[Federal Register Volume 62, Number 133 (Friday, July 11, 1997)]
[Notices]
[Pages 37234-37246]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-18256]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-748; FRL-5728-7]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-748, must 
be received on or before August 11, 1997.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7506C), Information Resources and Services 
Division, Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically 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:

[[Page 37235]]



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                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-            Davis Hwy,     
                                 mail:miller.joanne@ep   Arlington, VA  
                                 amail.epa.gov.                         
George LaRocca (PM 13)........  Rm. 204, CM #2, 703-    Do.             
                                 305-6100, e-mail:                      
                                 larocca.george@epamai
l.epa.gov.                             
James Tompkins (PM 25)........  Rm. 229, CM #2, 703-    Do.             
                                 305-7830, e-mail:                      
                                 tompkins.james@epamai
l.epa.gov.                             
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-748] (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 [PF-748] and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.

List of Subjects

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

    Dated: July 1, 1997.

James Jones,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim 
without editing them in any way. The petition summary announces the 
availability of a description of the analytical methods available to 
EPA for the detection and measurement of the pesticide chemical 
residues or an explanation of why no such method is needed.

1. DowElanco

PP 6G3306

    EPA has received a pesticide petition (PP) 6G3306 from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46268 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 renewing a temporary tolerance for 
the combined residues of herbicide triclopyr (3,5,6-trichloro-2-
pyridinyl)oxyacetic acid and its metabolites 3,5,6-trichloro-2-
pyridinol and 2-methoxy-3,5,6-trichloropyridine in or on the raw 
agricultural commodities fish and shellfish at 0.2 part per million 
(ppm). An allowable residue level of 0.5 ppm in potable water is also 
being renewed. The proposed analytical method is gas chromatography. 
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. Triclopyr Uses

    Triclopyr as the triethylamine salt solution is currently 
registered for use on rights-of-way, industrial sites, non-crop areas, 
forest sites, rangeland, permanent grass pastures, roadsides, fence 
rows, ornamental turf, non-irrigation ditchbanks, and rice. It is 
recommended for the selective control of unwanted woody plants and 
annual and perennial broadleaf weeds on these sites.
    Triclopyr is to be experimentally used for the selective control of 
aquatic weeds such as alligatorweed, Eurasian watermilfoil, parrot's 
feather, pickerelweed, purple loosestrife, and water hyacinth growing 
in lakes, ponds, reservoirs, and wetlands. It will also be tested for 
the control of woody brush and herbaceous weeds growing in wetlands and 
the banks and shores of aquatic sites. Application timing will coincide 
with the seasons of the year when the target species are actively 
growing. The maximum rates for triclopyr are 2 gallons per acre for the 
treatment of floating or emerged weeds, 3 gallons per acre for 
treatment of woody plants, and 2.5 ppm in water for treatment of 
submersed weeds.

B. 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 detection limits range from 0.01 to 10 ppm depending on 
the compound being analyzed.
    2. Magnitude of residues. In field studies, triclopyr in water has 
a half-life of 0.5 - 3.5 days. Triclopyr residues were below 0.5 ppm 
after 3 days. The metabolite, 3,5,6-trichloro-2-pyridinol was not 
detected within the treatment area. Within the treatment area, 
triclopyr was detected at <0.01 - 0.03 ppm in water collected 21 days 
after application. The average concentration did not exceed 0.5 ppm at 
600 ft from the border of the treated area. Residues of triclopyr and 
its metabolites 3,5,6-trichloro-2-pyridinol and 2-methoxy-3,5,6-
trichloropyridine were detectable only at the limit of detection, 0.01 
ppm and non-detectable after day eight in fish flesh. Shellfish 
residues were

[[Page 37236]]

greater, with less than 0.1 ppm remaining in the edible portion after 
two weeks of treatment.

C. Toxicology Profile

    1. Acute toxicity. Acute toxicity studies conducted with the 
triethylamine salt of triclopyr indicate low toxicity with the 
exception of eye irritation. The acute oral LD50, in rats 
with the triethylamine salt of triclopyr is 2,574 mg/kg (males) or 
1,847 mg/kg (females) (Toxicity Category III.) The acute dermal LD, in 
rabbits using the triethylamine salt of triclopyr was > 2,000 mg/kg 
(Toxicity Category III.) The acute inhalation LD50, in rats 
was > 2.6 mg/L (maximum attainable concentration) with a Toxicity 
Category of III. In a primary eye irritation study in rabbits the 
triethylamine salt of triclopyr was found to be corrosive, with corneal 
involvement present through day 21 post-dose. The triethylamine salt of 
triclopyr was found to be non-irritating to the skin of white rabbits. 
In dermal sensitization studies in guinea pigs, sensitization was 
observed with the triethylamine salt of triclopyr.
    2. Genotoxicity. The genotoxic potential of triclopyr has been 
evaluated in a range of assays in vivo and in vitro. These assays 
demonstrate triclopyr is non-mutagenic in vivo and in vitro. 
Mutagenicity data included gene mutation assays with E. coli and S. 
typhimurium (negative); DNA damage assays with B. subtillis (negative); 
an unscheduled DNA synthesis with rat hepatocytes (negative), a 
chromosomal aberration test in Chinese hamster cells and rat cells 
(negative) and dominant lethal assays in rats and mice (negative).
    3. Reproductive and developmental toxicity. A developmental 
toxicity study in rats fed dosage levels of 0, 30, 100, and 300 mg/kg/
day, with a maternal lowest observed effect level (LOEL) = 300 mg/kg 
based on the increased incidence of salivation and mortality and a 
maternal no-observed effect level (NOEL) = 100 mg/kg. Developmental 
toxicity was evident in this study at the 300 mg/kg dose level, and 
included decreased mean fetal body weight, increased fetal and litter 
incidence of skeletal anomalies and an increase in the number of 
fetuses with unossified sternebrae. The developmental LOEL = 300 mg/kg-
based on decreased mean fetal weight, increased fetal and fitter 
incidence of skeletal anomalies, and increased fetal incidence of 
unossified sternebrae. The developmental NOEL = 100 mg/kg.
    A developmental toxicity study in rabbits fed dosage levels of 0, 
10, 30, and 100 mg/kg/day with a maternal LOEL = 100 mg/kg based on the 
decreased body weight gain, decreased food efficiency, and increased 
liver and kidney weight. The maternal NOEL = 30 mg/kg. Developmental 
toxicity was evident at the 100 mg/kg dose level in the form of reduced 
number of litters, reduced number of corpora lutea, reduced number of 
total implants, reduced total live fetuses, increased embryonic deaths 
and deaths/dam, and increased pre-implantation loss. The developmental 
LOEL =100 mg/kg based an the decreased number of live implants, 
decreased live fetuses, and increased embryonic deaths. The 
developmental NOEL = 30 mg/kg.
    A 2-generation reproduction study in rats fed dosages of 0, 5, 25, 
and 250 mg/kg/day with a Parental Systemic Toxicity NOEL = 5 mg/kg/day 
(males and females); the parental Systemic Toxicity LOEL = 25 mg/kg/
day, based on increased incidence of proximal tubular degeneration in 
male and female Pl and P2 rats. The Reproductive/
Systemic Toxicity NOEL = 25 mg/kg/day; the Reproductive/Systemic 
Toxicity LOEL = 250 mg/kg/day, based on decreased litter size, 
decreased body weight and weight gain, and decreased survival in the 
F1 and F2 litters.
    4. Subchronic toxicity. A subchronic oral toxicity study in rats 
receiving dietary concentrations of triclopyr at doses of 0, 5, 20, 50, 
or 250 mg/kg/day for 13 weeks with a systemic NOEL was 5 mg/kg/day, and 
the systemic LOEL of 20 mg/kg/day, based on histopathological changes 
in the kidneys of both sexes.
    A 183-day toxicity study in dogs receiving dietary doses of 
triclopyr technical at 0, 0.1, 0.5, or 2.5 mg/kg/day with decreased 
rate of phenolsulfanthalein (PSP) excretion was observed in dogs 
receiving 2.5 mg/kg/day triclopyr. This effect is a result of 
competition between triclopyr and PSP for renal excretion, and is not 
toxicologically relevant. The systemic NOEL is 2.5 mg/kg/day and the 
systemic LOEL is > 2.5 mg/kg/day in both sexes.
    5. Chronic toxicity. In a 1-year dietary toxicity study, triclopyr 
was administered to dogs at doses of 0, 0.5, 2.5, or 5.0 mg/kg/day. 
There were no significant effects of treatment on mortality, clinical 
signs, body weight, or food consumption in male and female dogs at any 
dose level treated. Increases in urea nitrogen and creatinine were 
observed at 2.5 and 5.0 mg/kg/day; these changes in clinical chemistry 
values do not represent a toxic response to the test chemical, but a 
physiologic response of the dog, based on the limited ability of the 
dog to excrete organic acids at higher plasma concentrations. The lack 
of histopathologic alterations in the kidneys of both sexes is 
supportive of this conclusion. The systemic NOEL is  5.0 mg/
kg/day for both sexes; the systemic LOEL is >5.0 mg/kg/day.
    In a chronic toxicity/carcinogenicity study, triclopyr was 
administered in the diet to mice at dose levels of 0, 50 ppm, 250 ppm, 
or 1,250 ppm. There were no compound-related tumors observed in mice. 
The LOEL was considered to be 143 mg/kg/day in male mice and 135 mg/kg/
day in female mice, based on the decreased body weight gain. The NOEL 
is considered to be 28.6 mg/kg/day in male mice, and 26.5 mg/kg/day in 
female mice.
    In a chronic toxicity/carcinogenicity study, triclopyr was 
administered to Fischer 344 rats for 2 years at dose levels of 0, 3, 
12, or 36 mg/kg/day. Mortality in treated groups of male rats was lower 
than that in the control group. Cumulative mortality was 50%, 32%, 26%, 
and 36% for control, low, mid, and high dose level male rats. Red cell 
count, hemoglobin, and hematocrit in male rats was numerically 
decreased at the high dose at 6, 12, and 24 months. Statistical 
significance was achieved for the decrease in red cells at 12 months, 
for hemoglobin at 6 months, and for hematocrit at 6 and 22 months. 
Absolute and relative kidney weight was significantly increased (10-
13%) at the high dose in male rats, with an apparent dose-related trend 
at 12 months. Female rats showed an increased incidence of pigmentation 
of the proximal descending tubule at all dose levels compared to 
control, while male rats in the 6-month satellite group showed 
increased incidence of proximal tubule degeneration at the 12 and 36 
mg/kg/day dose levels compared to control. There were no significant 
increasing trends in tumor incidence for rats.
    As a result of the August 9, 1995 meeting of the Health Effects 
Division Carcinogenicity Peer Review Committee, triclopyr was 
classified as a Group D chemical (not classifiable as to human 
carcinogenicity).
    6. Animal metabolism. Disposition and metabolism of 14C-
triclopyr was investigated in rats at a low oral dose (3 mg/kg), 
repeated low oral doses ( 3 mg/kg x 14 days), and a high dose (60 mg/
kg.) Comparison of disposition data in intravenously dosed and orally 
dosed rats demonstrated that triclopyr was well absorbed after oral 
administration. Excretion was relatively rapid at the low dose, with a 
majority of radioactivity eliminated in the urine by 24 hours. At 60 
mg/kg, urinary elimination of 14C-triclopyr derived 
radioactivity was decreased in rats from 0-12 hours, due to apparent 
saturation of renal

[[Page 37237]]

elimination mechanisms. Fecal elimination of 14C-Triclopyr 
derived radioactivity was a minor route of excretion, as was 
elimination via exhaled air. No significant effect was observed on 
metabolism or disposition of 14C-triclopyr from repeated low 
oral dosing.
    Urinary metabolites of 14C-triclopyr were isolated and 
identified by HPLC and GC/MS. 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 hr and zero-order kinetics from 0-12 hours at the 60 mg/kg dose.
    7. Bioequivalency. Toxicology studies conducted with triclopyr have 
been performed using either the free acid or the triethylamine salt 
form of triclopyr. Bioequivalency of the two chemical forms of 
triclopyr has been addressed through the conduct of special studies 
with the triethylamine form 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 pharmacokinetic data in demonstrating bioequivalence. 
Therefore, studies conducted with any one form of triclopyr can be used 
to support the toxicology database as a whole.

D. Aggregate Exposure

    1. Dietary exposure--i. Food. The Reference Dose (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% crop treated information to estimate the 
Theoretical Maximum Residue Contribution (TMRC) for the general 
population and 22 subgroups. Existing tolerances result in a TMRC which 
represents 0.81% 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% of the 
commodities assumed to be treated with triclopyr. Based on the risk 
estimates calculated in this analysis, it appears that 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) is 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 2,500 is above the 
acceptable level and demonstrates no acute dietary concern.
    An acute dietary exposure analysis was performed using tolerance 
level residues and 100% 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:

                                                                        
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   Population Subgroup Exposure      (mg/kgBW/day)            MOE       
------------------------------------------------------------------------
U.S. Population                   0.00230             13050             
Females                           0.00184             16277             
------------------------------------------------------------------------

    These high end MOE values are above the acceptable level and 
demonstrate no acute dietary concerns.
    ii. Drinking water. The use of triclopyr in the proposed EUP does 
not add any additional exposure of triclopyr to humans. The only 
additional source that needs to be considered is drinking water. The 
proposed EUP labeling requires that the product not be applied within 
one mile of a potable water intake, and treated water is not to be used 
for domestic purposes for 21 days after application. The basis for 
these restrictions is a study conducted at Lake Seminole, GA. In this 
study, triclopyr was not detected one mile downstream from the treated 
area for up to 42 days after treatment. Within the treatment area, 
triclopyr was detected at <0.01 - 0.03 ppm in water collected 21 days 
after application. At 1 hour after application, water from the treated 
area contained 2.6 ppm of triclopyr, and was below the temporary 
tolerance level of 0.5 ppm at 3 days after treatment.
    If the proposed labeling is followed precisely, that is, potable 
water is not collected within one mile of a treated area, triclopyr 
residues will not be detected (<0.01 ppm), and there will be no 
contribution from water to the ``risk cup'' for triclopyr. If water is 
collected from the treated area 21 days after treatment and used in 
drinking water supplies, the maximum residue of 0.03 ppm in the Lake 
Seminole study would increase the amount of the RfD used for non-
nursing infants (<1 yr old) from 2.6 % to 7.0 % for chronic exposure.
    For a worst case estimate of potential drinking water exposure, the 
water residue data from the treated area in the Lake Seminole study was 
utilized. It was assumed that potable water was collected from the 
treatment area during the 21 days following the application. The data 
were integrated over the time period to find an ``average'' value, 
which calculated to be 0.2 ppm. When this residue level is considered, 
the following analysis demonstrates the risk is minimal.
    Acute NOEL (Pregnant females) = 30 mg/kg/day; Acute NOEL (Children 
1-6 years); Chronic NOEL (all population subgroups) = 5 mg/kg/day Time 
weighted concentration during the mitigation period = 0.2 ppm = 2.0 X 
10-1 mg/L
    For a 10 kg child consuming 1 liter a day (Acute):
    (2.0 X 10-1 mg/L X 1 L/day) / 10 kg = 2.0 X 10-
2 mg/kg/day MOE = NOEL/Exposure = 5 mg/kg/day / 2.0 X 10-
2 mg/kg/day MOE = 250
    For a 10 kg child consuming 1 Liter a day (Chronic):
    Percent of RfD = (2.0 X 10-2 mg/kg/day / 0.05) X 100 = 
40%
    For a 60 Kg pregnant female consuming 2 Liters a day (Acute):
    (2.0 x 10-1 mg/L X 2 L/day) / 60 kg = 6.7 X 10-
3 mg/kg/day
    MOE = 30 mg/kg/day / 6.7 X 10-3 mg/kg/day = 4478
    For a 60 kg pregnant female consuming 2 Liters a day (Chronic):
    Percent of RfD = (6.7 X 10-3 mg/kg/day / 0.05) x 100 = 
13.4%
    2. 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

[[Page 37238]]

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 percent a.i., 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.

E. 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 well known. 
No reliable information exists to indicate that toxic effects produced 
by triclopyr would be cumulative with those of any other chemical 
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.

F. 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. Therefore, residential exposure was not considered in the 
aggregate risk calculation. The water exposure value used the time 
weighted concentration during the mitigation period = 0.2 ppm = 2.0 X 
10-1 mg/L in the calculations below for drinking water 
exposure. The high end (99.5 percentile) exposure from the acute 
dietary analysis is used for the populations below.
    13+ pregnant females Dietary + Drinking water
    0.0018 mg/kg/day + 6.7 X 10-3 mg/kg/day = 8.5 X 10-
3 mg/kg/day
    Acute MOE = 30 mg/kg/day / 8.5 X 10-3 mg/kg/day = 3529
    Non-nursing infants Dietary + Drinking water
    0.006 mg/kg/day + 0.02 mg/kg/day = 2.6 X 10-2 mg/kg/day
    Acute MOE = 5 mg/kg/day / 2.6 X 10-2 mg/kg/day = 192
    Children (1-6 years), Dietary + Drinking Water
    0.0035 mg/kg/day + 0.02 mg/kg/day = 2.35 X 10-2 mg/kg/
day
    Acute MOE = 5 mg/kg/day/2.35 X 10-2 mg/kg/day = 213
    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 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. Even using the time weighted concentration during the 
mitigation period for drinking water risk is minimal.

G. 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.

H. Endocrine Effects

    An evaluation of the potential effects on the endocrine systems of 
mammals has not been 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. (James Tompkins)

2. DowElanco

PP 4F4379, 8F3600, and 8H5551

    EPA has received pesticide petitions (PP) 4F4379 (sweet corn and 
popcorn) and 8F3600 and 8H5551 (sugar beets) 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 the herbicide clopyralid in or on the raw agricultural 
commodities (RACs) sweet corn, fodder at 10.0 ppm; sweet corn, forage 
and cannery waste at 3.0 ppm; sweet corn, grain at 1.0 ppm and kernel 
plus cob with husks removed (K + CWHR) at 0.5 ppm; and pop corn, fodder 
at 10.0 ppm, and pop corn, grain at 1.0 ppm; and revising the tolerance 
for residues of the herbicide clopyralid in or on the raw agricultural 
commodities sugar beet, roots at 1.0 ppm and sugar beet, tops at 1.0 
ppm and on the processed agricultural commodity (PAC) sugar beet, 
molasses at 8.0 ppm. The proposed analytical method is available for 
enforcement purposes.
    Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended, 
DowElanco has submitted the following summary of information, data and 
arguments in support of their pesticide petition. This summary was 
prepared by DowElanco and EPA has not fully evaluated the merits of the 
petition. EPA edited the summary to clarify that the conclusions and 
arguments were the petitioners and not necessarily EPAs and to remove 
certain extraneous material.

A. Residue Chemistry

    1. Plant metabolism. The metabolism in plants is adequately 
understood. No metabolites of significance were detected in plant 
metabolism studies.
    2. Analytical method. There is a practical analytical method for 
detecting and measuring levels of clopyralid in or on food with a limit 
of quantitation (LOQ) of 0.05 ppm that allows monitoring of food with 
residues at or above the levels set in these tolerances. EPA has 
provided information on this method to FDA. The method is available to 
anyone who is interested in pesticide residue enforcement.
    3. Magnitude of residues-- i. Sugar beets. Tolerances for residues 
of the herbicide clopyralid in or on the following raw agricultural 
commodities, sugar beet roots and tops and the processed agricultural 
commodity molasses, were established on August 12, 1988 (53 FR 33488, 
33489) at 0.5, 0.5, and 7.0 parts per million (ppm), respectively, 
based upon residue data generated by Craven Laboratories. The validity 
of these data were in question and DowElanco repeated the residue 
studies. The last of the required residue data were submitted to the 
Agency in June 1994. The range of the residues

[[Page 37239]]

found for sugar beet, roots was to no detected residues above the LOQ 
of the method - 0.7 ppm; sugar beet, tops; was to no detected residues 
above the LOQ of the method - 0.9 ppm; and the residues in the 
processed agricultural commodities when clopyralid was applied at the 
maximum labeled rate were 0.5, 0.09, and 6.3 ppm for pulp, sugar and 
molasses respectively. The proposed revised tolerances would adequately 
cover these anticipated residues.
    ii. Sweet corn. Clopyralid was applied at the maximum label rate 
and residues were detected at the following ppm ranges: Grain, 0.087 - 
0.12; Forage, 0.34 - 2.0; Ears (K + CWHR), 0.029 - 0.23 and Cannery 
Waste; no residues were detected above the LOQ of the method. The 
proposed tolerances would adequately cover these anticipated residues.
    iii. Pop corn. Clopyralid was applied at the maximum label rate and 
residues were detected at the following ppm ranges; Grain: 0.03 - 0.91, 
Fodder: No detectable residues above the LOQ of the method - 0.60, and 
Forage 0.14 - 1.2, The proposed tolerances would adequately cover these 
anticipated residues.

B. Toxicological Profile

    1. Acute toxicity. Clopyralid has low acute toxicity. The rat oral 
LD50 is 5,000 mg/kg or greater for males and females. The 
rabbit dermal LD50 is greater than 2,000 mg/kg and the rat 
inhalation LC50 is greater than 1.0 mg/L air (the highest 
attainable concentration). In addition, clopyralid is not a skin 
sensitizer in guinea pigs and is not a dermal irritant. Technical 
clopyralid is an ocular irritant but ocular exposure to the technical 
material would not normally be expected to occur to infants or children 
or the general public. End use formulations of clopyralid have similar 
low acute toxicity profiles and most have low ocular toxicity as well. 
Therefore based on the available acute toxicity data, clopyralid does 
not pose any acute dietary risks.
    2. Genotoxicity. Clopyralid is not genotoxic. The following studies 
have been conducted and all were negative for genotoxic responses. Ames 
bacterial mutagenicity assay (with and without exogenous metabolic 
activation); Host-Mediated assay In vivo cytogenetic test, rat; In vivo 
cytogenetic test, mouse; In vivo dominant lethal test, rat; In vitro 
unscheduled DNA synthesis assay in primary rat hepatocyte cultures; In 
vitro mammalian cell gene mutations assay in Chinese hamster ovary cell 
cultures (with and without exogenous metabolic activation).
    3. Reproductive and developmental toxicity. Developmental toxicity 
was studied using rats and rabbits. The developmental study in rats 
resulted in a developmental NOEL of >250 mg/kg/day (a maternally toxic 
dose) and a maternal toxicity NOEL of 75 mg/kg/day. A 1974 study in 
rabbits revealed no evidence of developmental or maternal toxicity at 
250 mg/kg/day; thus the developmental and maternal NOEL was >250 mg/kg/
day. A more recent study in rabbits (1990) resulted in developmental 
and maternal NOELs of 110 mg/kg/day based on maternal toxicity at 250 
mg/kg/day. Based on all of the data for clopyralid, there is no 
evidence of developmental toxicity at dose levels that do not result in 
maternal toxicity. In a 2-generation reproduction study in rats, pups 
from the high dose group which were fed diets containing clopyralid had 
a slight reduction in body weight during lactation and an increase in 
liver weights in F1a and F1b weanlings. The NOEL for parental systemic 
toxicity was 500 mg/kg/day. There was no effect on reproductive 
parameters at >1,500 mg/kg/day nor was there an adverse effect on the 
morphology, growth or viability of the offspring; thus, the 
reproductive NOEL is >1500 mg/kg/day.
    4. Subchronic toxicity. The following studies have been conducted 
using clopyralid. In a rat 90-day feeding study, Fischer 344 rats were 
fed diets containing clopyralid at doses of 5, 15, 50, or 150 mg/kg/day 
with no adverse effects attributed to treatment. In a second study, 
Fischer 344 rats were fed diets containing clopyralid at doses of 300, 
1,500, and 2,500 mg/kg/day. Effects at the highest doses were decreased 
food consumption accompanied by decreased body weights and weight gains 
in both males and females. Slightly increased mean relative liver and 
kidney weights were noted in males of all doses and in females at the 
top 2 doses. Because there were no other effects, the kidney and liver 
weight effects were judged as being adaptive rather than directly 
toxic. The no-observed-adverse-effect level (NOAEL) was 1,500 mg/kg/day 
for males and females. The no-observed-effect level (NOEL) was 300 mg/
kg/day for females. In a mouse 90-day feeding study, B6C3F1 mice were 
fed diets containing clopyralid at doses of 200, 750, 2,000 or 5,000 
mg/kg/day. A slight decrease in body weight occurred at the top dose in 
both sexes. The liver was identified as the target organ based on 
slight increases in liver weights and minimal microscopic alterations 
at the higher dose levels. The liver changes were considered to be 
reversible and adaptive. The NOEL for males was 2,000 mg/kg/day and for 
females was 750 mg/kg/day. In a 180-day feeding study, beagle dogs were 
fed diets containing clopyralid at doses of 15, 50, or 150 mg/kg/day; 
there were no adverse effects. In a second dietary study, dogs also 
were fed diets containing clopyralid at doses of 15, 50, or 150 mg/kg/
day; the only effect was an increase in the mean relative liver weight 
in females at the 150 mg/kg/day. In a 21-day dermal study, clopyralid 
was applied by repeated dermal application to New Zealand White rabbits 
at dose levels up to 1,000 mg/kg/day. Treatment produced no systemic 
effects.
    5. Chronic toxicity. In a chronic toxicity and oncogenicity study, 
Sprague-Dawley rats were fed diets containing clopyralid at doses of 5, 
15, 50 or 150 mg/kg/day. The only effect was a trend toward a decreased 
body weight of female rats receiving the 150 mg/kg/day dose with a NOEL 
of 50 mg/kg/day. In a second study clopyralid was fed to Fischer 344 
rats in the diet at doses of 15, 150, or 1,500 mg/kg/day. The effects 
were confined almost entirely to the 1,500 mg/kg/day dose groups and 
included slightly decreased food consumption and body weights, slightly 
increased liver and kidney weights and macroscopic and microscopic 
changes in the stomach. No tumorigenic response was present. The NOEL 
for this study was 150 mg/kg/day. B6C3F1 mice were maintained for 2 
years on diets formulated to provide targeted dose levels of 10, 500, 
or 2,000 mg/kg/day. The only evidence of toxicity was body weight 
depression in males dosed at 2,000 mg/kg/day. There was no evidence of 
tumorigenic response at any dose level. Based on the chronic toxicity 
data, EPA has established the RfD for clopyralid at 0.5 milligrams 
(mg)/kilogram (kg)/day. The RfD for clopyralid is based on a 2-year 
chronic oncogenicity study in rats with a no-observed-effect level 
(NOEL) of 50 mg/kg/day and an uncertainty (or safety) factor of 100. 
Thus, it would not be necessary to require the application of an 
additional uncertainty factor above the hundredfold factor already 
applied to the NOEL.
    6. Carcinogenicity. Using its Guidelines for Carcinogen Risk 
Assessment published September 24, 1986 (51 FR 33992), clopyralid would 
be classified as Group E for carcinogenicity (no evidence of 
carcinogenicity) based on the results of the carcinogenicity studies. 
There was no evidence of carcinogenicity in 2-year feeding studies in 
mice and rats at the dosage levels tested. The doses tested are 
adequate for identifying a cancer

[[Page 37240]]

risk. Thus, a cancer risk assessment would not be appropriate.
    7. Animal metabolism. Disposition and metabolism of clopyralid were 
tested in male and female rats at a dose of 5 mg/kg (oral). The 
majority of a radioactive dose was excreted in 24 hours of all dose 
groups. Fecal elimination was minor. Detectable levels of residual 
radioactivity were observed in the carcass and stomach at 72 hours 
post-dose. HPLC and TLC analysis of urine and fecal extracts showed no 
apparent metabolism of clopyralid.
    8. Metabolite toxicity. There are no clopyralid metabolites of 
toxicological significance.
    9. Endocrine effects. There is no evidence to suggest that 
clopyralid has an effect on any endocrine system.

C. Aggregate Exposure

    1. From food and feed uses. For purposes of assessing the potential 
dietary exposure under these tolerances, exposure is estimated based on 
the TMRC from the existing and pending tolerances for clopyralid on 
food crops. The TMRC is obtained by multiplying the tolerance level 
residues by the consumption data which estimates the amount of those 
food products eaten by various population subgroups. Exposure of humans 
to residues could also result if such residues are transferred to meat, 
milk, poultry or eggs. The following assumptions were used in 
conducting this exposure assessment: 100% of the crops were treated, 
the RAC residues would be at the level of the tolerance, certain 
processed food residues would be at anticipated (average) levels based 
on processing studies and all current and pending tolerances were 
included. This results in an overestimate of human exposure and a 
conservative assessment of risk. Based on a NOEL of 50 mg/kg/day in a 
2-year chronic feeding/oncogenicity study in the rat and a hundredfold 
safety factor, the reference dose (RfD) would be 0.5 mg/kg/day. 
Consequently, all existing and pending tolerances have a theoretical 
maximum residue contribution of 0.005135 mg/kgBW/day and would utilize 
less than 2.3% of the RfD.
    2. From potable water. Another potential source of dietary exposure 
to residues of pesticides are residues in drinking water. There is no 
established Maximum Concentration Level for residues of clopyralid in 
drinking water. Although there has been limited detections at ppb 
levels in some of the specially designed studies under highly 
vulnerable test conditions, no ongoing monitoring studies (U.S. 
Geological Survey, Selected Water Resources Abstracts, and Pesticides 
in Ground Water Database - A Compilation of Monitoring Studies: 1971-
1991 National Summary; U.S. Department of Agriculture, AGRICOLA 
database; and, U.S. Department of Commerce, National Technical 
Information Service) have reported residues of clopyralid in ground or 
surface waters.
    Based on the physical and chemical characteristics of clopyralid, 
such as water solubility and its stability under hydrolysis and 
photolysis, it has potential for downward movement through the soil 
profile. However, the behavior of the compound under field conditions 
demonstrates fairly rapid degradation and limited downward movement. 
Degradation based on 20 field dissipation sites indicated an average 
half-life of 34 days. Degradation is driven primarily by microbial 
processes. Downward movement through the soil profile was generally 
confined to the upper 18 inches of the soil profile. Validated computer 
modeling also predicted the maximum depth of residues to be 18-inches, 
with no detections predicted at 6 months after application. Because the 
laboratory derived physical/chemical properties of clopyralid indicate 
a potential for downward movement, lysimeter studies were conducted. In 
a U.S. study, undisturbed soil columns (lysimeters), 8 inches in 
diameter, and 3 feet deep, were treated with 950 g ae/ha (about 5 X 
labeled use rates) in actual field conditions. Residues of clopyralid 
in soil as well as soil-solution (leachate) were collected in the 
closed system. The average depth of movement for the majority of 
clopyralid (center of mass) was 11 inches, and no detectable residues 
were observed in the leachate. In a European study, lysimeters 1 - 3 
ft. diameter, and 3 ft. deep, were treated with 120 and 240 g ae/ha in 
actual field conditions. The average center of mass was 12 inches. No 
detectable residues were observed in the lysimeters. The amount of 
14C in leachate accumulated over 2 years in the degraded 
loess and silty sand lysimeters, was only 0.6% and 0.3% of applied, 
respectively. The leachate concentrations of 14C-labeled 
clopyralid in degraded loess and silty sand throughout the first 10-16 
months of the study ranged from 0.002-0.14 g/l (ppb) and 
0.003-0.02 ppb, respectively. A second European lysimeter study with 
silty sand lysimeters treated with 120 g ae/ha revealed a 2-year 
cumulative clopyralid leachate of only 0.1% of applied (0.04 ppb). 
These studies demonstrate that in lysimeter test systems, under field 
environmental conditions, clopyralid rapidly dissipates through 
mineralization to carbon dioxide. Also the very low levels observed in 
leachate demonstrate that there is very little potential for clopyralid 
to leach through soil and to contaminate ground water.
    In summary, these data on potential water exposure indicate 
insignificant additional dietary intake of clopyralid and any exposure 
is more than offset for in the conservative dietary risk evaluation. 
Therefore, it is concluded that there is a reasonable certainty of no 
harm even at potential upper limit exposures to clopyralid from 
drinking water.
    3. From non-dietary uses. There is only one non-dietary use 
registered under the Federal Insecticide, Fungicide and Rodenticide 
Act. The use is for weed control in residential turf. Potential 
exposures for children from non-occupational uses is therefore limited 
to turf re-entry and this exposure is low.
    4. Short-term or intermediate-term. The data for clopyralid does 
not indicate any evidence of significant toxicity by the dermal and 
inhalation routes. Consequently, there is no concern for short-term or 
intermediate-term residential risk. Therefore, a short-term or 
intermediate-term residential risk assessment would not be required.
    5. Chronic. As part of a hazard assessment process an endpoint of 
concern is determined for the chronic occupational or residential risk 
assessment. However, as indicated, the exposures that would result from 
the use of clopyralid are of an intermittent nature. The frequency and 
duration of these exposures do not exhibit a chronic exposure pattern. 
The exposure does not occur often enough to be considered a chronic 
exposure; i.e., a continuous exposure that occurs for a least several 
months. Therefore, it would not be appropriate to aggregate exposure 
from the residential use with exposure from food and drinking water.
    6. Acute. No concern would exist for an acute dietary assessment 
for clopyralid because the available data indicates no evidence of 
significant toxicity from a one day or single event exposure by the 
oral route. Therefore, an acute dietary risk assessment would not be 
required.

D. Cumulative Exposure to Substances with Common Mechanism of Toxicity

    The potential for cumulative effects of clopyralid and other 
substances that have a common mechanism of toxicity was considered. The 
mammalian toxicity of clopyralid is well defined. However, no reliable 
information exists to indicate that toxic effects produced

[[Page 37241]]

by clopyralid would be cumulative with those of any other chemical 
compound. Additionally, clopyralid does not appear to produce a toxic 
metabolite produced by other substances. Therefore, consideration of a 
common mechanism of toxicity with other compounds is not appropriate at 
this time. Thus only the potential exposures to clopyralid were 
considered in the aggregate exposure assessment.

E. Determination of Safety

    1. U.S. population in general. Based on a NOEL of 50.80 mg/kg/bwt/
day from a 2-year rat feeding study with a decreased mean body weight 
gain effect, and using an uncertainty factor of 100 to account for the 
interspecies extrapolation and intraspecies variability, a Reference 
Dose (RfD) of 0.5 mg/kg bwt/day was used for this assessment of chronic 
risk. As indicated, there is no endpoint of concern identified with 
acute and short- or intermediate-term exposures. Based on the known 
toxicity and exposure data, the proposed and existing tolerances would 
utilize approximately 2% of the RfD for the U.S. population. And, as 
indicated previously, whatever upper limit might be used for drinking 
water exposure, the exposure estimate for clopyralid would not exceed 
the RfD. Generally, exposures below 100% of the RfD are of no concern 
because the RfD represents the level at or below which daily aggregate 
dietary exposure over a lifetime will not pose appreciable risk to 
human health. Thus, there is a reasonable certainty that no harm will 
result from aggregate exposure to clopyralid residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of clopyralid, data 
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat were considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism during prenatal development resulting from 
pesticide exposure to one or both parents. Reproduction studies provide 
(1) information relating to effects from exposure to the pesticide on 
the reproductive capability of mating animals and (2) data on systemic 
toxicity.
    Developmental toxicity was studied using rats and rabbits. The 
developmental study in rats resulted in a developmental NOEL of >250 
mg/kg/day (a maternally toxic dose) and a maternal toxicity NOEL of 75 
mg/kg/day. A 1974 study in rabbits revealed no evidence of 
developmental or maternal toxicity at 250 mg/kg/day; thus the 
developmental and maternal NOEL was >250 mg/kg/day. A more recent study 
in rabbits (1990) resulted in developmental and maternal NOEL's of 110 
mg/kg/day based on severe maternal toxicity at 250 mg/kg/day. Based on 
all of the data for clopyralid, there is no evidence of developmental 
toxicity at dose levels that do not result in maternal toxicity.
    In a 2-generation reproduction study in rats, pups from the high 
dose group which were fed diets containing clopyralid had a slight 
reduction in body weight during lactation and an increase in liver 
weights in F1a and F1b weanlings. The NOEL for parental systemic 
toxicity was 500 mg/kg/day. There was no effect on reproductive 
parameters at >1500 mg/kg/day nor was there an adverse effect on the 
morphology, growth or viability of the offspring; thus, the 
reproductive NOEL is >1,500 mg/kg/day.
    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. These data suggest minimal concern for developmental or 
reproductive toxicity and do not indicate any increased pre- or post-
natal sensitivity. Therefore, an additional uncertainty factor is not 
necessary to protect the safety of infants and children and that the 
RfD at 0.5 mg/kg/day is appropriate for assessing aggregate risk to 
infants and children.
    The percent of the RfD that will be utilized by the aggregate 
exposure from all tolerances to clopyralid will be much less than 10% 
for non-nursing infants and for children (1 - 6 years of age). 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative exposure assessment, it is concluded that 
there is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to clopyralid residues.

F. International Tolerances

    There are no Codex maximum residue levels established for 
clopyralid. (Joanne Miller)

3. E.I. DuPont Company

PP 4F4391

    In the Federal Register of October 25, 1995, (60 FR 54607), EPA 
established a time-limited tolerance pursuant to the Federal Food Drug 
and Cosmetic Act (FFDCA) for residues of the herbicide pyrithiobac 
sodium salt (sodium 2-chloro-6-[(4,6-dimethoxypyrimidin-2-
yl)thio]benzoate) in or on the raw agricultural commodity cottonseed at 
0.02 part per million (ppm). The time-limited tolerance expires 
September 30, 1997. The tolerance was requested in pesticide petition 
(PP) 4F4391 by E. I. DuPont de Nemours and Co., Inc. (DuPont), Barley 
Mill Plaza, P.O. Box 80083, Wilmington, DE 19880-0038. The tolerance 
was issued as a time-limited tolerance because EPA required additional 
residue data on the commodity of cotton gin byproducts. The petitioner 
proposes to renew the time-limited tolerance for a 2-year period and 
retain the pesticide labeling previously accepted under the Federal 
Insecticide Fungicide and Rodenticide Act (FIFRA), as amended, which 
bears a restriction against feeding cotton gin byproducts from treated 
fields to livestock. DuPont has requested this tolerance extension 
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 
as amended, 21 U.S.C. 346a(d), by the Food Quality Protection Act of 
1996 (Pub. L. 104-170, 110 Stat. 1489). The request addresses the 
requirements of the new FFDCA Section 408(d)(2). The time-limited 
tolerance would expire on September 30, 1998. An adequately validated 
analytical method is available for enforcement purposes. Pursuant to 
section 408(d)(2)(A)(i) of the FFDCA, as amended, DuPont has submitted 
the following summary of information, data and arguments in support of 
its pesticide petition. This summary was proposed by DuPont and EPA has 
not yet fully evaluated the merits of the petition. EPA edited the 
summary to clarify that the conclusions and arguments presented are 
those of the petitioner and not necessarily EPA's and to remove certain 
extraneous material.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues of 
pyrithiobac sodium in cotton is adequately understood. Metabolism 
studies with pyrithiobac sodium indicate the major metabolic pathway 
being o-dealkylation of the parent compound resulting in o-desmethyl 
pyrithiobac sodium (O-DPS). O-DPS, both free and conjugated, was the 
major metabolite identified in cotton foliage. The results of a 
confined crop rotation study with pyrithiobac sodium revealed the 
presence of a metabolite 2-chloro-6-sulfobenzoic acid (CSBA) not seen 
in the cotton metabolism study. This metabolite appeared to originate 
from soil metabolism of pyrithiobac sodium. Since preemergence 
applications of pyrithiobac sodium are allowed, crop residues of CSBA 
were

[[Page 37242]]

considered a possibility. In consideration of PP 4F4391 CBTS, in 
consultation with the HED Metabolism Committee has previously concluded 
that for the proposed use on cotton, none of the pyrithiobac sodium 
metabolites including O-DPS and CSBA warrant inclusion in the tolerance 
regulation, and that the only residue of concern is the parent, 
pyrithiobac sodium.
    2. Analytical method. There is a adequately validated practical 
analytical method available using HPLC-UV with column switching, to 
measure levels of pyrithiobac sodium in or on cotton with a limit of 
quantitation that allows monitoring of cottonseed at or above tolerance 
levels. EPA has provided information on this method to FDA for future 
publication in PAM II.
    3. Magnitude of residues. Crop field trial residue data from a 60 
day PHI study shows that the established pyrithiobac sodium time-
limited tolerance on cottonseed of 0.02 ppm will not be exceeded when 
DuPont Staple Herbicide is used as directed. An adequate cottonseed 
processing study shows that pyrithiobac sodium does not concentrate in 
cottonseed processed commodities; thus no tolerances on these 
commodities are required.

B. Toxicological Profile

    1. Acute toxicity. Pyrithiobac sodium technical has been placed in 
EPA Toxicity Category II for acute eye irritation based on the test 
article inducing irritation in the form of corneal opacity, iritis and 
conjunctival redness, and discharge in the eyes of rabbits after 
receiving ocular doses of 36 mg (0.1 ml). Signs of irritation were 
clear within 14 days of treatment. Pyrithiobac sodium has been placed 
in Toxicity Category III for acute dermal toxicity based on the test 
article being nonlethal and nonirritating at the limit dose of 2,000 
mg/kg (highest dose tested). Pyrithiobac sodium has been placed in 
Toxicity Category III for acute oral toxicity based on acute oral 
LD50s of 3,200 mg/kg for both male and female rats. 
Pyrithiobac sodium has been placed in Category IV for the remaining 
acute toxicity tests based on the following: a rat acute inhalation 
study with an LC50 of >6.9 mg/l; and a primary dermal 
irritation test that did not induce a dermal irritation response. A 
dermal sensitization test with pyrithiobac sodium technical in guinea 
pigs demonstrated no significant effects. Based on these results, 
pyrithiobac sodium does not pose an acute dietary or exposure risk.
    2. Genotoxicty. Pyrithiobac sodium technical was negative (non-
mutagenic and non-genotoxic) in the following tests: Ames microbial 
mutation assay; the hypoxanthine-guanine phosphoribosyl transferase 
gene mutation assay using Chinese hamster ovary cells; and induction of 
unscheduled DNA synthesis (UDS) in primary rat hepatocytes. Pyrithiobac 
sodium was positive in an in vitro assay for chromosome aberrations in 
human lymphocytes. It was negative for the induction of micronuclei in 
the bone marrow cells of male and female CD-1 mice administered the 
test article by oral gavage at 500, 1,000 or 2,000 mg/kg. Based on the 
weight of these data, pyrithiobac sodium is neither genotoxic nor 
mutagenic.
    3. Reproductive and developmental toxicity. A 2-generation, 4 
litter reproduction study with CD rats treated at dietary levels of 0, 
25, 1,500, 7,500 or 20,000 ppm of pyrithiobac sodium demonstrated a 
maternal NOEL of 1,500 ppm (103 mg/kg/day) and a maternal LOEL of 7,500 
ppm (508 mg/kg/day), based on decreased body weight gain and food 
efficacy. An offspring NOEL of 7,500 ppm (508 mg/kg/day) and LOEL of 
20,000 ppm (1,551 mg/kg/day) were also demonstrated based on decreased 
offspring body weight. Pyrithiobac sodium was not teratogenic when 
administered to rats or rabbits. A developmental toxicity study with 
pyrithiobac sodium in rats demonstrated a maternal NOEL of 200 mg/kg 
and LOEL of 600 mg/kg due to increased incidence of salivation. A 
developmental NOEL of 600 mg/kg and LOEL of 1,800 mg/kg were 
demonstrated based on an increased incidence of skeletal variations. A 
developmental toxicity study with pyrithiobac sodium in rabbits 
demonstrated maternal and developmental NOELs of 300 mg/kg and a 
maternal LOEL of 1,000 mg/kg based on mortality, decreased body weight 
gain and feed consumption, increased incidence of clinical signs, and 
an increase in early resorptions. A developmental LOEL of 1,000 mg/kg 
was based on decreased fetal body weight gain. Based on the weight of 
these data, pyrithiobac sodium is not considered a reproductive or 
developmental hazard. In addition, there were no effects observed in 
offspring in the absence of maternal toxicity; therefore, the offspring 
were not uniquely susceptible to the effects of compound 
administration.
    4. Subchronic toxicity. In a 90-day feeding study in rats conducted 
with pyrithiobac sodium at dietary levels of 0, 10, 50, 500, 7,000 and 
20,000 ppm, the NOEL was 500 ppm (31.8 and 40.5 mg/kg/day, M/F) and the 
LOEL was 7,000 ppm (466 and 588 mg/kg/day, M/F) based on decreased body 
weight gains and increased rate of hepatic B-oxidation in males. In a 
90-day feeding study in mice conducted with pyrithiobac sodium at 
dietary levels of 0, 10, 50, 500, 1,500 and 7,000 ppm, the NOEL was 500 
ppm (83.1 and 112 mg/kg/day, M/F) and the L0EL was 1,500 ppm (263 and 
384 mg/kg/day, M/F) based on increased liver weight and increased 
incidence of hepatocellular hypertrophy in males and decreased 
neutrophil count in females. In a 90-day feeding study in dogs 
conducted with pyrithiobac sodium at dietary levels of 0, 50, 5,000, or 
20,000 ppm, the NOEL was 5,000 ppm (165 mg/kg/day) and the LOEL was 
20,000 ppm (626 mg/kg/day) based on decreased red blood cell count, 
hemoglobin, and hematocrit in females and increased liver weight in 
both sexes. In a 21-day dermal study with rats conducted with 
pyrithiobac sodium at exposure levels of 0, 50, 500, or 1,200 mg/kg/
day, the dermal irritation NOEL was 500 mg/kg/day and the dermal 
irritation LOEL was 1,200 mg/kg/day. There were no systemic effects 
observed at this high dose; therefore, the systemic NOEL is considered 
to be 1,200 mg/kg/day.
    5. Chronic toxicity. A 1-year feeding study in dogs conducted with 
pyrithiobac sodium at dietary levels of 0, 100, 5,000, and 20,000 ppm 
resulted in a NOEL of 5,000 ppm (143 and 166 mg/kg/day, M/F) and a LOEL 
of 20,000 ppm (580 and 647 mg/kg/day, M/F) based on decreases in body 
weight gain and increased liver weight. A 78-week oncogenicity study in 
mice was conducted with pyrithiobac sodium at dietary levels of 0, 10, 
150, 1,500 and 5,000 ppm. The systemic NOEL is 1,500 ppm (217 and 319 
mg/kg/day, M/F) and the LEL is 5,000 ppm (745 and 1,101 mg/kg/day, M/
F), based on decreased body weight gain and liver lesions. Kidney 
effects were also observed at 5,000 ppm; however, these were present at 
low incidence and were of minimal severity and were considered to be of 
only minimal biological significance. Increased incidence of foci/focus 
of hepatocellular alteration was observed in males fed 5,000 ppm diets. 
Increased incidences of hepatocellular neoplasms (adenomas or adenomas 
plus carcinomas) were observed only in 150 and 1,500 ppm males. The 
incidence of these liver tumors was not significantly increased in the 
5,000 ppm males or in females at any dose level; the 5,000 ppm male 
tumor incidence was within the historical control range. A 2-year study 
in rats was conducted at dietary pyrithiobac sodium levels of 0, 5, 25,

[[Page 37243]]

1,500 or 5,000 ppm for males and 0, 5, 25, 5,000 or 15,000 ppm for 
females. The NOEL for systemic effects was 1,500 ppm (58.7 mg/kg/day) 
for males and 5,000 ppm (278 mg/kg/day) for females. The LEL was 5,000 
ppm (200 mg/kg/day for males)/15,000 ppm (918 mg/kg/day) for females. 
The LEL was based on the following: decreased body weight, body weight 
gain and food efficiency (for females); mild changes in hematology and 
urinalysis, clinical signs indicative of urinary tract dysfunction 
(both sexes); increased incidence of focal cystic degereration in the 
liver and increased rate of hepatic peroxisome beta-oxidation (males); 
and an increased incidence of inflammatory and degenerative microscopic 
lesions in the kidney (females). There was evidence of oncogenicity 
based on an increased trend for kidney tubular combined adenoma/ 
carcinoma in male rats and an increased trend for kidney tubular 
adenomas in female rats. Although the incidences were low, they were 
statistically significant. The highest dose level tested in male rats 
(5,000 ppm) was considered adequate for assessment of oncogenic 
potential, that in female rats (15,000 ppm) exceeded the Maximum 
Tolerated Dose (MTD).
    6. Carcinogenicity. In consideration of PP 4F4391 the HED 
Carcinogenicity Peer Review Committee has previously concluded that the 
available data provide limited evidence of the carcinogenicity of 
pyrithiobac sodium in mice and rats and has classified pryithiobac 
sodium as a Group C (possible human carcinogen with limited evidence of 
carcinogenicity in animals) in accordance with Agency guidelines 
published in the Federal Register in 1986 (51 FR 33992, September 24, 
1986) and recommend that for the purpose of risk characterization a 
low-dose extrapolation model should be applied to the experimental 
animal tumor data for quantification for human risk (Q1*). This 
decision was based on liver adenomas, carcinomas and combined adenoma/
carcinomas in the male mouse and kidney tubular adenomas, carcinomas 
and combined adenoma/carcinomas in the male rat. The unit risk, Q1* 
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/day)-1 in 
human equivalents based on male kidney tumors.
    7. Animal metabolism. Disposition and metabolism of pyrithiobac 
sodium were tested in male and female rats using two radiolabeled forms 
of pyrithiobac sodium. Either phenyl-labeled or pryimidine-labeled 
compounds were administered orally at 5 or 250 mg/kg. In addition, i.v. 
administration was evaluated at 5 mg/kg. Essentially all of the dose 
was excreted in the urine and feces, with greater than 90% being 
excreted within 48 hours. No label was detected in the expired air. 
Only minute quantities of radioactivity (at or near the limit of 
detection) were detected in the major organs of metabolism and 
excretion. This study indicates that pyrithiobac sodium has low 
toxicity and does not accumulate within the body. The major compound 
eliminated in urine and feces was O-DPS (desmethyl metabolite), formed 
by demethylation of the pyrimidine ring. There was evidence that 
conjugation with glucuronic acid and 5-hydroxylation of the pyrimidine 
ring of pyrithiobac sodium were additional minor routes of metabolism 
in the rat.
    8. Metabolite toxicology. There is no evidence that the metabolites 
of pyrithiobac sodium as identified in either the plant metabolism, 
confined crop rotation, or animal metabolism studies are of any 
toxicological significance.
    9. Neurotoxicity. A 90-day rat neurotoxicity screen battery 
conducted with pyrithiobac sodium resulted in a systemic NOEL of 7,000 
ppm (466 and 588 mg/kg/day, M/F) and a systemic LOEL of 20,000 ppm 
(1,376 and 1,609 mg/kg/day, M/F) based on reduced body weight gain and 
food efficiency and increased liver weight. Slight reductions in hind-
leg grip strength and slightly increased foot splay in males were 
observed in 20,000 ppm males. However, because these were of small 
magnitude, lacked statistical significance and corresponding 
histopathology, pyrithiobac sodium was not considered a neurotoxin. The 
NOEL for neurotoxicity was 20,000 ppm [highest dose tested (HDT)].
    10. Endocrine effects. No special studies investigating potential 
estrogenic or other endocrine effects of pyrithiobac sodium have been 
conducted. However, the standard battery of required toxicology studies 
has been completed and found acceptable. These 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 to doses that far exceed likely human exposures. 
Based on these studies there is no evidence to suggest that pyrithiobac 
sodium has an adverse effect on the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. For purposes of assessing the 
potential dietary exposure under this tolerance, an estimate of 
aggregate exposure is made using the tolerance on cottonseed at 0.02 
ppm. The potential exposure is obtained by multiplying the tolerance 
level residues by the consumption data which estimates the amount of 
cottonseed products translated as cottonseed meal and cottonseed oil 
eaten by various population subgroups. Cottonseed is fed to animals, 
thus exposure of humans to residues of cottonseed might result if such 
residues are transferred to meat, milk, poultry, or eggs. However, in 
consideration of PP 4F4391 CBTS has previously concluded that secondary 
residues in meat, milk, poultry and eggs are not expected from the use 
of cottonseed (undelinted) as an animal feed. There are no other 
established tolerances or registered uses for pyrithiobac sodium in the 
United States. Based on a NOEL of 58.7 mg/kg/day, from the chronic rat 
toxicity study and a hundredfold safety factor, the reference dose 
(RfD) is 0.58 mg/kg/day. Assuming residues at tolerance levels and that 
100% of the crop is being treated, a theoretical maximum residue 
contribution (TMRC) of <0.000001 mg/kg/day is calculated. With the 
above assumptions which clearly overestimate potential human exposure 
and are a most conservative assessment of risk, dietary (food) exposure 
to pyrithiobac sodium will utilize significantly less than 1% of the 
RfD for the overall US population. For the most highly exposed 
subgroup, children aged 1 to 6 years, the TMRC is 0.000001 mg/kg/day, 
which is still less than 1% of the RfD. The unit risk, Q1* 
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/
day)-1 in human equivalents based on male kidney tumors. Based on this 
upper bound potency factor (Q1*), a 70-year life-span, and 
the assumption that 100% of the crop is treated with pyrithiobac 
sodium, the upper-bound limit of a dietary carcinogenic risk is 
calculated in the range of 1 incidence in a billion (1.0 x 10-
9).
    ii. Drinking water. Other potential dietary sources of exposure of 
the general population to pesticides are residues in drinking water. 
There is no Maximum Contaminant Level established for residues of 
pyrithiobac sodium. The petitioner has reported to the Environmental 
Fate and Groundwater Branch of EPA (EFGWB) the interim results of a 
prospective groundwater monitoring study conducted at a highly 
vulnerable site. In consideration of this information in support of PP 
4F4391 EFGWB has previously concluded by preliminary evaluation, that 
pyrithiobac sodium may

[[Page 37244]]

not be stable enough to leach to groundwater at most use sites, even in 
sandy soils. All other environmental fate data requirements for 
pyrithiobac sodium have been satisfied and based on these studies and 
the conditions of use, the potential for finding pyrithiobac sodium 
residues in drinking water is minimal.
    2. Non-dietary exposure. Pyrithiobac sodium is not registered for 
any use which could result in non-occupational, non-dietary exposure to 
the general population.

D. Cumulative Effects

    Pyrithiobac sodium is based on a new chemical class; there are no 
known registered herbicides with similar structure. Therefore, EPA 
should consider only the potential risks of pyrithiobac sodium in its 
exposure assessment. The herbicidal activity of pyrithiobac sodium is 
due to the inhibition of acetolactate synthase (ALS), an enzyme only 
found in plants. ALS is part of the biosynthetic pathway leading to the 
formation of branched chain amino acids. Animals lack ALS and this 
biosynthetic pathway. This lack of ALS contributes to the low toxicity 
of pyrithiobac sodium in animals. There is no evidence to indicate or 
suggest that pyrithiobac sodium has any toxic effects on mammals that 
would be cumulative with those of any other chemical.

E. Safety Determination

    1. U.S. population. Based on a complete and reliable toxicity 
database, the EPA has adopted an RfD value of 0.58 mg/kg/day using the 
NOEL of 58.7 mg/kg/day, from the 2-year chronic toxicity study in rats 
and a hundredfold safety factor. Using crop tolerance levels and 
assuming 100% of the crop being treated a Theoretical Maximum Residue 
Contribution (TMRC) was calculated for the overall US population and 22 
population subgroups. This analysis concluded that aggregate exposure 
to pyrithiobac sodium will utilize significantly less that 1 percent of 
the RfD for either the entire U.S. population or any subgroup 
population. The TMRC for the most highly exposed subgroup identified as 
children aged 1 thru 6 years was 0.000001 mg/kg/day. EPA generally has 
no concern for exposure below 100 percent of the RfD because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose appreciable risk to human health. Thus, 
there is a reasonable certainty that no harm will result from aggregate 
exposure to pyrithiobac sodium residues. The unit risk, Q1* 
(mg/kg/day)-1, of pyrithiobac sodium is 1.05 x 10-3 (mg/kg/
day)-1 in human equivalents based on male kidney tumors. Based on this 
upper bound potency factor (Q1*) and assuming a 70 year 
lifetime exposure an upper-bound limit of a dietary carcinogenic risk 
is calculated in the range of 1 incidence in a billion (1.0 x 10-
9). This indicates a negligible cancer risk.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of pyrithiobac sodium, 
data from the previously discussed developmental and reproduction 
toxicity studies were considered. Developmental studies are designed to 
evaluate adverse effects on the developing organism resulting from 
pesticide exposure during pre-natal development. Reproduction studies 
provide information relating to reproductive and other effects on 
adults and offspring from pre-natal and post-natal exposure to the 
pesticide. Based on the weight of these data, pyrithiobac sodium was 
not a reproductive toxicant. Maternal and developmental effects 
(NOEL's, LOEL's) were comparable indicating no increase in 
susceptibility of developing organisms. No evidence of endocrine 
effects were noted in any study. 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 current toxicological 
data requirements, the database for pyrithiobac sodium relative to pre- 
and post-natal effects for children is complete. The NOEL of 58.7 mg/
kg/day from the 2-year rat study with pyrithiobac sodium, which was 
used to calculate the RfD, is lower than any of the NOEL's defined in 
the developmental and reproductive toxicity studies with pyrithiobac 
sodium. When the weight of these facts is considered an additional 
safety factor is not warranted for developmental effects. As stated 
above, aggregate exposure assessments utilized significantly less than 
1% of the RfD for either the entire U.S. population or any of 22 
population subgroups including infants and children. Therefore, it may 
be concluded that there is reasonable certainty that no harm will 
result to infants and children from aggregate exposure to pyrithiobac 
sodium residues.

F. International Tolerances

    There are no established Codex MRLs for pyrithiobac sodium on 
cottonseed. An established Mexican tolerance for pyrithiobac sodium on 
cottonseed is identical to the U.S. tolerance. Compatibility is not a 
problem at this time. (James Tompkins)

4. Zeneca AG

PP 5F4588

    EPA has received a pesticide petition (PP 5F4588) from Zeneca Ag 
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, Delaware 
19850-5458, 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 combined residues of the insecticide 
lambda-cyhalothrin and its epimer in or on the raw agricultural 
commodities (RACs) alfalfa forage at 5.0 parts per million (ppm), 
alfalfa hay at 6.0 ppm, leaf lettuce at 2.0 ppm, head and stem Brassica 
crop subgroup at 0.4 ppm, aspirated grain fractions at 2.0 ppm and 
increasing the existing time-limited tolerance for poultry fat to 0.03 
ppm. The proposed analytical method is gas liquid chromatography with 
an electron capture detector.
    Pursuant to section 408 (d) (2) (A) (i) of the FFDCA, as amended, 
Zeneca Ag Products has submitted the following summary of information, 
data and arguments in support of their pesticide petition. This summary 
was prepared by Zeneca and EPA has not fully evaluated the merits of 
the petition. EPA edited the summary to clarify that the conclusions 
and arguments were the petitioner's and not necessarily EPA's.

A. Residue Chemistry

    1. Plant Metabolism. The metabolism of lambda-cyhalothrin in plants 
is adequately understood for this use. Any secondary residues occurring 
in meat and meat by-products will be covered by the existing tolerances 
with the exception of the fat of poultry, which is discussed under 
Magnitude of Residues.
    2. Analytical method. An adequate analytical method (gas liquid 
chromatography with an electron capture detector) is available for 
enforcement purposes.
    3. Magnitude of residues--i. Alfalfa. Sixteen field trials were 
carried out on alfalfa forage and hay in twelve states during 1990 in 
the USA. The trials were conducted in the states of Arizona, 
California, Iowa, Idaho, Kansas, Michigan, Minnesota, Montana, 
Nebraska, New York, South Dakota, and Wisconsin. The number and 
geographical distribution of the trials agrees with the recommendation 
given in the ``EPA Residue Chemistry Guidance'' (1994).
    In these trials, the maximum combined residues of lambda-
cyhalothrin and epimer in or on alfalfa

[[Page 37245]]

forage is 5.0 ppm and alfalfa hay is 6.0 ppm.
    ii. Leaf lettuce. Eight field trials were carried out on leaf 
lettuce in eight states during 1990 in the USA. The trials were 
conducted in Arizona, California, Colorado, Florida, Michigan, New 
York, Texas, and Washington. The number and geographical distribution 
of the trials agrees with the recommendation given in the ``EPA Residue 
Chemistry Guidance'' (1994).
    In these trials, the maximum combined residues of lambda-
cyhalothrin and epimer in or on leaf lettuce is 1.8 ppm.
    iii. Head and stem Brassica crop subgroup. No additional residue 
crop field data were conducted for the head and stem Brassica crop 
subgroup. The tolerance request is based on existing data and the 
existing time-limited tolerances for combined residues of lambda-
cyhalothrin and epimer in or the Brassica crops, cabbage, and broccoli 
at 0.4 ppm.
    iv. Aspirated grain fractions. The existing tolerance for wheat 
grain dust at 2.0 ppm is being revised to read ``aspirated grain 
fractions'' at the same tolerance level. This change reflects Agency 
policy to establish grain dust tolerances in terms of aspirated grain 
fractions which include a mixture of all aspirated grains for which the 
pesticide has a tolerance and is established at the highest current 
tolerance for any grain dust.
    v. Poultry fat. Alfalfa forage, hay, meal and silage are animal 
feed items for beef and dairy cattle. Alfalfa meal is a feed item for 
poutry and swine. No feed items are involved with the proposed uses on 
leaf lettuce and the head and stem Brassica crop subgroup. Based on 
calculated realistic worst case secondary dietary burdens for animal 
commodities, the maximum calculated residues expected for the fat of 
poultry is 0.0225 ppm compared to the existing tolerance of 0.01 ppm.

B. Toxicological Profile

    The following toxicity studies have been conducted to support the 
request for a regulation for residues of lambda-cyhalothrin in or on 
rice.
    1. Acute toxicity. Acute toxicity studies with the technical grade 
of the active ingredient lambda-cyahothrin: oral LD50 in the 
rat of 79 mg/kg (males) and 56 mg/kg (females), dermal LD50 
in the rat of 632 mg/kg (males) and 696 mg/kg females, primary eye 
irritation study showed mild irritation and primary dermal irritation 
study showed no irritation.
    2. Genotoxicity. The following genotoxicity tests were all 
negative: a gene mutation assay (Ames), a mouse micronucleus assay, an 
in-vitro cytogenetics assay, and a gene mutation study in mouse 
lymphoma cells.
    3. Reproductive and developmental toxicity. A 3-generation 
reproduction study in rats fed diets containing 0, 10, 30, and 100 ppm 
with no developmental toxicity observed at 100 ppm, the highest dose 
tested. The maternal NOEL (no-observed effect level) and LOEL (lowest 
observed effect level) for the study are established at 30 (1.5 mg/kg/
day) and 100 ppm (5 mg/kg/day), respectively, based upon decreased 
parental body weight gain. The reproductive NOEL and LOEL are 
established at 30 (1.5 mg/kg/day) and 100 ppm (5 mg/kg/day), 
respectively, based on decreased pup weight gain during weaning.
     A developmental toxicity study in rats given gavage doses of 0, 5, 
10, and 15 mg/kg/day with no developmental toxicity observed under the 
conditions of the study. The developmental NOEL is greater than 15 mg/
kg/day, the highest dose tested. The maternal NOEL and LOEL are 
established at 10 and 15 mg/kg/day, respectively, based on reduced body 
weight gain.
    A developmental toxicity study in rabbits given gavage doses of 0, 
3, 10, and 30 mg/kg/day with no developmental toxicity observed under 
the conditions of the study. The maternal NOEL and LOEL are established 
at 10 and 30 mg/kg/day, respectively based on decreased body weight 
gain. The developmental NOEL is greater than 30 mg/kg/day, the highest 
dose tested.
    4. Subchronic toxicity. A 90-day feeding study in rats fed doses of 
0, 10, 50 and 250 ppm with a NOEL of 50 ppm and a LOEL of 250 ppm based 
on body weight gain reduction.
    A 21-day study in rabbits exposed dermally to doses of 0, 10, 100, 
and 1,000 mg/kg/day, 6 hours/day, 5 days/week with a systemic NOEL 
>1,000 mg/kg/kg. There were no clinical signs of systemic toxicity at 
any dose level tested.
    5. Chronic toxicity. A 12-month feeding study in dogs fed dose (by 
capsule) levels of 0, 0.1, 0.5, 3.5 mg/kg/day with a NOEL of 0.1 mg/kg/
day. The LOEL for this study is established at 0.5 mg/kg/day based upon 
clinical signs of neurotoxicity.
    A 24-month chronic feeding/carcinogenicity study with rats fed 
diets containing 0, 10, 50, and 250 ppm. The NOEL was established at 50 
ppm and LOEL at 250 ppm based on reduced body weight gain. There were 
no carcinogenic effects observed under the conditions of the study.
    A carcinogenicity study in mice fed dose levels of 0, 20, 100, or 
500 ppm (0, 3, 15, or 75 mg/kg/day) in the diet for 2 years. A systemic 
NOEL was established at 100 ppm and systemic LOEL at 500 ppm based on 
decreased body weight gain in males throughout the study at 500 ppm. 
The Agency has classified lambda-cyhalothrin as a Group D carcinogen 
(not classifiable due to an equivocal finding in this study). It is 
Zeneca's position that no treatment-related carcinogenic effects were 
observed under the conditions of the study.
    6. Animal metabolism. Metabolism studies in rats demonstrated that 
distribution patterns and excretion rates in multiple oral dose studies 
are similar to single-dose studies. Accumulation of unchanged compound 
in fat upon chronic administration with slow elimination. Otherwise, 
lambda-cyhalothrin was rapidly metabolized and excreted. The metabolism 
of lambda-cyhalothrin in livestock is also adequately understood for 
the proposed use on alfalfa.
    7. Metabolite toxicology. The Agency has previously determined that 
the metabolites of lambda-cyhalothrin are not of toxicological concern 
and need not be included in the tolerance expression. Given this 
determination, it is concluded that there is no need to discuss 
metabolite toxicity.

C. Aggregate Exposure

    1. Dietary exposure--i Food. For the purposes of assessing the 
potential dietary exposure for all existing and pending tolerances for 
lambda-cyhalothrin, Zeneca has utilized available information on 
anticipated residues and percent crop treated. For all existing and 
pending tolerances the Anticipated Residue Contribution (ARC) is 
estimated at 0.000310 mg/kg/bwt/day.
    ii. Drinking water. Laboratory and field data have demonstrated 
that lambda-cyhalothrin and its degradates are immobile in soil and 
will not leach into groundwater. Other data show that lambda-
cyhalothrin is virtually insoluble in water and extremely lipophilic. 
As a result, residues reaching surface waters from field runoff will 
quickly adsorb to sediment particles and be partitioned from the water 
column. Together these data indicate that residues are not expected in 
drinking water.
    2. Non-dietary exposure. Other potential sources of exposure are 
from non-occupational sources such as structural pest control and 
ornamental plant and lawn use of lambda-cyhalothrin. Zeneca has no data 
upon which to estimate exposure from these

[[Page 37246]]

uses. However, given the extremely low vapor pressure of lambda-
cyhalothrin (1.5 x 10-9 millimeters of Hg) and the low use 
rates, it is anticipated that inhalation and dermal exposure from these 
uses will be insignificant.

D. Cumulative Effects

    At this time, Zeneca cannot make a determination based on available 
and reliable information that lambda-cyhalothrin and other substances 
that may have a common mechanism of toxicity would have cumulative 
effects. Therefore for purposes of these tolerances it is appropriate 
only to consider the potential risks of lambda-cyhalothrin in an 
aggregate exposure assessment.

E. Safety Determination

    The acceptable Reference Dose (RfD) based on a NOEL of 0.1 mg/kg/
body weight/day from the chronic dog study and a safety factor of 100 
is 0.001 mg/kg/body weight/day. A chronic dietary exposure/risk 
assessment has been performed for lambda-cyhalothrin using the above 
RfD. Available information on anticipated residues and percent crop 
treated was incorporated into the analysis to estimate the Anticipated 
Residue Contribution (ARC) for all existing and the proposed 
tolerances. The ARC is generally considered a more realistic estimate 
than an estimate based on tolerance level residues.
    1. US population. The ARC from established tolerances and the 
current and pending actions are estimated to be 0.000310 mg/kg/bwt/day 
and utilize 31.04 per cent of the RfD for the U.S. population.
    2. Infants and children. The ARC for children, aged 1 to 6 years 
old, and nonnursing infants (subgroups most highly exposed) utilizes 60 
and 67% of the RfD, respectively. Generally speaking, the Agency has no 
cause for concern if anticipated residues contribution for all 
published and proposed tolerances is less than the RfD.

F. International Tolerances

    There are no Codex maximum residue levels [MRL] established for 
residues of lambda-cyhalothrin in or on alfalfa hay, forage, leaf 
lettuce, or Brassica crop subgroup. (George LaRocca)

[FR Doc. 97-18256 Filed 7-10-97; 8:45 am]
BILLING CODE 6560-50-F