allows only slight additional exposure of triclopyr to humans. The 
proposed labeling requires that the product not be applied within one-
quarter mile of a potable water intake and that treated water not be 
used for domestic purposes until the residue level is demonstrated to 
be at or below 0.5 ppm as determined by laboratory analysis or 
immunoassay. The basis for these restrictions is a series of aquatic 
dissipation studies conducted in lakes and ponds. In these studies, 
triclopyr was applied to lakes and ponds at the maximum concentration 
of 2.5 ppm triclopyr in water. Triclopyr residues in the lakes at one-
quarter mile from the treatment areas were well below 0.1 ppm 
throughout the study, with a maximum reported value of 0.058 ppm. 
Within the treatment area, triclopyr residues of less than 0.5 ppm were 
reported at 3 - 14 days after treatment in the Lake Minnetonka and Lake 
Seminole studies. In seven test ponds treated with triclopyr at a water 
concentration of 2.5 ppm, total residues of triclopyr were less than 
0.5 ppm by 28 days after application, with the highest residue value 
being 0.193 ppm. At 42 days after treatment, total residues in both 
treated lakes and ponds ranged from non-detectable to 0.013 ppm.
    If the proposed labeling is followed precisely, that is, potable 
water is not collected within one-quarter mile of a treated area, there 
will be little contribution from water to the ``risk cup'' for 
triclopyr. If drinking water is collected from the treatment area when 
water analysis indicates triclopyr residues are 0.5 ppm or less, the 
risk is still acceptable on an acute basis. On a chronic basis, the 
value of 0.013 ppm, found to be the highest triclopyr residue at 42 
days after treatment in all studies, uses only 0.9% of the RfD for 
females (13+, pregnant, not nursing) and 2.6% of the RfD for children 
(1-6 years).
    For a worst case estimate of potential drinking water exposure, the 
water residue at the proposed allowable water level at 0.5 ppm was 
utilized. When this residue level is considered, the following analysis 
indicates no level of concern for acute exposure:
    For a 60 kg pregnant female consuming 2 liters a day (Acute)
    (0.5 mg/L  x  2 L/day) / 60 kg = 0.0167 mg/kg/day
    MOE = NOEL / Exposure = (30 mg/kg/day) / (0.0167 mg/kg/day) = 
1796


    For a 60 kg pregnant female consuming 2 liters a day (Chronic)
    (0.013 mg/kg/day  x  2 L/day) / 60 kg = 0.00043 mg/kg/day
    % RfD = (0.00043 mg/kg/day  x  100) / (0.05 mg/kg/day) = 0.9 %


    For a 10 kg child consuming 1 liter a day (Acute)
    (0.5 mg/L  x  1 L/day) / 10 kg = 0.05 mg/kg/day
    MOE = (30 mg/kg/day) / (0.05 mg/kg/day) = 600


    For a 10 kg child consuming 1 liter a day (Chronic)
    (0.013 mg/L  x  1 L/day) / 10 kg = 0.0013 mg/kg/day
    % RfD = (0.0013 mg/kg/day  x  100) / (0.05 mg/kg/day) = 2.6 %


    3. Non-dietary exposure. There are potential exposures to 
homeowners during usual use-patterns associated with triclopyr. These 
involve application of triclopyr-containing products by means of 
aerosol cans, pump spray bottles, squeeze bottles, ``weed sticks,'' 
hose-end sprayers, power sprayers, paint brush, rotary and drop 
spreaders. It is unlikely that power sprayers will be used by 
homeowners; this is an application method requiring special applicator 
equipment more apt to be used by agricultural or commercial applicator.
    Homeowner exposure will not be significant for the following 
reasons: the

[[Page 9522]]

percent ai in products for homeowner use is less than that for 
agricultural or industrial use; the areas treated are usually limited 
in size; all products are intended for outdoor use which is likely to 
reduce the concentration in the environment by allowing dissipation in 
the outdoor air; the application methods recommended or commonly used 
by homeowners are not expected to provide significant exposure. 
Additionally, no toxicological endpoints of concern have been 
identified by EPA for dermal exposure to triclopyr, therefore, no 
exposure assessment is required for this exposure; an inhalation 
exposure assessment is also not required and no chronic use pattern is 
expected for homeowner use of triclopyr products.
    There is a potential for post-application exposure to swimmers 
following applications to aquatic sites that may be used for 
recreational purposes. There are no triclopyr-specific exposure data to 
assess swimmer exposure. However, an assessment was conducted using 
information provided in EPA's Dermal Exposure Assessment: Principles 
and Applications. The dermal permeability constant (Kp) was calculated 
to be 6.5  x  10-8 mg/cm2/hr. The assessment of 
swimmer exposure was based on a 6-year old boy having a body weight of 
21.9 kg and a surface area of 0.88 m2. The swimming period 
was assumed to be 3 hours on the day of treatment in water containing 
2.5 ppm triclopyr.
    Total dermal exposure (mg) = 3 hr/day  x  0.88 m2  x  
104 cm2/m2  x  6.5  x  10-8 
mg/cm2/hr = 1.716  x  10-3 mg/day
    Oral absorption could also account for a portion of the exposure. 
It was assumed that 1% of the water in residence in the mouth while 
breathing will be swallowed.
    Oral exposure = 3 hr/day  x  0.05 L/hr  x  2.5 mg/L = 0.375 mg/day
    Combining the dermal exposure and oral exposure for a 21.9 kg 
child, the swimming exposure for one day was estimated to be 0.377 mg/
day  21.9 kg = 0.017 mg/kg/day. Compared to the acute NOEL of 
30 mg/kg/day, an MOE of 1,765 was obtained. No dermal or inhalation 
endpoint has been established for triclopyr, so this represents a very 
conservative estimate of the risk due to swimming in triclopyr-treated 
waters.

D. Cumulative Effects

    The potential for cumulative effects of triclopyr and other 
substances that have a common mechanism of toxicity was considered. The 
mammalian toxicity of triclopyr is well defined. However, the 
biochemical mechanism of toxicity of this compound is not known. No 
reliable information exists to indicate that toxic effects produced by 
triclopyr would be cumulative with those of other similar compounds. 
Therefore, consideration of a common mechanism of toxicity with other 
compounds is not appropriate. Thus, only the potential risks of 
triclopyr are considered in the aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Because of the toxicological characteristics of 
triclopyr (no dermal endpoint of concern), post-application exposure 
assessment was not necessary. Residential exposure is considered to be 
negligible. Swimming in treated water was shown to be a minimal risk. 
Therefore, residential and swimming exposure were not considered in the 
aggregate risk calculation.
    For the population subgroup of concern, pregnant females age 13 and 
older, an MOE of 857 was estimated for the acute aggregate dietary risk 
(food + water) from exposures to triclopyr residues.
    MOE = (30 mg/kg/day) / (0.0183 + 0.0167) mg/kg/day = 857
    Using the TMRC exposure assumptions described above, the percentage 
of the RfD that will be utilized by aggregate exposures (food + water) 
to residues of triclopyr ranges from 2.1% to 5.3% for the U.S. 
population. The major identifiable subgroup with the highest aggregate 
exposure is non-nursing infants <1 year old. The water exposure value 
used the highest water residue concentration at 42 days after treatment 
of lakes and ponds (the longest sampling time interval common to all 
studies), 0.013 ppm, in the calculations below:
    Total U.S. Population (Dietary + Drinking Water)
    (0.00062 + 0.00043) mg/kg/day  x  100 / (0.05 mg/kg/day) = 2.1% 
RfD


    Non-nursing Infants (Dietary + Drinking Water)
    (0.00133 + 0.0013) mg/kg/day  x  100 / (0.05 mg/kg/day) = 5.3% 
RfD


    Determination of Safety for U.S. Population
    Based on the current state of knowledge for this chemical, the 
RfD approach accurately reflects the exposure of the U.S. 
population, infants and children to triclopyr.


    2. Infants and children. Studies cited earlier in this document 
indicate that triclopyr is not a selective developmental toxicant, and 
an additional uncertainty factor for infants and children is 
unnecessary. This decision is based on the following data.
    Since the developmental and reproductive NOELs were either the same 
or greater than the maternal or parental, it is unlikely that there is 
additional risk concern for immature or developing organisms which is 
not reflected by the risk assessment utilizing the established 
reference dose. The effects noted for the RfD NOEL are parental 
effects, not developmental.

F. International Tolerances

    There are no established or proposed Codex MRLs for triclopyr 
residues. Therefore, there are no issues of compatibility with respect 
to U.S. tolerances and Codex MRLs.    (PM 25)

2. DuPont Agricultural Products

PP 4F3003, 4F3120, 0F3852

    EPA has received a pesticide petition (PP 4F3003, 4F3120, 0F3852) 
from DuPont Agricultural Products, PO 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 by 
establishing tolerances for residues of esfenvalerate (Asana XL 
Insecticide), ((S)-cyano-(3-phenoxyphenyl) methyl (S)-4-chloro-alpha-
(1-methylethyl) benzeneacetate) in or on the raw agricultural 
commodities sorghum, sugarbeets and head lettuce (see section A3 for 
specific tolerance levels). The proposed analytical method involves 
homogenization, filtration, partition and cleanup with analysis by high 
performance liquid chromatography using ultra violet (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 and Animal 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 previously submitted to the Agency. These studies have 
demonstrated that the parent compound is the only residue of 
toxicological significance. EPA has concluded that the qualitative 
nature of

[[Page 9523]]

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 (S,S; R,S; S,R; and R,R). Technical Asana 
(esfenvalerate) is enriched in the insecticidally active S,S-isomer 
(84%). Tolerance expressions are proposed for esfenvalerate based on 
the sum of all isomers. Tolerance of 5 parts per million (ppm) for head 
lettuce, 5.0 ppm for sorghum grain, 10.0 ppm for sorghum forage, 10.0 
ppm for sorghum fodder, 0.03 ppm for whole eggs, 0.03 ppm for poultry 
meat, 0.3 ppm for poultry fat, 0.3 ppm for poultry meat by-products 
(except liver), and 0.03 ppm for poultry liver, 5 ppm for sugarbeet 
tops, 0.5 ppm for sugarbeet roots and 2.5 ppm sugarbeet pulp are 
proposed. Magnitude of residue studies support the proposed tolerance.

B. Toxicological Profile

    1. Acute toxicity. A battery of acute toxicity studies places 
technical esfenvalerate in Toxicity Category II for acute oral toxicity 
(rat 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 a.i. waived due to 
negligible vapor pressure. A dermal sensitization test on esfenvalerate 
in guinea pigs showed no sensitization.
    2. Genotoxicty. 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 intraperitoneally. Esfenvalerate did not 
induce unscheduled 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 on 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 does 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 
pilot study. The developmental NOEL was > 20 mg/kg/day.
    A two-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). Three-month 
subchronic study in dogs was satisfied by one-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 an NOEL of 1,000 mg/kg/day.
    5. Chronic toxicity. In a one-year study, dogs were fed 0, 25, 50, 
or 200 ppm esfenvalerate with no treatment related effects at any 
dietary level. The NOEL was 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 two 
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 oncogenicity 
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 two-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 
noncarcinogenicity for humans.
    6. Animal metabolism. After oral dosing with 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.
    8. Other potential toxicology considerations - endocrine effects.

[[Page 9524]]

 Estrogenic effects have not been observed in any studies conducted on 
fenvalerate or esfenvalerate. In subchronic or chronic studies there 
were no lesions in reproductive systems of males or females. In the 
recent reproduction study with esfenvalerate, full histopathological 
examination of the pituitary and the reproductive systems of males and 
females was conducted. There were no compound-related gross or 
histopathological effects. There were also no compound-related changes 
in any measures of reproductive performance including mating, 
fertility, or gestation indices or gestation length in either 
generation. There have been no effects on offspring in developmental 
toxicity studies. EPA is required to develop an endocrine disrupter 
screening program by August 3, 1999. EPA will decide whether further 
testing of esfenvalerate is required at that time.

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 sugarbeets, 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 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 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. There is no evidence 
of carcinogenicity in either rats or mice.
    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 Reference Dose (RfD) 
utilized by the most sensitive sub-population, children 1-6 yrs., 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 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. 
Esfenvalerate is classified as a Group E carcinogen - no evidence of 
carcinogenicity in rats or mice. Therefore, a carcinogenicity risk 
analysis is not required.
    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. EPA 
considered these data 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 Margins of Exposure (MOEs) for the most sensitive sub-population 
(children 1-6 yr.) 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 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 (62 FR 63019).
    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).
    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 parts per billion. 
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 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

[[Page 9525]]

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 one year old. EPa concluded (62 FR 63019) that the potential non-
dietary exposure for esfenvalerate are associated with substantial 
margins of safety.
    5. Aggregate exposure - dietary and non-dietary exposure. 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 (62 FR 63019) 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 
(62 FR 63019) 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 
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

    Both the chronic and acute toxicological endpoints are derived from 
maternal NOEL's of 2.0 mg/kg/day in developmental studies in rats and 
rabbits. There were no fetal effects. In addition, no other studies 
conducted with fenvalerate or esfenvalerate indicate that immature 
animals are more sensitive than adults. Therefore, the safety factor 
used for protection of adults is fully appropriate for the protection 
of infants and children; no additional safety factor is necessary as 
described below.
    1. U.S. population. A chronic dietary exposure assessment using 
anticipated residues, monitoring information, and percent crop treated 
indicated the percentage of the Reference Dose (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 Margin of Exposure (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

[[Page 9526]]

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 (62 FR 63019), 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 two 
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 yr 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 year, 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. There is reasonable certainty that no harm will result to 
infants and children from aggregate exposure to esfenvalerate residues 
(62 FR 63019).

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 is a Codex MRL of 2 ppm fenvalerate on head lettuce. 
Thus any imported head lettuce is expected to have lower residue values 
than the proposed section 408 tolerance of 5 ppm esfenvalerate on head 
lettuce. There are also some minimal differences between the section 
408 tolerances and certain Codex MRl values for other 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 will be required.    (PM 
13)

3. Interregional Research Project No. 4 (IR-4)

PP 5E4598

    EPA has received a pesticide petition (PP) from the Interregional 
Research Project No. 4 (IR-4), New Jersey Agricultural Experiment 
Station, P.O. Box 231, Rutgers University, New Brunswick, NJ 08903, 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.472 by extending 
the effective date for the time-limited tolerance established for 
indirect or inadvertant combined residues of the insecticide 
imidacloprid in or on the raw agricultural commodity cucurbit vegetable 
crop group at 0.2 parts per million (ppm). EPA has determined that the 
petition contains data or information regarding the elements set forth 
in section 408(d)(2) of the FFDCA; however, EPA has not fully 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 nature of the imidacloprid residue in 
plants and livestock is adequately understood. The residues of concern 
are combined residues of imidacloprid and it metabolites containing the 
6-chloropyridinyl 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 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.

B. Toxicological Profile

    1. Acute toxicity. The acute oral LD50 values for 
imidacloprid technical ranged from 424 - 475 milligram (mg)/kilogram 
(kg) body weight (bwt) in the rat. The acute dermal LD50 was 
greater than 5,000 mg/kg in rats. The 4-hour rat inhalation 
LC50 was > 69 mg/meter3 (m3) air (aerosol). Imidacloprid was 
not irritating to rabbit skin or eyes. Imidacloprid did not cause skin 
sensitization in guinea pigs.
    2. Genotoxicty. Extensive mutagenicity studies conducted to 
investigate point and gene mutations, DNA damage and chromosomal 
aberration, both using in vitro and in vivo test systems show 
imidacloprid to be non-genotoxic.
    3. Reproductive and developmental toxicity. A 2-generation rat 
reproduction study gave a no-observed-effect level (NOEL) of 100 ppm (8 
mg/kg/bwt). Rat and rabbit developmental toxicity studies were negative 
at doses up to 30 mg/kg/bwt and 24 mg/kg/bwt, respectively.
    4. Subchronic toxicity. 90-day feeding studies were conducted in 
rats and dogs. The NOEL's for these tests were 14 mg/kg bwt/day (150 
ppm) and 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 had 
a NOEL of 1,000 ppm (208 mg/kg/day).
    6. Plant and animal metabolism. The nature of the imidacloprid 
residue in plants and livestock is adequately understood. The residues 
of concern are combined residues of imidacloprid and

[[Page 9527]]

it metabolites containing the 6-chloropyridinyl moiety, all calculated 
as imidacloprid.
    7. Endocrine disruption. The toxicology database for imidacloprid 
is current and complete. Studies in this database include evaluation of 
the potential effects on reproduction and development, and an 
evaluation of the pathology of the endocrine organs following short- or 
long-term exposure. Bayer has concluded that these studies revealed no 
primary endocrine effects due to imidacloprid.

C. Aggregate Exposure

    Imidacloprid is a broad-spectrum insecticide with 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. These potential exposures are addressed below:
    1. Dietary exposure. For purposes of assessing the potential acute 
and chronic dietary exposure, Bayer has estimated exposure based on the 
Theoretical Maximum Residue Contribution (TMRC). The TMRC is obtained 
by using a model which multiplies the tolerance level residue for each 
commodity by consumption data. The consumption data, based on the 
National Food Consumption Survey data base, estimates the amount of 
each commodity and products derived from the commodities that are eaten 
by the U.S. population and various population subgroups.
    2. Food --i. Acute. For acute dietary exposure the model calculates 
a margin of exposure (MOE) by dividing the estimated human exposure 
into the NOEL from the appropriate animal study. Commonly, EPA finds 
MOEs lower than 100 to be unacceptable. The EPA has determined that a 
NOEL of 24 mg/kg/day from a developmental toxicity study in rabbits 
should be used to assess acute toxicity.
    The MOE for imidacloprid derived from previously established 
tolerances and pending tolerances, including IR-4's cucurbit petition, 
would be 366 for the U.S. population (48 states), 323 for non-nursing 
infants, 101 for children (ages 1-6 years), 420 for children (ages 7-12 
years), 622 for males 13+ years, and 554 for females 13+ years at the 
99.9 percentile. These MOEs do not exceed the EPA's level of concern 
for acute dietary exposure.
    ii. Chronic. For purposes of assessing the potential chronic 
dietary exposure, the model uses the reference dose (RfD) which the EPA 
has determined to be 0.057 mg/kg/day. This is based on the 2-year rat 
feeding/carcinogenic study with a NOEL of 5.7mg/kg/bwt and 100-fold 
uncertainty factor. In conducting this exposure assessment, very 
conservative assumptions (100% of all commodities contain imidacloprid 
residues and those residues are at the level of the tolerance) result 
in a large overestimate of human exposure.
    3. Drinking water. The EPA has determined that imidacloprid is 
persistent and could potentially leach into groundwater. However, there 
is no established Maximum Contamination Level (MCL) or health advisory 
levels established for imidacloprid in drinking water. EPA's 
``Pesticides in Groundwater Database'' has no entry for imidacloprid. 
In addition, Bayer 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. Therefore, Bayer concludes that contributions 
to the dietary burden from residues of imidacloprid in water would be 
inconsequential.
    4. Non-dietary exposure --i. Residential Tur.  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 are young 
children. Margins of safety (MOS) of 7,587 - 41,546 for 10-year-old 
children and 6,859 - 45,249 for 5-year-old children were estimated by 
comparing dermal exposure doses to the imidacloprid no-observable 
effect level of 1,000 mg/kg/day established in a 15-day dermal toxicity 
study in rabbits. The estimated safe residue levels of imidacloprid on 
treated turf for 10-year-old children ranged from 5.6 - 38.2 
g/cm2 and for 5-year-old children from 5.1 - 33.5 
g/cm2. This compares with the average imidacloprid 
transferable residue level of 0.080 g/cm2 present 
immediately after the sprays have dried. These data indicate that 
children can safely contact imidacloprid-treated turf as soon after 
application as the spray has dried.
    ii. Termiticide. Imidacloprid is registered as a termiticide. Due 
to the nature of the treatment for termites, exposure would be limited 
to that from inhalation and was evaluated by EPA's Occupational and 
Residential Exposure Branch's (OREB) and Bayer. Data indicate that the 
Margins of Safety for the worst case exposures for adults and infants 
occupying a treated building who are exposed continuously (24 hours/
day) are 8.0  x  107 and 2.4  x  108, 
respectively - and exposure can thus be considered negligible.
    iii. Tobacco Smoke. Studies have been conducted to determine 
residues in tobacco and the resulting smoke following treatment. 
Residues of imidacloprid in cured tobacco following treatment were a 
maximum of 31 ppm (7 ppm in fresh leaves). When this tobacco was burned 
in a pyrolysis study only 2 percent of the initial residue was 
recovered in the resulting smoke (main stream plus side stream). This 
would result in an inhalation exposure to imidacloprid from smoking of 
approximately 0.0005 mg per cigarette. Using the measured subacute rat 
inhalation NOEL of 5.5 mg/m3, it is apparent that exposure to 
imidacloprid from smoking (direct and/or indirect exposure) would not 
be significant.
    iv. Pet Treatment. Human exposure from the use of imidacloprid to 
treat dogs and cats for fleas has been addressed by EPA's Occupational 
and Exposure Branch (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. Cumulative Effects

    No other chemicals having the same mechanism of toxicity are 
currently registered, therefore, Bayer concludes that there is no risk 
from cumulative effects from other substances with a common mechanism 
of toxicity.

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 
imidacloprid from all current uses including those currently proposed 
will utilize little more than 14.3% of the RfD for the U.S. population 
from food, water and non-occupational sources. 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. In addition, 
the MOEs for all population groups does not exceed the EPA's level of 
concern for acute dietary exposure. Thus, Bayer concludes 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

[[Page 9528]]

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 under 
aggregate exposure, Bayer has determined from a chronic dietary 
analysis that the percent of the RfD utilized by aggregate exposure to 
residues of imidacloprid ranges from 9.3% for nursing infants up to 
32.2% for children (1-6 years). EPA generally has no concern for 
exposure below 100 percent of the RfD. In addition, the MOEs for all 
infant and children population groups do not exceed EPA's level of 
concern for acute dietary exposure. Therefore, based on the 
completeness and 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 imidacloprid, including all 
anticipated dietary exposure and all other non-occupational exposures.

F. International Tolerances

    No Codex Maximum Residue Levels (MRLs) have been established for 
residues of imidacloprid on any crops at this time.    (PM 05)

[FR Doc. 98-4803 Filed 2-24-98; 8:45 am]
BILLING CODE 6560-50-F