Notice of Filing of Pesticide Petitions

ENVIRONMENTAL PROTECTION AGENCY

[PF-798; FRL-5777-5]

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 agricultural commodities.

DATES: Comments, identified by the docket control number PF-798, must

be received on or before April 6, 1998.

ADDRESSES: By mail submit written comments to: Public Information and

Records Integrity Branch, Information Resources and Services Divison

(7502C), Office of Pesticides Programs, Environmental Protection

Agency, 401 M St., SW., Washington, DC 20460. In person bring comments

to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.

Comments and data may also be submitted electronically to: opp-

[email protected]. Following the instructions under

``SUPPLEMENTARY INFORMATION.'' No confidential business information

should be submitted through e-mail.

Information submitted as a comment concerning this document may be

claimed confidential by marking any part or all of that information as

``Confidential Business Information'' (CBI). CBI should not be

submitted through e-mail. Information marked as CBI will not be

disclosed except in accordance with procedures set forth in 40 CFR part

2. A copy of the comment that does not contain CBI must be submitted

for inclusion in the public record. Information not marked confidential

may be disclosed publicly by EPA without prior notice. All written

comments will be available for public inspection in Rm. 119 at the

address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,

excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Product

Manager (PM) 10, Registration Division, (7505C), Office of Pesticide

Programs, Environmental Protection Agency, 401 M St., SW., Washington,

DC 20460. Office location, telephone number, and e-mail address: Rm.

214, CM#2, 1921 Jefferson Davis Hwy., Arlington, VA. 22202, (703) 305-

6411; e-mail: [email protected].

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as

follows proposing the establishment and/or amendment of regulations for

residues of certain pesticide chemicals in or on various raw

agricultural commodities under section 408 of the Federal Food, Drug,

and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these

petitions contain data or information regarding the elements set forth

in section 408(d)(2); however, EPA has not fully evaluated the

sufficiency of the submitted data at this time or whether the data

supports grantinig of the petition. Additional data may be needed

before EPA rules on the petition.

The official record for this notice, as well as the public version,

has been established for this notice of filing under docket control

number PF-798 (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,

[[Page 11241]]

excluding legal holidays. The official record is located at the address

in ``ADDRESSES'' at the beginning of this document.

Electronic comments can be sent directly to EPA at:

[email protected]

Electronic comments must be submitted as an ASCII file avoiding the

use of special characters and any form of encryption. Comment and data

will also be accepted on disks in Wordperfect 5.1/6.1 file format or

ASCII file format. All comments and data in electronic form must be

identified by the docket control number PF-798 and appropriate petition

number. Electronic comments on this notice may be filed online at many

Federal Depository Libraries.

Authority: 21 U.S.C. 346a.

List of Subjects

Environmental protection, Agricultural commodities, Food additives,

Feed additives, Pesticides and pests, Reporting and recordkeeping

requirements.

Dated: March 2, 1998.

Peter Caulkins,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

Below summaries of the pesticide petitions are printed. The

summaries of the petitions were prepared by the petitioners. The

petition summary announces the availability of a description of the

analytical methods available to EPA for the detection and measurement

of the pesticide chemical residues or an explanation of why no such

method is needed.

1. Rohm and Haas Company

PP 3G4274

EPA has received a pesticide petition (PP 3G4274)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 triazamate [Acetic acid, [{1-

{(dimethylamino) carbonyl}-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-y1}

thio]-,ethyl ester] and its metabolite Acetic acid,[{1-{(dimethylamino)

carbonyl}-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-y1}thio]-(code

number RH-0422 in or on the raw agricultural commodity fresh apples at

0.1 parts per million (ppm). EPA has determined that the petition

contains data or information regarding the elements set forth in

section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated

the sufficiency of the submitted data at this time or whether the data

supports granting of the petition. Additional data may be needed before

EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of triazamate in plants

(apples) is adequately understood for the purposes of this tolerance.

The metabolism of triazamate involves oxidative demethylation of the

carbamoyl group. Parent compound is rapidly metabolized and is either

not found or found at trace levels in apples. The majority of the total

dosage is present as other non-cholinesterase inhibiting metabolites

whose structures do not contain the dimethylcarbamoyl moiety. Because

the proposed experimental use program is for fresh apples, livestock

metabolism studies are not required. Tolerances for residues of

triazamate should be expressed as the total residue from triazamate and

its only cholinesterase-inhibiting metabolite RH-0422.

2. Analytical method. The metabolism of triazamate in plants

(apples) is adequately understood for the purposes of this tolerance.

The metabolism of triazamate involves oxidative demethylation of the

carbamoyl group. Parent compound is rapidly metabolized and is either

not found or found at trace levels in apples. The majority of the total

dosage is present as other non-cholinesterase inhibiting metabolites

whose structures do not contain the dimethylcarbamoyl moiety. Because

the proposed experimental use program is for fresh apples, livestock

metabolism studies are not required. Tolerances for residues of

triazamate should be expressed as the total residue from triazamate and

its only cholinesterase-inhibiting metabolite RH-0422.

3. Magnitude of residues. A total of 14 field residue trials in

apples was conducted with a 25WP formulation in geographically

representative regions of the U.S. Three applications were made at

either 0.25 or 0.38 lb. a.i./acre. Fruit were harvested at 40 days

after the last application. Only trace residues of triazamate were

detected and residues of RH-0422 did not exceed 0.06 ppm.

B. Toxicological Profile

1. Acute toxicity. Triazamate is a moderately toxic cholinesterase

inhibitor belonging to the carbamate class. Triazamate Technical was

moderately toxic to rats following a single oral dose (LD50

= 50-200 milligram/kilograms (mg/kg)), and after a 4-hr inhalation

exposure (LC50 value of >0.47 mg/L); and was minimally to

slightly toxic to rats following a single dermal dose (LD50

>5,000 mg/kg). In a guideline acute neurotoxicity study with triazamate

in the rat, the NOEL for clinical signs was 5 mg/kg based on the

observation of cholinergic signs in 1 of 10 male rats at 25 mg/kg.

Triazamate was practically non-irritating to the skin, moderately

irritating to eyes in rabbits and did not produce delayed contact

hypersensitivity in the guinea pig.

2. Genotoxicity. Triazamate is not mutagenic or genotoxic.

Triazamate Technical was negative (non-mutagenic) in an Ames assay with

and without hepatic enzyme activation. Triazamate 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, triazamate did not induce unscheduled DNA synthesis (UDS)

or repair when tested up to the maximum soluble concentration in

culture medium. Triazamate did not produce chromosome aberrations in an

in vitro assay using Chinese hamster ovary cells (CHO) or an in vivo

mouse micronucleus assay.

3. Reproductive and developmental toxicity. In a developmental

toxicity study in rats with Triazamate Technical, the no-observed-

effect-level (NOEL) for developmental toxicity was 64 mg/kg (highest

dose tested) (HDT). The NOEL for maternal toxicity was 16 mg/kg based

on clinical signs of cholinergic toxicity at 64 mg/kg.

In a developmental toxicity study in rabbits with Triazamate

Technical, the NOEL for developmental toxicity was 10 mg/kg (HDT). The

NOEL for maternal toxicity was 0.5 mg/kg based on clinical signs and

decreased body weight at 10 mg/kg.

In a 2-generation reproduction study in rats with Triazamate

Technical, the NOEL for reproductive effects was 1,500 ppm (101 and 132

milligram/kilograms/day (mg/kg/day) for males and females,

respectively; HDT). The NOEL for parental toxicity was 10 ppm (0.7 and

0.9 mg/kg/day for males and females, respectively) based on decreased

plasma and RBC cholinesterase activities at 250 ppm (17 and 21 mg/kg/

day for males and females, respectively).

The acceptable developmental studies (prenatal developmental

toxicity studies in rats and rabbits and 2-generation reproduction

study in rats) provided no

[[Page 11242]]

indication of increased sensitivity of rats or rabbits to in utero and

or post-natal exposure to triazamate. Triazamate Technical is not a

developmental or reproductive toxicant.

4. Subchronic toxicity. In subacute and subchronic dietary toxicity

studies, Triazamate Technical produced no evidence of adverse effects

other than those associated with cholinesterase inhibition:

i. In a 90-day dietary toxicity study with Triazamate Technical in

the rat, the NOEL for blood cholinesterase inhibition was 50 ppm (3.2

and 3.9 mg/kg/day for males and females, respectively), based on

decreases in plasma and RBC cholinesterase activities at 500 ppm (32

and 39 mg/kg/day for males and females, respectively). The NOEL for

brain cholinesterase inhibition and/or clinical signs was 500 ppm (32

and 39 mg/kg/day for males and females respectively) based on decreased

brain cholinesterase activity and decreased body weight gain and feed

consumption at 1,500 ppm (93 and 117 mg/kg/day for males and females,

respectively).

ii. In a guideline subchronic neurotoxicity study (90-day dietary

feeding) with Triazamate Technical in the rat, the NOEL for blood

cholinesterase inhibition was 10 ppm (0.6 and 0.7 mg/kg/day for males

and females, respectively), based on reductions in plasma and RBC

cholinesterase activities at 250 ppm (14.3 and 17.1 mg/kg/day for males

and females, respectively). The NOEL for brain cholinesterase

inhibition and/or clinical signs was 250 ppm (14.3 and 17.1 mg/kg/day

for males and females respectively) based on decreases in brain

cholinesterase activity and cholinergic signs at 1,500 ppm (87 and 104

mg/kg/day for males and females, respectively).

iii. In a 90-day dietary toxicity study with Triazamate Technical

in the mouse, the NOEL for blood cholinesterase inhibition was 2 ppm

(0.4 and 0.5 mg/kg/day for males and females, respectively) based on

decreases in plasma cholinesterase activity at 25 ppm (4 and 6 mg/kg/

day for males and females, respectively). The NOEL for brain

cholinesterase and/or clinical signs was 250 ppm (46 and 67 mg/kg/day

for males and females, respectively) based on decreases brain

cholinesterase and decreases body weight and feed consumption at 1,000

ppm (164 and 222 mg/kg/day for males and females, respectively).

iv. In a 90-day dietary toxicity study with Triazamate Technical in

the dog, the NOEL for blood cholinesterase inhibition was 1 ppm for

males only (0.03 mg/kg/day) based on decreases in plasma cholinesterase

at 10 ppm (0.3 mg/kg/day). The dose of 1 ppm was a lowest-observed-

effect-level (LOEL) for females based on the presence of decreased

plasma cholinesterase activity (24%). The NOEL for clinical signs was

10 ppm (0.3 mg/kg/day for males and females) based a few clinical signs

at 100 ppm (3.1 mg/kg/day for males and females).

v. In a 21-day dermal toxicity study with Triazamate Technical, the

NOEL blood and brain cholinesterase inhibition was 10 mg/kg based on

decreases plasma, RBC and brain cholinesterase activities at 100 mg/kg.

5. Chronic toxicity-- i. Rat, mouse, and dog studies. In chronic

dietary toxicity studies, Triazamate Technical produced no evidence of

adverse effects other than those associated with cholinesterase

inhibition and was not oncogenic in the rat and mouse.

In a combined chronic dietary toxicity/oncogenicity study (24

months) in rats with Triazamate Technical, no evidence of oncogenicity

was observed at doses up to 1,250 ppm (62.5 mg/kg/day for males and

females; HDT). The NOEL for blood cholinesterase inhibition was 10 ppm

(0.5 and 0.6 mg/kg/day for males and females, respectively) based on

decreases in plasma and RBC cholinesterase activity at 250 ppm (11.5

and 14.5 mg/kg/day in males and females, respectively). The NOEL for

brain cholinesterase inhibition and/or clinical signs was 250 ppm (11.5

and 14.5 mg/kg/day in males and females, respectively) based on

clinical signs and decreases in brain cholinesterase inhibition at

1,250 ppm (62.5 mg/kg/day for males and females).

In a combined chronic dietary toxicity study (18 months) in mice

with Triazamate Technical, no evidence of oncogenicity was observed at

doses up to 1,000-1,500 ppm (130-195 mg/kg/day for males and females;

HDT). The NOEL for blood cholinesterase inhibition was 1 ppm (0.1 and

0.2 mg/kg/day for males and females, respectively) based on decreased

plasma cholinesterase activity at 50 ppm (6.7 and 8.4 mg/kg/day for

males and females, respectively). The NOEL for brain cholinesterase

inhibition and/or clinical signs was 50 ppm (6.7 and 8.4 mg/kg/day for

males and females, respectively) based on decreased brain

cholinesterase activity and other evidence of systemic toxicity at

1,000-1,500 ppm (130-195 mg/kg/day for males and females).

In a chronic dietary toxicity study (12 months) in dogs with

Triazamate Technical, the NOEL for blood cholinesterase inhibition was

0.9 ppm (0.023 and 0.025 mg/kg/day for males and females, respectively)

based on decreased plasma cholinesterase activity at 15.0 ppm (0.42 mg/

kg/day for both males and females). The NOEL for brain cholinesterase

inhibition was 15.0 ppm (0.42 mg/kg/day for both males and females)

based on decreased brain cholinesterase activity at 150 ppm (4.4 and

4.7 mg/kg/day for males and females, respectively).

ii. Human studies. A randomized double blind ascending dose study

was conducted in human male volunteers to determine the safety and

tolerability of Triazamate Technical and to establish a NOEL for

adverse clinical toxicity. Single doses of Triazamate Technical, when

administered orally by capsule to healthy male subjects, were tolerated

up to and including a dose of 1.0 mg/kg. The 3.0 mg/kg dose of

triazamate was not clinically tolerated well. Clinically, the NOEL was

0.3 mg/kg of triazamate based on minimal clinical signs at 1.0 mg/kg

that were considered possibly related to treatment. Transient decreases

in plasma and RBC cholinesterase occurred at doses lower than the dose

that elicited adverse clinical signs.

Using its Guidelines for Carcinogen Risk Assessment published

September 24, 1986 (51 FR 33992), Rohm and Haas Company considers

triazamate to be classified as a Group ``E,'' not a likely human

carcinogen.

A Reference dose (RfD) of 0.01 mg/kg/day is proposed for humans,

based on the clinical NOEL in the human study (0.3 mg/kg) and dividing

by a safety factor of 30. The dose of 0.3 mg/kg was the highest dose in

humans that did not produce toxicologically significant adverse effects

(i.e., signs of cholinergic toxicity) and is 10 times lower than a dose

that produced unequivocal signs of cholinergic toxicity in man. In

addition, the clinical NOEL in humans is comparable to the no-

observable-adverse-effect level (NOAEL) of 0.42 mg/kg/day following

chronic dosing in the dog, the most sensitive laboratory animal

species. A safety factor of 10 is applied to the clinical NOEL in

humans to account for potential variability within humans with respect

to sensitivity towards triazamate. An additional, safety factor of 3 is

included, since at 0.03 mg/kg (i.e., 1/10th the dose that

was a clinical NOEL) there was a transient but measurable depression in

plasma cholinesterase in humans. Although a change in the plasma

pseudo-cholinesterase (i.e., butyl-cholinesterase) is not

toxicologically significant since this enzyme is not molecularly

similar to acetyl-cholinesterase, the additional uncertainty factor of

3 establishes a RfD at a level where one would predict no

[[Page 11243]]

measurable response of any kind, irrespective of the toxicological

significance of the finding.

6. Animal metabolism. The adsorption, distribution, excretion and

metabolism of triazamate in rats, dogs and goats was investigated.

Triazamate is rapidly absorbed when given orally (capsule or gavage)

but slower following dietary intake. Peak blood levels following

dietary administration were 10-fold lower than after gavage

administration of an equivalent mg/kg/dose. Elimination is

predominately by urinary excretion and triazamate does not accumulate

in tissues. The metabolism of triazamate proceeds via ester hydrolysis

and then a rapid stepwise cleavage of the carbamoyl group. The free

acid, (RH-0422) is the only toxicologically significant metabolite,

given that it contains the carbamoyl group. Other metabolites of

triazamate, which are seen in other animal and plant metabolism

studies, do not contain the carbamoyl group and do not produce

cholinesterase inhibition.

7. Metabolite toxicology. Common metabolic pathways for triazamate

have been identified in both plants (apple) and animals (rat, goat,

hen). The metabolic pathway common to both plants and animals involves

oxidative demethylation of the carbamoyl group. 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 triazamate shows

no evidence of physiological effects characteristic of the disruption

of mammalian hormones. In developmental and reproductive studies there

was no evidence of developmental or reproductive toxicity. In addition,

the molecular structure of triazamate does not suggest that this

compound would disrupt the mammalian hormone system. Overall, the

weight of evidence provides no indication that triazamate has endocrine

activity in vertebrates.

C. Aggregate Exposure

1. Dietary exposure. A RfD of 0.01 mg/kg/day is proposed for

humans, based on the clinical NOEL in the human study (0.3 mg/kg) and

dividing by a safety factor of 30.

2. Food-- i. Acute risk. An acute dietary risk assessment (Dietary

Exposure Evaluation Model, Novigen Sciences Inc., 1997) was conducted

for triazamate using two approaches: (a) a Tier 1 approach using a

tolerance level residue of 0.1 ppm and (b) Monte Carlo simulations

using an entire distribution of field trial residues for pome fruit and

adjusted for percent crop treated (Tier 3). Using the Tier 1 approach

margins of exposure (MOEs) at the 95th and 99th

percentiles of exposure for the overall U.S. population were 572 and

199, respectively. Using the Tier 3 procedure in which residues were

adjusted for percent crop treated, the MOEs for the 95th and

99th percentiles were 8,769 and 1,511, respectively. Acute

exposure was also estimated for non-nursing infants, the most sensitive

sub-population. For this population, MOEs at the 95th and

99th percentiles of exposure were 113 and 83, respectively.

Using the Tier 3 method, MOEs were 909 and 396, respectively. Acute

dietary risk is considered acceptable if the MOE is greater than 30, an

appropriate safety factor when based on a human clinical study. Even

under the conservative assumptions presented here, the more realistic

estimates of dietary exposure (Tier 3 analyses) clearly demonstrate

adequate MOEs up to the 99th percentile of exposure for all

population subgroups.

ii. Chronic risk. Chronic dietary risk assessments (Dietary

Exposure Evaluation Model, Novigen Sciences Inc., 1997) were conducted

for triazamate using two approaches: (a) using a tolerance level

residue of 0.1 ppm assuming 100% of crop is treated and (b) using a

tolerance level residue of 0.1 ppm adjusted for projected percent crop

treated. The Theoretical Maximum Residue Contribution (TMRC) from the

proposed pome fruit tolerance represents 0.91% of the 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 6.3% of the RfD. The chronic dietary risks from

this use do not exceed EPA's level of concern.

3. Drinking water. Both triazamate and its cholinesterase-

inhibiting metabolite RH-0422 are degraded rapidly in soil. This rapid

degradation has been observed in both laboratory and field studies and

makes it highly unlikely that measurable residues of either compound

would be found in ground or surface water when triazamate is applied

according to the proposed EUP label directions.

4. Non-dietary exposure. Triazamate 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 triazamate with other

substances that have a common mechanism of toxicity was considered. It

is recognized the triazamate, although structurally a pseudo-carbamate,

exhibits toxicity similar to the carbamate class of insecticides, and

that these compounds produce a reversible inhibition of the enzyme

cholinesterase. However, Rohm and Haas Company concludes that

consideration of a common mechanism of toxicity is not appropriate at

this time since EPA does not have the methodology to resolve this

complex scientific issue concerning common mechanisms of toxicity.

Based on these points, Rohm and Haas Company has considered only the

potential risks of triazamate and RH-0422 in its cumulative exposure

assessment.

E. Safety Determination

1. U.S. population. The acute and chronic dietary exposure to

triazamate and its metabolite from the proposed use on pome fruit were

evaluated. Exposure to triazamate and its toxicologically significant

metabolite on pome fruit does not pose an unreasonable health risk to

consumers including the sensitive subgroup non-nursing infants. In Tier

1 and Tier 3 acute analyses for the 95th percentile

exposures, MOEs were greater than 100 for the general U.S. population.

Using the TMRC and assuming 100% of crop treated, the most conservative

chronic approach, chronic dietary exposures represents 0.6% of the RfD

for the U.S. population. 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.

Using the two conservative exposure assessments described above and

taking into account the completeness and reliability of the toxicity

data, Rohm and Haas Company concludes that there is a reasonable

certainty that no harm will result from aggregate exposure to residues

of triazamate and its toxicologically significant metabolite to the

U.S. population.

2. Infants and children. In assessing the potential for additional

sensitivity of infants and children to residues of triazamate, 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

[[Page 11244]]

to one 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.

FFDCA section 408 provides that EPA may apply an additional safety

factor for infants and children in the case of threshold effects to

account for pre-and post- natal effects and the completeness of the

toxicity database. Based on current toxicological data requirements,

the toxicology database for triazamate relative to pre- and post- natal

effects is complete. For triazamate, developmental toxicity was not

observed in developmental studies using rats and rabbits. The NOEL for

developmental effects in rats was 64 mg/kg/day and rabbits was 10 mg/

kg/day. In the 2-generation reproductive toxicity study in the rat, the

reproductive/ developmental toxicity NOEL was 101-132 mg/kg/day. These

NOELs are 10-fold or higher than those observed for systemic toxicity,

i.e., cholinesterase inhibition.

In Tier 1 and Tier 3 acute dietary analyses for the 95th

percentile exposures, MOEs were greater than 100 for non-nursing

infants. Using the TMRC and assuming 100% of crop treated, the most

conservative chronic approach, chronic dietary exposures represents

6.3% of the RfD for non-nursing infants under 1 year old. Therefore

Rohm and Haas Company concludes that there is a reasonable certainty

that no harm will result from aggregate exposure to residues of

triazamate and its toxicologically significant metabolite to infants

and children.

F. International Tolerances

There are no approved CODEX maximum residue levels (MRLs)

established for residues of triazamate. MRLs have been established for

apples at 0.1 ppm in the Czech Republic, at 0.02 ppm in Hungary, and at

0.2 ppm in Korea.

2. Rohm and Haas Company

PP 6E4679

EPA has received a pesticide petition (PP 6E4679) from Rohm and

Haas Company, 100 Independence Mall West, Philadelphia, PA 19106.

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 wine grapes at 0.5 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 and

hens proceeds along the same metabolic pathway as observed in plants.

No accumulation of residues in tissues, milk or eggs occurred. Because

wine grape processed fractions are not fed to livestock, there is no

reasonable expectation that measurable residues of tebufenozide will

occur in meat, milk, eggs, or poultry.

2. Analytical method. A high performance liquid chromatographic

(HPLC) analytical method using ultraviolet (UV) detection has been

validated for grapes and wine. For these matrices, 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 limit of quantitation

of the method is 0.01 ppm for grapes and 0.005 ppm for wine.

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 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-hour 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. Genotoxicity. 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. NOELs for developmental

and maternal toxicity to tebufenozide were established at 1,000 mg/kg/

day (HDT) in both the rat and rabbit. No signs of developmental

toxicity were exhibited.

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.

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. 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 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 = 1,330 mg/kg/day for males, 1,650 mg/

kg/day for females).

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

[[Page 11245]]

(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.

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.

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 weeks, 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-week 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.

In a 28-day dermal toxicity study in the rat, the NOEL was 1,000

mg/kg/day, the highest dose tested. 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. 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.

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.

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-- i. Acute risk. 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 values are used and the assumption that all of these crops

which are consumed in the U.S. will contain residues at the tolerance

level. The TMRC using existing and future potential tolerances for

tebufenozide on food crops is obtained by multiplying the tolerance

level residues (existing and proposed) 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 grown in

the U.S. are treated with tebufenozide. The TMRC from current and

future tolerances 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 20.1% of the 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

52.0% of the RfD. Using anticipate residue levels for these crops

utilizes 3.38% of the RfD for the U.S. population and 12.0% for non-

nursing infants. The chronic dietary risks from these uses do not

exceed EPA's level of concern.

2. 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 tolerance) and on walnuts at 0.1 ppm (see 40

CFR 180.482). In addition to this action, a request to establish a

tolerance in or on wine grapes, other petitions are pending for the

following tolerances: pome fruit, livestock commodities, pecans,

cotton, the crop subgroups leafy greens, leaf petioles, head and stem

Brassica and leafy Brassica greens, and kiwifruit (import tolerance).

3. 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

[[Page 11246]]

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.

4. 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 future tolerances will utilize 20.1% of the RfD

for the U.S. population and 52.0% for non-nursing infants under 1-year

old. Using anticipate residue levels for these crops utilizes 3.38% of

the RfD for the U.S. population and 12.0% for non-nursing infants. 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 one 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.

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

grapes and proposed an MRL (Step 3) of 0.5 mg/kg.

3. Valent U.S.A. Corporation

PP 6F4737

EPA has received a pesticide petition (PP 6F4737) 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 of pyriproxyfen, 2-[ 1-methyl-2-

(4-phenoxyphenoxy) ethoxy) ethoxy] pyridine in or on the raw

agricultural commodity cottonseed at 0.05 ppm and cotton gin byproducts

at 2.0 ppm. EPA has determined that the petition contains data or

information regarding

[[Page 11247]]

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--Nature of the residues in food, feed and

secondary residues. The residue of concern is best defined as the

parent, pyriproxyfen.

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 residue 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-- Pyriproxyfen and metabolites. Practical

analytical methods for detecting and measuring levels of pyriproxyfen

(and relevant metabolites) have been developed and validated in cotton

raw agricultural commodities, respective processing fractions, animal

tissues, and environmental samples. The methods have been independently

validated in cottonseed, apples, soil, and oranges and the extraction

methodology has been validated using aged radiochemical residue samples

from metabolism studies. EPA has successfully validated the analytical

method for analysis of cottonseed raw agricultural commodity (personal

communication). 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 proposed for the tolerances.

3. Magnitude of residues-- i. Cotton. Data from fifteen field

trials in cotton conducted in 1994 and 1995, showed that mean

pyriproxyfen residues from duplicate samples were Insect Growth Regulator label. No concentration of

residues was observed from processing cottonseed treated with an 12.8 x

application rate into hulls, meal, crude oil or refined oil.

ii. Secondary residues. Since low residues were detected in cotton

derived animal feed items and since 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.

iii. Rotational crops. The results of a confined rotational crops

accumulation study indicate that no rotational crop planting

restrictions or rotational crop tolerances are required.

B. Toxicological Profile

1. Acute toxicity. The acute toxicity of technical grade

pyriproxyfen is low by all routes. The compound is 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.

2. Genotoxicity. 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 or reproductive toxicant. Developmental toxicity studies

have been performed in rats and rabbits, and multigenerational effects

on reproduction were tested in rats. These studies have been reviewed

and found to be acceptable to the Agency.

In the developmental toxicity study conducted with rats, technical

pyriproxyfen was administered by gavage at levels of 0, 100, 300, and

1,000 mg/kg bw/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 body

weight/day (bw/day) and greater. The maternal NOEL was 100 mg/kg bw/

day. A transient increase in skeletal variations was observed in rat

fetuses from females exposed to 300 mg/kg bw/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 bw/day. An increased incidence of visceral and

skeletal variations was observed postnatally at 1,000 mg/kg bw/day. The

NOEL for postnatal developmental toxicity was 300 mg/kg bw/day.

In the developmental toxicity study conducted with rabbits,

technical pyriproxyfen was administered by gavage at levels of 0, 100,

300, and 1,000 mg/kg bw/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 bw/day or higher.

The maternal NOEL was 100 mg/kg bw/day. No developmental effects were

observed in the rabbit fetuses. The NOEL for developmental toxicity in

rabbits was 1,000 mg/kg bw/day.

In the rat reproduction study, pyriproxyfen was administered in the

diet at levels of 0, 200, 1,000, and 5,000 ppm through two 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 bw/day in males, 498 mg/kg bw/day in females

during the pre-mating period). The systemic NOEL was 1,000 ppm (87 mg/

kg bw/day in males, 96 mg/kg bw/day in females). No effects on

reproduction were produced at 5,000 ppm, the HDT.

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

bw/day for males, 27.7 mg/kg bw/day for females) in rats, 1,000 ppm

(149.4 mg/kg bw/day for males, 196.5

[[Page 11248]]

mg/kg bw/day for females) in mice, and 100 mg/kg bw/day in dogs.

In a four 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

bw/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 bw/day (HDT) for systemic effects, and a NOEL for

skin irritation of 100 mg/kg bw/day.

5. Chronic toxicity. Pyriproxyfen technical has been tested in

chronic studies with dogs, rats and mice. EPA has established a RfD for

pyriproxyfen of 0.35 mg/kg bw/day, based on the NOEL in female rats

from the two year chronic/oncogenicity study. Effects cited by EPA in

the Reference Dose 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 have

shown 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 two-year chronic feeding/

oncogenicity study or in a seventy-eight week study on mice . The

oncogenicity classification of pyriproxyfen is ``E'' (no evidence of

carcinogenicity for humans).

Pyriproxyfen technical was administered to dogs in capsules at

doses of 0, 30, 100, 300 and 1,000 mg/kg bw/day for one year. Dogs

exposed to dose levels of 300 mg/kg bw/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 bw/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 bw/day in males, 109.5 mg/kg bw/day

in females), and a LOEL of 3,000 ppm (420 mg/kg bw/day in males, 547

mg/kg bw/day in females) was established based on an increase in kidney

lesions.

In a two-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 bw/day

in males, 35.1 mg/kg bw/day in females). A LOEL of 3,000 ppm (138 mg/kg

bw/day in males, 182.7 mg/kg bw/day in females) was established based

on a depression in body weight gain in females.

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 bw (phenoxyphenyl and

pyridyl label), and after a single oral dose of 2 mg/kg bw

(phenoxyphenyl label only) following 14 daily oral doses at 2 mg/kg bw

of unlabelled material. 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. Seven days after dosing,

tissue residues were generally low, accounting for no more than 0.3% of

the dosed 14C. Radiocarbon concentrations in fat were the

higher than in other tissues analyzed. Recovery in tissues over time

indicates that the potential for bioaccumulation is minimal. There were

no significant sex or dose-related differences in excretion or

metabolism.

7. Metabolite toxicology. Metabolism studies of pyriproxyfen in

rats, goats and hens, as well as the fish bioaccumulation study

demonstrate that the parent is very rapidly metabolized and eliminated.

In the rat, most (88-96%) of the administered radiolabel was excreted

in the urine and feces within 2 days of dosing, and 92-98% of the

administered dose was excreted within 7 days. Seven days after dosing,

tissue residues were low, accounting for no more than 0.3% of the dosed

14C. Because parent and metabolites are not retained in the

body, the potential for acute toxicity from in situ formed metabolites

is low. The potential for chronic toxicity is adequately tested by

chronic exposure to the parent at the MTD and consequent chronic

exposure to the internally formed metabolites.

Seven metabolites of pyriproxyfen, 4,-OH-pyriproxyfen,

5-OH-pyriproxyfen, desphenyl-pyriproxyfen, POPA,

PYPAC, 2-OH-pyridine and 2,5-diOH-pyridine, have been tested for

mutagenicity (Ames) and acute oral toxicity to mice. All seven

metabolites were tested in the Ames assay with and without S9 at doses

up to 5,000 micro-grams per plate or up to the growth inhibitory dose.

The metabolites did not induce any significant increases in revertant

colonies in any of the test strains. Positive control chemicals showed

marked increases in revertant colonies. The acute toxicity to mice of

4,-OH-pyriproxyfen, 5-OH-pyriproxyfen,

desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to markedly

differ from pyriproxyfen, with all metabolites having acute oral

LD50 values greater than 2,000 mg/kg bw. The two pyridines,

2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral LD50

values of 124 (male) and 166 (female) mg/kg bw, and 1,105 (male) and

1,000 (female) mg/kg bw, respectively.

8. Endocrine disruption. Pyriproxyfen is specifically designed to

be an insect growth regulator and is known to produce juvenoid effects

on arthropod development. However, this mechanism-of-action in target

insects and other arthropods has no relevance to mammalian endocrine

systems. 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 including detailed histopathology of

numerous tissues. The results of these studies show no 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. EPA has established a RfD for pyriproxyfen of

0.35 mg/kg bw/day, based on the rat 2 year chronic/oncogenicity study

and a safety factor of 100. The chronic dietary risk can be evaluated

using this endpoint. 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 bw/day as the

short term study with the lowest exposure endpoint. This figure will be

used for all acute and short term risk analyses.

2. Food. Chronic and acute dietary exposure analyses have been

performed for pyriproxyfen using (proposed) tolerance level and

anticipated residues and 100% of the crop treated. Included in the

analyses are cottonseed, cotton gin trash and secondary residues in

meat, milk, and eggs. These exposure/risk analyses have been submitted

to the Agency along with a detailed description of the methodology and

assumptions used.

i. Chronic. Long term dietary exposure was calculated for the U.S.

population and 26 population subgroups. The results from several

[[Page 11249]]

representative subgroups are listed below. The highest exposed sub-

population, Children (1 - 6 Years) with tolerance level exposure,

showed an occupancy of the RfD of 0.03%. In all other cases, chronic

dietary exposure was below 0.03 % of the RfD.

Potential Chronic Dietary Exposure to Pyriproxyfen Residues

------------------------------------------------------------------------

Exposure (mg/kg bw/day)

Population Subgroup -------------------------------------

Tolerances Anticipated

------------------------------------------------------------------------

U.S.population - 48 States - All

seasons.......................... 0.000026 0.000016

U.S. population - Autumn season... 0.000027 0.000017

Midwest Region.................... 0.000030 0.000018

All infants....................... 0.000049 0.000030

Non-nursing infants (th and 99.9 th

percentiles, of the subgroups. It should be noted that the population

sizes are small at the lower probability exposures (e.g. 99

th and 99.9 th percentiles) oftentimes leading to

unrealistically high calculated exposures. In all cases, MOEs to

pyriproxyfen residues exceed one-million.

3. Drinking water. Since pyriproxyfen is to be applied outdoors to

growing cotton crops, the potential exists for the parent or its

metabolites to reach ground or surface water that may be used for

drinking water.

i. Ground water. Pyriproxyfen is extremely insoluble in water

(0.367 mg/L at 25 deg.C), with high octanol/water partitioning

coefficient (Log P o/w = 5.37 at 25 deg.C), 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.

ii. Surface water. In connection with the potential for dietary

exposure from surface potable water, a simulation of expected

environmental concentration (EEC) values in aquatic systems has been

performed using the Pesticide Root Zone Model (PRZM-2.3) and the

Exposure Analysis Modeling System, version 2.95 (EXAMSII). The

simulation was designed to approximate as closely as possible the

conditions associated with two aerial applications totaling 0.084 lb.

a.i. per acre to cotton with a 28-day interval. This use pattern

exceeds the presently proposed use pattern by approximately 1.2 x. The

results of the modeling estimate that the maximum upper tenth

percentile concentrations modeled in water adjacent to treated fields

are instantaneous, 0.23 ppb; 96-hour, 0.14 ppb; and 21 day, 0.08 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 (static, stagnant farm ponds)

adjacent to treated cotton fields. Standard, conservative exposure

assumptions of body weight and water consumption (adult 70 kg, 2 kg

water per day; child 10 kg, 1 kg water) will be used.

iii Chronic. The 21 day concentration, 0.08 ppb (0.00008 mg/kg), is

used to represent chronic exposure. The highest possible exposure would

be 2.3 x 10-6 and 8 x 10-6 mg/kg bw/day for an

adult and child, respectively. This very small, but probably

exaggerated, exposure would occupy 0.00065 (adult) and 0.0023 (child)

percent of the chronic RfD of 0.35 mg/kg bw/day.

iv. Acute. The modeled instantaneous concentration of 0.23 ppb

(0.00023 mg/kg), can be used to represent potential acute exposure to

pyriproxyfen in surface source drinking water. A corresponding

calculation shows that the maximum acute exposure would be 6.6 x

10-6 and 2.3 x 10-5 mg/kg bw/day for the adult

and child, respectively. When compared to the short term endpoint of

23.5 mg/kg bw/day, MOEs for both adults and children exceed one

million.

4. Non-dietary exposure. Pyriproxyfen is the active ingredient in

numerous registered products for household use -- primarily for 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 pyriproxyfen has a relatively

short elimination half-life, cumulative toxicological effects resulting

from bioaccumulation are not plausible following short-term,

intermittent exposures. Further, pyriproxyfen is short-lived in the

environment and this indoor domestic use of pyriproxyfen provides only

relatively short-term reservoirs.

This non-dietary exposure assessment for pyriproxyfen

conservatively focuses on upper-bound estimates of potential applicator

(adult) and post-application (adult and child - less than one 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 estimates exposures for selected consumer uses

that are 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 applicator exposures (dermal and inhalation),

and post-application adult (inhalation) and child (inhalation, dermal,

incidental oral ingestion associated with hand-to-mouth behavior)

exposures associated with consumer use of an aerosol carpet spray

product.

The risk analyses use a combination of representative models.

Information from the pesticide handlers exposure data base (PHED) was

used to estimate exposures to applicators (adult). Surrogate data from

a study of exposure to indoor broadcast applications were used to

calculate a series of absorbed dose estimates for adult applicators,

and

[[Page 11250]]

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

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. Application exposures on non-application days would be

zero.

Further, the Agency has not identified acute or short term toxicity

endpoints of concern for oral inhalation or dermal exposure. Endpoints

that could be considered for short term and intermediate exposures

include developmental toxicity NOEL values of 100 mg/kg bw/day (rat and

rabbit), rat 21-day dermal systemic NOEL values of 1,000 mg/kg bw/day

(technical grade and end-use product), a four week rat inhalation

toxicity NOEL of 482 mg/m3, and, the endpoint chosen by

Valent to be used in these analyses, the 90-day rat oral toxicity NOEL

of 23.5 mg/kg bw/day. There are no dermal absorption data for

pyriproxyfen.

The largest 1 day exposure is calculated for the applicator of the

pet spray (0.085 mg/kg bw/day). This value 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 bw/day). Furthermore, the return frequency is

much different. Label instructions allow treatment of the pet every 14-

days during the flea season, while the carpet can be treated only each

120 days. The 1 day exposure is compared to the smallest short term

endpoint choosen by Valent, the 90-day rat oral toxicity NOEL of 23.5

mg/kg bw/day, and a MOE can be calculated. This compares an acute, one

day, dermal exposure to a sub-chronic 90-day dietary endpoint.

MOE = Toxicity Endpoint (mg/kg bw/day) Daily Short Term

Exposure (mg/kg bw/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 bw/day) = Applicator Exposure (mg/kg bw/day)

Frequency (days)

MOEPet Spray Applicator = 3,900

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 subsequent exposure must be less than exposure on the

day of application.

MOECarpet Spray, Crawling Infant = 15,700

There is usually no cause for concern if MOEs exceed 100. All other

MOEs 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.

5. Summary of acute and chronic 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.

i. Acute and short term non-occupational exposures. Potential acute

and short term non-occupational exposures to pyriproxyfen are

associated with food, water, and household uses -- applicator 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 MOE. Valent has identified the 90-day rat oral

toxicity with a NOEL of 23.5 mg/kg bw/day as the short term study with

the lowest exposure endpoint. In general, if exposure estimates are

conservative and the resulting MOE values are greater than 100, the

Agency has no cause for concern.

It is possible to sum calculated acute exposures from various

sources as shown in the table below. However, summation is exceedingly

conservative because the approach assumes that two or more low

probability events occurr symultaneously. For example, it is highly

unlikely that an individual consuming the 99.9th percentile

dietary exposure (one-in-a-thousand), also treats a large dog for

fleas, and consumes all drinking water from a pond surrounded by

treated cotton fields in a single day. Even so, the short term non-

occupational exposures shown below that sum exposures from food,

drinking water and household uses of pyriproxyfen gives MOE values all

much larger than 100. These calculated acute and short term exposures

are very conservative, and are small enough to be of little

significance.

[[Page 11251]]

Aggregate Acute Exposure to Pyriproxyfen for Two Representative U.S.

Populations

(summation of low probability maximum values)

------------------------------------------------------------------------

Exposure (mg/kg bw/day)

-------------------------------------

Exposure Medium Non-Nursing

U.S. Population Infant (less than

(all seasons) 1 year)

------------------------------------------------------------------------

Non-dietary....................... 0.085 0.0015

Food.............................. 0.000012 0.000012

Drinking water.................... 0.0000066 0.000023

Sum of acute exposures............ 0.0850186 0.001535

Margin of exposure................ 276 15,300

------------------------------------------------------------------------

ii. 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 of

0.35 mg/kg bw/day. If the occupancy of the RfD is less than 100%, the

Agency usually has little cause for concern. From the table, it can be

seen that the total potential chronic exposure to pyriproxyfen is truly

insignificant, and should not be cause for concern.

Aggregate Chronic Exposure to Pyriproxyfen for Two Representative U.S. Populations

----------------------------------------------------------------------------------------------------------------

Exposure (mg/kg bw/day)

--------------------------------------------------------

Exposure Medium Non-Nursing

U.S. Population Infant (less than Children (1 - 6

(all seasons) 1 year) Years)

----------------------------------------------------------------------------------------------------------------

Food................................................... 0.000026 0.000065 0.000095

Drinking water......................................... 0.0000023 0.000008 0.000008

Sum of chronic exposures............................... 0.0000283 0.000073 0.000103

Occupancy of RfD (percent)............................. 0.0081 0.021 0.029

----------------------------------------------------------------------------------------------------------------

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that the Agency must consider

``available information'' concerning the cumulative effects of a

particular pesticide's residues and ``other substances that have a

common mechanism of toxicity''. ``Available information'' in this

context include not only toxicity, chemistry, and exposure data, but

also scientific policies and methodologies for understanding common

mechanisms of toxicity and conducting cumulative risk assessments. For

most pesticides, although the Agency has some information in its files

that may turn out to be helpful in eventually determining whether a

pesticide shares a common mechanism of toxicity with any other

substances, EPA does not at this time have the methodologies to resolve

the complex scientific issues concerning common mechanism of toxicity

in a meaningful way.

There are no other pesticidal compounds that appear to be

structurally, closely related to pyriproxyfen and may have similar

effects on animals. In consideration of potential cumulative effects of

pyriproxyfen and other substances that may have a common mechanism of

toxicity, there are currently no available data or other reliable

information indicating that any toxic effects produced by pyriproxyfen

would be cumulative with those of other chemical compounds. Thus, only

the potential risks of pyriproxyfen have been considered in this

assessment of aggregate exposure and effects.

Valent will submit information for EPA to consider concerning

potential cumulative effects of pyriproxyfen consistent with the

schedule established by EPA at 62 FR 42020 (Aug. 4, 1997) (FRL-5734-6)

and other EPA publications pursuant to the Food Quality Protection Act.

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 bw/day using

the NOEL from the chronic rat feeding study and a 100-fold uncertainty

factor.

i. Chronic. The aggregate chronic exposure to pyriproxyfen will

utilize much less than 0.1% of the RfD for the U.S. population. Because

estimated exposures are far below 100% of the RfD, Valent concludes

that there is a reasonable certainty that no harm will result from

chronic aggregate exposure to pyriproxyfen residues.

ii. Acute. Assessment of aggregate acute exposure to food and non-

food uses of pyriproxyfen to the U.S. population and numerous sub-

populations has demonstrated that exposures are small. MOE values using

very conservative assumptions and a conservative toxicity endpoint are

all greater than 100 and it can be concluded that there is reasonable

certainty of no harm from acute exposures to pyriproxyfen.

2. Infants and children-- i. Chronic. 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 0.021% for Non-Nursing Infants, and 0.029% for Children (1 - 6

Years), the most highly exposed child population subgroup. Because

estimated exposures to infants and children are far below 100% of the

RfD, Valent concludes that there is a reasonable certainty that no harm

will result from chronic aggregate exposure to pyriproxyfen residues.

ii. Acute. Assessment of aggregate acute exposure to food and non-

food uses of pyriproxyfen to infants and children has demonstrated that

exposures allow calculation of acceptable MOE values. Using very

conservative assumptions and a

[[Page 11252]]

conservative toxicity endpoint are all MOE values are greater than 100.

Therefore, it can be concluded that there is reasonable certainty of no

harm to infants and children from potential acute exposures to

pyriproxyfen.

3. Additional safety factor to provide additional protection to

infants and children. Pyriproxyfen is supported by a complete, reviewed

and reliable toxicology database. The toxicology of pyriproxyfen has

been extensively evaluated in acute, sub-chronic, chronic,

developmental, and reproductive toxicology studies including detailed

histopathology of numerous tissues. The results of these studies show

no evidence of any unique pathology or other effects to fetal or

developing young experimentsl animals. In all these studies there is no

indication that young or developing animals are any more sensitive to

toxicity from pyriproxyfen or its metabolites than adult animals. The

developmental toxicity studies and reproduction study all demonstrated

that any toxicity attributable to pyriproxyfen was observed in adults

at lower levels than in fetuses or in developing young animals. There

is no indication that a higher safety factor, other than 100, is needed

for additional protection for infants and children.

F. International Tolerances

There are presently no Codex maximum residue levels established for

residues of pyriproxyfen on any crop.

[FR Doc. 98-5985 Filed 3-5-98; 8:45 am]

BILLING CODE 6560-50-F