Notice of Filing of Pesticide Petitions

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:

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Office location/

Product Manager telephone number Address

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Ann Sibold.................... Rm. 212, CM #2, 703- 1921 Jefferson

305-6502, e- Davis Hwy,

mail:[email protected] Arlington, VA

il.epa.gov.

Joseph M. Tavano.............. Rm. 214, CM #2, 703- Do.

305-6411, e-mail:

[email protected]

.epa.gov.

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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 (160 ppm (-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 (-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