[Federal Register Volume 63, Number 59 (Friday, March 27, 1998)]
[Notices]
[Pages 14926-14936]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-8065]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-799; FRL-5579-6]


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-799, must 
be received on or before April 27, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7506C), 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 reviewer listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Ann Sibold....................  Rm. 212, CM #2, 703-    1921 Jefferson  
                                 305-6502, e-            Davis Hwy,     
                                 mail:sibold.ann@epama   Arlington, VA  
                                 il.epa.gov.                            
Joseph M. Tavano..............  Rm. 214, CM #2, 703-    Do.             
                                 305-6411, e-mail:                      
                                 tavano.joseph@epamail                  
                                 .epa.gov.                              
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data 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-799] (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

[[Page 14927]]

Wordperfect 5.1 file format or ASCII file format. All comments and data 
in electronic form must be identified by the docket number (insert 
docket number) and appropriate petition number. Electronic comments on 
notice may be filed online at many Federal Depository Libraries.

List of Subjects

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

    Dated: March 19, 1998

Peter Caulkins,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

1. American Cyanamid Company

PP 6F4623

    EPA has received a pesticide petition (PP 6F4623) from American 
Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400, 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 
of 0.5 ppm for residues of 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-
5-(trifluoromethyl)-1-pyrrole-3-carbonitrile, (chlorfenapyr) in or on 
the raw agricultural commodity citrus. As citrus processed commodities 
fed to food animals may be transferred to milk and edible tissues, 
tolerances are also proposed for the following ruminant food items: 
milk at 0.01 parts per million (ppm); milk fat at 0.15 ppm; meat at 
0.01 ppm; and meat by-products (including fat) at 0.10 ppm.
    The proposed analytical method is capillary gas chromatography 
using an electron capture detector. 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 residues of chlorfenapyr in 
plants is adequately understood and the residue of concern in citrus 
consists of the parent molecule. Expressed on a whole basis, the parent 
compound accounted for 56-75% of the total radioactive residue (TRR), 
98% of which was associated with the external rinse and peel.
    2. Analytical method. The GC analytical method, M2284, which is 
proposed as the enforcement method for the residues of chlorfenapyr in 
citrus, has a limit of detection (LOD) of 0.01 ppm (0.025 ppm for 
juice) and a limit of quantitation (LOQ) of 0.05 ppm.
    3. Magnitude of residues. Extensive citrus field trials have been 
conducted over multiple growing seasons in all major citrus growing 
regions of the US. The results of these studies indicate that at the 
highest proposed use rate of 1.05 lbs ai/A, the maximum expected 
chlorfenapyr residues are 0.4 ppm in oranges, 0.38 ppm in lemons and 
0.27 ppm in grapefruit in/on citrus samples harvested 7 days following 
the last application. These field trial data are adequate to support 
the proposed tolerance of 0.5 ppm in/on citrus harvested 7-days 
following the last application. The results of processing studies 
indicate that chlorfenapyr residues do not concentrate in molasses and 
juice. The actual concentration factors in dried pulp (2.4x) and citrus 
oil (70x) are well below the maximum theoretical concentration factors 
for these commodities. Although citrus oil is not considered to be a 
ready-to-eat item and is not expected to contribute to the dietary 
exposure, a tolerance at 35 ppm (0.5 ppm x 70) is proposed for 
enforcement purposes.

B. Toxicological Profile

    1. Acute toxicity. Based on the EPA's toxicity category criteria, 
the acute toxicity category for chlorfenapyr technical is Category II 
or moderately toxic (signal word WARNING) and the acute toxicity 
category for the 2SC formulation is Category III or slightly toxic 
(signal word CAUTION). Males appear to be more sensitive to the effects 
of chlorfenapyr than females. The acute toxicity profile indicates that 
absorption by the oral route appears to be greater than by the dermal 
route. The following are the results from the acute toxicity tests 
conducted on the technical material:
    i. Rat Oral LD50: 441/1152 milligram/kilograms (mg/kg) 
bwt.(M/F) -- Tox. Category II
    ii. Rabbit Dermal LD50: >2,000 mg/kg bwt.(M/F) -- Tox. 
Category III
    iii. Acute Inhal. LC50: 0.83/>2.7 mg/L (M/F) -- Tox. 
Category III
    iv. Eye Irritation: Moderately Irritating -- Tox. Category III
    v. Dermal Irritation: Non-Irritating -- Tox. Category IV
    vi. Dermal Sensitization: Non-Sensitizer -- Non Sensitizer
    vii. Acute Neurotoxicity: NOEL 45 mg/kg bwt. -- Not An Acute 
Neurotoxicant
    2. Genotoxicty. Chlorfenapyr technical (94.5% a.i.) was examined in 
a battery ofin vitro and in vivo tests to assess its genotoxicity and 
its potential for carcinogenicity. These tests are summarized below.
    Microbial/Microsome Mutagenicity Assay: Non-mutagenic
    Mammalian Cell CHO/HGPRT Mutagenicity Assay: Non-mutagenic
    In Vivo Micronucleus Assay: Non-genotoxic
    In Vitro--Chromosome Aberration Assay in CHO: Non-clastogenic
    In Vitro--Chromosome Aberration Assay in CHLC: Non-clastogenic
    Unscheduled DNA Synthesis (UDS) Assay: Non-genotoxic.
    3. Reproductive and developmental toxicity. Chlorfenapyr is neither 
a reproductive or developmental toxicant and is not a teratogenic agent 
in the Sprague-Dawley rat or the New Zealand white rabbit. This is 
demonstrated by the results of the following studies:
    Rat Oral Teratology -- No-Observed-Effect-Level (NOEL) for maternal 
toxicity 25 mg/kg bwt./day and NOEL for fetal/develop. toxicity 225 
milligram/kilograms body weight/day (mg/kg bwt./day)
    Rabbit Oral Teratology -- NOEL for maternal toxicity 5 mg/kg bwt./
day and NOEL for fetal/develop. toxicity 30 mg/kg bwt./day
    Rat 2-Generation Reproduction -- NOEL for parental toxicity /growth 
and offspring development 60 ppm (5 mg/kg bwt./day)
NOEL for reproductive performance 600 ppm (44 mg/kg bwt./day).
    4. Subchronic toxicity. The following are the results of the 
subchronic toxicity tests that have been conducted with chlorfenapyr:
    28-Day Rabbit Dermal -- NOEL 100 mg/kg bwt./day
    28-Day Rat Feeding -- NOEL >600 ppm (< 71.6 mg/kg bwt./day)
    28-Day Mouse Feeding -- NOEL >160 ppm (<32 mg/kg bwt./day)
    13-Week Rat Dietary -- NOAEL 150 ppm (11.7 mg/kg bwt./day)

[[Page 14928]]

    13-Week Mouse Dietary -- NOEL 40 ppm (8.2 mg/kg bwt./day)
    13-Week Dog Dietary -- NOAEL 120 ppm (4.2 mg/kg bwt./day)
    5. Chronic toxicity. Chlorfenapyr is not oncogenic in either 
Sprague Dawley rats or CD-1 mice and is not likely to be carcinogenic 
in humans. The following are the results of the chronic toxicity tests 
that have been conducted with chlorfenapyr:
    1-Year Neurotoxicity in Rats -- NOEL 60 ppm (2.6/3.4 mg/kg bwt./day 
M/F)
    1-Year Dog Dietary -- NOEL 120 ppm (4.0/4.5 mg/kg bwt./day M/F)
    24-Month Rat Dietary -- NOEL for Chronic Effects 60 ppm (2.9/3.6 
mg/kg bwt./day M/F) and NOEL for Oncogenic Effects 600 ppm (31/37 mg/kg 
bwt./day M/F)
    18-Month Mouse Dietary -- NOEL for Chronic Effects 20 ppm (2.8/3.7 
mg/kg bwt./day M/F) and NOEL for Oncogenic Effects 240 ppm (34.5/44.5 
mg/kg bwt./day M/F)
    6. Animal metabolism. A metabolism study was conducted in Sprague 
Dawley rats at approximately 20 and 200 mg/kg bwt. using radiolabeled 
chlorfenapyr. Approximately 65% of the administered dose was eliminated 
during the first 24 hours (62% in feces and 3% in urine) and by 48 
hours following dosing, approximately 85% of the dose had been excreted 
(80% in feces and 5% in urine). The absorbed chlorfenapyr-related 
residues were distributed throughout the body and detected in tissues 
and organs of all treatment groups. The principal route of elimination 
was via feces, mainly as unchanged parent plus minor N-dealkylated, 
debrominated and hydroxylated oxidation products.
    The metabolic pathway of chlorfenapyr in the laying hen and the 
lactating goat was also similar to that in laboratory rats.
    7. Metabolite toxicology. The parent molecule is the only moiety of 
toxicological significance which needs regulation in plant and animal 
commodities.
    8. Endocrine effects. Collective organ weights and 
histopathological findings from the 2-generation rat reproduction 
study, as well as from the subchronic and chronic toxicity studies in 
two or more animal species, demonstrate no apparent estrogenic effects 
or effects on the endocrine system. There is no information available 
which suggests that chlorfenapyr would be associated with endocrine 
effects.

C. Aggregate Exposure

    1. Dietary exposure-- i. Food. For purposes of assessing the 
potential dietary exposure, a Theoretical Maximum Residue Contribution 
(TMRC) has been calculated from the tolerance of chlorfenapyr in/on 
citrus at 0.5 ppm. This exposure assessment is based on very 
conservative assumptions, namely 100% of all citrus is treated with 
chlorfenapyr and that the residues of chlorfenapyr in citrus are at the 
tolerance level. Although there are no other established US permanent 
tolerances for chlorfenapyr, a petition for a permanent tolerance at 
0.5 ppm in cottonseed is pending at the Agency. Therefore, the dietary 
exposures to residues of chlorfenapyr in or on food will be limited to 
residues in cottonseed, citrus and food and feed items derived from 
them. As dried citrus pulp is a dairy and beef cattle feed item, a cold 
feeding study with dairy cattle was conducted. Since this study 
demonstrated that measurable residues of chlorfenapyr may occur in 
milk, meat and meat by products, appropriate residue tolerances for 
these items are proposed. The contribution of the citrus tolerances 
alone to the daily consumption uses only 0.23% of the reference dose 
(RfD) for the overall US population. The combined contributions of the 
citrus and the pending cottonseed tolerances to the daily consumption 
uses less than 1% (actual 0.85%) of the reference dose for the overall 
US population and less than 3% (actual 2.23%) and less than 1% (actual 
0.89%) of the reference doses for children aged 1-6 and for non-nursing 
infants, respectively.
    ii. Drinking water. There is no available information about 
chlorfenapyr exposures via levels in drinking water. There is no 
concern for exposure to residues of chlorfenapyr in drinking water 
because of its extremely low water solubility (120 ppb at 25 deg.). 
Chlorfenapyr is also immobile in soil and does not leach because it is 
strongly adsorbed to all common soil types. In addition, the label 
explicitly prohibits applications near aquatic areas
    There is a reasonable certainty that no harm will result from 
dietary exposure to chlorfenapyr, because dietary exposure to residues 
on food will use only a small fraction of the (RfD) (including exposure 
of sensitive subpopulations), and exposure through drinking water is 
expected to be insignificant.
    2. Non-dietary exposure. There is no available information 
quantifying non-dietary exposure to chlorfenapyr. However, based on the 
physico-chemical characteristics of the compound, the proposed use 
pattern and available information concerning its environmental fate, 
non-dietary exposure is expected to be negligible. The vapor pressure 
of chlorfenapyr is less than 1 x 10-7 mm of Hg; therefore, 
the potential for non-occupational exposure by inhalation is 
insignificant. Moreover, the current proposed registration is for 
outdoor, terrestrial uses which severely limit the potential for non-
occupational exposure.

D. Cumulative Effects

    The pyrrole insecticides represent a new class of chemistry with a 
unique mechanism of action. The parent molecule, AC 303,630 is a pro-
insecticide which is converted to the active form, CL 303,268, via 
rapid metabolism by mixed function oxidases (MFOs). The active form 
uncouples oxidative phosphorylation in the insect mitochondria by 
disrupting the proton gradient across the mitochondrial membrane. The 
production of ATP is inhibited resulting in the cessation of all 
cellular functions. Because of this unique mechanism of action, it is 
highly unlikely that toxic effects produced by chlorfenapyr would be 
cumulative with those of any other pesticide chemical.
    In mammals, there is a lower titer of MFOs, and chlorfenapyr is 
metabolized by different pathways (including dehalogenation, oxidation 
and ring hydroxylation) to other polar metabolites without any 
significant accumulation of the potent uncoupler, CL--303,268. In the 
rat, approximately 85 % of the administered dose is excreted in the 
feces within 48-hours, thereby reducing the levels of AC 303,630 and CL 
303,268 that are capable of reaching the mitochondria. This 
differential metabolism of AC 303,630 to CL 303,268 in insects versus 
to other polar metabolites in mammals is responsible for the selective 
insect toxicity of the pyrroles.

E. Safety Determination

    1. U.S. population. The RfD of 0.03 mg/kg bwt./day for the residues 
of chlorfenapyr in citrus is calculated by applying a 100-fold safety 
factor to the overall NOEL of 3 mg/kg bwt./day. This NOEL is of based 
on the results of the chronic feeding studies in the rat and mouse and 
the 2-generation reproduction study in the rat (see Item 2). The TMRC 
for the proposed tolerances in citrus alone, (0.0000692 mg/kg bwt./
day), will utilize only 0.23% of the RfD for the general U.S. 
population and the combined TMRC for the proposed chlorfenapyr 
tolerances in cottonseed, citrus, milk and meat (0.0002558 mg/kg bwt./
day) will utilize approximately 0.85% of the RfD for the general U.S. 
population.
    2. Infants and children. The TMRC in milk consumed by a non-nursing 
infant

[[Page 14929]]

(>1-year of age) is 0.0002435 mg/kg bwt./day. The combined tolerances 
will use less than 1% (actual 0.89%) of the RfD for non-nursing 
infants. The TMRC in milk consumed by a child (1-6 years of age) is 
0.0003886 mg/kg bwt./day. The combined TMRC for the proposed 
chlorfenapyr tolerances in cottonseed, citrus meat and milk consumed by 
a child 1-6 years of age is 0.0006708 mg/kg bwt./day, which is less 
than 3% (actual 2.23%) of the RfD. Therefore, the results of the 
toxicology and metabolism studies support both the safety of 
chlorfenapyr to humans based on the intended use as an insecticide-
miticide on citrus and cottonseed and the granting of the requested 
tolerances in cottonseed, citrus, milk, milk fat solids, meat and meat 
by-products.
    Based on the conservative assumptions used in proposing the above 
tolerances and the absence of other non-dietary routes of exposure to 
chlorfenapyr, and since the calculated exposures are well below 100% of 
the reference dose, there is a reasonable certainty that no harm will 
result from aggregate exposure to residues of chlorfenapyr, including 
all anticipated dietary exposure and all other non-occupational 
exposures. The use of a 100-fold safety factor ensures an acceptable 
margin of safety for both the overall U. S. population as well as 
infants and children. As the toxicology database (reproduction/
developmental and teratology studies) is complete, valid and reliable, 
no additional safety factor is needed.
    The 100-fold margin of safety is adequate to assure a reasonable 
certainty of no harm to infants and children from the proposed use. As 
stated earlier, the NOEL is based on the effects observed in the rat 
and mouse chronic oncogenicity studies, (reduced body weight gains, 
increased globulin and cholesterol values and increased liver weights 
in the rat and reduced body weight gains and vacuolation of white 
matter of the mouse brain), the one-year neurotoxicity study in the 
rat, (reduced body weight gains and vacuolar myelinopathy of the brain 
and spinal cord that is completely reversible following termination of 
treatment and is not associated with any damage to neuronal cell bodies 
or axons; vacuolation of the white matter is a consequence of edema 
(water) formation between the myelin layers which result from the 
unrestricted movement of ions across the cell membranes) and the 2-
generation rat reproduction study, (reduced body weight gains for 
parental animals and reduced pup body weights for the F1 and F2 
litters; however no behavioral changes were observed in either F1 or F2 
offsprings in the 2-generation reproduction study). Moreover, as the 
NOELs for fetal/developmental toxicity are significantly higher than 
those for maternal toxicity, the results indicate that chlorfenapyr is 
neither a developmental toxicant nor a teratogenic agent in either the 
Sprague-Dawley rat or New Zealand White rabbit. Thus, there is no 
reliable information to indicate that there would be a variability in 
the sensitivities of infants and children and adults to the effects of 
exposure to chlorfenapyr.

F. International Tolerances

    Section 408 (b)(4) of the amended FFDCA requires EPA to determine 
whether a maximum residue level has been established for the pesticide 
chemical by the Codex Alimentarius Commission.
    There is neither a Codex proposal, nor Canadian or Mexican 
tolerances/limits for residues of chlorfenapyr in/on citrus. Therefore, 
a compatibility issue is not relevant to the proposed tolerance.

2. Rohm and Haas Company

PP 6G4681

    EPA has received a pesticide petition (PP 6G4681) from Rohm and 
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399. 
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 tebufenozide, benzoic acid, 
3,5-dimethyl-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide in or 
on the raw agricultural commodity pears at 1.5 (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 metabolism of tebufenozide in plants 
(grapes, apples, rice and sugar beets) is adequately understood for the 
purposes of these tolerances. The metabolism of tebufenozide in all 
crops was similar and involves oxidation of the alkyl substituents of 
the aromatic rings primarily at the benzylic positions. The extent of 
metabolism and degree of oxidation are a function of time from 
application to harvest. In all crops, parent compound comprised the 
majority of the total dosage. None of the metabolites were in excess of 
10% of the total dosage. The metabolism of tebufenozide in goats 
proceeds along the same metabolic pathway as observed in plants. No 
accumulation of residues in tissues or milk occurred. Because apple 
pomace is not fed to poultry, there is no reasonable expectation that 
measurable residues of tebufenozide will occur in eggs, poultry meat or 
poultry meat by-products.
    2. Analytical method. A high performance liquid chromatographic 
(HPLC) analytical method using ultraviolet (UV) or mass selective 
detection have been validated for apples. The method involves 
extraction by blending with solvents, purification of the extracts by 
liquid-liquid partitions and final purification of the residues using 
solid phase extraction column chromatography. The limits of 
quantitation is 0.02 ppm for apples.

B. Toxicological Profile

    1. Acute toxicity. Tebufenozide has low acute toxicity. 
Tebufenozide Technical was practically non-toxic by ingestion of a 
single oral dose in rats and mice (LD50 > 5,000 milligram/
kilograms (mg/kg) and was practically non-toxic by dermal application 
(LD50 > 5,000 mg/kg). Tebufenozide Technical was not 
significantly toxic to rats after a 4-hr inhalation exposure with an 
LC50 value of 4.5 mg/L (highest attainable concentration), 
is not considered to be a primary eye irritant or a skin irritant and 
is not a dermal sensitizer. An acute neurotoxicity study in rats did 
not produce any neurotoxic or neuropathologic effects.
    2. Genotoxicty. Tebufenozide technical was negative (non-mutagenic) 
in an Ames assay with and without hepatic enzyme activation and in a 
reverse mutation assay with E. coli. Tebufenozide technical was 
negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT) 
gene mutation assay using Chinese hamster ovary (CHO) cells in culture 
when tested with and without hepatic enzyme activation. In isolated rat 
hepatocytes, tebufenozide technical did not induce unscheduled DNA 
synthesis (UDS) or repair when tested up to the maximum soluble 
concentration in culture medium. Tebufenozide did not produce 
chromosome effects in vivo using rat bone marrow cells or in vitro 
using Chinese hamster ovary cells (CHO). On the basis of the results 
from this battery of tests, it is concluded that tebufenozide is not 
mutagenic or genotoxic.
    3. Reproductive and developmental toxicity--i. NOELs for 
developmental and maternal toxicity to tebufenozide

[[Page 14930]]

were established at 1,000 milligram/kilograms/day (mg/kg/day) highest 
dose tested (HDT) in both the rat and rabbit. No signs of developmental 
toxicity were exhibited.
    ii. In a 2-generation reproduction study in the rat, the 
reproductive/developmental toxicity (NOEL) of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOEL 10 ppm 0.85 mg/
kg/day. Equivocal reproductive effects were observed only at the 2,000 
ppm dose.
    iii. In a second rat reproduction study, the equivocal reproductive 
effects were not observed at 2,000 ppm (the NOEL equal to 149-195 mg/
kg/day) and the NOEL for systemic toxicity was determined to be 25 ppm 
(1.9-2.3 mg/kg/day).
    4. Subchronic toxicity-- i. The NOEL in a 90-day rat feeding study 
was 200 ppm (13 mg/kg/day for males, 16 mg/kg/day for females). The 
lowest-observed-effect-level (LOEL) was 2,000 ppm (133 mg/kg/day for 
males, 155 mg/kg/day for females). Decreased body weights in males and 
females was observed at the LOEL of 2,000 ppm. As part of this study, 
the potential for tebufenozide to produce subchronic neurotoxicity was 
investigated. Tebufenozide did not produce neurotoxic or 
neuropathologic effects when administered in the diets of rats for 3-
months at concentrations up to and including the limit dose of 20,000 
ppm (NOEL = 1330 mg/kg/day for males, 1,650 mg/kg/day for females).
    ii. In a 90-day feeding study with mice, the NOEL was 20 ppm (3.4 
and 4.0 mg/kg/day for males and females, respectively). The LOEL was 
200 ppm (35.3 and 44.7 mg/kg/day for males and females, respectively). 
Decreases in body weight gain were noted in male mice at the LOEL of 
200 ppm.
    iii. A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/
day for males and females). The LOEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the LOEL, females 
exhibited a decrease in rate of weight gain and males presented an 
increased reticulocyte
    iv. A 10-week study was conducted in the dog to examine the 
reversibility of the effects on hematological parameters that were 
observed in other dietary studies with the dog. Tebufenozide was 
administered for 6-weeks in the diet to 4 male dogs at concentrations 
of either 0 or 1,500 ppm. After the 6-week, the dogs receiving treated 
feed were switched to the control diet for 4- weeks. Hematological 
parameters were measured in both groups prior to treatment, at the end 
of the 6-weeks treatment, after 2-weeks of recovery on the control diet 
and after 4-weeks of recovery on the control diet. All hematological 
parameters in the treated/recovery group were returned to control 
levels indicating that the effects of tebufenozide on the hemopoietic 
system are reversible in the dog.
    v. In a 28-day dermal toxicity study in the rat, the NOEL was 1,000 
mg/kg/day, (HDT). Tebufenozide did not produce toxicity in the rat when 
administered dermally for 4-weeks at doses up to and including the 
limit dose of 1,000 mg/kg/day.
    5. Chronic toxicity--i. A 1-year feeding study in dogs resulted in 
decreased red blood cells, hematocrit, and hemoglobin and increased 
Heinz bodies, reticulocytes, and platelets at the (LOEL) of 8.7 mg/kg/
day. The NOEL in this study was 1.8 mg/kg/day.
    ii. An 18-month mouse carcinogenicity study showed no signs of 
carcinogenicity at dosage levels up to and including 1,000 ppm, the 
highest dose tested.
    iii. In a combined rat chronic/oncogenicity study, the NOEL for 
chronic toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and 
females, respectively) and the LOEL was 1,000 ppm (48 and 61 mg/kg/day 
for males and females, respectively). No carcinogenicity was observed 
at the dosage levels up to 2,000 ppm (97 mg/kg/day and 125 mg/kg/day 
for males and females, respectively).
    6. Animal metabolism. The adsorption, distribution, excretion and 
metabolism of tebufenozide in rats was investigated. Tebufenozide is 
partially absorbed, is rapidly excreted and does not accumulate in 
tissues. Although tebufenozide is mainly excreted unchanged, a number 
of polar metabolites were identified. These metabolites are products of 
oxidation of the benzylic ethyl or methyl side chains of the molecule. 
These metabolites were detected in plant and other animal (rat, goat, 
hen) metabolism studies.
    7. Metabolite toxicology. Common metabolic pathways for 
tebufenozide have been identified in both plants (grape, apple, rice 
and sugar beet) and animals (rat, goat, hen). The metabolic pathway 
common to both plants and animals involves oxidation of the alkyl 
substituents (ethyl and methyl groups) of the aromatic rings primarily 
at the benzylic positions. Extensive degradation and elimination of 
polar metabolites occurs in animals such that residue are unlikely to 
accumulate in humans or animals exposed to these residues through the 
diet.
    8. Endocrine disruption. The toxicology profile of tebufenozide 
shows no evidence of physiological effects characteristic of the 
disruption of the hormone estrogen. Based on structure-activity 
information, tebufenozide is unlikely to exhibit estrogenic activity. 
Tebufenozide was not active in a direct in vitro estrogen binding 
assay. No indicators of estrogenic or other endocrine effects were 
observed in mammalian chronic studies or in mammalian and avian 
reproduction studies. Ecdysone has no known effects in vertebrates. 
Overall, the weight of evidence provides no indication that 
tebufenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure. Use of an agricultural pesticide may result, 
directly or indirectly in pesticide residues in food. These residues 
are determined by chemical analysis. Data from field studies are 
evaluated to determine the appropriate level of residue that would not 
be exceeded if the pesticide were used according to the label use 
directions.
    2. Plant and animal metabolism. The metabolism of tebufenozide in 
plants (grapes, apples, rice and sugar beets) is adequately understood 
for the purposes of these tolerances. The metabolism of tebufenozide in 
all crops was similar and involves oxidation of the alkyl substituents 
of the aromatic rings primarily at the benzylic positions. The extent 
of metabolism and degree of oxidation are a function of time from 
application to harvest. In all crops, parent compound comprised the 
majority of the total dosage. None of the metabolites were in excess of 
10% of the total dosage. The metabolism of tebufenozide in goats 
proceeds along the same metabolic pathway as observed in plants. No 
accumulation of residues in tissues or milk occurred. Because apple 
pomace is not fed to poultry, there is no reasonable expectation that 
measurable residues of tebufenozide will occur in eggs, poultry meat or 
poultry meat by-products.
    3. Analytical methods. A high performance liquid chromatographic 
(HPLC) analytical method using ultraviolet (UV) or mass selective 
detection have been validated for apples. The method involves 
extraction by blending with solvents, purification of the extracts by 
liquid-liquid partitions and final purification of the residues using 
solid phase extraction column chromatography. The limits of 
quantitation is 0.02 ppm for apples.
    4. Food. Tolerances for residues of tebufenozide are currently 
expressed as benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2(4-
ethylbenzoyl) hydrazide. Tolerances currently exist for residues on 
apples at 1.0 ppm (import

[[Page 14931]]

tolerance) and on walnuts at 0.1 ppm (see 40 CFR 180.482).
    5. Acute risk--i. No appropriate acute dietary endpoint was 
identified by the Agency. This risk assessment is not required.
    ii. Chronic risk. For chronic dietary risk assessment, the 
tolerance and temporary tolerance values are used and the assumption 
that all walnuts, imported apples and pears which are consumed in the 
U.S. will contain residues at the tolerance level. The theoretical 
maximum residue contribution (TMRC) using existing tolerances and 
temporary tolerances for tebufenozide on food crops is obtained by 
multiplying the tolerance level residues by the consumption data which 
estimates the amount of those food products consumed by various 
population subgroups and assuming that 100% of the food crops are 
treated with tebufenozide. The Theoretical Maximum Residue Contribution 
(TMRC) from current tolerances and temporary tolerances (MRID 44319101) 
is calculated using the Dietary Exposure Evaluation Model (Version 
5.03b, licensed by Novigen Sciences Inc.) which uses USDA food 
consumption data from the 1989-1992 survey.
    With the current and proposed uses of tebufenozide, the TMRC 
estimate represents 4.31% of the Reference dose (RfD) for the U.S. 
population as a whole. The subgroup with the greatest chronic exposure 
is non-nursing infants (less than 1-year old), for which the TMRC 
estimate represents 20.3% of the RfD. The chronic dietary risks from 
these uses do not exceed EPA's level of concern.
    6. Drinking water. An additional potential source of dietary 
exposure to residues of pesticides are residues in drinking water. 
Review of environmental fate data by the Environmental Fate and Effects 
Division concludes that tebufenozide is moderately persistent to 
persistent and mobile, and could potentially leach to groundwater and 
runoff to surface water under certain environmental conditions. 
However, in terrestrial field dissipation studies, residues of 
tebufenozide and its soil metabolites showed no downward mobility and 
remained associated with the upper layers of soil. Foliar interception 
(up to 60% of the total dosage applied) by target crops reduces the 
ground level residues of tebufenozide. There is no established Maximum 
Concentration Level (MCL) for residues of tebufenozide in drinking 
water. No drinking water health advisory levels have been established 
for tebufenozide.
    There are no available data to perform a quantitative drinking 
water risk assessment for tebufenozide at this time. However, in order 
to mitigate the potential for tebufenozide to leach into groundwater or 
runoff to surface water, precautionary language has been incorporated 
into the product label. Also, to the best of our knowledge, previous 
experience with more persistent and mobile pesticides for which there 
have been available data to perform quantitative risk assessments have 
demonstrated that drinking water exposure is typically a small 
percentage of the total exposure when compared to the total dietary 
exposure. This observation holds even for pesticides detected in wells 
and drinking water at levels nearing or exceeding established MCLs. 
Considering the precautionary language on the label and based on our 
knowledge of previous experience with persistent chemicals, significant 
exposure from residues of tebufenozide in drinking water is not 
anticipated.
    7. Non-dietary exposure. Tebufenozide is not registered for either 
indoor or outdoor residential use. Non-occupational exposure to the 
general population is therefore not expected and not considered in 
aggregate exposure estimates.

D. Cumulative Effects

    The potential for cumulative effects of tebufenozide with other 
substances that have a common mechanism of toxicity was considered. 
Tebufenozide belongs to the class of insecticide chemicals known as 
diacylhydrazines. The only other diacylhydrazine currently registered 
for non-food crop uses is halofenozide. Tebufenozide and halofenozide 
both produce a mild, reversible anemia following subchronic/chronic 
exposure at high doses; however, halofenozide also exhibits other 
patterns of toxicity (liver toxicity following subchronic exposure and 
developmental/systemic toxicity following acute exposure) which 
tebufenozide does not. Given the different spectrum of toxicity 
produced by tebufenozide, there is no reliable data at the molecular/
mechanistic level which would indicate that toxic effects produced by 
tebufenozide would be cumulative with those of halofenozide (or any 
other chemical compound).
    In addition to the observed differences in mammalian toxicity, 
tebufenozide also exhibits unique toxicity against target insect pests. 
Tebufenozide is an agonist of 20-hydroxyecdysone, the insect molting 
hormone, and interferes with the normal molting process in target 
lepidopteran species by interacting with ecdysone receptors from those 
species. Unlike other ecdysone agonists such as halofenozide, 
tebufenozide does not produces symptoms which may be indicative of 
systemic toxicity in beetle larvae (Coleopteran species). Tebufenozide 
has a different spectrum of activity than other ecdysone agonists. In 
contrast to the other agonists such as halofenozide which act mainly on 
coleopteran insects, tebufenozide is highly specific for lepidopteran 
insects.
    Based on the overall pattern of toxicity produced by tebufenozide 
in mammalian and insect systems, the compound's toxicity appears to be 
distinct from that of other chemicals, including organochlorines, 
organophosphates, carbamates, pyrethroids, benzoylureas, and other 
diacylhydrazines. Thus, there is no evidence to date to suggest that 
cumulative effects of tebufenozide and other chemicals should be 
considered.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and taking into account the completeness and 
reliability of the toxicity data, the dietary exposure to tebufenozide 
from the current and proposed tolerances will utilize 4.31% of the RfD 
for the U.S. population and 20.3% for non-nursing infants under 1-year 
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. Rohm and Haas concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to 
tebufenozide residues to the U.S. population and non-nursing infants.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of tebufenozide, data 
from developmental toxicity studies in the rat and rabbit and 2-
generation reproduction studies in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development to 1 or both parents. Reproduction studies provide 
information relating to effects from exposure to the pesticide on the 
reproductive capability of mating animals and data on systemic 
toxicity. Developmental toxicity was not observed in developmental 
studies using rats and rabbits. The NOEL for developmental effects in 
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for 
testing in developmental studies.

[[Page 14932]]

    In the 2-generation reproductive toxicity study in the rat, the 
reproductive/ developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold 
higher than the parental (systemic) toxicity NOEL (0.85 mg/kg/day). The 
reproductive (pup) LOEL of 171.1 mg/kg/day was based on a slight 
increase in both generations in the number of pregnant females that 
either did not deliver or had difficulty and had to be sacrificed. In 
addition, the length of gestation increased and implantation sites 
decreased significantly in F1 dams. These effects were not replicated 
at the same dose in a second 2-generation rat reproduction study. In 
this second study, reproductive effects were not observed at 2,000 ppm 
(the NOEL equal to 149-195 mg/kg/day) and the NOEL for systemic 
toxicity was determined to be 25 ppm (1.9-2.3 mg/kg/day).
    Because these reproductive effects occurred in the presence of 
parental (systemic) toxicity and were not replicated at the same doses 
in a second study, these data do not indicate an increased pre-natal or 
post-natal sensitivity to children and infants (that infants and 
children might be more sensitive than adults) to tebufenozide exposure. 
FFDCA section 408 provides that EPA shall 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 
data base unless EPA concludes that a different margin of safety is 
appropriate. Based on current toxicological data discussed above, an 
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and 
children. Rohm and Haas concludes that there is a reasonable certainty 
that no harm will occur to infants and children from aggregate exposure 
to residues of tebufenozide.

F. International Tolerances

     There are no approved CODEX maximum residue levels (MRLs) 
established for residues of tebufenozide. At the 1996 Joint Meeting for 
Pesticide Residues, the FAO expert panel considered residue data for 
pome fruit and proposed an MRL (Step 3) of 1.0 mg/kg.

3. Valent U.S.A. Corporation

PP 7F4882

    EPA has received a pesticide petition (PP 7F4882) from Valent 
U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek, CA 94596. 
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 pyriproxyfen, 2-[ 1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine in or on the raw agricultural commodity 
Pome Fruits(Crop Group 11, including apples and pears) at 0.2 (ppm), 
Walnuts at 0.02 ppm, and Apple Pomace,wet at 0.8 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 residues in cotton, apples, 
and animals is adequately understood. Metabolism of 14C-pyriproxyfen 
labelled in the phenoxyphenyl ring and in the pyridyl ring was studied 
in cotton, apples, lactating goats, and laying hens (and rats). The 
nature of the residue is defined by the metabolism studies primarily as 
pyriproxyfen. The major metabolic pathways in plants is hydroxylation 
and cleavage of the ether linkage, followed by further metabolism into 
more polar products by oxidation or conjugation reactions, however, the 
bulk of the radiochemical residues was parent. Comparing metabolites 
from cotton, apple, goat and hen (and rat) shows that there are no 
significant metabolites in plants which are not also present in the 
excreta or tissues of animals.
    Ruminant and poultry metabolism studies demonstrated that transfer 
of administered 14C residues to tissues was low. Total 14C residues in 
goat milk, muscle and tissues accounted for less than 2% of the 
administered dose, and were less than 1 ppm in all cases. In poultry, 
total 14C residues in eggs, muscle and tissues accounted for about 2.7% 
of the administered dose, and were less than 1 ppm in all cases except 
for gizzard.
    2. Analytical method. Practical analytical methods for detecting 
and measuring levels of pyriproxyfen (and relevant metabolites) have 
been developed and validated for the raw agricultural commodities, 
their respective processing fractions, and animal tissues. The methods 
have been independently validated in cottonseed and apples (and 
oranges) and the extraction methodology has been validated using aged 
radiochemical residue samples from metabolism studies. EPA has(personal 
communication) successfully validated the analytical method for 
analysis of cottonseed raw agricultural commodity. The limit of 
detection of pyriproxyfen in the methods is 0.01 ppm which will allow 
monitoring of food with residues at or above the levels set for the 
proposed tolerance.
    3. Magnitude of residues--i. Apples. A total of fifteen trials were 
conducted in 1994, 1995, and 1996 to determine the magnitude of the 
residue in apples and apple processing commodities from regions 
representing approximately 97% of the commercial U.S. apple acreage. 
The mean residue of pyriproxyfen found in these samples was 0.091 ppm 
with a standard deviation (, n-1 degrees of freedom) of 0.035 
ppm and a maximum residue of 0.18 ppm. Apples from two sites were 
processed into juice and wet pomace. The results from the processing 
samples show that pyriproxyfen was substantially retained with the wet 
pomace fraction, resulting in a 5 x concentration in this fraction. The 
average processing concentration factor for pyriproxyfen from fruit 
into apple pomace, wet, was 4.89 x. No residues of pyriproxyfen above 
the 0.01 LOD was detected in the juice fractions.
    ii. Pears. A total of eight trials were conducted in 1994, 1995, 
and 1996 to determine the magnitude of the residue of pyriproxyfen in 
pears from regions representing approximately 95% of the commercial 
U.S. pear acreage. The mean residue of pyriproxyfen found in these 
samples was 0.039 ppm with a standard deviation (, n-1 degrees 
of freedom) of 0.016 ppm and a maximum residue of 0.07 ppm.
    iii. Walnuts. A total of 4 trials were conducted in 1996 to 
determine the magnitude of the residue of pyriproxyfen in walnut 
nutmeats all in region x where 98% of the commercial walnut acreage is 
located. No residues of pyriproxyfen above the 0.01 ppm limit of 
detection were found in any walnut nutmeat collected for this study.
    4. Secondary residues. Since low residues were detected in animal 
feed items (cotton gin byproducts, apple pomace, wet) and animal 
metabolism studies do not show potential for significant residue 
transfer, detectable secondary residues in animal tissues, milk, and 
eggs are not expected. Therefore, tolerances are not needed for these 
commodities.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of technical grade 
pyriproxyfen is low by all routes, classified as Category III for acute 
dermal and inhalation toxicity, and Category IV for acute oral 
toxicity, and skin/eye irritation. Pyriproxyfen is not a skin 
sensitizing agent.

[[Page 14933]]

    2. Genotoxicty. Pyriproxyfen does not present a genetic hazard. 
Pyriproxyfen was negative in the following tests for mutagenicity: Ames 
assay with and without S9, in vitro unscheduled DNA synthesis in HeLa 
S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in 
vitro chromosomal aberration with and without S9 in Chinese hamster 
ovary cells.
    3. Reproductive and developmental toxicity. Pyriproxyfen is not a 
developmental toxicant. In the rat teratology study, maternal toxicity 
was observed at doses of 300 mg/kg/day and greater, the NOEL for 
prenatal developmental toxicity was 100 mg/kg/day. A rabbit teratology 
study resulted in a maternal NOEL of 100 mg/kg/day, with no 
developmental effects observed in the rabbit fetuses.
    In the study conducted with rats, technical pyriproxyfen was 
administered by gavage at levels of 0, 100, 300, and 1,000 mg/kg/day 
during gestation days 7-17. Maternal toxicity (mortality, decreased 
body weight gain and food consumption and clinical signs of toxicity) 
was observed at doses of 300 mg/kg/day and greater. The maternal NOEL 
was 100 mg/kg/day. A transient increase in skeletal variations was 
observed in rat fetuses exposed to 300 mg/kg/day and greater. These 
effects were not present in animals examined at the end of the 
postnatal period, therefore, the NOEL for prenatal developmental 
toxicity was 100 mg/kg/day. An increased incidence of visceral and 
skeletal variations was observed postnatally at 1,000 mg/kg/day. The 
NOEL for postnatal developmental toxicity was 300 mg/kg/day. In the 
study conducted with rabbits, technical pyriproxyfen was administered 
by gavage at levels of 0, 100, 300, and 1,000 mg/kg/day during 
gestation days 6-18. Maternal toxicity (clinical signs of toxicity 
including one death, decreased body weight gain and food consumption, 
and abortions or premature deliveries) was observed at oral doses of 
300 mg/kg/day or higher. The maternal NOEL was 100 mg/kg/day. No 
developmental effects were observed in the rabbit fetuses. The NOEL for 
developmental toxicity in rabbits was 1,000 mg/kg/day.
    Pyriproxyfen is not a reproductive toxicant. Pyriproxyfen was 
administered in the diet at levels of 0, 200, 1,000, and 5,000 ppm 
through 2- generations of rats. Adult systemic toxicity (reduced body 
weights, liver and kidney histopathology, and increased liver weight) 
was produced at the 5,000 ppm dose (453 mg/kg/day in males, 498 mg/kg/
day in females during the pre-mating period). The systemic NOEL was 
1,000 ppm (87 mg/kg/day in males, 96 mg/kg/day in females). No effects 
on reproduction were produced even at 5,000 ppm, the highest dose 
tested.
    4. Subchronic toxicity. Subchronic oral toxicity studies conducted 
with pyriproxyfen technical in the rat, mouse and dog indicate a low 
level of toxicity. Effects observed at high dose levels consisted 
primarily of decreased body weight gain; increased liver weights; 
histopathological changes in the liver and kidney; decreased red blood 
cell counts, hemoglobin and hematocrit; altered blood chemistry 
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in 
survival rates. The NOELs from these studies were 400 ppm (23.5 mg/kg/
day for males, 27.7 mg/kg/day for females) in rats, 1,000 ppm (149.4 
mg/kg/day for males, 196.5 mg/kg/day for females) in mice, and 100 mg/
kg/day in dogs.
    In a 4-week inhalation study of pyriproxyfen technical in rats, 
decreased body weight and increased water consumption were observed at 
1,000 mg/m3 . The NOEL in this study was 482 mg/m3.
     A 21-day dermal toxicity study in rats with pyriproxyfen technical 
did not produce any signs of dermal or systemic toxicity at 1,000 mg/
kg/day, the highest dose tested. In a 21-day dermal study conducted 
with KNACK Insect Growth Regulator the test material produced a NOEL of 
1,000 mg/kg/day (highest dose tested) for systemic effects, and a NOEL 
for skin irritation of 100 mg/kg/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in 
chronic studies with dogs, rats and mice.
    Pyriproxyfen technical was administered to dogs in capsules at 
doses of 0, 30, 100, 300 and 1,000 mg/kg/day for 1-year. Dogs exposed 
to dose levels of 300 mg/kg/day or higher showed overt clinical signs 
of toxicity, elevated levels of blood enzymes and liver damage. The 
NOEL in this study was 100 mg/kg/day.
    Pyriproxyfen technical was administered to mice at doses of 0, 120, 
600 and 3,000 ppm in diet for 78-weeks. The NOEL for systemic effects 
in this study was 600 ppm (84 mg/kg/day in males, 109.5 mg/kg/day in 
females), and a LOEL of 3,000 ppm (420 mg/kg/day in males, 547 mg/kg/
day in females) was established based on an increase in kidney lesions.
    In a 2-year study in rats, pyriproxyfen technical was administered 
in the diet at levels of 0, 120, 600, and 3,000 ppm. The NOEL for 
systemic effects in this study was 600 ppm (27.31 mg/kg/day in males, 
35.1 mg/kg/day in females). A LOEL of 3,000 ppm (138 mg/kg/day in 
males, 182.7 mg/kg/day in females) was established based on a 
depression in body weight gain in females.
    EPA has established a RfD for pyriproxyfen of 0.35 mg/kg/day, based 
on the rat 2-year chronic/oncogenicity study. Effects cited by EPA in 
the RfD Tracking Report include negative trend in mean red blood cell 
volume; increased hepatocyte cytoplasm and cytoplasm:nucleus ratios; 
and decreased sinusoidal spaces.
    Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen show 
that repeated high dose exposures produced changes in the liver, kidney 
and red blood cells, but did not produce cancer in test animals. No 
oncogenic response was observed in a rat 2-year chronic feeding/
oncogenicitystudy or in a 78-week study on mice.
    Pyriproxyfen's oncogenicity classification is ``E'' (no evidence of 
carcinogenicity for humans).
    6. Animal metabolism. The mammalian metabolism of pyriproxyfen is 
understood. The absorption, tissue distribution, metabolism and 
excretion of 14C-labeled pyriproxyfen were studied in rats after single 
oral doses of 2 or 1,000 mg/kg (phenoxyphenyl and pyridyl label), and 
after a single oral dose of 2 mg/kg (phenoxyphenyl label only) 
following 14 daily oral doses at 2 mg/kg of unlabelled material.
    Both the phenoxyphenyl-label and pyridyl-label studies exhibited 
very similar results. For all dose groups, most (88-96%) of the 
administered radiolabel was excreted in the urine and feces within 2-
days after radiolabeled test material dosing, and 92-98% of the 
administered dose was excreted within 7-days. 7-days after dosing, 
tissue residues were generally low, accounting for no more than 0.3% of 
the dosed 14C. 14C concentrations in fat were the 
highest in tissues analyzed. Recovery in tissues over time indicates 
that the potential for bioaccumulation is minimal. There are no 
significant sex or dose-related differences in excretion or metabolism.
    7. Endocrine disruption. Pyriproxyfen is specifically designed to 
be an insect growth regulator and is known to produce juvenile hormone-
mediated effects in arthropods. However, this mechanism-of-action in 
target insects has no relevance to the mammalian endocrine system. 
While specific tests, uniquely designed to evaluate the potential 
effects of pyriproxyfen on mammalian endocrine systems have not been 
conducted, the toxicology of pyriproxyfen has been extensively 
evaluated in acute, sub-chronic, chronic, developmental, and 
reproductive toxicology studies. The results of these studies show no

[[Page 14934]]

evidence of any endocrine-mediated effects and no pathology of the 
endocrine organs. Consequently, it is concluded that Sumilarv does not 
possess estrogenic or endocrine disrupting properties applicable to 
mammals.

C. Aggregate Exposure

    1. Dietary exposure. A chronic dietary exposure and risk assessment 
based on anticipated residues from samples from field residue studies 
was performed in cotton, apple, pear, and walnut and assumed that 100% 
of the crops were treated. The exposure analysis also reflected the 
contribution of meat and milk residues, without regard to 
detectability, based on commodities used for feed containing residues 
at anticipated residue levels.
    Using mean anticipated residue values and 100% of the crop treated, 
exposure to the U.S. population - 48 States - all seasons is calculated 
to be only 0.000049 mg/kg body-wt/day. The most exposed sub-population, 
non-nursing infants (<1-year), is calculated to be 0.000273 mg/kg bwt./
day. These calculated exposures represent, respectively, 0.014, and 
0.078 percent occupancy of the RfD of 0.35 mg/kg body-wt/day. Chronic 
dietary risk from exposure to pyriproxyfen residues on the proposed 
crops may be characterized as negligible.
    2. Drinking water. Since pyriproxyfen is to be applied outdoors to 
growing agricultural crops, the potential exists for the parent or its 
metabolites to reach ground or surface water that may be used for 
drinking water.
    3. Ground water. Pyriproxyfen is extremely insoluble in water 
(0.367 mg/L at 25 deg., with high octanol/water partitioning constant 
(Log P O/W = 5.37 at 25 deg., and relatively short soil half-life 
(aerobic soil metabolism T \1/2\ = 6 to 9 days). Given the low use 
rates, the immobility of the parent and the instability of the soil 
metabolites in soil, it is very unlikely that pyriproxyfen or its 
metabolites could leach to and contaminate potable groundwater.
    4. Surface water. In connection with the potential for dietary 
exposure from surface potable water, a simulation of expected exposure 
concentration (EEC) values in aquatic systems has been performed using 
the Pesticide Root Zone Model (PRZM-3) and the Exposure Analysis 
Modeling System, version 2.97 (EXAMSII). The simulation was designed to 
approximate as closely as possible the conditions associated with the 
high rate proposed use on tree crops. The results of the 
modelingdemonstrate that the maximum upper tenth percentile 
concentrations modeled in water adjacent to treated fields are 
instantaneous, 0.36 ppb; 96-hour, 0.23 ppb; and 21-day, 0.14 ppb.
    To obtain a very conservative estimate of a possible dietary 
exposure from drinking water, it could be assumed that all water 
consumed contains pyriproxyfen at the maximum upper tenth percentile 
concentrations modeled in aquatic systems adjacent to treated orchards. 
The 21-day concentration, 0.14 ppb (0.00014 mg/kg), is used because 
drinking water is considered to be a chronic exposure, and there are no 
identified acute or short term endpoints of concern. Using standard 
assumptions of body weight and water consumption (adult 70 kg, 2 kg 
water per day; child 10 kg, 1 kg water), the highest possible exposure 
would be 4.0 x 10-6 and 1.4 x 10-5 mg/kg bwt./day for the adult and 
child, respectively. This very small, but probably exaggerated, 
exposure would occupy 0.00114 (adult) and 0.004 (child) percent of the 
chronic reference dose of 0.35 mg/kg body-wt/day.
    5. Non-dietary exposure. Pyriproxyfen has numerous registered 
products for household use primarily of indoor, non-food applications 
by consumers. The consumer uses of pyriproxyfen typically do not 
involve chronic exposure. Instead, consumers are exposed intermittently 
to a particular product (e.g., pet care pump spray) containing 
pyriproxyfen. Since the pharmacokinetics of pyriproxyfen indicate a 
relatively short elimination half-life, cumulative toxicological 
effects resulting from bioaccumulation are not plausible following 
these short-term, intermittent exposures. Further, pyriproxyfen is very 
short-lived in the environment and this indoor domestic use of 
pyriproxyfen may provide only relatively short-term reservoirs.
    The most relevant exposure for non-dietary exposure assessment is 
short-term to intermediate average daily exposure estimates. The non-
dietary exposure assessment for pyriproxyfen conservatively focuses on 
upper-bound estimates of potential applicator (adult) and post-
application (adult and child - less than 1-year old) exposures on the 
day of application. Subsequent days present no applicator exposure, and 
a decreasing contribution to short-term total exposure.
    The assessment presented herein estimates exposures for selected 
consumer uses that are considered representative, plausible, and 
reasonable worst case exposure scenarios. The scenarios selected 
include:
    (i) Potential exposures associated with adult application (dermal 
and inhalation exposures) and post-application (adult and child 
inhalation exposures) of pyriproxyfen-containing pet care products; and
    (ii) Potential adult application exposures (dermal and inhalation), 
and adult (inhalation) and child exposures (inhalation, dermal, 
incidental oral ingestion associated with hand-to-mouth behavior) post-
application exposures associated with consumer use of a carpet spray 
product.
    Using a combination of representative information from the PHED 
data base for applicators (adult), and surrogate data from a study of 
exposure to indoor broadcast applications (post-application adult and 
child) a series of adsorbed dose estimates were calculated for adult 
applicators, and post-application exposures to adults and children by 
dermal, inhalation, and (hand-to-mouth) oral routes. The methodology, 
assumptions, and estimates are presented in detail in the full FQPA 
exposure analysis, the table below presents the results.

Summary of Estimated Human Application and Post-Application Exposures Associated With Use of Pet Spray and Carpet Spray Products Containing Pyriproxyfen
                                                                as the Active Ingredient                                                                
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                       Daily Dose (mg/kg bw/day)                        
             Product                    Population        Timing of Exposure ---------------------------------------------------------------------------
                                                                                Inhalation\1\        Dermal\2\           Oral\1\             Total      
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pet Spray........................  Adults..............  Application........         4.3 x 10-6              0.085                3NA              0.085
                                                         Post-Application...         1.8 x 10-5                 NA                 NA         1.8 x 10-5
                                                         TOTAL..............         2.2 x 10-5              0.085                 NA              0.085
                                   Children............  Post-Application...         3.7 x 10-5                 NA                 NA         3.7 x 10-5
Carpet Spray.....................  Adults..............  Application........         1.3 x 10-6         5.1 x 10-4                 NA         5.1 x 10-4
                                                         Post-Application...         5.4 x 10-6                 NA                 NA         5.4 x 10-6

[[Page 14935]]

                                                                                                                                                        
                                                         TOTAL..............         6.7 x 10-6         5.1 x 10-4                 NA         5.2 x 10-4
                                   Crawling Infant.....  Post-Application...         1.5 x 10-5         1.3 x 10-3         2.1 x 10-4        1.5 x 10-3 
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ 100 % adsorption.                                                                                                                                   
\2\ Conservatively assumes a dermal absorption factor of 50%.                                                                                           
\3\ Exposure pathway not applicable.                                                                                                                    

    It is important to emphasize that the exposures summarized in the 
table are based on conservative assumptions and surrogate data. 
Further, the exposures are calculated for the day of application. 
Subsequent daily exposures would be less as pyriproxyfen is adsorbed 
into substrate, or dissipates and becomes unavailable by other 
mechanisms. Exposures to applicators on non-application days would be 
zero.
    Further, the Agency has not identified acute or short term toxicity 
endpoints of concern. Endpoints that could be considered for short term 
and intermediate exposures include a developmental toxicity no observed 
effect level (NOEL) of 100 mg/kg/day (rat and rabbit), a rat 21-day 
dermal systemic NOEL of 1,000 mg/kg/day (technical grade and end-use 
products), a 4-week rat inhalation toxicity NOEL of 482 mg/m3, and a 
90-day rat oral toxicity NOEL of 23.5 mg/kg/day. There are no dermal 
absorption data for pyriproxyfen. The 1-day exposure calculated for the 
applicator of the pet spray (0.085 mg/kg/day) is 57-times larger than 
the next highest calculated exposure which is the total exposure to a 
crawling infant on the day of application of the carpet spray (1.5 x 
10-3 mg/kg/day). Furthermore, the return frequency is much different. 
Label instructions allow treatment of the dog every 14-days during the 
flea season, while the carpet can be treated only each 120-days. The 1-
day exposure can be compared to the smallest short term endpoint, that 
from the 90-day rat oral toxicity NOEL of 23.5 mg/kg/day, and a Margin 
of Exposure (MOE) can be calculated. This compares an acute exposure to 
a sub-chronic endpoint.
    MOE = Toxicity Endpoint (mg/kg/day)  Daily Short Term 
Exposure (mg/kg/day)
    MOEPet Spray Applicator, One day = 276
    Probably more realistic, a short term daily exposure to the adult 
applicator can be calculated and compared to the same endpoint.
    Daily Exposure (mg/kg/day) = Applicator Exposure (mg/kg/day) 
 Frequency (days)
    MOEPet Spray Applicator = 3900
    Based on the available toxicity data and the conservative exposure 
assumptions, and because infants and children are not applicators in 
the household, the smallest acute and short term MOE value for children 
is based on post-application exposures. The day of application exposure 
to a crawling infant is the sum of inhalation, dermal adsorption, and 
oral (hand to mouth) exposures. Subsequent daily exposures are not 
quantified, but because of dissipation of the active ingredient in the 
home environment but must be smaller than on the day of application.
    MOECarpet Spray, Crawling Infant = 15,700
    There is usually no cause for concern if margins of exposure exceed 
100. All other margins of exposure that can be calculated from the non-
occupational, non-dietary exposures summarized in the table above are 
considerably larger than that for the pet spray applicator and (post 
carpet spray application) crawling infant.
     Summary of Aggregate Non-Occupational Exposures. Aggregate 
exposure is defined as the sum all non-occupational exposures to the 
general U.S. population and relevant sub-populations to the single 
active ingredient, pyriproxyfen. These exposures can be classified as 
acute, short term, and chronic.
    Acute and Short Term Non-Occupational Potential acute and short 
term non-occupational exposures to pyriproxyfen are associated with 
household uses -- applicator, bystander, and post-application 
exposures. For preliminary risk analysis, these exposures, oftentimes 
calculated using conservative assumptions and surrogate data, are 
compared to appropriate acute and short term toxicity endpoints to 
yield margins of exposure (MOE). In general, if exposure estimates are 
conservative and the resulting MOE values are greater than 100, the 
Agency is not concerned. In contrast, if conservative MOE values are 
less than 100, then more refined exposure estimates and/or exposure 
mitigation are required.
    The Agency has not identified acute or short term toxicity 
endpoints of concern for pyriproxyfen. Valent has identified the 90-day 
rat oral toxicity with a NOEL of 23.5 mg/kg/day as the short term study 
with the lowest exposure endpoint. Comparing this endpoint with the 
short term non-occupational exposures calculated for the household uses 
of pyriproxyfen gives MOE values all much larger than 100. These acute 
and short term exposures are small enough to be of little significance.

C. Chronic Exposures

    Potential chronic exposures to pyriproxyfen are considered to be 
derived from dietary exposures to primary and secondary residues in 
food, and to potential residues in drinking water. To calculate the 
total potential chronic exposure from food and drinking water, the 
calculated exposures from both media can be summed. To assess risk 
these totals can then be compared to the chronic RfD.

  Summation of the Calculated Potential Chronic Exposure to Pyriproxyfen in Food and Drinking Water and Percent 
                                  Occupancy of the RfD for Two U.S. Populations                                 
----------------------------------------------------------------------------------------------------------------
                                                                        General                                 
                   Medium(mg/kg body-wt/day)                       Population(adult)      Non-NursingInfant ( 1)
----------------------------------------------------------------------------------------------------------------
Food..........................................................                 0.000049                 0.000273
Drinking Water................................................                 0.000004                 0.000014

[[Page 14936]]

                                                                                                                
Total.........................................................                 0.000053                 0.000287
%RfD(0.35 mg/kg body-wt/day)..................................                    0.015                    0.082
----------------------------------------------------------------------------------------------------------------

    If the occupancy of the RfD is less than 100%, the Agency usually 
has little cause for concern. From the table above, it can be seen that 
the total potential chronic exposure to pyriproxyfen is truly 
insignificant, and should not be cause for concern.

D. Cumulative Effects

    Valent has considered the potential for cumulative exposure to 
substances with a common mechanism of toxicity to pyriproxyfen. 
However, a cumulative exposure assessment is not appropriate at this 
time because there is no available information to indicate that the 
effects of pyriproxyfen would be cumulative with those of any other 
chemical compound. Therefore, Valent is considering only the potential 
risk of pyriproxyfen in its aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based on a complete and reliable toxicity 
database, EPA has established an RfD value of 0.35 mg/kg bwt./day using 
the NOEL from the chronic rat feeding study and a 100-fold uncertainty 
factor. The aggregate chronic exposure to pyriproxyfen will utilize 
less than 0.1% of the RfD for the U.S. population. Because estimated 
exposures are far below 100 percent of the RfD, Valent concludes that 
there is a reasonable certainty that no harm will result from aggregate 
exposure to pyriproxyfen residues.
    2. Infants and children. Using the same conservative exposure 
assumptions as for the general population, the percent of the RfD 
utilized by aggregate chronic exposure to residues of pyriproxyfen is 
0.082% for non-nursing infants, the most highly exposed population 
subgroup. Valent concludes that there is a reasonable certainty that no 
harm will result to infants and children from aggregate exposure to 
residues of pyriproxyfen.

F. International Tolerances

     There are presently no Codex maximum residue levels established 
for residues of pyriproxyfen on any crop.
[FR Doc. 98-8065 Filed 3-26-98; 8:45 am]
BILLING CODE 6560-50-F