Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50337

hazard evaluation and reduction

program and meet the scope of section

405(f)?

2. Which lead hazard reduction

products are going to be required to be

tested before they can be registered

under this program?

There are several factors affecting the

first question, such as the cost and size

of the program; timeliness of

implementation; cost to the government

and industry; and acceptance by

industry, state regulators, and

consumers. The acceptance of a program

will depend in part on the expertise of

the staff administering the program and

the recognition of the organization as an

accredited certification/registration

body.

Several issues associated with the

second question will need to be

discussed, such as testing methods, and

protocols, development of testing

criteria, voluntary consensus standards,

cost of testing products, and reciprocity

between states.

V. Public Docket

The official record for this notice has

been established under docket control

number ‘‘OPPTS–00224.’’ The record is

available for inspection from 12 noon to

4:00 p.m., Monday through Friday,

excluding legal holidays. The record is

located at: TSCA Docket (7407), Office

of Pollution Prevention and Toxics,

Environmental Protection Agency,

Room E–G99, 401 M St., SW.,

Washington, DC. 20460.

List of Subjects

Environmental protection.

Dated: September 18, 1997

William H. Saunders III,

Director, Office of Pollution Prevention

and Toxics.

[FR Doc.97–25500 Filed 9–22–97; 3:06 p.m.]

Billing Code 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–767; FRL–5748–2]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

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–767, must be

received on or before October 27, 1997.

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 to: oppdocket@epamail.epa.gov. Follow 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:By

mail: George LaRocca, Registration

Division [PM-13], Office of Pesticide

Programs, 401 M St., SW., Washington,

DC 20460. Office location, telephone

number and e-mail address: Rm. 204,

Crystal Mall #2, 1921 Jefferson Davis

Hwy., Arlington, VA, (703) 305–6100, email: larocca.george@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has

received pesticide petitions as follows

proposing the establishment and/or

amendment of regulations for residues

of certain pesticide chemicals in or on

various food commodities under section

408 of the Federal Food, Drug, and

Comestic Act (FFDCA), 21 U.S.C. 346a.

EPA has determined that these petitions

contain data or information regarding

the elements set forth in section

408(d)(2); however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data supports granting of the

petition. Additional data may be needed

before EPA rules on the petition.

The official record for this notice of

filing, as well as the public version, has

been established for this notice of filing

under docket control number [PF–767]

(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:

opp-docket@epamail.epa.gov

Electronic comments must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption. Comment and data will

also be accepted on disks in

Wordperfect 5.1 file format or ASCII file

format. All comments and data in

electronic form must be identified by

the docket controlnumber [PF–767] and

appropriate petition number. Electronic

comments on this notice may be filed

online at many Federal Depository

Libraries.

List of Subjects

Environmental protection,

Agricultural commodities, Food

additives, Feed additives, Pesticides and

pests, Reporting and recordkeeping

requirements.

Dated: September 19, 1997.

James Jones,

Acting Director, Registration Division, Office

of Pesticide Programs.

Summaries of Petitions

Petitioner summaries of the pesticide

petitions are printed below as required

by section 408(d)(3) of the FFDCA. The

summaries of the petitions were

prepared by the petitioners and

represent the views of the petitioners.

EPA is publishing the petition

summaries verbatim without editing

them in any way. The petition summary

announces the availability of a

description of the analytical methods

available to EPA for the detection and

measurement of the pesticide chemical

residues or an explanation of why no

such method is needed.

1. AgrEvo USA Company

PP 2F4055, 6F3436, 4F2993, 6F3309

EPA has received a request from

AgrEvo USA Company (acting as

registered US agent for Hoechst

Schering AgrEvo, S. A., Little Falls

Centre, 2711 Centerville Road,
50338 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

Wilmington, DE 19808, 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

removing the time limitation for

tolerances established for residues of the

insecticides and pyrethroid

Deltamethrin and Tralomethrin in or on

the following raw agricultural

commodities: Deltamethrin - cottonseed

at 0.04 parts per million (ppm) and

cottonseed oil at 0.2 ppm; and

Tralomethrin - broccoli at 0.50 ppm,

cottonseed at 0.02 ppm, lettuce, head at

1.00 ppm, lettuce, leaf at 3.00 ppm,

soybeans at 0.05 ppm, sunflower seed at

0.05 ppm and cottonseed oil at 0.20

ppm. The IUPAC name for deltamethrin

is [(1R, 3R)-3(2,2-dibromovinyl)-2,2-

dimethylcyclopropanecarboxylic acid

(S)-alpha-cyano-3-phenoxybenzyl ester]

and for tralomethrin is [(1R, 3S)3[(1′

RS)(1′,2′,2′,2′,-tetrabromo-ethyl)]-2,2-

dimethylcyclopropane-carboxylic acid

(S)-alpha-cyano-3-phenoxybenzyl ester].

The tolerances were originally requested

in Pesticide Petition Numbers 2F4055,

6F3436, 4F2993, 6F3309. Based on the

fact that tralomethrin is rapidly

metabolized in plants and animals to

deltamethrin, and the toxicological

profile of the two compounds is similar,

it is appropriate to consider combined

exposure assessments for tralomethrin

and deltamethrin. EPA has determined

that the request 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 permanent tolerance.

Additional data may be needed before

EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. Deltamethrin

metabolism studies in tomatoes, corn,

apples, and cotton demonstrate the

same metabolic pathway. Furthermore,

plant metabolism studies have been

conducted following application of

tralomethrin in cotton, corn, cabbage,

and tomatoes. These studies have

demonstrated that the metabolism of

tralomethrin involves debromination to

deltamethrin and its isomers. Thus, a

similar metabolic pathway has been

shown to occur in a variety of crops

following either direct application of

deltamethrin (cotton, corn, apples, and

tomatoes) or in-plant formation of

deltamethrin via debromination of

applied tralomethrin (tomatoes, cotton,

corn, and cabbage). As a result of this

substantial information base, it is

concluded that the residues of

toxicological concern in/on growing

crops following application of

tralomethrin or deltamethrin are

tralomethrin, cis-deltamethrin, and its

isomers, trans-deltamethrin and alphaR-deltamethrin.

2. Analytical method. Analytical

methods for determining residues of

tralomethrin and deltamethrin in the

commodities for which registrations

have been approved, have been

previously submitted to, and reviewed

by, the Agency. These methods, based

on gas nyhromatography (GLC)

equipped with an electron capture

detector (ECD) and a DB-1 (or

equivalent) capillary column, are used

for the determination of tralomethrin,

cis-deltamethrin, trans-deltamethrin,

and alpha-R-deltamethrin in various

raw agricultural, animal derived, and

processed commodities. These methods

were independently validated and are

appropriate for the determination of

residues of tralomethrin and

deltamethrin in various food and feed

commodities after application of these

ingredients to target growing crops, and

after use in food/feed handling

establishments.

3. Magnitude of residues. Residues of

tralomethrin, deltamethrin, and its

metabolites are not expected to exceed

the established tolerance levels as a

result of the use of these active

ingredients on target crops.

B. Toxicological Profile

1. Acute toxicity. The acute oral LD50

values for deltamethrin in the rat are

66.7 mg/kg for males, 86 mg/kg for

females and for tralomethrin 99 mg/kg

for males, 157 mg/kg for females when

administered in sesame oil. The oral

LD50 for deltamethrin when

administered in aqueous methyl

cellulose was greater than 5,000 mg/kg

for both sexes. The dermal LD50 in

rabbits was greater than 2,000 mg/kg for

both materials. Inhalation 4–hour LC50

values in the rat are 2.2 mg/L for

deltamethrin and greater than 0.286 mg/

L for tralomethrin.

2. Genotoxicity. No indication of

genotoxicity was noted in a battery of in

vivo and in vitro studies conducted with

either deltamethrin or tralomethrin.

3. Reproductive and developmental

toxicity— a. Deltamethrin A rat

developmental toxicity study conducted

with deltamethrin indicated a maternal

no-observed-effect levels (NOEL) of 3.3

mg/kg/day based on clinical

observations, decreased weight gain and

mortality. The developmental NOEL

was 11 mg/kg/day [highest dose tested]

(HDT). In a rabbit developmental

toxicity study with deltamethrin, the

maternal NOEL was considered to be 10

mg/kg/day based on decreased

defecation at 25 and 100 mg/kg/day, and

mortality at 100 mg/kg/day. The

developmental NOEL was considered to

be 25 mg/kg/day based on retarded

ossification of the pubic and tail bones

at 100 mg/kg (HDT). A three-generation

rat reproduction study and a more

recent, two-generation rat reproduction

study with deltamethrin indicated the

NOEL for both parents and offspring

was 80 ppm (4–12 mg/kg/day for adults

and 18–44 mg/kg/day for offspring)

based on clinical signs of toxicity,

reduced weight gain and mortality at

320 ppm (HDT).

b. Tralomethrin. In a rat

developmental toxicity study with

tralomethrin the NOEL for maternal and

developmental toxicity was judged to be

greater than or equal to 18 mg/kg/day

(HDT). No evidence of developmental

toxicity was observed in either of two

rabbit developmental toxicity studies

conducted with tralomethrin. In one

study, the maternal NOEL was 12.5 mg/

kg/day based on mortality while the

developmental NOEL was judged to be

greater than or equal to 25 mg/kg/day

(HDT). In the second study, the

maternal NOEL was 8 mg/kg/day based

on body weight effects while the

developmental NOEL was 32 mg/kg/day

(HDT). In a two-generation reproduction

study with tralomethrin in rats, the

parental NOEL was 0.75 mg/kg/day

based on body weight deficits while the

NOEL for offspring was 3.0 mg/kg/day,

also based on body weight deficits.

4. Subchronic toxicity— a.

Deltamethrin. A 90–day rat oral toxicity

study was conducted with deltamethrin

which was administered by gavage. The

NOEL was judged to be 1.0 mg/kg/day

based on reduced body weight gain and

slight hypersensitivity. In a more recent

90–day rat dietary study with

deltamethrin, the NOEL was judged to

be 300 ppm (∼23.9 mg/kg/day for males,

30.5 mg/kg/day for females) based on

uncoordinated movement, unsteady

gait, tremors, increased sensitivity to

sound, shakes and spasmodic

convulsions. The difference in the

NOEL between the two studies is

attributed to the different routes of

exposure (gavage in oil vs. administered

in diet). A 12-week study was

conducted with deltamethrin in mice.

The NOEL was 300 ppm (∼61.5 mg/kg/

day in males and 77.0 mg/kg/day in

females) based on chronic contractions,

convulsions, poor condition, decreased

weight gain and mortality. Two 13–

week dog studies were conducted with

deltamethrin. In the first study, beagle

dogs were administered deltamethrin by

capsule using PEG 200 as a vehicle. The

NOEL for this study was 1 mg/kg/day

based on tremors, unsteadiness, jerking

movements, salivation, vomiting, liquid
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50339

feces and/or dilatation of the pupils. In

the second study, deltamethrin was

administered by capsule without a

vehicle to beagle dogs. The NOEL for

this study was 10 mg/kg/day based on

unsteady gait, tremors, head shaking,

vomiting and salivation. The difference

in toxicity between the two studies is

attributed to the enhanced absorption

resulting from the use of PEG 200 as a

vehicle in the first study. A 21–day

dermal toxicity study was conducted

with deltamethrin in rats. The NOEL for

systemic toxicity was determined to be

1,000 mg/kg/day. In a subchronic

inhalation study, rats were exposed to

aerosolized deltamethrin for 6 hours per

day, 5 days per week, for a total of 14

days over 3 weeks. Based on slightly

decreased body weights and

neurological effects at higher dose

levels, it was concluded that 3 μg/l was

the NOEL for systemic effects in this

study.

b. Tralomethrin. Tralomethrin was

administrated by gavage in corn oil to

rats for 13 weeks. Based on mortality,

decreased activity and motor control,

soft stools, labored breathing and

significantly lower absolute and relative

mean liver weights, the NOEL was

considered to be 1 mg/kg/day.

Tralomethrin was administered by

capsule to beagle dogs for 13 weeks. The

NOEL for this study was 1.0 mg/kg/day

based on refusal of milk supplement,

tremors, exaggerated patellar response,

unsteadiness and uncoordinated

movement. A 21-day dermal toxicity

study was conducted with tralomethrin

on rats. No systemic effects were

observed, therefore, the systemic NOEL

for this study was 1,000 mg/kg/day.

5. Chronic toxicity— a. Deltamethrin.

Deltamethrin was administered in the

diet to beagle dogs for 2 years. No

treatment-related effects were observed

and the NOEL was judged to be 40 ppm

(∼1.1 mg/kg/day). In a more recent

study, deltamethrin was administered

by capsule (without a vehicle) to beagle

dogs for 1–year. The NOEL in this study

was considered to be 1 mg/kg/day based

on clinical signs, decreased food

consumption and changes in several

hematology and blood chemistry

parameters. Two rat chronic toxicity/

oncogenicity studies were conducted

with deltamethrin. In the first study, the

test substance was administered via the

diet to rats for 2 years. The NOEL for

this study was 20 ppm (∼1 mg/kg/day)

based on slightly decreased weight gain.

In a more recent study, deltamethrin

was administered to rats in the diet for

2 years. The NOEL for this study was

considered to be 25 ppm (∼1.1 and 1.5

mg/kg/day for males and females,

respectively), based on neurological

signs, weight gain effects and increased

incidence and severity of eosinophilic

hepatocytes and/or balloon cells. No

evidence of carcinogenicity was noted

in either study. Two mouse

oncogenicity studies were conducted

with deltamethrin. In the first study,

deltamethrin was administered in the

diet for 2 years. No adverse effects were

observed and the NOEL was judged to

be 100 ppm (∼12 and 15 mg/kg/day,

respectively, for males and females). In

a more recent study, deltamethrin was

administered in the diet to mice for 97

weeks. The NOEL was considered to be

1,000 ppm (∼15.7 and 19.6 mg/kg/day)

based on a higher incidence of poor

physical condition and a slight transient

weight reduction. There was no

evidence of oncogenicity in either

study.

b. Tralomethrin. Tralomethrin was

administered to beagle dogs by capsule

for 1–year at initial dosages of 0, 0.75,

3.0 and 10.0 mg/kg/day. Due to

trembling, ataxia, prostration and

convulsions, the high dosage was

lowered to 8 mg/kg/day at study week

4 and lowered again to 6 mg/kg/day on

study week 14. On the fourteenth week

of study, the 0.75 mg/kg/day dosage was

raised to 1.0 mg/kg/day. Based on body

weight changes, convulsions, tremors,

ataxia and salivation, the NOEL for this

study was considered to be 1 mg/kg/

day. Tralomethrin was administered by

gavage to rats for 24 months. The NOEL

for this study was 0.75 mg/kg/day based

on salivation, uncoordinated movement,

inability to support weight on limbs and

decreased body weight parameters. No

evidence of carcino-genicity was

observed. A 2–year mouse oncogenicity

study was conducted with tralomethrin

administered by gavage. The NOEL was

judged to be 0.75 mg/kg/day based on

higher incidences of dermatitis and

mortality, salivation, uncoordinated

involuntary movements and

aggressiveness. No evidence of

oncogenicity was observed.

6. Animal metabolism— a.

Deltamethrin. The absorption of

deltamethrin appears to be highly

dependent upon the route and vehicle

of administration. Once absorbed,

deltamethrin is rapidly and extensively

metabolized and excreted, primarily

within the first 48 hours.

b. Tralomethrin. Tralomethrin is

rapidly metabolized to deltamethrin

after debromination. The metabolic

pattern of the debrominated

tralomethrin is exactly the same as that

of the metabolic pattern of deltamethrin.

7. Neurotoxicity. Acute delayed

neurotoxicity studies in hens were

conducted for both deltamethrin and

tralomethrin. In both cases, the study

results were negative indicating that

neither material causes delayed

neurotoxicity.

8. Endocrine effects. No special

studies have been conducted to

investigate the potential of deltamethrin

or tralomethrin to induce estrogenic or

other endocrine effects. However, the

standard battery of required toxicity

studies has been completed. These

studies include an evaluation of the

potential effects on reproduction and

development, and an evaluation of the

pathology of the endocrine organs

following repeated or long-term

exposure. These studies are generally

considered to be sufficient to detect any

endocrine effects, yet no such effects

were detected. Thus, the potential for

deltamethrin or tralomethrin to produce

any significant endocrine effects is

considered to be minimal.

C. Aggregate Exposure

Based on the fact that tralomethrin is

rapidly metabolized in plants and

animals to deltamethrin, and the

toxicological profile of the two

compounds is similar, it is appropriate

to consider combined exposure

assessments for tralomethrin and

deltamethrin. Deltamethrin and

tralomethrin are broad spectrum

insecticides used to control pests of

crops, ornamental plants and turf, and

domestic indoor and outdoor (including

dog collars), commercial, and industrial

food use areas. Thus, aggregate nonoccupational exposure would include

exposures resulting from non-food uses

in addition to consumption of potential

residues in food and water. Exposure

via drinking water is expected to be

negligible since deltamethrin binds

tightly to soil and rapidly degrades in

water.

1. Dietary exposure— a. Food. Food

tolerances have been established (with

expiration dates of November 15, 1997),

for residues of tralomethrin and/or

deltamethrin and its metabolites in or

on a variety of raw agricultural

commodities. These tolerances, in

support of registrations, currently exist

for residues of tralomethrin on broccoli,

cottonseed, head lettuce, leaf lettuce,

soybeans, sunflower seed, and

cottonseed oil. Also, such tolerances, in

support of registrations, currently exist

for deltamethrin on cottonseed and

cottonseed oil. Additionally, tolerances

which are not time-limited have been

established for tralomethrin to support

its use in food/feed handling

establishments, and for deltamethrin on

tomatoes and concentrated tomato

products to support the importation of

tomato commodities treated with

deltamethrin. Further, a food/feed
50340 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

handling establishment use, and

associated tolerances, is pending for

deltamethrin. Potential acute exposures

from food commodities were estimated

using a Tier 3 acute dietary risk

assessment (Monte Carlo Analysis)

following EPA guidance. Potential

chronic exposures from food

commodities under the established food

and feed additive tolerances for

deltamethrin and tralomethrin, plus the

pending tolerances for deltamethrin

associated with use in food/feed

handling areas, were estimated using

NOVIGEN’s DEEM (Dietary Exposure

Evaluation Model). This chronic risk

assessment was conducted using

anticipated residues based on field trial

or monitoring data, percent crop treated,

and percent food handling

establishments treated.

b. Drinking water. Tralomethrin and

deltamethrin are immobile in soil and,

therefore, will not leach into

groundwater. Additionally, due to the

insolubility and lipophilic nature of

deltamethrin and tralomethrin, any

residues in surface water will rapidly

and tightly bind to soil particles and

remain with sediment, therefore not

contributing to potential dietary

exposure from drinking water. A

screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in ground

water at depths of 1 and 2 meters are

essentially zero (much less than 0.001

parts per billion (ppb)). Surface water

concentrations for pyrethroids were

estimated using PRZM3 and Exposure

Analysis Modeling System (EXAMS)

using Standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pond model since

drinking water derived from surface

water would normally be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible.

2. Non-dietary exposure. As noted

above, deltamethrin and tralomethrin

are broad spectrum insecticides

registered for use on a variety of food

and non-food agricultural commodities.

Additionally, registrations are held for

non-agricultural applications including

turf and lawn care treatments, broadcast

carpet treatments (professional use

only), indoor fogger, spot, crack and

crevice treatments, insect baits, lawn

and garden sprays and indoor and

outdoor residential, industrial and

institutional sites including those for

Food/Feed Handling Establishments.

To evaluate non-dietary exposure, the

‘‘flea infestation control’’ senario was

chosen to represent a plausible but

worst case non-dietary (indoor and

outdoor) non-occupational exposure.

This scenario provides a situation where

deltamethrin and/or tralomethrin is

commonly used and they can be used

concurrently for a multitude of uses,

e.g., spot and/or broadcast treatment of

infested indoor surfaces such as carpets

and rugs, treatment of pets and

treatment of the lawn. This hypothetical

situation provides a very conservative,

upper bound estimate of potential nondietary exposures. Consequently, if

health risks are acceptable under these

conditions, the potential risks

associated with other more likely

scenarios would also be acceptable.

Because tralomethrin is rapidly

metabolized to deltamethrin, and the

toxicology profiles of deltamethrin and

tralomethrin are virtually identical, a

non-dietary and aggregate (non-dietary +

chronic dietary) exposure/risk

assessment has been conducted for the

combination of both active ingredients.

The total exposure to both materials was

expressed as ‘‘deltamethrin equivalents’’

and these were compared to the

toxicology endpoints identified for

deltamethrin.

C. Cumulative Effects

When considering a tolerance, the

Agency must consider ‘‘available

information’’ concerning the cumulative

effects of a particular pesticides residues

and ‘‘other substances that have a

common mechanism of toxicity’’.

AgrEvo USA Company, acting as

registered US agent for Hoechst

Schering AgrEvo SA, believes that

‘‘available information’’ in this context

includes not only toxicity, chemistry,

and exposure data, but also scientific

policies and methodologies for

understanding common mechanisms of

toxicity and conducting cumulative risk

assessments.

Further, AgrEvo does not have, at this

time, available data to determine

whether tralomethrin and/or

deltamethrin have a common

mechanism of toxicity with other

substances. For the purposes of this

tolerance action, therefore, no

assumption has been made that

tralomethrin and/or deltamethrin have a

common mechanism of toxicity with

other substances.

AgrEvo USA Company, acting as

registered US agent for Hoechst

Schering AgrEvo SA, will submit

information for EPA to consider

concerning potential cumulative effects

of deltamethrin and/or tralomethrin

consistent with the schedule established

by EPA at 62 FR 42020 (August 4, 1997,)

and other EPA publications pursuant to

the Food Quality Protection Act (FQPA).

D. Safety Determination

1. U.S. population. The toxicity and

residue data base for deltamethrin and

tralomethrin are considered to be valid,

reliable and essentially complete

according to existing regulatory

requirements. No evidence of

oncogenicity has been observed for

either compound. For acute exposures,

the toxicology endpoint from the

deltamethrin rat development toxicity

study, 3.3 mg/kg/day, is used. For

chronic exposures to deltamethrin and

tralomethrin, the Reference Dose (RfD)

of 0.01 mg/kg bodyweight/day

established for deltamethrin based on

the NOEL from the 2–year rat feeding

study and a 100-fold safety factor to

account for interspecies extrapolation

and intraspecies variation is used.

For the overall U.S. population, acute

dietary exposure at the 99.9th percentile

results in a Margin of Exposure (MOE)

of 5,382; the MOE for the 99th

percentile is 16,661; and at the 95th

percentile the MOE is 57,470. For the

overall US population, chronic dietary

exposure results in a utilization of 0.2

percent of the reference dose. Using an

upper bound estimate of potential nondietary exposures for a worst case

scenario (flea treatment) results in an

MOE of 160,000 for adults. Utilizing the

scenario of chronic dietary exposure

plus an upper bound estimate of

potential non-dietary exposure from a

worst case scenario (flea treatment), it is

shown that for aggregate exposure to

deltamethrin and tralomethrin there is

an MOE of 83,000 for adults. There is

generally no concern for MOE greater

than 100. For chronic exposure, there is

generally no concern for exposure below

100 percent of the RfD because the RfD

represents the level at or below which

daily aggregate dietary exposure over a

lifetime will not pose appreciable risks

to human health.

In conclusion, there is reasonable

certainty that no harm will result to the

U.S. population, in general, from dietary

or aggregate exposure to either

deltamethrin and/or tralomethrin.

2. Infants and children. Data from

developmental toxicity studies in rats

and rabbits, and multigeneration

reproduction studies in rats are

generally used to assess the potential for

increased sensitivity of infants and

children. The developmental toxicity

studies are designed to evaluate adverse

effects on the developing organism
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50341

resulting from pesticide exposure

during prenatal development.

Reproduction studies provide

information relating to reproductive and

other effects on adults and offspring

from pre-natal and post-natal exposure

to the pesticide. None of these studies

conducted with deltamethrin or

tralomethrin indicated developmental

or reproductive effects as a result of

exposure to these materials.

FFDCA section 408 provides that EPA

may apply an additional safety factor for

infants and children in the case of

threshold effects to account for pre-and

post-natal toxicity and the completeness

of the database. Based on the current

toxicological data requirements, the

database relative to pre- and post-natal

effects in children is complete.

Although no indication of increased

susceptibility to younger animals was

noted in any of the above studies, or in

the majority of studies with other

pyrethroids, several recent publications

have reported that deltamethrin is more

toxic to neonate and weanling animals

than to adults. However, a joint industry

group currently investigating this issue

was unable to reproduce these findings.

Furthermore, the RfD (0.01 mg/kg/day)

that has been established for

deltamethrin is already more than

1,000-fold lower than the lowest NOEL

from the developmental and

reproduction studies. Therefore, the RfD

of 0.01 mg/kg/day is appropriate for

assessing chronic aggregate risk to

infants and children and an additional

uncertainty factor is not warranted.

Also, the NOEL of 3.3 mg/kg/day from

the rat developmental toxicity study is

appropriate to use in acute dietary, short

term non-dietary, and aggregate

exposure assessments.

For the population subgroup

described as non-nursing infants, less

than 1 year old, the MOE for acute

dietary exposure at the 99.9th percentile

is 13,853; at the 99th percentile the

MOE is 74,022; and at the 95th

percentile the MOE is 663,629. For the

population subgroup described as

children 1–6 years old, the MOE for

acute dietary exposure is 2,300 for the

99.9th percentile; at the 99th percentile

the MOE is 10,409; and at the 95th

percentile the MOE is 42,070. For nonnursing infants, chronic dietary

exposure results in a utilization of 0.3

percent of the reference dose, and for

children 1–6 years old 0.4 percent of the

reference dose is utilized. Using an

upper bound estimate of potential nondietary exposures for a worst case

scenario (flea treatment) results in an

MOE of 6,100 for infants less than 1 year

old, and an MOE of 6,600 for children

1–6 years old. Utilizing the scenario of

chronic dietary exposure plus an upper

bound estimate of potential non-dietary

exposure from a worst case scenario

(flea treatment) it is shown that for

aggregate exposure to deltamethrin and

tralomethrin, there is an MOE of 5,800

for infants less than 1–year old, and an

MOE of 6,100 for children 1-6 years old.

There is generally no concern for MOE

s greater than 100. For chronic

exposure, there is generally no concern

for exposure below 100 percent of the

RfD because the RfD represents the level

at or below which daily aggregate

dietary exposure over a lifetime will not

pose appreciable risks to human health.

In summary, there is reasonable

certainty that no harm will result to

infants and children from aggregate

exposure to either deltamethrin or

tralomethrin.

E. International Tolerances

The proposed/established CODEX

maximum residue levels (MRL) and for

deltamethrin are as follows: cotton at

0.05 ppm and food/feed handling uses

at 0.05 ppm. As far as can be

determined at this time, no CODEX

MRL’s are established or proposed for

tralomethrin.

F. Conclusions

The existing tolerances for

deltamethrin and tralomethrin do not

pose a significant risk to human health,

including that of children, and are in

compliance with the requirements of the

FQPA of 1996. Therefore, the time

limitations associated with these

tolerances can be removed. (John

Hebert)

2. Bayer Corporation

PP 4F3046, 9F3731, 3F4204, 4F4309,

4F4313, 2F4137, 4H5427, 9H5574,

3H5670, 4H5686, 4H5687

EPA has received a request regarding

pesticide petitions (PP 4F3046, 9F3731,

3F4204, 4F4309, 4F4313, 2F4137,

4H5427, 9H5574, 3H5670, 4H5686,

4H5687) from Bayer Corporation, 8400

Hawthorn Road, P.O. Box 4913, Kansas

City, MO 64210 to remove the time

limitations on the established tolerances

at 40 CFR § 180.436, § 185.1250 and

§ 186.1250 for the insecticide cyfluthrin,

[cyano[4-fluoro-3-phenoxyphenyl]-

methyl-3-[2,2-dicloroethenyl]-2,2-

dimethyl- cyclopropanecarboxylate] in

or on the raw agricultural commodities

alfalfa, forage, at 5.0 ppm; alfalfa, hay,

at 10.0 ppm; aspirated grain fractions at

300 ppm; carrots at 0.2 ppm; cattle, fat,

at 1.0 ppm; cattle, meat, at 0.4 ppm;

cattle, meat by-products (mbyp) at 0.4

ppm; corn, forage (sweet), at 15.0 ppm;

corn, fodder (sweet), at 30 ppm; corn

(sweet, K+CWHR), at 0.05 ppm;

cottonseed at 1.0 ppm; cottonseed, oil,

at 2.0 ppm; cottonseed, hulls, at 2.0

ppm; citrus, whole fruit, at 0.2 ppm;

citrus oil, at 0.3 ppm; citrus dried pulp,

at 0.3 ppm; eggs at 0.01 ppm; goats, fat,

at 1.0 ppm; goats, meat, at 0.4 ppm;

goats, meat by-products (mbyp) at 0.4

ppm; hogs, fat, at 1.0 ppm; hogs, meat,

at 0.4 ppm; hogs, meat by-products

(mbyp) at 0.4 ppm; horses, fat, at 1.0

ppm; horses, meat, at 0.4 ppm; horses,

meat by-products (mbyp) at 0.4 ppm;

milkfat, at 15.0 ppm (representing 0.5

ppm in whole milk); peppers, at 0.5

ppm; poultry, fat, at 0.01 ppm; poultry,

meat, at 0.01 ppm; poultry, meat byproducts (mbyp) at 0.01 ppm; radishes

at 1.0 ppm; sheep, fat, at 1.0 ppm;

sheep, meat, at 0.4 ppm; sheep, meat byproducts (mbyp) at 0.4 ppm; sorghum,

fodder, at 5.0 ppm; sorghum, forage, at

2.0 ppm; sorghum, grain at 4.0 ppm,

sunflower, forage, at 1.0 ppm;

sunflower, seed, at 0.02 ppm; sugarcane,

at 0.05 ppm; sugarcane, molasses, at 0.2

ppm; tomatoes, at 0.2 ppm; tomato,

concentrated products, at 0.5 ppm; and

tomato, pomace (wet and dry) at 5.0

ppm. All data requested by EPA have

been submitted. Therefore, a request for

unconditional registration and removal

of the time limitations on established

tolerances is being made.

Consistent with section 408(d) of

FFDCA, as recently amended by the

Food Quality Protection Act, Bayer

submitted a summary and authorization

for the summary to be published in the

Federal Register in a notice of receipt of

the request. The summary represents the

views of Bayer; EPA is in the process of

evaluating the request. Consistent with

section 408(d)(3), EPA is including the

summary as a part of this notice of

filing. EPA has not fully evaluated the

sufficiency of the submitted data at this

time or whether the data support

granting the request.

A. Residue Chemistry

1. Plant metabolism. The metabolism

of cyfluthrin in plants is adequately

understood. Studies have been

conducted to delineate the metabolism

of radio labeled cyfluthrin in various

crops all showing similar results. The

residue of concern is cyfluthrin.

2. Analytical method. Adequate

analytical methodology (gas/liquid

chromatography with an electron

capture detector) is available for

enforcement purposes.

3. Magnitude of residues. Cyfluthrin is

the active ingredient in the registered

end-use product Baythroid 2

Emulsifiable Pyrethroid Insecticide,

EPA Reg. No. 3125–351. Baythroid 2 is

registered for use on alfalfa, carrots,
50342 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

citrus, cotton, peppers, radishes,

sorghum, sugarcane, sweet corn,

sunflowers and tomatoes.

Tolerances to support these uses were

proposed in pesticide petitions 4F3046,

9F3731, 3F4204, 4F4309, 4F4313,

2F4137, and 4F4313 and food/feed

additive petitions 4H5427, 9H5574,

3H5670, 4H5686, and 4H5687. Residue

data covering all the uses associated

with these petitions have been

previously submitted to EPA for review

and have been found by EPA to support

the establishment of the tolerances.

Consequently, regulations establishing

these tolerances were promulgated in

response to these petitions. See [53 FR

30676] (cottonseed), [60 FR 28353]

(carrots, radishes, peppers and

tomatoes), [60 FR 28353] (sugarcane),

[61 FR 10678] (alfalfa, sunflowers, and

sweet corn), [61 FR 39883] (sorghum),

and [62 FR 25518] (citrus).

B. Toxicological Profile

The database for cyfluthrin is current

and complete. Toxicology data cited in

support of these tolerances include:

1. Acute toxicity. There is a battery of

acute toxicity studies for cyfluthrin

supporting an overall toxicity Category

II.

2. Genotoxicty. Mutagenicity tests

were conducted, including several gene

mutation assays (reverse mutation and

recombination assays in bacteria and a

Chinese hamster ovary (CHO)/HGPRT

assay); a structural chromosome

aberration assay (CHO/sister chromatid

exchange assay); and an unscheduled

DNA synthesis assay in rat hepatocytes.

All tests were negative for genotoxicity.

3. Reproductive and developmental

toxicity. An oral developmental toxicity

study in rats with a maternal and fetal

NOEL of 10 milligrams/kilogram of

body weight/day (mg/kg bw/day)

(highest dose tested).

An oral developmental toxicity study

in rabbits with a maternal NOEL of 20

mg/kg bw/day and a maternal Lowest

Effect Level (LEL) of 60 mg/kg bw/day,

based on decreased body weight gain

and decreased food consumption during

the dosing period. A fetal NOEL of 20

mg/kg bw/day and a fetal LEL of 60 mg/

kg bw/day were also observed in this

study. The LEL was based on increased

resorptions and increased

postimplantation loss.

A three-generation reproduction study

in rats with systemic toxicity NOELs of

7.5 and 2.5 mg/kg bw/day for parental

animals and their offspring,

respectively. At higher dose levels, the

body weights of parental animals and

their offspring were reduced.

4. Subchronic toxicity. A subchronic

toxicity feeding study using rats

demonstrated a NOEL of 22.5 mg/kg bw/

day, the highest dose tested.

A 6–month toxicity feeding study in

dogs established a NOEL of 5 mg/kg bw/

day. The LEL was 15 mg/kg bw/day

based on clinical signs and reduced

thymus weights.

5. Chronic toxicity. A 12–month

chronic feeding study in dogs

established a NOEL of 4 mg/kg bw/day.

The lowest effect level (LEL) for this

study is established at 16 mg/kg bw/day,

based on slight ataxia, increased

vomiting, diarrhea and decreased body

weight.

A 24–month chronic feeding/

carcinogenicity study in rats

demonstrated a NOEL of 2.5 mg/kg bw/

day and LEL of 6.2 mg/kg bw/day, based

on decreased body weights in males,

decreased food consumption in males,

and inflammatory foci in the kidneys in

females.

A 24–month carcinogenicity study in

mice was conducted. Under the

conditions of the study there were no

carcinogenic effects observed. A 24–

month chronic feeding/carcinogenicity

study in rats was conducted. There were

no carcinogenic effects observed under

the conditions of the study.

6. Animal metabolism. A metabolism

study in rats showed that cyfluthrin is

rapidly absorbed and excreted, mostly

as conjugated metabolites in the urine,

within 48 hours. An enterohepatic

circulation was observed.

7. Metabolite toxicology. No

toxicology data have been required for

cyfluthrin metabolites. The residue of

concern is cyfluthrin.

8. Endocrine effects. There is no

evidence of endocrine effects in any of

the studies conducted with cyfluthrin,

thus, there is no indication at this time

that cyfluthrin causes endocrine effects.

C. Aggregate Exposure

1. Dietary exposure— Food. Dietary

exposure was estimated using Novigen’s

Dietary Exposure Evaluation Model

(DEEMa) software; results from field

trial and processing studies;

consumption data from the USDA

Continuing Surveys of Food Intake by

Individuals (CSFIIs), conducted from

1989 through 1992; and information on

the percentages of the crop treated with

Cyfluthrin.

Cyfluthrin is registered for use in

alfalfa, citrus, sweet corn, cotton,

sorghum, sunflower, sugarcane, carrots,

peppers, radishes and tomatoes. In

addition, it has an import tolerance for

hops. Various formulations are

registered for use in food handling

establishments and in combination with

another active ingredient, for use in

field corn, pop corn and sweet corn.

Chronic dietary exposure estimates

for the overall U.S. population were

0.5% of the Reference dose (RfD) (0.008

mg/kg bw/day). For the most highly

exposed population subgroup, children

1 to 6 years of age, the exposure was

estimated to be 0.000062 mg/kg bw/day,

or 0.8% of the RfD. Acute dietary

exposures were estimated for the overall

US population, females 13 years and

older, children, ages 1–6 and 7–12

years, infants, non-nursing and nursing.

The exposure was compared to the

NOEL of 20 mg/kg bw/day to estimate

the Margins of Exposures (MOEs).

For the overall U.S. population the

95th, 99th and 99.9th percentile of

exposure the MOEs were calculated as

29,981; 9,519; and 3,658 respectively.

For women aged 13 years and older

the 95th, 99th and 99.9th percentile of

exposure the MOEs were calculcated as

45,996; 20,103 and 10,011 respectively.

Lastly, for the potentially highest

exposed population subgroup, nonnursing infants, the 95th, 99th and

99.9th percentile of exposure to the

MOEs were calculated at 16,107; 3,072;

and 1,343, respectively.

2. Drinking water. Cyfluthrin is

immobile in soil, therefore, will not

leach into groundwater. Additionally,

due the insolubility and lipophilic

nature of cyfluthrin, any residues in

surface water will rapidly and tightly

bind to soil particles and remain with

sediment, therefore not contributing to

potential dietary exposure from

drinking water.

A screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in ground

water at 2 meters are essentially zero

(much less than 0.001 parts per billion

(ppb)). Surface water concentrations for

pyrethroids were estimated using

PRZM3 and Exposure Analysis

Modeling System (EXAMS) using

Standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 52 parts per

trillion. Concentration in actual

drinking water would be much lower.

Based on these analyses, the

contribution of water to the dietary risk

estimate is negligible.

3. Non-dietary exposure. Nonoccupational exposure to cyfluthrin may

occur as a result of inhalation or contact

from indoor residential, indoor

commercial, and outdoor residential

uses. Pursuant to the requirements of

FIFRA as amended by the Food Quality

Protection Act of 1996, non-dietary and

aggregate risk analyses for cyfluthrin
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50343

were conducted. The analyses include

evaluation of potential non-dietary

acute application and post-application

exposures. Non-occupational, nondietary exposure was assessed based on

the assumption that a flea infestation

control scenario represents a ‘‘worst

case’’ scenario. For the flea control

infestation scenario indoor fogger, and

professional residential turf same day

treatments were included for cyfluthrin.

Deterministic (point values) were used

to present a worse case upper-bound

estimate of non-dietary exposure. The

non-dietary exposure estimates were

expressed as systemic absorbed doses

for a summation of inhalation, dermal,

and incidental ingestion exposures.

These worst-case non-dietary exposures

were aggregated with chronic dietary

exposures to evaluate potential health

risks that might be associated with

cyfluthrin products. The chronic dietary

exposures were expressed as an oral

absorbed dose to combine with the nondietary systemic absorbed doses for

comparison to a systemic absorbed dose

(NOEL). Results for each potential

exposed subpopulation (of adults,

children 1–6 years, and infants <1 year)

were compared to the systemic absorbed

dose NOEL for cyfluthrin to provide

estimates of MOE.

The large MOEs for cyfluthrin clearly

demonstrate a substantial degree of

safety. The total non-dietary MOEs are

3,800, 2,700, and 2,500 for adults,

children (1–6 years), and infants (<1

year), respectively. The aggregate MOE

for adults is approximately 3,800 and

the MOEs for infants and children

exceed 2,500.

The non-dietary methods used in the

analyses can be characterized as highly

conservative. This is due to the

conservatism inherent in the calculation

procedures and input assumptions. An

example of this is the conservatism

inherent in the jazzercise over

representation of residential postapplication exposures. It is important to

acknowledge that these MOEs are likely

to significantly underestimate actual

MOEs due to a variety of conservative

assumptions and biases inherent in the

derivatization of exposure by this

method. Therefore, it can be concluded

that large MOEs associated with

potential non-dietary and aggregate

exposures to cyfluthrin will result in

little or no health risks to exposed

persons. The aggregate risk analysis

demonstrates compliance with the

health-based requirements of the Food

Quality Protection Act of 1996 and

supports the continued registration and

use of residential, commercial, and

agricultural products containing

cyfluthrin.

D. Cumulative Effects

Further, Bayer does not have, at this

time, available data to determine

whether cyfluthrin has a common

mechanism of toxicity with other

substances. For the purposes of this

tolerance action, therefore, no

assumption has been made that

cyfluthrin has a common mechanism of

toxicity with other substances.

Bayer will submit information for

EPA to consider concerning potential

cumulative effects of cyfluthrin

consistent with the schedule established

by EPA in the Federal Register of

August 4, 1997, (62 FR 42020) and other

EPA publications pursuant to the Food

Quality Protection Act.

E. Safety Determination

1. U.S. population. Based on the

exposure assessments described above

and on the completeness and reliability

of the toxicity data, it can be concluded

that total aggregate exposure to

cyfluthrin from all uses will utilize less

than 1% percent of the RfD for chronic

dietary exposures and that MOEs in

excess of 1,000 exist for aggregate

exposure to cyfluthrin for nonoccupational exposure. EPA generally

has no concerns for exposures below

100 percent of the RfD, because the RfD

represents the level at or below which

daily aggregate exposure over a lifetime

will not pose appreciable risks to

human health. Margins of exposure of

100 or more (300 for infants and

children) also indicate an adequate

degree of safety. Thus, it can be

concluded that there is a reasonable

certainty that no harm will result from

aggregate exposure to cyfluthrin

residues.

2. Infants and children. In assessing

the potential for additional sensitivity of

infants and children to residues of

cyfluthrin, the data from developmental

studies in both rat and rabbit and a twogeneration reproduction study in the rat

can be considered. The developmental

toxicity studies evaluate any potential

adverse effects on the developing

animal resulting from pesticide

exposure of the mother during prenatal

development. The reproduction study

evaluates any effects from exposure to

the pesticide on the reproductive

capability of mating animals through

two generations, as well as any observed

systemic toxicity.

The toxicology data which support

these tolerances include:

An oral developmental toxicity study

in rats with a maternal and fetal NOEL

of 10 mg/kg bw/day (HDT).

An oral developmental toxicity study

in rabbits with a maternal NOEL of 20

mg/kg bw/day and a maternal LEL of 60

mg/kg bw/day, based on decreased body

weight gain and decreased food

consumption during the dosing period.

A fetal NOEL of 20 mg/kg bw/day and

a fetal LEL of 60 mg/kg bw/day were

also observed in this study. The LEL

was based on increased resorptions and

increased postimplantation loss.

An oral developmental toxicity study

performed with beta-cyfluthrin, the

resolved isomer mixture of cyfluthrin,

has been submitted to the Agency and

is currently under review.

A developmental toxicity study in rats

exposed via inhalation to liquid aerosols

of cyfluthrin revealed developmental

toxicity, but only in the presence of

maternal toxicity. The developmental

NOEL was 0.46 mg/m3 on the basis of

reduced placental and fetal weights, and

delayed ossification. The NOEL for

overt maternal toxicity was < 0.46 mg/

m3, the lowest dose tested (LDT).

A three-generation reproduction study

in rats with systemic toxicity NOELs of

7.5 and 2.5 mg/kg bw/day for parental

animals and their offspring,

respectively. At higher dose levels, the

body weights of parental animals and

their offspring were reduced. Another

multiple-generation reproduction study

in rats has been submitted to the Agency

and is currently under review.

The Agency used the rabbit

developmental toxicity study with a

maternal NOEL of 20 mg/kg bw/day to

assess acute dietary exposure and

determine a MOE for the overall U.S.

population and certain subgroups. Since

this toxicological endpoint pertains to

developmental toxicity the population

group of concern for this analysis was

women aged 13 and above, the subgroup

which most closely approximates

women of child-bearing age. The MOE

is calculated as the ratio of the NOEL to

the exposure. The Agency calculated the

MOE to be over 600. Generally, MOE’s

greater than 100 for data derived from

animal studies are regarded as showing

no appreciable risk.

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.

The results of the three-generation

study in rats provided evidence

suggesting that, with respect to effects of

cyfluthrin on body weight, pups were

more sensitive than adult rats. Thus, the

Agency determined that an additional

3–fold uncertainty factor (UF) should be

used in risk assessments to ensure

adequate protection of infants and

children.
50344 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

Generally, EPA considers MOEs of at

least 100 to indicate an adequate degree

of safety. With an additional 3×

uncertainty factor, this would be 300 for

infants and children. Using the

exposure assessments described above

and based on the described toxicity data

aggregate exposure to infants and

children indicate a MOE in excess of

2,500. Thus, it can be concluded that

there is a reasonable certainty that no

harm will result to infants and children

from aggregate exposure to cyfluthrin

residues.

3. Conclusions. The available data

indicate that there is reasonable

certainty of no harm from the aggregate

exposure from all currently registered

uses of cyfluthrin. Thus, consistent with

the provisions of the FFDCA as

amended August 3, 1996, the time

limitations on established cyfluthrin

tolerance should be removed.

F. International Tolerances

Codex maximum residue levels

(MRLs) are established for residues of

cyfluthrin on milk (0.01 mg/kg);

cottonseed (0.05 mg/kg); peppers, sweet

(0.2 mg/kg); and tomatoes (0.5 mg/kg).

(Stephanie Willett)

3. DuPont Agricultural Products

PP–7F2013

EPA has received a request from

DuPont Agricultural Products, P. O. Box

80038, Wilmington, DE 19880–0038

proposing pursuant to section 408(d) of

the Federal Food, Drug and Cosmetic

Act (FFDCA), 21 U.S.C. 346a(d), to

amend 40 CFR part 180 by removing the

time limitation for a tolerance

established for residues of the

insecticide and pyrethroid fenvalerate,

including the s,s-enriched isomer

esfenvalerate (Asana XL Insecticide),

((S)-cyano-(3-phenoxyphenyl)methyl

(S)-4-chloro-alpha-(1-

methylethyl)benzeneacetate in or on the

raw agricultural commodity cottonseed

at 0.2 parts per million (ppm). The

tolerance was originally requested in

PP–7F2013. EPA has determined that

the request 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

and chemical nature of residues of

fenvalerate in plants is adequately

understood. The fate of fenvalerate has

been extensively studied using

radioactive tracers in plant and animal

metabolism/nature of the residue

studies previously submitted to the

Agency. These studies have

demonstrated that the parent compound

is the only residue of toxicological

significance.

2. Analytical method. There is a

practical analytical method utilizing

electron-capture gas chromatography

with nitrogen phosphorous detection

available for enforcement with a limit of

detection that allows monitoring food

with residues at or above tolerance

levels.

3. Magnitude of residues. Tolerances

are based on the sum of all isomers of

fenvalerate. Fenvalerate is a racemic

mixture of four isomers (about 25%

each). This product was registered as

Pydrin . However since 1992, an S,Sisomer enriched formulation, Asana

(esfenvalerate), has been the only

fenvalerate formulation sold in the U.S.

for agricultural use. Since the S,Sisomer is the insecticidally active

isomer, the use rate for Asana is four

times lower than that for Pydrin . A

petition is pending (PP–4F4329), to

convert tolerances (still to be expressed

as the sum of all isomers) based on the

use rates for Asana. Bridging residue

studies have shown Asana residues to

be 3–4 times lower than Pydrin

residues.

EPA has established a tolerance of 0.2

ppm for fenvalerate on cottonseed.

Magnitude of residue and processing

studies support this tolerance. This

request is for the removal of the time

limitation currently imposed on the

tolerance of 0.2 ppm for fenvalerate on

cottonseed.

B. Toxicological Profile

The following studies have been

submitted to EPA:

1. Acute toxicity. A rat acute oral

study on esfenvalerate technical has an

LD50 of 87.2 milligram (mg)/kilogram

(kg). A rabbit acute dermal study on

esfenvalerate has an LD50 of >2,000 mg/

kg. Acute inhalation on technical grade

active ingredient (a.i.) waived due to

negligible vapor pressure. A primary eye

irritation test using esfenvalerate in the

rabbit showed mild irritation

(conjunctivitis) that cleared by day 7. A

primary dermal irritation test using

esfenvalerate in the rabbit which

showed minimal irritation that reversed

within 72 hours after treatment. A

dermal sensitization test on

esfenvalerate in guinea pigs which

showed no sensitization.

2. Genotoxicty. Esfenvalerate was not

mutagenic in reverse mutation assays in

Salmonella and E. Coli in vitro assay in

Chinese hamster lung cells.

Esfenvalerate did not induce

chromosome aberrations in an in vitro

assay in Chinese hamster ovary cells.

Esfenvalerate did not induce

micronuclei in bone marrow of mice

given up to 150 mg/kg intraperitoneally.

Esfenvalerate did not induce

unscheduled DNA synthesis in HeLa

cells.

3. Reproductive and developmental

toxicity. In a pilot developmental study

in the rat with doses of 0, 1, 2, 3, 4, 5,

and 20 mg/kg/day esfenvalerate

maternal clinical signs of abnormal gait

or mobility occurred at 4 mg/kg/day and

above. In a developmental study in the

rat with doses of 0, 2.5, 5, 10, and 20

mg/kg/day esfenvalerate by gavage

maternal signs observed at 2.5 mg/kg/

day were erratic jerking and extension

of forelimbs, rapid side-to-side head

movement, and excessive grooming.

There was no maternal No-ObservedEffect-Level (NOEL) in the main study

but a NOEL of 2 mg/kg/day was

established on the pilot study. There

were no fetal or developmental effects

in either study at 20 mg/kg/day, the

highest dose tested. Therefore, the fetal/

developmental NOEL was  ́20 mg/kg/

day.

In a pilot developmental study in the

rabbit with doses of 0, 2, 3, 4, 4.5, 5, and

20 mg/kg/day esfenvalerate by gavage.

The maternal NOEL was 2 mg/kg/day

based on excessive grooming at 3 mg/

kg/day and above. In a developmental

study in the rabbit with doses of 0, 3,

10, and 20 mg/kg/day esfenvalerate by

gavage there was no maternal NOEL in

the main study, but a maternal NOEL of

2 mg/kg/day was established in the pilot

study. There were no fetal or

developmental effects in either study at

the highest dose tested. Therefore, the

fetal/developmental NOEL was  ́20 mg/

kg/day.

A two-generation feeding study with

esfenvalerate in the rat at dietary levels

of 0, 75, 100, or 300 ppm. The high

dietary concentration was lowered to

150 ppm for the second generation. Very

mild body weight effects and sores at 75

ppm in both generations were

considered secondary effects caused by

scratching related to skin stimulation

from dermal exposure. Therefore 75

ppm (4.2 mg/kg/day for first generation

parental males, 5.6 mg/kg/day for first

generation parental females, 6.0 mg/kg/

day for second generation parental

males, and 7.3 mg/kg/day for second

generation parental females) was

considered an No-Observed-AdverseEffect-Level (NOAEL) for both adult rats

and their offspring. Effects were

observed in adults and pups of both

generations at 100 ppm and above. Pups
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50345

were no more sensitive than adult

animals.

4. Subchronic toxicity. A 90–day

feeding study in rats was conducted at

0, 75, 100, 125, and 300 ppm

esfenvalerate with a NOEL of 125 ppm

(6.3 mg/kg/day). This study provided

intermediate dose levels to supplement

a 90–day feeding study in rats

conducted at 0, 50, 150, 300 and 500

ppm esfenvalerate with a NOEL of 50

ppm (2.5 mg/kg/day) based on jerky leg

movements at 150 ppm (7.5 mg/kg/day)

and above.

A 90–day feeding study in mice was

conducted at 0, 50, 150, and 500 ppm

esfenvalerate and 2,000 ppm fenvalerate

with a NOEL of 50 ppm esfenvalerate

(10.5 mg/kg/day) based on lower

glucose and triglycerides at 150 ppm.

Neurologic symptoms were observed

with 500 ppm esfenvalerate and 2,000

ppm fenvalerate.

A 3–month subchronic study in dogs

is satisfied by a 1–year oral study in

dogs, in which the NOEL was 200 ppm

(5 mg/kg/day).

A 21–day dermal study in rabbits

with fenvalerate was conducted at 100,

300, and 1,000 mg/kg/day with an

NOAEL of 1,000 mg/kg/day.

5. Chronic toxicity. In a 1–year study

in which dogs were fed 0, 25, 50, or 200

ppm esfenvalerate with no treatment

related effects at any dietary level the

NOEL was 200 ppm (5 mg/kg/day). An

effect level for dietary administration of

esfenvalerate for dogs of 300 ppm had

been established earlier in the 2–week

pilot study used to select dose levels for

the chronic-dog study.

In a 20–month study with fenvalerate

in mice fed 0, 10, 30, 100, and 300 ppm

the NOEL was 30 ppm (∼ 6 mg/kg/day)

based on red blood cell effects and

granulomatous changes at 100 ppm.

Fenvalerate was not carcinogenic at any

concentration.

In a 18–month study in mice fed 0,

35, 150, and 350 ppm esfenvalerate.

Mice fed the 350 ppm dose were

sacrificed within the first two months of

the study, after excessive morbidity and

mortality due to self-trauma induced by

pharmacological effects related to skin

stimulation. Therefore, data collected

from the 350 ppm group were not used

in the evaluation of the oncogenic

potential of esfenvalerate. The NOEL

was 35 ppm (4.29 and 5.75 mg/kg/day

for males and females, respectively)

based on lower body weight and bodyweight gain at 150 ppm. Esfenvalerate

did not produce carcinogenicity.

In a 2–year study with fenvalerate in

rats fed 1, 5, 25, and 250 ppm a 1,000

ppm group was added to establish an

effect level. The NOEL was 250 ppm

(12.5 mg/kg/day). At 1,000 ppm, hind

limb weakness, lower body weight, and

higher organ-to-body weight ratios were

observed. Fenvalerate was not

carcinogenic at any concentration.

EPA has classified esfenvalerate in

Group E—evidence of

noncarcinogenicity for humans.

6. Animal metabolism. After oral

dosing with fenvalerate, the majority of

the administered radioactivity was

eliminated in the initial 24 hours. The

metabolic pathway involved cleavage of

the ester linkage followed by

hydroxylation, oxidation, and

conjugation of the acid and alcohol

moieties.

7. Metabolite toxicology. The parent

molecule is the only moiety of

toxicological significance appropriate

for regulation in plant and animal

commodities.

8. Endocrine effects. Estrogenic effects

have not been observed in any studies

conducted on fenvalerate or

esfenvalerate. In subchronic or chronic

studies there were no lesions in

reproductive systems of males or

females. In the recent reproduction

study with esfenvalerate, full

histopathological examination of the

pituitary and the reproductive systems

of males and females was conducted.

There were no compound-related gross

or histopathological effects. There were

also no compound-related changes in

any measures of reproductive

performance including mating, fertility,

or gestation indices or gestation length

in either generation. There have been no

effects on offspring in developmental

toxicity studies.

C. Aggregate Exposure

1. Dietary exposure. For purposes of

assessing dietary exposure, chronic and

acute dietary assessments have been

conducted using all existing and

pending tolerances for esfenvalerate.

The toxicological endpoints used in

both dietary assessments are derived

from maternal NOEL’s of 2.0 mg/kg/day

from rat and rabbit teratology studies.

There were no fetal effects in these

studies.

2. Food. A chronic dietary exposure

assessment using anticipated residues

and monitoring data and adjusting for

percent crop treated, found the

percentages of the Reference Dose (RfD)

utilized by the most sensitive subpopulation (children 1–6 years) to be

5.2%. Chronic exposure for the overall

U.S. population was 2.1% of the RfD.

This assessment included pending

tolerances and all food tolerances for

incidental residues from use in food

handling establishments.

A Tier 3 acute dietary assessment

indicated the most sensitive subpopulation was children 1–6 years with

Margin of Exposures (MOEs) of 352,

200, and 103 at the 95th, 99th, and 99.9th

percentile of exposure, respectively. The

MOEs for nursing infants are 410, 199,

and 151 at the 95th, 99th, and 99.9th

percentile of exposure, respectively. The

MOEs for non-nursing infants are 661,

270, and 134 at the 95th, 99th, and 99.9th

percentile of exposure, respectively. The

MOEs for the general population are

742, 352, and 170 at the 95th, 99th, and

99.9th percentile of exposure,

respectively. This analysis used field

trial data to estimate exposure and

market share information for the percent

of crop treated. It used Monte Carlo

modeling and appropriate processing

factors for processed food and

distribution analysis. Food handling

establishment commodities are not

relevant to this type of analysis and EPA

methodology does not include them in

Tier 3 exposure modeling.

3. Drinking water. Esfenvalerate is

immobile in soil and, therefore, will not

leach into groundwater. Additionally,

due to the insolubility and lipophilic

nature of esfenvalerate, any residues in

surface water will rapidly and tightly

bind to soil particles and remain with

sediment, therefore not contributing to

potential dietary exposure from

drinking water.

A screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in ground

water at depths of 1 and 2 meters are

essentially zero (much less than 0.001

parts per billion (ppb)). Surface water

concentrations for pyrethroids were

estimated using PRZM3 and Exposure

Analysis Modeling System (EXAMS)

using standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pound model since

drinking water derived from surface

water would be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible.

4. Non-dietary exposure.

Esfenvalerate is registered for non-crop

uses including spray treatments in and

around commercial and residential

areas, treatments for control of

ectoparasites on pets, home care

products including foggers, pressurized

sprays, crack and crevice treatments,

lawn and garden sprays, and pet and pet

bedding sprays. For the non-agricultural
50346 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

products, the very low amounts of

active ingredient they contain,

combined with the low vapor pressure

(1.5 x 10-9 millimeters (mm) Mercury at

25°C) and low dermal penetration,

would result in minimal inhalation and

dermal exposure.

Individual non-dietary risk exposure

analyses were conducted using a flea

infestation scenario that included pet

spray, carpet and room treatment, and

lawn care, respectively. The pet spray

product assessment indicated MOEs of

740,000, 2,600, and 2,500 for adults,

children 1–6 years, and children < 1

year, respectively. The carpet and room

treatment assessment indicated MOEs of

110,000, 4,500, and 4,200 for adults,

children 1–6 years, and children < 1

year, respectively. The lawn care

assessment indicated MOEs of 700,000,

26,000, and 24,000 for adults, children

1–6 years, and children < 1 year,

respectively.

5. Aggregate exposure— Dietary and

non-dietary. Based on the toxicity

endpoints selected for esfenvalerate,

absorbed doses were combined and

compared to the relevant systemic

NOEL for estimating MOEs.

The non-dietary risk analysis MOEs

combined with the chronic dietary risk

analysis MOEs indicated aggregate

MOEs of 4,400, 860, and 1,000 for

adults, children 1–6 years, and children

< 1 year, respectively.

It is important to acknowledge that

these MOEs are likely to significantly

underestimate the actual MOEs due to a

variety of conservative assumptions and

biases inherent in the exposure

assessment methods used for their

derivation. Therefore, it can be

concluded that the potential non-dietary

and dietary aggregate exposures for

esfenvalerate are associated with a

substantial degree of safety. The

aggregate risk analyses demonstrate

compliance with the health-based

requirements of the Food Quality

Protection Act of 1996 (FQPA) (7 U.S.C.

136 note) and supports the continued

registration and use of residential,

agricultural, and commercial products

containing this a.i.

D. Cumulative Effects

Section 408(b)(2)(D)(v) of the FFDCA

requires that, when considering whether

to establish, modify, or revoke a

tolerance, the Agency consider

‘‘available information’’ concerning the

cumulative effects of a particular

pesticide’s residues and ‘‘other

substances that have a common

mechanism of toxicity’’. At this time,

available methodologies do not exist to

resolve the complex scientific issues

concerning common mechanism of

toxicity of pyrethroids in a meaningful

way. DuPont intends to submit

information for EPA to consider

concerning potential cumulative effects

of esfenvalerate consistent with the

schedule established by EPA at 62 FR

42020 (August 4, 1997)(FRL–5734–6)

and other EPA publications pursuant to

the FQPA.

In consideration of potential

cumulative effects of esfenvalerate and

other substances that may have a

common mechanism of toxicity, to our

knowledge there are currently no

available data or other reliable

information indicating that any toxic

effects produced by esfenvalerate would

be cumulative with those of other

chemical compounds. In addition, since

esfenvalerate does not appear to

produce a toxic metabolite produced by

other substances; only the potential

risks of esfenvalerate have been

considered in this assessment of its

aggregate exposure.

E. Safety Determination

Both the chronic and acute

toxicological endpoints are derived from

maternal NOEL’s of 2.0 mg/kg/day in

developmental studies in rats and

rabbits. There were no fetal effects. In

addition, no other studies conducted

with fenvalerate or esfenvalerate

indicate that immature animals are more

sensitive than adults. Therefore, the

safety factor used for protection of

adults is fully appropriate for the

protection of infants and children; no

additional safety factor is necessary.

1. U.S. population. A chronic dietary

exposure assessment using anticipated

residues, monitoring information, and

percent crop treated indicated the

percentage of the RfD utilized by the

general population to be 2.1%. There is

generally no concern for exposures

below 100% of the RfD because the RfD

represents the level at or below which

daily aggregate dietary exposure over a

lifetime will not pose appreciable risks

to human health.

For acute exposure, a MOE of greater

than 100 is considered an adequate

MOE. A Tier 3 acute dietary exposure

assessment found the general

population to have MOE’s of 742, 352,

170 at the 95th, 99th, and 99.9th

percentile of exposure, respectively.

These values were generated using

actual field trial residues and market

share data for percentage of crop treated.

These results depict an accurate

exposure pattern at an exaggerated daily

dietary exposure rate.

The aggregate exposure to use of

esfenvalerate as pet spray, carpet

treatment, lawn care, and in the diet

indicated an MOE of 4,400 for adults.

Therefore, there is a reasonable

certainty that no harm will result from

chronic dietary, acute dietary, nondietary, or aggregate exposure to

esfenvalerate residues.

2. Infants and children. A chronic

dietary exposure assessment found the

percentages of the RfD utilized by the

most sensitive sub-population to be

5.2% for children 1–6 years. The acute

dietary exposure assessment found the

most sensitive sub-population to be

children 1–6 years with MOEs of 352,

200, and 103 at the 95th, 99th, and 99.9th

percentile of exposure, respectively.

Nursing infants had MOEs of 410, 199,

and 151 at the 95th, 99th, and 99.9th

percentile of exposure, respectively.

Non-nursing infants had MOEs of 661,

270, and 134 at the 95th, 99th, and 99.9th

percentile of exposure, respectively. The

aggregate exposure to use of

esfenvalerate as pet spray, carpet

treatment, lawn care, and in the diet

indicated an MOE of 860 for children 1–

6 years and an MOE of 1,000 for

children < 1 year.

Thus, there is reasonable certainty

that no harm to infants and children

will result from chronic dietary, acute

dietary, non-dietary, or aggregate

exposure to esfenvalerate residues.

F. International Tolerances

Codex Maximum Residue Levels

(MRL’s) have been established for

residues of fenvalerate on a number of

crops that also have U.S. tolerances.

Several of these MRL’s are different than

the proposed U.S. tolerances for

esfenvalerate. Therefore, some

harmonization of these maximum

residue levels is desirable. (John Hebert)

4. FMC Corporation

PP 2F2623, 4F2986, 3F2824, 7F3498,

and 4F3011

EPA has received a request regarding

pesticide petitions (PP 2F2623, 4F2986,

3F2824, 7F3498, and 4F3011) from FMC

Corporation, 1735 Market Street,

Philadelphia, PA 19103. The request

proposes to remove any time limitations

on established tolerances for residues of

the insecticide zeta-cypermethrin (sCyano(3-phenoxyphenyl)methyl (±) cis,

trans 3-(2,2-dichloroethenyl)-2,2-

dimethylcyclopropanecarboxylate) in or

on the raw agricultural commodities

cottonseed at 0.5 ppm, pecans 0.05

ppm, lettuce, head at 10.0 ppm, onions,

bulb at 0.10 ppm and cabbage at 2.0

ppm (established at 40 CFR 180.418).

These tolerances were established under

(PP) 2F2623, 4F2986, 3F2824, 7F3498,

and 4F3011. EPA has determined that

the request contains data or information

regarding the elements set forth in
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50347

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 requests. Additional data

may be needed before EPA rules on the

requests.

A. Residue Chemistry

1. Plant metabolism. The metabolism

of cypermethrin in plants is adequately

understood. Studies have been

conducted to delineate the metabolism

of radiolabelled cypermethrin in various

crops all showing similar results. The

residue of concern is the parent

compound only.

2. Analytical method. There is a

practical analytical method for detecting

and measuring levels of cypermethrin in

or on food with a limit of detection that

allows monitoring of food with residues

at or above the levels set in these

tolerances Gas Chromatography with

Electron Capture Detection (GC/ECD).

3. Magnitude of residues. Crop field

trial residue data from studies

conducted at the maximum label rates

for cotton, pecans, head lettuce, bulb

onions, and cabbage show that the

established cypermethrin tolerances on

cottonseed of 0.5 ppm, pecans 0.05

ppm, lettuce, head at 10.0 ppm, onions,

bulb at 0.10 ppm and cabbage at 2.0

ppm, will not be exceeded when the

zeta-cypermethrin products labeled for

these uses are used as directed.

B. Toxicological Profile

1. Acute toxicity. For the purposes of

assessing acute dietary risk, FMC has

used the NOEL of 0.5 mg/kg/day based

on the NOEL of 1.0 mg/kg/day from the

cypermethrin chronic toxicity study in

dogs and a correction factor of two to

account for the differences in the

percentage of the biologically active

isomer. The LOEL of this study of 5.0

mg/kg/day was based on gastrointestinal

disturbances observed in the first week

of the study. This acute dietary

endpoint is used to determine acute

dietary risks to all population

subgroups.

2. Genotoxicity. The following

genotoxicity tests were all negative: in

vivo chromosomal aberration in rat bone

marrow cells; in vitro cytogenic

chromosome aberration; unscheduled

DNA synthesis; CHO/HGPTT mutagen

assay; weakly mutagenic: gene mutation

(Ames).

3. Reproductive and developmental

toxicity. No evidence of additional

sensitivity to young rats was observed

following pre- or postnatal exposure to

zeta-cypermethrin.

a. A two-generation reproductive

toxicity study with zeta-cypermethrin in

rats demonstrated a NOEL of 7.0 mg/kg/

day and a LOEL of 27.0 mg/kg/day for

parental/systemic toxicity based on

body weight, organ weight, and clinical

signs. There were no adverse effects in

reproductive performance. The NOEL

for reproductive toxicity was considered

to be > 45.0 mg/kg/day (the highest dose

tested).

b. A developmental study in rats

demonstrated a maternal NOEL of 12.5

mg/kg/day and a LOEL of 25 mg/kg/day

based on decreased maternal body

weight gain, food consumption and

clinical signs. There were no signs of

developmental toxicity at 35.0 mg/kg/

day, the highest dose level tested.

c. A developmental study with

cypermethrin in rabbits demonstrated a

maternal NOEL of 100 mg/kg/day and a

LOEL of 450 mg/kg/day based on

decreased body weight gain. There were

no signs of developmental toxicity at

700 mg/kg/day, the highest dose level

tested.

4. Subchronic toxicity—Short- and

intermediate-term toxicity. The systemic

NOEL of 2.5 mg/kg/day based on the

systemic NOEL of 5.0 mg/kg/day from

the cypermethrin chronic toxicity study

in dogs and a correction factor of two to

account for the biologically active

isomer would also be used for shortand intermediate-term MOE

calculations (as well as acute, discussed

in (1) above). This NOEL was based on

neurotoxic clinical signs observed in the

first week of treatment of the study.

5. Chronic toxicity—a. The RfD has

been established at 0.0050 mg/kg/day.

This RfD is based on a cypermethrin

chronic toxicity study in dogs with a

NOEL of 1.0 mg/kg/day, based on

gastrointestinal disturbances observed at

the LOEL of 5.0 mg/kg/day during the

first week of the study; an uncertainty

factor of 200 is used to account for the

differences in the percentage of the

biologically active isomer.

b. Cypermethrin is classified as a

Group C chemical (possible human

carcinogen with limited evidence of

carcinogenicity in animals) based upon

limited evidence for carcinogenicity in

female mice; assignment of a Q* has not

been recommended.

6. Animal metabolism. The

metabolism of cypermethrin in animals

is adequately understood. Cypermethrin

has been shown to be rapidly absorbed,

distributed, and excreted in rats when

administered orally. Cypermethrin is

metabolized by hydrolysis and

oxidation.

7. Metabolite toxicology. The Agency

has previously determined that the

metabolites of cypermethrin are not of

toxicological concern and need not be

included in the tolerance expression.

8. Endocrine Disruption. No special

studies investigating potential

estrogenic or other endocrine effects of

cypermethrin have been conducted.

However, no evidence of such effects

were reported in the standard battery of

required toxicology studies which have

been completed and found acceptable.

Based on these studies, there is no

evidence to suggest that cypermethrin

has an adverse effect on the endocrine

system.

C. Aggregate Exposure

1. Dietary exposure—a. Food.

Tolerances have been established for the

residues of the insecticide zetacypermethrin, in or on a variety of raw

agricultural commodities. Tolerances, in

support of registrations, currently exist

for residues of zeta-cypermethrin on

cottonseed; pecans; lettuce, head;

onions, bulb; and cabbage and livestock

commodities of cattle, goats, hogs,

horses, and sheep. For the purposes of

assessing the potential dietary exposure

for these existing tolerances, FMC has

utilized available information on

anticipated residues, monitoring data

and percent crop treated as follows:

b. Acute exposure and risk. Acute

dietary exposure risk assessments are

performed for a food-use pesticide if a

toxicological study has indicated the

possibility of an effect of concern

occurring as a result of a one day or

single exposure. For the purposes of

assessing acute dietary risk for zetacypermethrin, FMC has used the NOEL

of 0.5 mg/kg/day based on the NOEL of

1.0 mg/kg/day from the cypermethrin

chronic toxicity study in dogs and a

correction factor of two to account for

the differences in the percentage of the

biologically active isomer. The LOEL of

this study of 5.0 mg/kg/day was based

on gastrointestinal disturbances

observed in the first week of the study.

This acute dietary endpoint is used to

determine acute dietary risks to all

population subgroups. Available

information on anticipated residues,

monitoring data and percent crop

treated was incorporated into a Tier 3

analysis, using Monte Carlo modeling

for commodities that may be consumed

in a single serving. These assessments

show that the margins of exposure

(MOE) are significantly greater than the

EPA standard of 100 for all

subpopulations.

The 95th percentile of exposure for

the overall U.S. population was

estimated to be 0.000528 mg/kg/day

(MOE of 947); 99th percentile 0.001746

mg/kg/day (MOE of 286); and 99.9th

percentile 0.004069 mg/kg/day (MOE of

123).
50348 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

The 95th percentile of exposure for all

infants < 1 year old was estimated to be

0.000560 mg/kg/day (MOE of 892); 99th

percentile 0.000885 mg/kg/day (MOE of

565); and 99.9th percentile 0.001260 mg/

kg/day (MOE of 397).

The 95th percentile of exposure for

nursing infants < 1 year old was

estimated to be 0.000207 mg/kg/day

(MOE of 2,417); 99th percentile 0.000569

mg/kg/day (MOE of 879); and 99.9th

percentile 0.001442 mg/kg/day (MOE of

347).

The 95th percentile of exposure for

non-nursing infants < 1 year old was

estimated to be 0.000607 mg/kg/day

(MOE of 824); 99th percentile 0.000925

mg/kg/day (MOE of 540); and 99.9th

percentile 0.001190 mg/kg/day (MOE of

420).

The 95th percentile of exposure for

children 1 to 6 years old and 7 to 12

years old (the most highly exposed

population subgroup) was estimated to

be, respectively, 0.000740 mg/kg/day

(MOE of 676) and 0.000596 mg/kg/day

(MOE of 839); 99th percentile 0.001856

mg/kg/day (MOE of 269) and 0.002047

mg/kg/day (MOE 244); and 99.9th

percentile 0.005021 mg/kg/day (MOE of

100) and 0.004843 (MOE of 103).

Therefore, FMC concludes that the acute

dietary risk of zeta-cypermethrin, as

estimated by the dietary risk

assessment, does not appear to be of

concern.

c. Chronic exposure and risk. The

acceptable reference dose (RfD) of

0.0050 mg/kg/day for zeta-cypermethrin

is based on a NOEL of 1.0 mg/kg/day

from the cypermethrin chronic dog

study and an uncertainty factor of 200

(used to account for the differences in

the percentage of the biologically active

isomer). The endpoint effect of concern

were based on gastrointestinal

disturbances observed in the first week

of the study at the LOEL of 5.0 mg/kg/

day. A chronic dietary exposure/risk

assessment has been performed for zetacypermethrin using the above RfD.

Available information on anticipated

residues, monitoring data and percent

crop treated was incorporated into the

analysis to estimate the Anticipated

Residue Contribution (ARC).

The ARC is generally considered a

more realistic estimate than an estimate

based on tolerance level residues. The

ARC are estimated to be 0.000017 mg/

kg body weight (bwt)/day and utilize 0.3

percent of the RfD for the overall U. S.

population. The ARC for non-nursing

infants (<1 year) and nursing infants (<1

year) are estimated to be 0.000011 mg/

kg/day and 0.000002 mg/kg/day and

utilizes 0.2 percent and 0 percent of the

RfD, respectively. The ARC for children

1–6 years old and children 7–12 years

old (subgroups most highly exposed) are

estimated to be 0.000027 mg/kg bwt/day

and 0.000022 mg/kg bwt/day and

utilizes 0.5 percent and 0.4 percent of

the RfD, respectively. Generally

speaking, the EPA has no cause for

concern if the total dietary exposure

from residues for uses for which there

are published and proposed tolerances

is less than 100 percent of the RfD.

Therefore, FMC concludes that the

chronic dietary risk of cypermethrin, as

estimated by the dietary risk

assessment, does not appear to be of

concern.

2. Drinking water. Laboratory and

field data have demonstrated that

cypermethrin is immobile in soil and

will not leach into groundwater. Other

data show that cypermethrin is virtually

insoluble in water and extremely

lipophilic. As a result, FMC concludes

that residues reaching surface waters

from field runoff will quickly adsorb to

sediment particles and be partitioned

from the water column. Further, a

screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in

groundwater at depths of 1 and 2 meters

are essentially zero (<<0.001 parts per

billion).

Surface water concentrations for

pyrethroids were estimated using

PRZM3 and Exposure Analysis

Modeling System (EXAMS) using

standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 0.052 parts per

billion. Concentrations in actual

drinking water would be much lower

than the levels predicted in the

hypothetical, small, stagnant farm pond

model since drinking water derived

from surface water would normally be

treated before consumption. Based on

these analyses, the contribution of water

to the dietary risk estimate is negligible.

Therefore, FMC concludes that together

these data indicate that residues are not

expected to occur in drinking water.

3. Non-dietary exposure. Zetacypermethrin is registered for

agricultural crop applications only,

therefore non-dietary exposure

assessments are not warranted.

D. Cumulative Effects

In consideration of potential

cumulative effects of cypermethrin and

other substances that may have a

common mechanism of toxicity, to our

knowledge there are currently no

available data or other reliable

information indicating that any toxic

effects produced by cypermethrin

would be cumulative with those of other

chemical compounds; thus only the

potential risks of cypermethrin have

been considered in this assessment of its

aggregate exposure. FMC intends to

submit information for the EPA to

consider concerning potential

cumulative effects of cypermethrin

consistent with the schedule established

by EPA at 62 FR 42020 (August 4, 1997)

and other EPA publications pursuant to

the Food Quality Protection Act.

E. Safety Determination

1. U.S. population. Based on a

complete and reliable toxicology

database, the acceptable reference dose

(RfD) for zeta-cypermethrin is 0.0005

mg/kg/day, based on a NOEL of 1.0 mg/

kg/day and a LOEL of 5.0 mg/kg/day

from the cypermethrin chronic dog

study and an uncertainty factor of 200.

Available information on anticipated

residues, monitoring data and percent

crop treated was incorporated into an

analysis to estimate the Anticipated

Residue Contribution (ARC) for 26

population subgroups.

The ARC is generally considered a

more realistic estimate than an estimate

based on tolerance level residues. The

ARC are estimated to be 0.000017 mg/

kg body weight (bwt)/day and utilize 0.3

percent of the RfD for the overall U. S.

population. The ARC for non-nursing

infants (<1 year) and nursing infants (<1

year) are estimated to be 0.000011 mg/

kg/day and 0.000002 mg/kg/day and

utilizes 0.2 percent and 0 percent of the

RfD, respectively. The ARC for children

1–6 years old and children 7–12 years

old (subgroups most highly exposed) are

estimated to be 0.000027 mg/kg bwt/day

and 0.000022 mg/kg bwt/day and

utilizes 0.5 percent and 0.4 percent of

the RfD, respectively. Generally

speaking, the EPA has no cause for

concern if the total dietary exposure

from residues for uses for which there

are published and proposed tolerances

is less than 100 percent of the RfD.

Therefore, FMC concludes that the

chronic dietary risk of zetacypermethrin, as estimated by the

aggregate risk assessment, does not

appear to be of concern.

For the overall U.S. population, the

calculated margins of exposure (MOE) at

the 95th percentile was estimated to be

947; 286 at the 99th percentile; and 123

at the 99.9th percentile.

For all infants < 1 year old, the

calculated margins of exposure (MOE) at

the 95th percentile was estimated to be

892; 565 at the 99th percentile; and 397

at the 99.9th percentile.

For nursing infants < 1 year old, the

calculated margins of exposure (MOE) at
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50349

the 95th percentile was estimated to be

2,417; 879 at the 99th percentile; and 347

at the 99.9th percentile.

For non-nursing infants < 1 year old,

the calculated margins of exposure

(MOE) at the 95th percentile was

estimated to be 824; 540 at the 99th

percentile; and 420 at the 99.9th

percentile. For the most highly exposed

population subgroups, children 1–6

years old and children 7–12 years old,

the calculated MOEs at the 95th

percentile were estimated to be,

respectively, 676 and 839; 269 and 244

at the 99th percentile; and 100 and 103

at the 99.9th percentile. Therefore, FMC

concludes that there is reasonable

certainty that no harm will result from

acute exposure to zeta-cypermethrin.

2. Infants and children— a. General.

In assessing the potential for additional

sensitivity of infants and children to

residues of zeta-cypermethrin, FMC

considered data from developmental

toxicity studies in the rat and rabbit,

and a two-generation reproductive study

in the rat. The data demonstrated no

indication of increased sensitivity of

rats to zeta-cypermethrin or rabbits to

cypermethrin in utero and/or postnatal

exposure to zeta-cypermethrin or

cypermethrin. 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.

FFDCA section 408 provides that EPA

may apply an additional margin of

safety for infants and children in the

case of threshold effects to account for

pre- and post-natal toxicity and the

completeness of the database.

b. Developmental toxicity studies. In

the prenatal developmental toxicity

studies in rats and rabbits, there was no

evidence of developmental toxicity at

the highest doses tested (35.0 mg/kg/day

in rats and 700 mg/kg/day in rabbits).

Decreased body weight gain was

observed at the maternal LOEL in each

study; the maternal NOEL was

established at 12.5 mg/kg/day in rats

and 100 mg/kg/day in rabbits.

c. Reproductive toxicity study. In the

two-generation reproduction study in

rats, offspring toxicity (body weight)

and parental toxicity (body weight,

organ weight, and clinical signs) was

observed at 27.0 mg/kg/day and greater.

The parental systemic NOEL was 7.0

mg/kg/day and the parental systemic

LOEL was 27.0 mg/kg/day. There were

no developmental (pup) or reproductive

effects up to 45.0 mg/kg/day, highest

dose tested.

d. Pre- and post-natal sensitivity— i.

Pre-natal. There was no evidence of

developmental toxicity in the studies at

the highest doses tested in the rat (35.0

mg/kg/day) or in the rabbit (700 mg/kg/

day). Therefore, there is no evidence of

a special dietary risk (either acute or

chronic) for infants and children which

would require an additional safety

factor.

ii. Post-natal. Based on the absence of

pup toxicity up to dose levels which

produced toxicity in the parental

animals, there is no evidence of special

post-natal sensitivity to infants and

children in the rat reproduction study.

F. Conclusion

Based on the above, FMC concludes

that reliable data support use of the

standard 100–fold uncertainty factor,

and that an additional uncertainty factor

is not needed to protect the safety of

infants and children. As stated above,

aggregate exposure assessments utilized

significantly less than 1 percent of the

RfD for either the entire U. S.

population or any of the 26 population

subgroups including infants and

children. Therefore, it may be

concluded that there is reasonable

certainty that no harm will result to

infants and children from aggregate

exposure to cypermethrin residues.

Subchronic toxicity— Short- and

intermediate-term toxicity. The systemic

NOEL of 2.5 mg/kg/day based on the

systemic NOEL of 5.0 mg/kg/day from

the cypermethrin chronic toxicity study

in dogs and a correction factor of two to

account for the biologically active

isomer would also be used for shortand intermediate-term MOE

calculations (as well as acute, discussed

in (1) above). This NOEL was based on

neurotoxic clinical signs observed in the

first week of treatment of the study.

G. International Tolerances

There are no Codex, Canadian, or

Mexican residue limits for residues of

zeta-cypermethrin in or on cotton,

pecans, lettuce, head, onions, bulb, or

cabbage. (Stephanie Willett)

5. FMC Corporation

PP 2F2623, 4F2986, 3F2824, 7F3498,

4F3011, 4F4291

EPA has received a request regarding

(PP 2F2623, 4F2986, 3F2824, 7F3498,

4F3011, 4F4291) from FMC Corporation,

1735 Market Street, Philadelphia, PA

19103. The request proposes to remove

any time limitations on established

tolerances for residues of the insecticide

cypermethrin (±-alpha -Cyano(3-

phenoxyphenyl)methyl (±) cis, trans 3-

(2,2-dichloroethenyl)-2,2-

dimethylcyclopropanecarboxylate) in or

on the raw agricultural commodities

cottonseed at 0.5 ppm, pecans 0.05

ppm, lettuce, head at 10.0 ppm, onions,

bulb at 0.10 ppm, cabbage at 2.0 ppm,

Brassica, head and stem at 2.0 ppm and

Brassica, leafy at 14.0 ppm (established

at 40 CFR 180.418). These tolerances

were established under [PP] 2F2623,

4F2986, 3F2824, 7F3498, 4F3011, and

4F4291. EPA has determined that the

request 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 requests. Additional data

may be needed before EPA rules on the

requests.

A. Residue Chemistry

1. Plant metabolism. The metabolism

of cypermethrin in plants is adequately

understood. Studies have been

conducted to delineate the metabolism

of radiolabelled cypermethrin in various

crops all showing similar results. The

residue of concern is the parent

compound only.

2. Analytical method. There is a

practical analytical method for detecting

and measuring levels of cypermethrin in

or on food with a limit of detection that

allows monitoring of food with residues

at or above the levels set in these

tolerances (Gas Chromatography with

Electron Capture Detection - GC/ECD).

3. Magnitude of residues. Crop field

trial residue data from studies

conducted at the maximum label rates

for cotton, pecans, head lettuce, bulb

onions, cabbage, Brassica, head and

stem, and Brassica, leafy show that the

established cypermethrin tolerances on

cottonseed of 0.5 ppm, pecans 0.05

ppm, lettuce, head at 10.0 ppm, onions,

bulb at 0.10 ppm, cabbage at 2.0 ppm,

Brassica, head and stem at 2.0 ppm and

Brassica, leafy at 14.0 ppm will not be

exceeded when the cypermethrin

products labeled for these uses are used

as directed.

B. Toxicological Profile

1. Acute toxicity. For the purposes of

assessing acute dietary risk, FMC has

used the NOEL of 1.0 mg/kg/day from

the chronic toxicity study in dogs. The

LOEL of this study of 5.0 mg/kg/day was

based on gastrointestinal disturbances

observed in the first week of the study.

This acute dietary endpoint is used to

determine acute dietary risks to all

population subgroups.

2. Genotoxicty. The following

genotoxicity tests were all negative:
50350 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

gene mutation (Ames); chromosome

aberration in Chinese hamster bone

marrow cells; host mediated assay in

mice; dominant lethal assay in mice.

3. Reproductive and developmental

toxicity. No evidence of additional

sensitivity to young rats or rabbits was

observed following pre- or postnatal

exposure to cypermethrin.

a. A three-reproductive toxicity study

in rats demonstrated a NOEL of 2.5 mg/

kg/day and a LOEL of 7.5 mg/kg/day for

parental/systemic toxicity based on

decreased body weight gain in both

sexes. There were no adverse effects in

reproductive performance. The NOEL

for reproductive toxicity was considered

to be 37.5 mg/kg/day, the highest dose

level tested.

b. A developmental study in rats

demonstrated a maternal NOEL of 17.5

mg/kg/day and a LOEL of 35 mg/kg/day

based on decreased body weight gain.

There were no signs of developmental

toxicity at 70 mg/kg/day, the highest

dose level tested.

c. A developmental study in rabbits

demonstrated a maternal NOEL of 100

mg/kg/day and a LOEL of 450 mg/kg/

day based on decreased body weight

gain. There were no signs of

developmental toxicity at 700 mg/kg/

day, the highest dose level tested.

4. Subchronic toxicity. Short- and

intermediate-term toxicity. The systemic

NOEL of 5.0 mg/kg/day from the

chronic toxicity study in dogs is also

used for short- and intermediate-term

MOE calculations (as well as acute,

discussed in (1) above). This NOEL was

based on neurotoxic clinical signs

observed in the first week of treatment

of the study.

5. Chronic toxicity— a. The RfD has

been established at 0.010 mg/kg/day.

This RfD is based on a chronic toxicity

study in dogs with a NOEL of 1.0 mg/

kg/day, based on gastrointestinal

disturbances observed at the LOEL of

5.0 mg/kg/day during the first week of

the study; an uncertainty factor of 100

is used.

b. Cypermethrin is classified as a

Group C chemical (possible human

carcinogen with limited evidence of

carcinogenicity in animals) based upon

limited evidence for carcinogenicity in

female mice; assignment of a Q* has not

been recommended.

6. Animal metabolism. The

metabolism of cypermethrin in animals

is adequately understood. Cypermethrin

has been shown to be rapidly absorbed,

distributed, and excreted in rats when

administered orally. Cypermethrin is

metabolized by hydrolysis and

oxidation.

7. Metabolite toxicology. The Agency

has previously determined that the

metabolites of cypermethrin are not of

toxicological concern and need not be

included in the tolerance expression.

8. Endocrine disruption . No special

studies investigating potential

estrogenic or other endocrine effects of

cypermethrin have been conducted.

However, no evidence of such effects

were reported in the standard battery of

required toxicology studies which have

been completed and found acceptable.

Based on these studies, there is no

evidence to suggest that cypermethrin

has an adverse effect on the endocrine

system.

C. Aggregate Exposure

1. Dietary exposure— Food .

Tolerances have been established for the

residues of cypermethrin, in or on a

variety of raw agricultural commodities.

Tolerances, in support of registrations,

currently exist for residues of

cypermethrin on cottonseed; pecans;

lettuce, head; onions, bulb; cabbage;

Brassica, head and stem; Brassica, leafy

and livestock commodities of cattle,

goats, hogs, horses, and sheep. A

pending tolerance for onions, green also

exists. For the purposes of assessing the

potential dietary exposure for these

existing and pending tolerances, FMC

has utilized available information on

anticipated residues, monitoring data

and percent crop treated as follows:

i. Acute exposure and risk . Acute

dietary exposure risk assessments are

performed for a food-use pesticide if a

toxicological study has indicated the

possibility of an effect of concern

occurring as a result of a one day or

single exposure. For the purposes of

assessing acute dietary risk for

cypermethrin, the maternal NOEL of 1.0

mg/kg/day from the chronic toxicity

study in dogs was used. The LOEL of

this study of 5.0 mg/kg/day was based

on gastrointestinal disturbances

observed in the first week of the study.

This acute dietary endpoint was used to

determine acute dietary risks to all

population subgroups. Available

information on anticipated residues,

monitoring data and percent crop

treated was incorporated into a Tier 3

analysis, using Monte Carlo modeling

for commodities that may be consumed

in a single serving. These assessments

show that the MOEs are significantly

greater than the EPA standard of 100 for

all subpopulations. The 95th percentile

of exposure for the overall U. S.

population was estimated to be 0.00067

mg/kg/day (MOE of 1,493); 99th

percentile 0.002109 mg/kg/day (MOE of

474); and 99.9th percentile 0.004543 mg/

kg/day (MOE of 220). The 95th

percentile of exposure for all infants <

1 year old was estimated to be 0.000562

mg/kg/day (MOE of 1,780); 99th

percentile 0.000896 mg/kg/day (MOE of

1,116); and 99.9th percentile 0.001362

mg/kg/day (MOE of 734). The 95th

percentile of exposure for nursing

infants < 1 year old was estimated to be

0.000213 mg/kg/day (MOE of 4,706 );

99th percentile 0.000587 mg/kg/day

(MOE of 1,704); and 99.9th percentile

0.001660 mg/kg/day (MOE of 602). The

95th percentile of exposure for nonnursing infants < 1 year old was

estimated to be 0.000613 mg/kg/day

(MOE of 1,631); 99th percentile

0.000939 mg/kg/day (MOE of 1,065);

and 99.9th percentile 0.001224 mg/kg/

day (MOE of 817). The 95th percentile of

exposure for children 1 to 6 years old

(the most highly exposed population

subgroup) was estimated to be 0.000819

mg/kg/day (MOE of 1,221); 99th

percentile 0.002400 mg/kg/day (MOE of

417); and 99.9th percentile 0.005694 mg/

kg/day (MOE of 176). Therefore, FMC

concludes that the acute dietary risk of

cypermethrin, as estimated by the

dietary risk assessment, does not appear

to be of concern.

ii. Chronic exposure and risk. The

acceptable RfD is based on a NOEL of

1.0 mg/kg/day from the chronic dog

study and an uncertainty factor of 100

is 0.010 mg/kg/day. The endpoint effect

of concern were based on

gastrointestinal disturbances observed

in the first week of the study at the

LOEL of 5.0 mg/kg/day. A chronic

dietary exposure/risk assessment has

been performed for cypermethrin using

the above RfD. Available information on

anticipated residues, monitoring data

and percent crop treated was

incorporated into the analysis to

estimate the anticipated residue

contribution (ARC). The ARC is

generally considered a more realistic

estimate than an estimate based on

tolerance level residues. The ARC are

estimated to be 0.000024 mg/kg bwt/day

and utilize 0.2% of the RfD for the

overall U. S. population. The ARC for

non-nursing infants (< 1 year) and

children 1–6 years old (subgroups most

highly exposed) are estimated to be

0.000018 mg/kg bwt/day and 0.000042

mg/kg bwt/day and utilizes 0.2% and

0.4% of the RfD, respectively. Generally

speaking, the EPA has no cause for

concern if the total dietary exposure

from residues for uses for which there

are published and proposed tolerances

is less than 100% of the RfD. Therefore,

FMC concludes that the chronic dietary

risk of cypermethrin, as estimated by

the dietary risk assessment, does not

appear to be of concern.

2. Drinking water. Laboratory and

field data have demonstrated that

cypermethrin is immobile in soil and
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50351

will not leach into groundwater. Other

data show that cypermethrin is virtually

insoluble in water and extremely

lipophilic. As a result, FMC concludes

that residues reaching surface waters

from field runoff will quickly adsorb to

sediment particles and be partitioned

from the water column. Further, a

screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in

groundwater at depths of 1 and 2 meters

are essentially zero (much less than

0.001 parts per billion (ppb)). Surface

water concentrations for pyrethroids

were estimated using PRZM3 and

Exposure Analysis Modeling System

(EXAMS) using standard EPA cotton

runoff and Mississippi pond scenarios.

The maximum concentration predicted

in the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pond model since

drinking water derived from surface

water would normally be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible. Therefore,

FMC concludes that together these data

indicate that residues are not expected

to occur in drinking water.

3. Non-dietary exposure. Analyses

were conducted which included an

evaluation of potential non-dietary

(residential) applicator, post-application

and chronic dietary aggregate exposures

associated with cypermethrin products

used for residential flea infestation

control and agricultural/commercial

applications. The aggregate analysis

conservatively assumes that a person is

concurrently exposed to the same active

ingredient via the use of consumer or

professional flea infestation control

products and to chronic level residues

in the diet.

In the case of potential non-dietary

health risks, conservative point

estimates of non-dietary exposures,

expressed as total systemic absorbed

dose for each product use category

(indoor total release fogger and lawn

care) and exposed population group

(adults, children 1–6 years, and infants

< 1 year) are compared to the systemic

absorbed dose No-Observed-EffectsLevel (NOEL) for cypermethrin to

provide estimates of the MOEs. Based

on the toxicity endpoints selected by

EPA for cypermethrin, inhalation and

incidental oral ingestion absorbed doses

were combined and compared to the

relevant systemic NOEL for estimating

MOEs.

In the case of potential aggregate

health risks, the above mentioned

conservative point estimates of nondietary exposure (expressed as systemic

absorbed dose) are combined with

estimates (arithmetic mean values) of

chronic average dietary (oral) absorbed

doses. These aggregate absorbed dose

estimates are also provided for adults,

children 1–6 years and infants < 1 year.

The combined or aggregated absorbed

dose estimates (summed across nondietary and chronic dietary) are then

compared with the systemic absorbed

dose NOEL to provide estimates of

aggregate MOEs.

The total non-dietary MOEs

(combined across all product use

categories) for the inhalation +

incidental oral routes are 97,000 for

adults, 2,100 for children 1–6 years old,

and 1,900 for infants (< 1 year). The

aggregate MOE (inhalation + incidental

oral + chronic dietary, summed across

all product use categories) was

estimated to be 66,000 for adults, 2,000

for children 1–6 years old and 1,900 for

infants (<1 year). It can be concluded

that the potential non-dietary and

aggregate (non-dietary + chronic dietary)

exposures for cypermethrin are

associated with substantial margins of

safety.

D. Cumulative Effects

In consideration of potential

cumulative effects of cypermethrin and

other substances that may have a

common mechanism of toxicity, to our

knowledge there are currently no

available data or other reliable

information indicating that any toxic

effects produced by cypermethrin

would be cumulative with those of other

chemical compounds; thus only the

potential risks of cypermethrin have

been considered in this assessment of its

aggregate exposure. FMC intends to

submit information for the EPA to

consider concerning potential

cumulative effects of cypermethrin

consistent with the schedule established

by EPA at 62 FR 42020 (August 4, 1997)

and other EPA publications pursuant to

the Food Quality Protection Act.

E. Safety Determination

1. U.S. population. Based on a

complete and reliable toxicology

database, the acceptable RfD is 0.010

mg/kg/day, based on a LOEL of 5.0 mg/

kg/day from the chronic dog study and

an uncertainty factor of 100. Available

information on anticipated residues,

monitoring data and percent crop

treated was incorporated into an

analysis to estimate the Anticipated

Residue Contribution (ARC) for 26

population subgroups. The ARC is

generally considered a more realistic

estimate than an estimate based on

tolerance level residues. The ARC are

estimated to be 0.000024 mg/kg body

weight (bwt)/day and utilize 0.2% of the

RfD for the overall U. S. population. The

ARC for non-nursing infants (<1 year)

and children 1–6 years old (subgroups

most highly exposed) are estimated to

be 0.000018 mg/kg bwt/day and

0.000042 mg/kg bwt/day and utilizes

0.2% and 0.4% of the RfD, respectively.

Generally speaking, the EPA has no

cause for concern if the total dietary

exposure from residues for uses for

which there are published and proposed

tolerances is less than 100% of the RfD.

Therefore, FMC concludes that the

chronic dietary risk of cypermethrin, as

estimated by the aggregate risk

assessment, does not appear to be of

concern.

For the overall U.S. population, the

calculated MOE at the 95th percentile

was estimated to be 1,493; 474 at the

99th percentile; and 220 at the 99.9th

percentile. For all infants < 1 year old,

the calculated MOE at the 95th

percentile was estimated to be 1,780;

1,116 at the 99th percentile; and 734 at

the 99.9th percentile. For nursing infants

< 1 year old, the calculated MOE at the

95th percentile was estimated to be

4,706; 1,704 at the 99th percentile; and

602 at the 99.9th percentile. For nonnursing infants < 1 year old, the

calculated MOE at the 95th percentile

was estimated to be 1,631; 1,065 at the

99th percentile; and 817 at the 99.9th

percentile. For the most highly exposed

population subgroup, children 1 – 6

years old, the calculated MOE at the 95th

percentile was estimated to be 1,221 ;

417 at the 99th percentile; and 176 at the

99.9th percentile. Therefore, FMC

concludes that there is reasonable

certainty that no harm will result from

acute exposure to cypermethrin.

2. Infants and children— a. General.

In assessing the potential for additional

sensitivity of infants and children to

residues of cypermethrin, FMC

considered data from developmental

toxicity studies in the rat and rabbit,

and a three-reproductive study in the

rat. The data demonstrated no

indication of increased sensitivity of

rats or rabbits to in utero and/or

postnatal exposure to cypermethrin. 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.
50352 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

FFDCA section 408 provides that EPA

may apply an additional margin of

safety for infants and children in the

case of threshold effects to account for

pre- and post-natal toxicity and the

completeness of the database.

b. Developmental toxicity studies. In

the prenatal developmental toxicity

studies in rats and rabbits, there was no

evidence of developmental toxicity at

the highest doses tested (70 mg/kg/day

in rats and 700 mg/kg/day in rabbits).

Decreased body weight gain was

observed at the maternal LOEL in each

study; the maternal NOEL was

established at 17.5 mg/kg/day in rats

and 100 mg/kg/day in rabbits.

c. Reproductive toxicity study. In the

three-reproduction study in rats,

offspring toxicity (reduced mean litter

weight gain) was observed only at the

highest dietary level tested (37.5 mg/kg/

day), while toxicity in the parental

animals was observed at the lower

treatment levels. The parental systemic

NOEL was 2.5 mg/kg/day and the

parental systemic LOEL was 7.5 mg/kg/

day. There were no developmental

(pup) or reproductive effects up to 37.5

mg/kg/day (highest dose tested).

d. Pre- and post-natal sensitivity—i.

Pre-natal. There was no evidence of

developmental toxicity in the studies at

the highest doses tested in the rat (70

mg/kg/day) or in the rabbit (700 mg/kg/

day). Therefore, there is no evidence of

a special dietary risk (either acute or

chronic) for infants and children which

would require an additional safety

factor.

ii. Post-natal. Based on the absence of

pup toxicity up to dose levels which

produced toxicity in the parental

animals, there is no evidence of special

post-natal sensitivity to infants and

children in the rat reproduction study.

e. Conclusion . Based on the above,

FMC concludes that reliable data

support use of the standard 100–fold

uncertainty factor, and that an

additional uncertainty factor is not

needed to protect the safety of infants

and children. As stated above, aggregate

exposure assessments utilized

significantly less than 1% of the RfD for

either the entire U. S. population or any

of the 26 population subgroups

including infants and children.

Therefore, it may be concluded that

there is reasonable certainty that no

harm will result to infants and children

from aggregate exposure to

cypermethrin residues.

F. International Tolerances

There are no Codex, Canadian, or

Mexican residue limits for residues of

cypermethrin in or on cotton; pecans;

lettuce, head; onions, bulb; cabbage;

Brassica, head and stem, or Brassica,

leafy. (Stephanie Willett)

6. FMC Corporation, Agricultural

Products Group

PP 6F3453, 7F3546, 5F4484, and

0E3921

EPA has received a request to remove

the time limitations on established

tolerances from FMC Corporation,

Agricultural Products Group, 1735

Market Street, Philadelphia,

Pennsylvania 19103 and from the

Interregional Research Project No. 4 (IR4), New Jersey Agricultural Experiment

Station, P.O. Box 231, Rutgers

University, New Brunswick, NJ 08903.

The request proposes to remove the time

limitations on established tolerances for

residues of the insecticide bifenthrin

((2-methyl [1,1′-biphenyl]-3-yl) methyl3-(2-chloro-3,3,3,-trifluoro-1-propenyl)-

2,2-dimethylcyclopropanecarboxylate),

in or on the raw agricultural

commodities cottonseed at 0.5 parts per

million (ppm); corn, grain (field, seed,

and pop) at 0.05 ppm; hops, dried at

10.0 ppm; and strawberries at 3.0 ppm

(established at 40 CFR 180.442). These

tolerances were established under [PP]

6F3453, 7F3546, 5F4484, and 0E3921.

EPA has determined that the request

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 requests. Additional data may be

needed before EPA rules on the

requests.

A. Residue Chemistry

1. Plant metabolism. The metabolism

of bifenthrin in plants is adequately

understood. Studies have been

conducted to delineate the metabolism

of radiolabeled bifenthrin in various

crops all showing similar results. The

residue of concern is the parent

compound only.

2. Analytical method. There is a

practical analytical method for detecting

and measuring levels of bifenthrin in or

on food with a limit of detection that

allows monitoring of food with residues

at or above the levels set in these

tolerances (Gas Chromatography with

Electron Capture Detection (GC/ECD)

analytical method P-2132M.

3. Magnitude of residues. Crop field

trial residue data from studies

conducted at the maximum label rates

for cotton; corn (field, seed, pop);

strawberries, and hops show that the

established bifenthrin tolerances on

cottonseed of 0.5 ppm; corn, grain (field,

seed, and pop) of 0.05 ppm; corn, fodder

of 5.0 ppm; corn, forage of 2.0 ppm;

strawberries of 3.0 ppm, and hops, dried

of 10.0 ppm will not be exceeded when

the bifenthrin products labeled for these

uses are used as directed.

B. Toxicological Profile

1. Acute toxicity. For the purposes of

assessing acute dietary risk, FMC has

used the maternal NOEL of 1.0 mg/kg/

day from the oral developmental

toxicity study in rats. The maternal LEL

of this study of 2.0 mg/kg/day was based

on tremors from day 7-17 of dosing.

This acute dietary endpoint is used to

determine acute dietary risks to all

population subgroups.

2. Genotoxicty. The following

genotoxicity tests were all negative:

gene mutation in Salmonella (Ames);

chromosomal aberrations in Chinese

hamster ovary and rat bone marrow

cells; HGPRT locus mutation in mouse

lymphoma cells; and unscheduled DNA

synthesis in rat hepatocytes.

3. Reproductive and developmental

toxicity— a. Parental toxicity. In the rat

reproduction study, parental toxicity

occurred as decreased body weight at

5.0 mg/kg/day with a NOEL of 3.0 mg/

kg/day. There were no developmental

(pup) or reproductive effects up to 5.0

mg/kg/day (highest dose tested).

b. Post-natal sensitivity. Based on the

absence of pup toxicity up to dose levels

which produced toxicity in the parental

animals, there is no evidence of special

post-natal sensitivity to infants and

children in the rat reproduction study.

4. Subchronic toxicity. Short- and

intermediate-term toxicity. The

maternal NOEL of 1.0 mg/ kg/day from

the oral developmental toxicity study in

rats is also used for short- and

intermediate-term margins of exposure

(MOE) calculations (as well as acute,

discussed in (1) above). The maternal

lowest effect level (LEL) of this study of

2.0 mg/kg/day was based on tremors

from day 7–17 of dosing.

5. Chronic toxicity—a. The reference

dose (RfD) has been established at 0.015

mg/kg/day. This RfD is based on a 1

year oral feeding study in dogs with a

NOEL of 1.5 mg/kg/day, based on

intermittent tremors observed at the

Lowest Observed Effect Level (LOEL) of

3.0 mg/kg/day; an uncertainty factor of

100 is used.

b. Bifenthrin is classified as a Group

C chemical (possible human carcinogen)

based upon urinary bladder tumors in

mice; assignment of a Q* has not been

recommended.

6. Animal metabolism. The

metabolism of bifenthrin in animals is

adequately understood. Metabolism

studies in rats with single doses

demonstrated that about 90% of the
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50353

parent compound and its hydroxylated

metabolites are excreted.

7. Metabolite toxicology. The Agency

has previously determined that the

metabolites of bifenthrin are not of

toxicological concern and need not be

included in the tolerance expression.

8. Endocrine disruption. No special

studies investigating potential

estrogenic or other endocrine effects of

bifenthrin have been conducted.

However, no evidence of such effects

were reported in the standard battery of

required toxicology studies which have

been completed and found acceptable.

Based on these studies, there is no

evidence to suggest that bifenthrin has

an adverse effect on the endocrine

system.

C. Aggregate Exposure

1. Dietary exposure— Food.

Tolerances have been established for the

residues of bifenthrin, in or on a variety

of raw agricultural commodities.

Tolerances, in support of registrations,

currently exist for residues of bifenthrin

on hops; strawberries; corn grain, forage,

and fodder; cottonseed; and livestock

commodities of cattle, goats, hogs,

horses, sheep, and poultry.

Additionally, time-limited tolerances

associated with emergency exemptions

were recently established for broccoli,

cauliflower, raspberries, cucurbits, and

canola. A pending tolerance for

artichokes also exists. For the purposes

of assessing the potential dietary

exposure for these existing and pending

tolerances as well as the existing timelimited tolerances under FIFRA section

18 emergency exemptions, FMC has

utilized available information on

anticipated residues, monitoring data

and percent crop treated as follows:

i. Acute exposure and risk. Acute

dietary exposure risk assessments are

performed for a food-use pesticide if a

toxicological study has indicated the

possibility of an effect of concern

occurring as a result of a 1 day or single

exposure. For the purposes of assessing

acute dietary risk for bifenthrin, the

maternal NOEL of 1.0 mg/kg/day from

the oral developmental toxicity study in

rats was used. The maternal LEL of this

study of 2.0 mg/kg/day was based on

tremors from day 7–17 of dosing. This

acute dietary endpoint was used to

determine acute dietary risks to all

population subgroups. Available

information on anticipated residues,

monitoring data and percent crop

treated was incorporated into a Tier 3

analysis, using Monte Carlo modeling

for commodities that may be consumed

in a single serving. These assessments

show that the MOE are significantly

greater than the EPA standard of 100 for

all subpopulations. The 95th percentile

of exposure for the overall U.S.

population was estimated to be

0.000362 mg/kg/day (MOE of 2,762);

99th percentile 0.000732 mg/kg/day

(MOE of 1,367); and 99.9th percentile

0.002282 mg/kg/day (MOE of 438). The

95th percentile of exposure for all

infants < 1 year old was estimated to be

0.000652 mg/kg/day (MOE of 1,534);

99th percentile 0.001138 mg/kg/day

(MOE of 879); and 99.9th percentile

0.001852 mg/kg/day (MOE of 540). The

95th percentile of exposure for nursing

infants < 1 year old was estimated to be

0.000193 mg/kg/day (MOE of 5,180);

99th percentile 0.000456 mg/kg/day

(MOE of 2,192); and 99.9th percentile

0.000475 mg/kg/day (MOE of 2,107).

The 95th percentile of exposure for nonnursing infants < 1 year old was

estimated to be 0.000766 mg/kg/day

(MOE of 1,306 ); 99th percentile

0.001203 mg/kg/day (MOE of 832); and

99.9th percentile 0.001977 mg/kg/day

(MOE of 506). The 95th percentile of

exposure for children 1 to 6 years old

(the most highly exposed population

subgroup) was estimated to be 0.000632

mg/kg/day (MOE of 1,583); 99th

percentile 0.001196 mg/kg/day (MOE of

836); and 99.9th percentile 0.005277

mg/kg/day (MOE of 190). Therefore,

FMC concludes that the acute dietary

risk of bifenthrin, as estimated by the

dietary risk assessment, does not appear

to be of concern.

ii. Chronic exposure and risk. The

acceptable RfD is based on a NOEL of

1.5 mg/kg/day from the chronic dog

study and an uncertainty factor of 100

is 0.015 mg/kg/day. The endpoint effect

of concern were tremors in both sexes

of dogs at the LEL of 3.0 mg/kg/day. A

chronic dietary exposure/risk

assessment has been performed for

bifenthrin using the above RfD.

Available information on anticipated

residues, monitoring data, and percent

crop treated was incorporated into the

analysis to estimate the anticipated

residue contribution (ARC). The ARC is

generally considered a more realistic

estimate than an estimate based on

tolerance level residues. The ARC are

estimated to be 0.00002 mg/kg body

weight (bwt)/day and utilize 0.1% of the

RfD for the overall U.S. population. The

ARC for non-nursing infants (< 1 year)

and children 1–6 years old (subgroups

most highly exposed) are estimated to

be 0.000042 mg/kg bwt/day and

0.000032 mg/kg bwt/day and utilizes

0.3% and 0.2% of the RfD, respectively.

Generally speaking, the EPA has no

cause for concern if the total dietary

exposure from residues for uses for

which there are published and proposed

tolerances is less than 100% of the RfD.

Therefore, FMC concludes that the

chronic dietary risk of bifenthrin, as

estimated by the dietary risk

assessment, does not appear to be of

concern.

2. Drinking water. Laboratory and

field data have demonstrated that

bifenthrin is immobile in soil and will

not leach into groundwater. Other data

show that bifenthrin is virtually

insoluble in water and extremely

lipophilic. As a result, FMC concludes

that residues reaching surface waters

from field runoff will quickly adsorb to

sediment particles and be partitioned

from the water column. Further, a

screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethroid in

groundwater at depths of 1 and 2 meters

are essentially zero (much less than

0.001 parts per billion (ppb)). Surface

water concentrations for pyrethroids

were estimated using PRZM3 and

Exposure Analysis Modeling System

(EXAMS) using standard EPA cotton

runoff and Mississippi pond scenarios.

The maximum concentration predicted

in the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pond model since

drinking water derived from surface

water would normally be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible. Therefore,

FMC concludes that together these data

indicate that residues are not expected

to occur in drinking water.

3. Non-dietary exposure. Analyses

were conducted which included an

evaluation of potential non-dietary

(residential) applicator, post-application

and chronic dietary aggregate exposures

associated with bifenthrin products

used for residential flea infestation

control and agricultural/commercial

applications. The aggregate analysis

conservatively assumes that a person is

concurrently exposed to the same active

ingredient via the use of consumer or

professional flea infestation control

products and to chronic level residues

in the diet. In the case of potential nondietary health risks, conservative point

estimates of non-dietary exposures,

expressed as total systemic absorbed

dose (summed across inhalation and

incidental ingestion routes) for each

relevant product use category (i.e., lawn

care) and receptor subpopulation (i.e.,

adults, children 1–6 years and infants <

1 year) are compared to the systemic
50354 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

absorbed dose NOEL for bifenthrin to

provide estimates of the MOEs. Based

on the toxicity endpoints selected by

EPA for bifenthrin, inhalation and

incidental oral ingestion absorbed doses

were combined and compared to the

relevant systemic NOEL for estimating

MOEs. In the case of potential aggregate

health risks, the above-mentioned

conservative point estimates of

inhalation and incidental ingestion nondietary exposure (expressed as systemic

absorbed dose) are combined with

estimates (arithmetic mean values) of

chronic average dietary (oral) absorbed

doses. These aggregate absorbed dose

estimates are also provided for adults,

children 1–6 years and infants < 1 year.

The combined or aggregated absorbed

dose estimates (summed across nondietary and chronic dietary) are then

compared with the systemic absorbed

dose NOEL to provide estimates of

aggregate MOEs. The non-dietary and

aggregate (non-dietary + chronic dietary)

MOEs for bifenthrin indicate a

substantial degree of safety. The total

non-dietary (inhalation + incidental

ingestion) MOEs for post-application

exposure for the lawn care product

evaluated was estimated to be > 51,000

for adults, 1,900 for children 1–6 years

old and 1,800 for infants < 1 year. The

aggregate MOE (inhalation + incidental

oral + chronic dietary, summed across

all product use categories) was

estimated to be 25,000 for adults, 1,800

for children 1–6 years old and 1,600 for

infants (< 1 year). It can be concluded

that the potential non-dietary and

aggregate (non-dietary + chronic dietary)

exposures for bifenthrin are associated

with substantial margins of safety.

D. Cumulative Effects

In consideration of potential

cumulative effects of bifenthrin and

other substances that may have a

common mechanism of toxicity, to our

knowledge there are currently no

available data or other reliable

information indicating that any toxic

effects produced by bifenthrin would be

cumulative with those of other chemical

compounds; thus only the potential

risks of bifenthrin have been considered

in this assessment of its aggregate

exposure. FMC intends to submit

information for the EPA to consider

concerning potential cumulative effects

of bifenthrin consistent with the

schedule established by EPA in the

Federal Register of August 4, 1997 (62

FR 42020) (FRL–5734–6), and other EPA

publications pursuant to the FQPA.

E. Safety Determination

1. U.S. population. Based on a

complete and reliable toxicology data

base, the acceptable reference dose (RfD)

is 0.015 mg/kg/day, based on a NOEL of

1.5 mg/kg/day from the chronic dog

study and an uncertainty factor of 100.

Available information on anticipated

residues, monitoring data and percent

crop treated was incorporated into an

analysis to estimate the Anticipated

Residue Contribution (ARC) for 26

population subgroups. The ARC is

generally considered a more realistic

estimate than an estimate based on

tolerance level residues. The ARC are

estimated to be 0.00002 mg/kg body

weight (bwt)/day and utilize 0.1% of the

RfD for the overall U.S. population. The

ARC for non-nursing infants (< 1 year)

and children 1–6 years old (subgroups

most highly exposed) are estimated to

be 0.000042 mg/kg bwt/day and

0.000032 mg/kg bwt/day and utilizes

0.3% and 0.2% of the RfD, respectively.

Generally speaking, the EPA has no

cause for concern if the total dietary

exposure from residues for uses for

which there are published and proposed

tolerances is less than 100% of the RfD.

Therefore, FMC concludes that the

chronic dietary risk of bifenthrin, as

estimated by the aggregate risk

assessment, does not appear to be of

concern. For the overall U.S.

population, the calculated MOE at the

95th percentile was estimated to be

2,762; 1,367 at the 99th percentile; and

438 at the 99.9th percentile. For all

infants < 1 year old, the calculated MOE

at the 95th percentile was estimated to

be 1,534; 879 at the 99th percentile; and

540 at the 99.9th percentile. For nursing

infants < 1 year old, the calculated MOE

at the 95th percentile was estimated to

be 5,180; 2,192 at the 99th percentile;

and 2,107 at the 99.9th percentile. For

non-nursing infants < 1 year old, the

calculated MOE at the 95th percentile

was estimated to be 1,306; 832 at the

99th percentile; and 506 at the 99.9th

percentile. For the most highly exposed

population subgroup, children 1–6 years

old, the calculated MOE at the 95th

percentile was estimated to be 1,583;

836 at the 99th percentile; and 190 at

the 99.9th percentile. Therefore, FMC

concludes that there is reasonable

certainty that no harm will result from

acute exposure to bifenthrin.

2. Infants and children— a. General.

In assessing the potential for additional

sensitivity of infants and children to

residues of bifenthrin, FMC considered

data from developmental toxicity

studies in the rat and rabbit, and a twogeneration reproductive study in the rat.

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.

FFDCA section 408 provides that EPA

may apply an additional margin of

safety 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.

b. Developmental toxicity studies. In

the rabbit developmental study, there

were no developmental effects observed

in the fetuses exposed to bifenthrin. The

maternal NOEL was 2.67 mg/kg/day

based on head and forelimb twitching at

the LOEL of 4 mg/kg/day. In the rat

developmental study, the maternal

NOEL was 1 mg/kg/day, based on

tremors at the LOEL of 2 mg/kg/day.

The developmental (pup) NOEL was

also 1 mg/kg/day, based upon increased

incidence of hydroureter at the LOEL 2

mg/kg/day. There were 5/23 (22%)

litters affected (5/141 fetuses since each

litter only had one affected fetus) in the

2 mg/kg/day group, compared with zero

in the control, 1, and 0.5 mg/kg/day

groups. According to recent historical

data (1992-1994) for this strain of rat,

incidence of distended ureter averaged

11% with a maximum incidence of

90%.

c. Reproductive toxicity study. In the

rat reproduction study, parental toxicity

occurred as decreased body weight at

5.0 mg/kg/day with a NOEL of 3.0 mg/

kg/day. There were no developmental

(pup) or reproductive effects up to 5.0

mg/kg/day (highest dose tested).

d. Pre- and post-natal sensitivity— i.

Pre-natal. Since there was not a doserelated finding of hydroureter in the rat

developmental study and in the

presence of similar incidences in the

recent historical control data, the

marginal finding of hydroureter in rat

fetuses at 2 mg/kg/day (in the presence

of maternal toxicity) is not considered a

significant developmental finding. Nor

does it provide sufficient evidence of a

special dietary risk (either acute or

chronic) for infants and children which

would require an additional safety

factor.

ii. Post-natal. Based on the absence of

pup toxicity up to dose levels which

produced toxicity in the parental

animals, there is no evidence of special

post-natal sensitivity to infants and

children in the rat reproduction study.

e. Conclusion. Based on the above,

FMC concludes that reliable data

support use of the standard 100–fold

uncertainty factor, and that an

additional uncertainty factor is not

needed to protect the safety of infants
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50355

and children. As stated above, aggregate

exposure assessments utilized

significantly less than 1% of the RfD for

either the entire U.S. population or any

of the 26 population subgroups

including infants and children.

Therefore, it may be concluded that

there is reasonable certainty that no

harm will result to infants and children

from aggregate exposure to bifenthrin

residues.

F. International Tolerances

There are no Codex, Canadian, or

Mexican residue limits for residues of

bifenthrin in or on cotton; corn, field,

seed, pop; strawberries; or hops. (Adam

Heyward)

7. McLaughlin Gormley King Company

PP 7F4915

EPA has received a pesticide petition

(PP 7F4915) from McLaughlin Gormley

King Company, 8810 Tenth Avenue

North, Minneapolis, MN 55427,

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 (RS)-2-Methyl-4-oxo-3-(2-

propynyl) cyclopent-2-enyl (1RS)-cis,

trans-chrysanthemate (common name,

prallethrin; trade name ETOC), a Type

I synthetic pyrethroid in or on food

commodities at 1 ppm. EPA has

determined that the petition contains

data or information regarding the

elements set forth in section 408(d)(2) of

the FFDCA; however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data supports granting of the

petition. Additional data may be needed

before EPA rules on the petition.

A. Residue Chemistry

1. Analytical method. An adequate

analytical method is available to detect

residues of ETOC in or on food

commodities. Prallethrin can be

extracted from samples and analyzed by

gas chromatography, with final electron

capture detection. The method has been

confirmed through an independent

laboratory validation.

2. Magnitude of residues. Studies

were conducted to determine residues

resulting from the application of ETOC

by ULV spray and contact spray in a

simulated feed or food processing

situation, and in a simulated warehouse

situation. No residues were detected

following contact sprays in either

situation, with the exception of a trace

amount in a peanut sample after the

tenth treatment at 4X the normal

application rate. No residues were

detected in covered commodities after

ULV spraying of ETOC, but residues

were detected in uncovered

commodities and samples with

permeable wrapping.

B. Toxicological Profile

1. Acute toxicity. An oral dosage rat

study reported Category II toxicity with

the LD50 being 640 mg/kg for males and

460 mg/kg for females. An acute dermal

study with rats reported Category IV

toxicity. An acute inhalation study with

rats reported Category II toxicity with an

LC50 of 0.288 mg/liter for males and

0.333 mg/liter for females. Rabbits were

tested for eye and skin irritation. Eye

irritation was minimal (Category III) and

there was no skin irritation (Category

IV). ETOC is not a skin sensitizer,

based on a Guinea Pig dermal

sensitization study. Rats were dosed at

30, 100, and 300 mg/kg by oral gavage

to test acute neurotoxicity. While there

was some temporary motor activity

reduction, there were no permanent

treatment-related anomalies.

2. Genotoxicity. A bacterial reverse

mutation test using Salmonella

typhimurium and Escherichia coli

indicated that ETOC was not

mutagenic. A gene mutation assay with

Chinese hamster lung cells in both the

presence and absence of S9 metabolic

activation reported no mutagenicity. An

in vitro chromosomal aberration test

reported clastogenic potential against

Chinese hamster ovary cells (CHO-K1)

in the presence of S9 mix. An in vivo

mouse bone marrow micronucleus test

did not induce micronuclei formation in

bone marrow cells of mice. An in vivo/

in vitro unscheduled DNA synthesis test

reported no induction of DNA damage

in rat hepatocytes in vivo.

3. Reproductive and developmental

toxicity. A range-finding study was

conducted by administering 30, 60, 100,

300, 600, and 800/1,000 mg/kd/day by

oral gavage to rabbits on days 7 through

19 of presumed gestation. Significantly

decreased body weights occurred in

those rabbits receiving 300 mg/kg/day

and above, food consumption decreased

at 100 mg/kg/day and above, and deaths

occurred at 300 mg/kg/day and above.

Doses as high as 100 mg/kg/day did not

produce adverse effects in the offspring.

ETOC was then administered by oral

gavage at doses of 10, 30, 100, and 200

mg/kg/day to rabbits on days 7 through

19 of presumed gestation. The maternal

NOAEL was 100 mg/kg/day. The 200

mg/kg/day dosage caused reduced

maternal body weight gains and reduced

absolute and relative feed consumption

values. The developmental NOAEL was

reported as 200 mg/kg/day. ETOC is

not considered a developmental toxin.

A teratology study was conducted by

administering 10, 30, 100, and 300 mg/

kg/day by oral gavage to rats on days 6–

15 of presumed gestation. The

developmental NOEL was >300 mg/kg/

day and the developmental LOEL was

not determined. Compound related

maternal mortality was reported at 300

mg/kg/day. The maternal LOEL was 30

mg/kg/day, as determined by increased

mortality at 300 mg/kg/day levels,

clinical signs at the 30, 100, and 300

mg/kg/day dosages, and decreased body

weight gain and food consumption. Rats

were dosed with 12.5, 25.0, and 50 mg/

kg/day by subcutaneous injection on

days 7 through 17 of presumed

gestation. No NOEL or LOEL was

established, but the occurrence of

lumbar rib variants was significantly

higher in the offspring of the 50 mg/kg/

day group than in the controls. Rabbits

were dosed at 1, 3, and 10 mg/kg/day by

subcutaneous injection on days 6

through 18 of presumed gestation. No

effects were reported on either the dams

or the offspring. ETOC was

incorporated into the feed at

concentrations of 120, 600, 3,000, and

6,000 ppm to evaluate the reproductive

effects on two generations of rats. The

systemic toxicity and reproductive

toxicity NOEL’s were both established at

600 ppm, and the LOEL’s were both

3,000 ppm, respectively. There were

dosage-dependent effects on weight

gains, body weights, feed consumption

values, liver weights, and reduction of

pup body weight at the 3,000 and 6,000

ppm dose levels. There were no adverse

effects on viability or fertility in either

generation up to the 6,000 ppm level.

4. Subchronic toxicity. A 21–day

dermal toxicity rat study was conducted

at 30, 150 and 750 mg/kg/day. The test

article was considered a mild irritant.

The dermal NOEL was 150 mg/kg/day

and the systemic NOEL was 30 mg/kg/

day. A 13–week oral mouse study was

conducted at inclusion levels of 300,

3,000, 6,000, or 12,000 ppm. The NOEL

was 3,000 ppm, and the LOEL was 6,000

ppm. A 3–month feeding study

incorporating 100, 300, 1,000, and 3,000

ppm into the diet of rats reported a

NOEL of 300 ppm, and a LOEL of 1,000

ppm. EPA later recommended raising

the NOEL to 1,000 ppm and the LOEL

to 3,000 ppm. A 3–month oral study on

beagle dogs dosed at 3, 10, and 30 mg/

kg/day, administered by capsule,

reported a NOEL of 3 mg/kg/day and a

LOEL of 10 mg/kg/day. A 4–week

inhalation study exposed rats to 1.01,

4.39, and 19.6 mg/m3 of 92.0% ETOC,

with median aerodynamic particle

diameter of 3.77 to 4.89 m. The NOEL

was 1.01 mg/m3 and the LOEL was 4.39

mg/m3.
50356 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

5. Chronic toxicity. A 52–week oral

toxicity study was conducted on beagle

dogs administered dosage levels of 2. 5,

5.0, 10.0 or 20.0 mg/kg/day. The NOEL

was reported at 2.5 mg/kg/day; EPA’s

RfD/Peer Review Committee later

recommended 5 mg/kg/day in a DER

dated June 6, 1995. The LOEL was 5.0

mg/kg/day based upon reduced weight

gain, clinical signs, elevated cholesterol

levels and deposition of lipofuscin in

renal and bladder epithelium. A 106–

week combined oral toxicity and

oncogenicity study was performed on

rats using dietary concentrations of 80,

400, and 2,000 ppm. It was determined

that there was no carcinogenic potential

in rats. The NOEL was 80 ppm, and the

LOEL was 400 ppm. There were no

ophthalmologic, biochemical changes,

or gross pathological treatment-related

effects except for increased liver and

thyroid weights in the 400 ppm and

above level. An 80 week dietary

oncogenicity study on rats with dose

levels of 120, 600, 3,000 and 6,000 ppm

showed that the principal effect of

ETOC was increased liver weights in

those rats given the 3,000 to 6,000 ppm

diet. There was no indication of any

treatment related effect on the incidence

of neoplastic findings.

6. Animal metabolism. Solutions of

(4S), (1R)-trans- and (4S), (1R)- cis-S4068SF (ETOC) labeled with 14C were

given to rats by single oral dose or

subcutaneous administration at 2 mg/kg.

Both isomers were rapidly absorbed,

widely distributed to various tissues,

and then readily metabolized and

excreted. Neither isomer was retained or

accumulated in any tissues. There was

no marked difference in metabolic fate

between sexes and administration

routes. The absorption and disposition

of 14C-S-4068SF cis and trans isomers in

rats was determined after oral

administration of the compounds at 2

and 100 mg/kg and at 2mg/kg after 14

daily doses of the non-labeled

compounds at the same dose level. The

results indicated that the dose was

rapidly eliminated at all dose levels. A

greater proportion was excreted in the

urine of rats receiving the transcompound compared to the ciscompound, indicating a greater ester

cleavage of the trans-isomer.

Concentrations of compound in tissues

were not significantly affected by repeat

doses of unlabelled compound and

concentrations at the higher dose level

were in proportion to the increase in

dose. The greatest concentrations were

detected in the organs responsible for

excretion and metabolism (liver and

kidneys). Concentrations in these

tissues were greater in females.

7. Endocrine effects. The standard

battery of required toxicity studies is

generally considered to be sufficient to

detect any endocrine effects, and is

complete for ETOC. No developmental

or reproductive effects were noted. The

potential for ETOC to produce any

significant endocrine effects is

considered minimal

8. Metabolite toxicology. There is no

evidence that prallethrin contains

metabolites of toxicological concern.

C. Aggregate Exposure

1. Dietary exposure. A chronic dietary

exposure analysis was conducted for

exposure to potential prallethrin

residues in all food commodities that

can be exposed to prallethrin by indoor

ULV fogging treatment, crack and

crevice, and hard surface applications in

food-handling establishments. Residue

amounts from MGK field trials in a

simulated warehouse situation were

used in the analysis. Chronic dietary

exposure to prallethrin has been

conservatively estimated to be less than

1% of the RfD for all population groups.

2. Drinking water. ETOC is presently

registered only for indoor, non-food

uses. No agricultural uses are planned

for ETOC, so residues in drinking

water are not likely to be present.

3. Non-dietary exposure. Acute and

short-term non-dietary exposure

assessments were conducted to

determine the non-dietary exposure risk

of prallethrin from both registered and

pending, occupational and residential

uses. These assessments considered

oral, dermal, and inhalation exposure to

prallethrin during application and postapplication of total release aerosols,

crack and crevice sprays, broadcast

carpet/hard surface sprays, pet dipping,

and indoor ULV fogging concentrate/

contact spray. Incidental ingestion of

ETOC residues by children’s hand-tomouth behavior was included in the

assessment. All of the MOE’s for the

occupational setting were greater than

5,200, the residential MOE’s were

greater than 4,900, and the aggregate

residential assessment was greater than

1,400. These MOE values allow a

reasonable certainty that no harm will

occur from exposure to residues of

prallethrin.

D. Cumulative Effects

The EPA guidelines for product safety

testing address noticeable toxic effects

rather than the underlying mode of

toxicity. There is very little information

or data available to determine whether

or not the toxic mode of action of

prallethrin is sufficiently similar to

other Type I pyrethroids to be

cumulative.

E. Safety Determination

1. U.S. population. Based on the

conservative aggregate exposure

estimates noted above and the complete

and reliable toxicology database for

prallethrin, it is safe to conclude that

the aggregate exposure of the whole U.S.

population to prallethrin will be 0.2%

or less of the RfD of 0.05 mg/kg bw/day.

Children from 1 to 6 years old may be

exposed to a slightly higher amount of

prallethrin; 0.3% of the RfD.

Generally speaking, EPA has no

concerns about exposures which are less

than 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. It is therefore

concluded that there is a reasonable

certainty that no harm will result from

aggregate exposure to prallethrin

residues.

2. Infants and children.

Developmental toxicity studies of

prallethrin orally administered to rats

and rabbits did not demonstrate any

pre-natal sensitivies for developing

fetuses. The maternal NOEL for rats was

10 mg/kg/day, and the maternal NOEL

for rabbits was 100 mg/kg/day.

A two-generation reproduction study

of rats administered prallethrin in their

feed did not reveal any treatmentrelated reproductive or developmental

effects in either generation. The NOEL

for adult rats was found to be 120 ppm

while the LEL was 600 ppm. The NOEL

for fetotoxicity was found to be 600 ppm

and the LEL was 3,000 ppm.

Since no special sensitivities to

offspring were noted in these studies,

there is no need for an additional fold

safety factor to be applied to risk

assessments.

F. International Tolerances

There are no international maximum

residue limits established for

prallethrin; therefore, incompatibility is

not an issue. (Adam Heyward)

8. Valent U. S. A. Corporation

PP 2F4144, 3F4186, 4F4327

EPA has received a request from

Valent U. S. A. Corporation, 1333 North

California Blvd., Walnut Creek, CA

94596–8025 pursuant to section 408(d)

of the Federal Food, Drug, and Cosmetic

Act, 21 U.S.C. 346a(d), to amend 40 CFR

180.466 to remove the time limitations

on tolerances for residues of the

pyrethroid insecticide chemical

fenpropathrin, alpha-cyano-3-

phenoxybenzyl 2,2,3,3-

tetramethylcyclo-propanecarboxylate, in

or on the raw agricultural commodities

cottonseed at 1.0 parts per million
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50357

(ppm), peanut nutmeat at 0.01 ppm,

peanut vine hay at 20 ppm, strawberry

at 2.0 ppm, tomato at 0.6 ppm, meat and

meat by-products of cattle, goats, hogs,

horses and sheep at 0.1 ppm, fat of

cattle, goats, hogs, horses and sheep at

1.0 ppm, milk fat (reflecting 0.08 ppm

in whole milk) at 2.0 ppm, and poultry

meat, fat, meat by-products and eggs at

0.05 ppm, and in the processed

products cottonseed oil at 3.0 ppm and

cottonseed soapstock at 2.0 ppm. The

tolerances were first established in

response to pesticide petitions PP

2F4144, 3F4186, and 4F4327 and were

only made time limited because of

concerns associated with toxicity to

aquatic arthropods. EPA has determined

that the request contains data or

information consistent with 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

request. Additional data may be needed

before EPA rules on the request.

A. Residue Chemistry

Summary. An extensive plant and

animal metabolism data base

demonstrates that the appropriate

definition of aged fenpropathrin residue

is parent. Ruminant and poultry feeding

studies have shown that feed to residue

ratios are very low in most

commodities, with higher (but still

relatively low) ratios in fat and milk fat.

This section will describe residue data

supporting the establishment of

tolerances for residues of fenpropathrin

in or on the raw agricultural

commodities cottonseed at 1.0 parts per

million (ppm), peanut nutmeat at 0.01

ppm, peanut vine hay at 20 ppm,

strawberry at 2.0 ppm, tomato at 0.6

ppm, meat and meat by-products of

cattle, goats, hogs, horses and sheep at

0.1 ppm, fat of cattle, goats, hogs, horses

and sheep at 1.0 ppm, milk fat

(reflecting 0.08 ppm in whole milk) at

2.0 ppm, and poultry meat, fat, meat byproducts and eggs at 0.05 ppm, and in

the processed products cottonseed oil at

3.0 ppm and cottonseed soapstock at 2.0

ppm. The approved analytical method is

capillary gas-liquid chromatography

with flame ionization detection.

1. Plant metabolism. The plant

metabolism of fenpropathrin has been

studied in five different crop plant

species: cotton, apple, tomato, cabbage,

and bean. Radiocarbon labeling has

been in the cyclopropyl ring of the acid,

in the aryl rings of the alcohol, and in

the nitrile of fenpropathrin, a

cyanohydrin ester. The permutations of

radiocarbon label position and plant

species yield a total of 17 separate,

reviewed studies. Each of the studies

involved foliar treatment of the plants

under either greenhouse or field

conditions and, while the actual

treatment conditions and times to

harvest varied from study to study, the

results of the many studies are

remarkably consistent. The total toxic

residue is best defined as parent,

fenpropathrin.

Fenpropathrin remains associated

with the site of application and only

traces are found in seeds (e.g., bean or

cotton) or in other parts of the plant not

directly exposed to the application.

Much of the parent residue can be

removed from the plant material with a

mild hexane/acetone or hexane rinse,

demonstrating that the residue is

located on or near the outside surface of

the plant material. The primary

metabolic pathway for fenpropathrin in

plants is similar to that in mammals.

There are no qualitatively unique plant

metabolites; the primary aglycones are

identical in both plants and animals.

2. Analytical method. Adequate

analytical methodology is available to

detect and quantify fenpropathrin (and

its metabolites) at residue levels in

numerous matrices. The methods use

solvent extraction and partition and/or

column chromatography clean-up steps,

followed by separation and quantitation

using capillary column gas-liquid

chromatography with flame ionization

detection. The extraction efficiency has

been validated using radiocarbon

samples from the plant and animal

metabolism studies. The enforcement

methods have been validated at

independent laboratories, and by EPA.

The limit of quantitation for

fenpropathrin in raw agricultural

commodity samples is 0.01 ppm.

3. Magnitude of residues— Cotton.

The time limited section 408 tolerance

for fenpropathrin in/on cottonseed is 1.0

ppm. The use pattern allows a

maximum single application rate of 0.3

lb ai/acre, a total maximum seasonal use

of 0.8 lb ai/acre, and a 21-day phi. The

field residue experiments were

performed in six years at thirty-three

sites in nine states. There were 38

separate treatments yielding 101

separate, treated samples for analysis.

The existing time limited tolerance of

1.0 ppm is based on all of the field

residue data, including treatments at

exaggerated rates. For the subset of the

field residue samples that most closely

match the present, labeled use pattern,

0.3 lb ai/acre, 5 applications, and a 21-

day phi, the average residue was 0.069

ppm (n = 14, σn-1 = 0.091). The highest

average residue (HAR) found in these

crop field trials for fenpropathrin in/on

cottonseed was 0.28 ppm.

There are existing time limited

section 408 tolerances for fenpropathrin

in the processed products cottonseed oil

(3.0 ppm) and cottonseed soapstock (2.0

ppm). Three processing studies yielding

hulls, extracted meal, crude cottonseed

oil, refined cottonseed oil, and

cottonseed soapstock were performed.

These studies demonstrated that

fenpropathrin residues were reduced in

extracted meal but did concentrate in

refined cottonseed oil (average

concentration factor = 2.77) and

soapstock. Tolerances for the processed

products cottonseed oil and cottonseed

soapstock were needed because the

concentration factors were greater than

unity. Soapstocks are no longer

considered significant feed

commodities. The HAR times the

average concentration factor for

cottonseed oil (0.28 ppm x 2.77 = 0.78

ppm) is less than the tolerance of 1.0

ppm. Under present residue chemistry

guidelines, tolerances for cottonseed oil

and soapstock would no longer be

required.

The calculated mean residue value for

cottonseed of 0.07 ppm was used in

both the chronic and acute dietary

exposure and risk assessments since

cottonseed is a blended commodity.

Processing factors used in the

assessments were refined cottonseed oil

(2.77), cottonseed meal (0.48), and

cottonseed hulls (0.90).

Peanut. The time limited section 408

tolerances for fenpropathrin in/on

peanut nutmeat is 0.01 ppm and in/on

peanut vine hay is 20.0 ppm. The use

pattern allows a maximum single

application rate of 0.3 lb ai/acre, a total

maximum seasonal use of 0.8 lb ai/acre,

and a 14-day interval before digging the

peanuts or feeding the vines or hay. The

field residue experiments were

performed in two years at seven sites in

five states. There were 9 separate

treatments yielding 22 separate, treated

samples for analysis for nutmeats, green

vines, and dried vine hay. Data from the

subset of the field residue samples that

most closely match the present, labeled

use pattern, 0.3 lb ai/acre, 2 or more

applications, and a 14-day phi were

used to support the tolerances.

Peanut nutmeats. No finite residues

were detected (< 0.01 ppm) in 17 of 18

samples. In a single sample a finite

residue of .01 ppm was detected.

Peanut vine hay. Field dried vines,

peanuts removed, were sampled at 14-

days plus 2- to 9-days field drying time

following the last application. The

average residue found in/on peanut vine

hay was 8.31 ppm (n = 16, σn-1 = 4.64

ppm). The HAR for peanut vine hay was

16 ppm. A peanut processing study

using a very highly exaggerated field
50358 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

application rate showed positive

concentration in peanut oil and other

processed products. However, Agency

guidance has indicated that no

additional tolerances are needed.

Except for a single sample of peanut

nutmeat (0.01 ppm) all appropriate field

trial data were non-detects. Therefore,

0.005, or half the limit of detection

(LOD), was used for the chronic dietary

risk assessment, and 0.01 ppm (full

LOD) was used for the acute assessment.

Calculated mean residue values were

used for peanut commodities in both the

chronic and acute assessments because

peanuts is a blended commodity. The

processing factor for deodorized

bleached refined oil (1.33) was used in

the risk assessments since this is the

grade of peanut oil available for human

consumption. For feed, the processing

value for expeller presscake (1.33) was

used for peanut meal.

Strawberry. The time limited section

408 tolerance for fenpropathrin in/on

strawberries is 2.0 ppm. The use pattern

allows a maximum single application

rate of 0.4 lb ai/acre, a minimum 30-day

interval between treatments, a total

maximum seasonal use of 0.8 lb ai/acre,

and a 2-day phi. The field residue

experiments were performed in three

years at twelve sites in six states. There

were 47 separate treatments yielding

128 separate, treated samples for

analysis. For the subset of the field

residue samples that most closely match

the present, labeled use pattern, 0.4 lb

ai/acre, 1 or 2 applications with a

(approximately) 30-day interval between

treatments, and a 2-day phi, the average

residue was 0.65 ppm (n = 34, σn-1 =

0.44). The HAR found in these crop

field trials in/on strawberries was 1.45

ppm.

For chronic dietary exposure and risk

assessment, the mean residue value

(0.65 ppm) was used. For acute

assessment, the complete distribution of

the appropriate field trial data was used.

Tomato. The time limited section 408

tolerance for fenpropathrin in/on tomato

is 0.6 ppm. The use pattern allows a

maximum single application rate of 0.2

lb ai/acre, a total maximum seasonal use

of 0.8 lb ai/acre, and a 3-day phi. The

field residue experiments were

performed in four years ateighteen sites

in eight states. There were 27 separate

treatments yielding 118 separate, treated

samples for analysis. For the subset of

the field residue samples that most

closely match the present, labeled use

pattern, 0.2 lb ai/acre, 4 (or more)

applications, and a 3-day phi, the

average residue was 0.166 ppm (n = 54,

σn-1 = 0.132). The highest average

residue (HAR) found in these crop field

trials for fenpropathrin in/on tomatoes

was 0.55 ppm.

A tomato processing study using an

exaggerated field application rate

showed positive concentration in wet

and dried tomato pomace. However,

Agency guidance has indicated that no

additional tolerances are needed.

The mean residue value of 0.17 ppm

was used for all tomatoes in the chronic

dietary assessment, and for the blended

commodities in the acute assessment

(paste, puree, juice, and catsup). In the

acute assessments, a complete

distribution of the appropriate field trial

data was used for whole and dried

tomatoes. Appropriate concentration

factors were used for processed

commodities: tomato juice (0.05),

canned tomatoes (0.08), tomato paste

(0.3).

Secondary residues. Residues in

animal feed may transfer to animal

products, meat, milk, and eggs, used in

human food. The existing time limited

tolerances are meat and meat byproducts of cattle, goats, hogs, horses

and sheep at 0.1 ppm, fat of cattle, goats,

hogs, horses and sheep at 1.0 ppm, milk

fat (reflecting 0.08 ppm in whole milk)

at 2.0 ppm, and poultry meat, fat, meat

by-products and eggs at 0.05 ppm. The

feed items that are associated with the

existing registered uses for beef and

dairy cattle are peanut hay, cottonseed,

cotton gin by-products (feeding

restriction), cottonseed hulls, cottonseed

meal and peanut meal in descending

order of the magnitude of the

anticipated residues. For poultry and

swine only cottonseed and peanut meals

are significant feed items. Tissue to feed

residue ratios vary from a high of 0.0139

in fat to 0.001625 in milk, to a low of

0.00004 in liver in cattle. In poultry,

tissue to feed ratios vary from a high of

0.0069 in fat to a low of 0.0002 in

muscle. Both chronic and acute dietary

assessments show very low residue

contribution from secondary residues in

animal products to all population subgroups.

B. Toxicological profile

Summary. The existing registrations

and tolerances of fenpropathrin are

supported at EPA by a complete

toxicology data base. Toxicity endpoints

of concern have been identified by the

Agency’s Health Effects Division,

Hazard Identification Assessment

Review Committee. The identified

endpoints are an Acute Dietary of 6.0

mg/kg/day (systemic) and a Chronic

Dietary of 2.5 mg/kg/day (RfD = 0.025

mg/kg/day, UF = 100). No endpoints of

concern were identified by the

Committee for occupational or

residential, dermal or inhalation

exposures of any duration.

1. Acute toxicity. The following acute

toxicity studies using fenpropathrin

technical as the test material have been

reviewed and accepted by EPA to

support registration.

Acute oral, rat. The rat oral LD50

values were determined to be 54.0 and

48.5 milligrams per kilogram body

weight (mg/kg) for male and female rats,

respectively. Toxicity Category I.

Acute dermal, rat. The rat dermal

LD50 values were determined to be 1600

and 870 mg/kg for male and female rats,

respectively. Toxicity Category II.

Acute inhalation, rat. A high dosage

inhalation study is technically not

possible because of the low vapor

pressure and thick, viscous nature of

fenpropathrin technical. The study has

been waived by the Agency. Toxicity

Category IV.

Primary eye irritation, rabbit. No

corneal involvement; mild iris and

conjunctival irritation. Toxicity

Category III.

Primary dermal irritation, rabbit. No

irritation. Toxicity Category IV.

Dermal sensitization, guinea pig. Not

a sensitizer.

Acute oral and acute dermal toxicity

studies have also been submitted on the

mouse and rabbit. In the acute oral and

dermal studies, clinical signs of toxicity

included tremors, hyperexcitability,

muscular fibrillation, ataxia of the hind

limbs, urinary incontinence, diarrhea,

and salivation. The intoxicated animals

from the oral studies showed no major

changes in tissues or organs at necropsy.

Where there were sexual differences in

toxicity, females were consistently

slightly more sensitive than males.

Surviving animals recovered in two

days in the case of rats and mice and

within 4 days in the case of rabbits. In

surviving animals, all clinical signs

were completely reversible.

2. Genotoxicty. Fenpropathrin does

not present a genetic hazard. The

Agency has reviewed, accepted, and

classed as negative the following

genotoxicity tests: A gene mutation

assay (Ames), a chromosomal aberration

study in rodents, an in vitro cytogenics

assay, a sister chromatide exchange on

CHO-K1 cells, and DNA damage/repair

in Bacillus subtilis.

3. Reproductive and developmental

toxicity. There is no evidence from

reproduction or developmental toxicity

studies that the developing fetus, young

growing and developing animals, or

adult reproducing animals are any more

sensitive to fenpropathrin effects than

mature adult animals. In addition,

reproductive parameters were
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50359

unaffected at dosages higher than those

that caused overt adult toxicity.

Three-generation reproduction study,

rats. Dietary concentrations of 0, 40,

120, and 360 ppm were fed

continuously to rats for three

generations to assess the effect of

fenpropathrin on reproductive function.

(Parent) Systemic no effect level (NOEL)

of 40 ppm (M/F 3.0/3.4 mg/kg/day).

Systemic lowest effect level (LEL) of 120

(M/F 8.9/10.1 mg/kg/day)—body

tremors with spasmodic muscle

twitches, increased sensitivity, and

maternal lethality. Reproductive NOEL

120 ppm (M/F 8.9/10.1 mg/kg/day).

Reproductive LEL 360 ppm (M/F 26.9/

32.0 mg/kg/day)—Decreased mean F2

loss. (Pups) Developmental NOEL 40

ppm (M/F 3.0/3.4 mg/kg/day).

Developmental LEL 120 ppm (M/F 8.9/

10.1 mg/kg/day)—body tremors,

increased mortality.

Developmental toxicity, rabbits.

Female rabbits were treated by gavage

on days 7 through 19 of pregnancy with

0, 4, 12, and 36 mg/kg/day in corn oil

to assess the maternal and

developmental toxicity of

fenpropathrin. Maternal NOEL 4 mg/kg/

day, maternal LEL 12 mg/kg/day

(grooming, anorexia, flicking of the

forepaws). Developmental NOEL > 36

mg/kg/day, there were no compoundrelated effects on development. Clinical

signs included grooming, anorexia,

flicking of the forepaws and hindfeet,

shaky movements, trembling, stamping

of the hindfeet, and lethargy.

Developmental toxicity, rats. Female

rats were treated by gavage on days 6

through 15 of pregnancy with 0, 0.4, 1.5,

2.0, 3.0, 6.0 and 10 mg/kg/day in corn

oil to assess the maternal and

developmental toxicity of

fenpropathrin. Maternal NOEL 6 mg/kg/

day, maternal LEL of 10 mg/kg/day

(death, moribundity, ataxia, sensitivity

to external stimuli, spastic jumping,

tremors, prostration, convulsion,

hunched posture, squinted eyes,

chromodacryorrhea, and lacrimation).

Developmental NOEL > 10 mg/day. No

developmental effects were observed at

a dose that was lethally neurotoxic to 7

of 30 dams.

4. Subchronic toxicity- Subchronic

feeding, rat 3-month. Fenpropathrin was

fed to rats at dietary concentrations of

0. 3, 30, 100, 300 and 600 ppm. The

NOEL was determined to be 300 ppm

(15 mg/kg/day). The LEL was 600 ppm

(30 mg/kg/day)—body weight reduction

(F), body tremors, reduced kaolincephalin clotting time (F), increased

alkaline phosphatase and potassium

(M), increased brain (F) and kidney (M)

weights.

Subchronic feeding, dog 3-month.

Groups of six male and six female

beagle dogs were fed diets containing

250, 500. and 750 ppm fenpropathrin

for 13 weeks. The NOEL was not

determined and is less than 250 ppm

(7.25 mg/kg/day). At this dosage there

were signs of GI tract disturbance (note

dog chronic, below). At higher feeding

levels the following effects were

observed: 500 ppm (15 mg/kg/day)

produced tremors and body weight loss

in females, 750 ppm (22.25 mg/kg/day)

produced tremors, ataxia and blood

changes (reduced RBC, HCT, HGB).

Dermal, rabbit 21-day. Ten rabbits of

each sex at each dose, half with intact

skin and half with abraded skin, were

treated dermally with 500, 1200 and

3000 mg/kg/day. The experimental

animals were treated 5 days per week

for three weeks. There was localized

dermal irritation but there were no

systemic effects. The systemic NOEL

was determined to be greater than 3000

mg/kg/day.

5. Chronic toxicity. A complete

chronic data base supported by

appropriate subchronic studies for

fenpropathrin is available to the

Agency. A chronic RfD has been

identified, and a safety factor of 100 is

appropriate. Fenpropathrin shows no

evidence of oncogenicity at maximum

tolerated dosages. Clinical signs of

chronic toxicity were observed as body

tremors, at high dosages with little other

effects noted.

Oral toxicity study, dogs 12-month.

Groups of male and female beagle dogs

were fed diets containing 0, 100, 250.

and 750 ppm fenpropathrin for 52

weeks. Systemic NOEL of 100 ppm (2.5

milligram (mg)/kilogram (kg)/day) and a

systemic LEL of 250 ppm (6.25 mg/kg/

day).

Chronic/carcinogenicity feeding, rat

24-month. Groups of male and female

Charles River CD rats were fed diets

containing 0, 50, 150, 450, and 600 ppm

fenpropathrin for 104 weeks. Systemic

NOEL’s of 450 ppm in males, 150 ppm

in females (17.06 mg/kg/day and 7.23

mg/kg/day, respectively). Systemic LEL

of 600 ppm [(HDT): 22.80 mg/kg/day] in

males (increased mortality, body

tremors, increased pituitary, kidney,

and adrenal weights), and systemic LEL

of 450 ppm (19.45 mg/kg/day) in

females (increased mortality and body

tremors). There were no oncogenic

effects observed at any dose level.

Chronic/carcinogenicity feeding

study, mouse 24-month. Groups of male

and female Charles River (UK) CD-1

mice were fed diets containing 0, 40,

150, and 600 ppm fenpropathrin for 104

weeks. Systemic NOEL greater than 600

ppm HDT (males and females; 56.0 and

65.2 mg/kg/day, respectively). There

were no indications of toxicity or

carcinogenicity other than marginally

increased hyperactivity in females

dosed at 600 ppm.

Carcinogenicity. Fenpropathrin has

been classified in EPA Weight-of-the

Evidence Category ‘‘Group E—Evidence

of Non-Carcinogenicity for Humans’’ for

carcinogenicity by the EPA/RFD/PR

committee reviewed 1/29/93 and EPA

verified 3/18/93. Studies in two species

with adequate dosing show no evidence

of oncogenicity.

6. Animal metabolism. Acceptable rat

metabolism studies have been

performed using single high (25 mg/kg),

and single and multiple low (2.5 mg/kg)

doses using both sexes. Elimination was

similar in both sexes. The urine: feces

ratio of elimination was 1:2 following

the high or low single dose, and 1:1

following the 15 daily doses. The half

life was 11-16 hours in the urine, and

7-9 hours in the feces. After 7 days,

greater than 99% of the administered

dose was excreted. A small percentage

of radiolabel was found in the tissues

(primarily in the fat). The major

biotransformations included cleavage of

the ester, oxidation at the methyl group

of the acid moiety, and hydroxylation at

the 4’-position of the alcohol moiety.

Ester cleavage products, 2,2,3,3-

tetramethylcyclopropanecarboxylic acid

and (after oxidation) 3-phenoxybenzoic

acid, were excreted either directly or

conjugated as sulfates or glucuronides.

Parent was detected in the feces, but not

in the urine. Eight urinary metabolites

and 4 fecal metabolites were identified.

There are no qualitatively unique

plant metabolites . The primary

aglycones are identical in both plants

and animals; the only difference is in

the nature of the conjugating moieties

employed.

7. Metabolite toxicology. The

metabolism and potential toxicity of the

small amounts of terminal plant

metabolites have been tested on

mammals. Glucoside conjugates of 3-

phenoxy-benzyl alcohol and 3-

phenoxybenzoic acid, administered

orally to rats, were absorbed as the

corresponding aglycones following

cleavage of the glycoside linkage in the

gut. The free or reconjugated aglycones

were rapidly and completely eliminated

by normal metabolic pathways. The

glucose conjugates of 3-phenoxybenzyl

alcohol and 3-phenoxy-benzoic acid are

less toxic to mice than the

corresponding aglycones.

8. Endocrine disruption. No special

studies to investigate the potential for

estrogenic or other endocrine effects of

fenpropathrin have been performed.

However, as summarized above, a large
50360 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

and detailed toxicology data base exists

for the compound including studies

acceptable to the Agency in all required

categories. These studies include

evaluations of reproduction and

reproductive toxicity and detailed

pathology and histology of endocrine

organs following repeated or long term

exposure. These studies are considered

capable of revealing endocrine effects

and no such effects were observed.

C. Aggregate Exposure

1. Dietary exposure. Toxicity

endpoints of concern have been

identified by the Agency’s Health

Effects Division, Hazard Identification

Assessment Review Committee (July 17

and 24, 1997). The identified endpoints

are a Chronic Dietary of 2.5 mg/kg/day

(RfD = 0.025 mg/kg/day, UF = 100) and

an Acute Dietary of 6.0 mg/kg/day

(systemic). Thus, both chronic and acute

exposure and risk analyses are

necessary.

2. Food. Chronic and acute dietary

exposure analyses were performed for

fenpropathrin using anticipated

residues and accounting for proportion

of the crop treated. The crops included

in the analyses are cottonseed, currants,

peanuts, strawberries, tomatoes, and the

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.

Chronic dietary exposure was

calculated for the U.S. population and

26 population subgroups. The results

from several representative subgroups

are listed below. In all cases, chronic

dietary exposure was at or below 0.2 %

of the reference dose and strawberries

was the commodity contributing the

most exposure.

Population subgroup Exposure (mg/kg bw/day) Percent of RfD

Total U.S. Population 0.000020 008

Females (13+/Nursing) 0.000036 0.14

Non-Hispanic other than B/W 0.000053 0.21

Children (1-6 Years) 0.000035 0.14

All Infants (<1 Year Old) 0.000002 0.008

Non-Nursing Infants (<1 Year Old) 0.000003 0.012

Acute dietary exposure was

calculated for the U.S. population and

five children subgroups. The calculated

exposures and margins of exposure

(MOE) for the higher exposed

proportions of the subgroups are listed

below. It should be noted that the

population sizes are small at the lower

probability exposures (e.g. 99th and

99.9th percentiles) oftentimes leading to

unrealistically high calculated

exposures. In all cases, margins of

exposure exceed one-hundred.

Calculated Acute Dietary Exposures to Fenpropathrin Residues in Food

Population Subgroup

99th Percentile 99.9th Percentile

Exposure (mg/kg

bw/day) MOE Exposure (mg/kgbw/day) MOE

U.S. Population .000682 8,804 .002800 2,143

Children 1-6 .000916 6,547 .007465 804

Children 7-12 .000619 9,687 .003012 1,992

All Infants .001084 5,533 .001510 3,974

Nursing Infants (<1) .000297 20,230 .000416 14,412

Non-Nursing Infants (<1) .001237 4,851 .001572 3,816

3. Drinking water. Since

fenpropathrin is applied outdoors to

growing agricultural crops, the potential

exists for fenpropathrin or its

metabolites to reach ground or surface

water that may be used for drinking

water. Fenpropathrin is extremely

insoluble in water (14 ppb), with a high

octanol/water partitioning coefficient

(Kow 1.19 x 105) and a relatively short

soil half-life for parent and

environmental metabolites. The Agency

has determined that it is unlikely that

fenpropathrin or its metabolites can

leach to potable groundwater. The

residence time of fenpropathrin in

surface water is short because of its very

low water solubility and high affinity to

bind to soil. In pond studies,

fenpropathrin half-lives in the water

column were less than 1.5 days.

To quantify the potential small

exposure from drinking water, screening

evaluations of leaching potential of a

typical pyrethroid, cypermethrin, were

conducted using EPA’s Pesticide Root

Zone Model (PRIZM3). Based on this

assessment, the potential concentrations

of the pyrethroid in groundwater at

depths of 1 to 2 meters are essentially

zero (<< 0.001 parts per billion).

Potential surface water concentrations

for the pyrethroid were estimated using

PRIZM3 coupled with EPA’s Exposure

Analysis Modeling System (EXAMS)

using standard EPA cotton runoff and

Mississippi farm pond scenarios. The

maximum concentration predicted in

the simulated pond water was 0.052

ppb. Using standard assumptions about

body weight and water consumption,

the chronic exposure from this drinking

water would be 1.5 x 10-6 and 5.2 x 10-6

mg/kg bw/day for adults and children,

respectively; less than 0.02 percent of

the RfD for children. Concentrations in

actual drinking water would be much

lower than the levels predicted in the

hypothetical small stagnant farm pond

modeled, since drinking water from

surface sources receives treatment prior

to consumption. Based on these

analyses, the contribution of water to

any the dietary risk analyses is

negligible.

4. Non-dietary exposure.

Fenpropathrin, as the product TAME
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50361

2.4 EC Spray, is registered for

professional non-food use both indoors

and outdoors on ornamentals and nonbearing nursery fruit trees.

Fenpropathrin has no animal health,

homeowner, turf, termite, or industrial

uses. Quantitative information

concerning human exposure from this

ornamental use is not available, but

exposure to the general public from this

use of fenpropathrin is expected to be

minimal. It is important to note that no

endpoints of concern were identified by

the Health Effects Division, Hazard

Identification Assessment Review

Committee for occupational or

residential, dermal or inhalation

exposures of any duration. Thus, no risk

assessment is needed.

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 numerous other pesticidal

compounds, pyrethroids and natural

pyrethrins, that are structurally related

to fenpropathrin and may have similar

effects on animals. In consideration of

potential cumulative effects of

fenpropathrin 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 fenpropathrin would be

cumulative with those of other chemical

compounds. Thus, only the potential

risks of fenpropathrin have been

considered in this assessment of

aggregate exposure and effects.

Valent will submit information for

EPA to consider concerning potential

cumulative effects of fenpropathrin

consistent with the schedule established

by EPA at 62 FR 42020 (August 4, 1997)

and other EPA publications pursuant to

the Food Quality Protection Act.

E. Safety Determination

The Food Quality Protection Act

introduces a new standard of safety, a

reasonable certainty of no harm. To

make this determination, at this time the

Agency should consider only the

incremental risk of fenpropathrin in its

exposure assessment. Since the

potential chronic and acute exposures to

fenpropathrin are small (<< 100% of

RfD, MOE >> 100) the provisions of the

FQPA of 1996 will not be violated.

1. U.S. population— Chronic. Using

the dietary exposure assessment

procedures described above for

fenpropathrin, chronic dietary exposure

is minimal with all population

subgroups at or below 0.2 percent of the

RfD. Addition of the small potential

chronic exposure from drinking water

(calculated above) increases the

occupancy of the RfD by only 0.006

percent. Generally, the Agency has no

cause for concern if total residue

contribution is less than 100 percent of

the RfD.

Acute. The potential acute exposure

from food to the U.S. population (shown

above) provides an MOE greatly

exceeding 100. In a conservative policy,

the Agency has no cause for concern if

total acute exposure calculated for the

99.9th percentile yields a MOE of 100 or

larger.

2. Infants and children— Safety factor

for infants and children. In assessing the

potential for additional sensitivity of

infants and children to residues of

fenpropathrin, FFDCA section 408

provides that EPA shall apply an

additional margin of safety, up to tenfold, for added protection for infants

and children in the case of threshold

effects unless EPA determines that a

different margin of safety will be safe for

infants and children.

The toxicological data base for

evaluating pre- and post-natal toxicity

for fenpropathrin is complete with

respect to current data requirements.

There are no special pre- or post-natal

toxicity concerns for infants and

children, based on the results of the rat

and rabbit developmental toxicity

studies or the three-generation

reproductive toxicity study in rats. EPA

HED Hazard ID Committee has

concluded that reliable data support use

of the standard 100-fold uncertainty

factor and that an additional uncertainty

factor is not needed to be further

protective of infants and children.

Chronic risk. Using the conservative

exposure assumptions described above,

the percentage of the RfD that will be

utilized by dietary (food only) exposure

to residues of fenpropathrin ranges from

0.14 % for children (1–6 years old) and

0.012% for non-nursing infants (< 1 year

old). Addition of the small potential

chronic exposure from drinking water

(calculated above) increases the

occupancy of the RfD by only 0.02

percent. Generally, the Agency has no

cause for concern if total residue

contribution is less than 100 percent of

the RfD.

Acute. The potential acute exposure

from food to populations of infants and

children (shown above) provide MOE

values greatly exceeding 100 In a

conservative policy, the Agency has no

cause for concern if total acute exposure

calculated for the 99.9th percentile

yields a MOE of 100 or larger.

Aggregate acute or chronic dietary

exposure to various sub-populations of

children and adults demonstrate

acceptable risk. Chronic exposures to

fenpropathrin occupy considerably less

than 100% of the RfD, and all acute

MOE values exceed 100. Chronic and

acute dietary risk to children from

fenpropathrin should not be of concern.

Further, fenpropathrin has no other

uses, such as indoor pest control,

homeowner or turf, that could lead to

unique, enhanced exposures to

vulnerable sub-groups of the

population. It can be concluded that

there is a reasonable certainty that no

harm will result to any sub-group of the

U.S. population, including infants and

children, from aggregate chronic or

acute exposure to fenpropathrin

residues.

F. International Tolerances

Codex Maximum Residue Limits

186 Fenpropathrin

Main uses 8 Insecticide/acaracide

JMPR 83

ADI 0.03 mg/kg body weight (1993)
50362 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

Codex Maximum Residue Limits—Continued

Residue Fenpropathrin (fat soluble)

Commodity

MRL (mg/kg) Step JMPR CCPR

Code Name

MM 0812 Cattle meat 0.5 (fat) 6 93

ML 0812 Cattle milk 0.1 F 6st 93

MO 0812 Cattle, Edible offal of 0.05 CXL (1995)

SO 0691 Cotton seed 1 CXL (1995)

OC 0691 Cotton seed oil, Crude 3 CXL (1995)

VO 0440 Egg plant 0.2 6 93

PE 0112 Eggs 0.01 (*) CXL (1995)

VC 0425 Gherkin 0.2 CXL (1995)

FB 0269 Grapes 5 6 93

VO 0445 Peppers, Sweet 1 CXL (1995)

FP 0009 Pome fruits 5 CXL (1995)

PM 0110 Poultry meat 0.02 (fat) CXL (1995)

PO 0111 Poultry, Edible offal of 0.01 (*) CXL (1995)

VO 0448 Tomato 1 CXL (1995)

There are small differences between

the section 408 tolerances and the

Codex MRL values for secondary

residues in animal products. These

minor differences are mainly caused by

differences in the methods used to

calculate animal feed dietary exposure.

The only substantial difference between

the US tolerance and the Codex MRL

value is for tomatoes. The JMPR

reviewer required that the MRL exceed

the highest field residue, and rounded

to unity. The EPA reviewer agreed with

Valent that one set of field residue

samples was possibly compromised by

the presence of a high rate processing

treatment nearby. High outliers were

ignored, and the tolerance was set at 0.6

ppm. (Adam Heyward)

9. Zeneca Ag Products

PP 7G3518, 7F3521, 4F4406

EPA has received a request from

Zeneca Ag Products, P. O. Box 15458,

Wilmington, DE, 19850–5458 proposing

pursuant to section 408(d) of the Federal

Food, Drug and Cosmetic Act (FFDCA),

21 U.S.C. 346a(d), to amend 40 CFR part

180 by removing the time limitation for

tolerances established for residues of the

insecticide and pyrethriod Tefluthrin in

or on the raw agricultural commodities

corn, grain, field and pop; corn, forage

and fodder, field, pop and sweet; and

corn, fresh (including sweet K and corn

with huskremoved (CWHR)) at 0.06

ppm. The International Union of Pure

and Applied Chemist (IUPAC) name for

tefluthrin is (2,3,5,6-tetrafluro-4-

methylphenyl)methyl-(1 alpha, 3 alpha)-

(Z)-(+/¥)-3(2-chloro-3,3,3-trifluoro-1-

propenyl)-2,2-

dimethylcyclopropanecarboxylate) and

its metabolite (Z)-3-(2-chloro-3,3,3-

trifluroro-1-propenyl)-2,2-

dimethylcyclopropanecarboxylic acid.

The tolerances were originally requested

in Pesticide Petition Numbers 7G3518,

7F3521, and 4F4406. 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

tefluthrin residues in plants and

animals for corn use is adequately

understood. The residue of concern is

tefluthrin and its metabolite. There is no

reasonable expectation of secondary

residues in animal tissues and milk

from the use as delineated in 40 CFR

180.6(a)(3).

2. Analytical method. An adequate

analytical method, gas liquid

chromatography with an electron

capture detector, is available for

enforcement purposes. The enforcement

methodology has been submitted to the

Food and Drug Administration, and is

published in the Pesticide Analytical

Manual Vol. II (PAM II).

3. Magnitude of residues. Tefluthrin

(also know as FORCE Insecticide) is an

effective granular soil insecticide

registered for use against a number of

soil corn pest; the most economically

significant being soil dwelling pest,

such as corn rootworm, wireworm,

cutworm, and white grubs. Residue data

covering all the uses associated with the

permanent tolerances requested by this

petition have been previously submitted

to EPA for review and have been found

by EPA to support the requested

tolerances. See February 1, 1989 (54 FR

5080); and May 3, 1996 (61 FR 19852)

(FRL–5358–5).

B. Toxicological Profile

1. Acute toxicity. Acute toxicity

studies with the technical grade of the

active ingredient tefluthrin: Oral LD50 in

the rat is 22 mg/kg) for (males) and 35

mg/kg for (females); dermal LD50 in the

rat is 316 mg/kg in (males) and 177 mg/

kg in (females); acute inhalation LC50 in

the rat is 0.04 milligram/liter (mg/l) and

0.05 mg/l in female and male rats,

respectively; primary eye irritation in

the rabbit study showed slight irritation;

primary dermal irritation in the rabbit

study showed none to slight irritation,

and the dermal sensitization in the

guinea pig study showed no skin

sensitization.

2. Genotoxicty. The following

genotoxicity test were all negative: A

gene mutation assay (Ames), dominant

lethal (mouse in vivo), mouse

micronucleus (in vivo), acute

cytogenetic study in the rat,

unscheduled DNA synthesis and a

mouse lymphoma cells test.

3. Reproductive and developmental

toxicity. In a rat developmental study,
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50363

delayed ossification was noted in the

highest dose group (5 mg/kg/day), along

with significant maternal toxicity

(decreased body weight (bwt)). The

developmental no observed effect level

(NOEL) for this study was established at

3 mg/kg/day. However, the effects

observed were most likely a secondary

effect resulting from maternal stress.

In a developmental toxicity study in

rabbits given gavage doses of 0, 3, 6, and

12 mg/kg/day, the maternal NOEL is 3

mg/kg/day and the developmental

NOEL is > 12 mg/kg/day. No

developmental effects were observed

under the conditions of the study.

In a rat multi-generation reproduction

study, conducted at 0, 15, 50, and 250

ppm with tefluthrin in the diet, a

reproductive NOEL was established at

50 ppm (3.4 mg/kg/day) based on

reduced pup weight and litter size

observed at 250 ppm (12.5 mg/kg/day).

Parental toxicity (in the form of

abnormal, sprayed, or high-stepping

gait) was also observed at 250 ppm.

Thus, the effects observed in offspring at

250 ppm is considered to be secondary

to maternal toxicity.

4. Subchronic toxicity. A 90–day

feeding study in which rats were fed

doses of 0, 50, 150, and 350 ppm with

a NOEL of 50 ppm and a lowest

observed effect level (LOEL) of 150 ppm

based on mild dose changes in

hemoglobin, cholesterol, and liver

weight.

A 90–day feeding study in which dogs

were fed doses of 0, 0.1, 0.5, and 1.5 mg/

kg with a NOEL of 0.5 mg/kg and a

LOEL of 1.5 mg/kg based on increased

triglycerides and AST.

A 21–day dermal study in which rats

were exposed dermally to doses of 1, 5,

and 50 mg/kg/day, 6 hours/day with a

toxicological NOEL of 1mg/kg.

5. Chronic toxicity. A 12–month

feeding study in dogs was conducted

with a NOEL of 0.5 mg/kg/day. The

LOEL for this study is established at 2

mg/kg/day based upon ataxia.

A 24–month rat and mouse chronic

feeding/oncogenicity studies were

conducted with systemic NOEL’s of

1.1mg/kg/day and 3.4 mg/kg/day with

no oncogenic effects observed at dose

levels up to and including 18.2 mg/kg/

day and 54.4 mg/kg/day, the highest

dose levels tested for rats and mice,

respectively.

6. Animal metabolism. A metabolism

study in the rat demonstrated that

distribution patterns and excretion rates

in multiple oral dosing periods are

similar to single-dose studies. The

metabolism of tefluthrin in livestock has

been studied in the goat and chicken.

The nature of tefluthrin residue in

animals for corn use is adequately

understood. The residue of concern is

tefluthrin and its metabolite. There is no

reasonable expectation of secondary

residues in animal tissues and milk

from the use as delineated in 40 CFR

180.6(a)(3).

7. Metabolite toxicology. The nature of

tefluthrin residue in plants and animals

for corn use is adequately understood.

The residue of concern is tefluthrin and

its metabolite. There is no reasonable

expectation of secondary residues in

animal tissues and milk from the use as

delineated in 40 CFR 180.6(a)(3). An

adequate analytical method, gas liquid

chromatography with an electron

capture detector, is available for

enforcement purposes. The enforcement

methodology has been submitted to the

Food and Drug Administration, and is

published in the Pesticide Analytical

Manual Vol. II (PAM II).

8. Endocrine disruption. EPA is

required to develop a screening program

to determine whether certain substances

(including all pesticides and inerts)

‘‘may have an effect produced by a

naturally occurring estrogen, or such

other endocrine effect... .’’ The Agency

is currently working with interested

stakeholders, including other

government agencies, public interest

groups, industry and research scientists,

in developing a screening and testing

program and a priority setting scheme to

implement this program. Congress has

allowed 3 years from passage of the

Food Quality Protection Act (FQPA)

(August 3, 1999) to implement this

program. At that time, EPA may require

further testing of this active ingredient

and end use products for endocrine

disrupter effects.

C. Aggregate Exposure

The primary source of human

exposure to tefluthrin will be from

ingestion of raw and processed food

commodities which have been treated

with tefluthrin. These commodities

include corn, grain, field and pop; corn,

forage and fodder, field, pop and sweet;

and corn, fresh (including sweet K and

CWHR) as listed in 40 CFR 180.440.

There is no reasonable expectation of

secondary residues in animal tissues,

milk, or eggs from use as delineated in

40 CFR 180.6(a)(3).

1. Dietary exposure. For purposes of

assessing the potential dietary exposure

under these tolerances, aggregate

exposure is estimated based on the

Theoretical Maximum Residue

Contribution (TMRC) from the existing

tolerances for tefluthrin in food crops.

The TMRC is obtained by multiplying

the tolerance level residues by the

consumption data which estimates the

amount of those food products eaten by

various population subgroups. The

following assumptions were used in

conducting this exposure assessment:

100 percent of the crops were treated,

and the raw agricultural commodities

(RAC) residues would be at the level of

the tolerance. This results in an

overestimate of human exposure and a

conservative assessment of risk.

2. Food. The acute dietary risk

assessment used tolerance level residues

and assumed that 100 percent of all

crops were treated. Thus, this acute

dietary exposure estimate is considered

‘‘worst-case’’ and severely overestimates

potential exposure. The acute dietary

Margin of Exposure (MOE) for the most

highly exposed population subgroup

was children ages one to six. The MOE’s

were 2,436 at the 95th percentile, 1,342

at the 99th percentile, and 738 at the

99.9th percentile. EPA concludes that

there is a reasonable certainty of no

harm for MOE of 100 or greater.

Therefore, the acute dietary risk

assessment for tefluthrin clearly

indicates a reasonable certainty of no

harm.

For the chronic dietary assessment

Zeneca used the standard EPA

conservative exposure assumptions (i.e.

tolerance level residues and 100 percent

market share), and based on the

completeness and reliability of the

toxicity data Zeneca has concluded that

the aggregate exposure to this chemical

will utilize less than one percent (0.40

percent) of the reference dose (RfD) for

the U. S. population. The most highly

exposed population subgroup was

children ages one to six with a total

dietary exposure of 0.000049 mg/kg

bwt/day (1.0 percent of the RfD). Since

EPA generally has no concern for

exposures below 100 percent of the RfD,

there is a reasonable certainty that no

harm will result from aggregate

exposure to residues.

3. Drinking water. Tefluthrin is

immobile in soil and, therefore, will not

leach into ground water. Additionally,

due to the insolubility and lipophilic

nature of tefluthrin, any residues in

surface water will rapidly and tightly

bind to soil particles and remain with

sediment, therefore not contributing to

potential dietary exposure from

drinking water.

A screening evaluation of leaching

potential of a typical synthetic

pyrethroid was conducted using EPA’s

Pesticide Root Zone Model (PRZM3).

Based on this screening assessment,

potential concentrations of a pyrethroid

in ground water at depths of 1 to 2

meters are essentially zero (<0.001 ppb).

Surface water concentrations for

pyrethroids were estimated using

PRZM3 and Exposure Analysis
50364 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

Modeling Systems (EXAMS) using

standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pond model since

drinking water derived from surface

water would normally be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible.

4. Non-dietary exposure. The

potential for non-occupational exposure

to the general population is expected to

be essentially zero. Tefluthrin is not

registered for aquatic and/or domestic

outdoor or indoor uses. The major use

(corn) is applied only once per year at

planting as a granular formulation. The

other use is limited to commercial seed

treatment of field corn, popcorn,

seedcorn, and sweet corn seed. There is

a commercial use in liquid slurry seed

treaters and seed coating equipment,

which is not for use on agricultural

establishments in hopper-box, planterbox, slurry-box, or other seed treatment

applications. The other minor use is for

the treatment of fire ants for

containerized and balled nursery stock

under the USDA/APHIS Imported Fire

Ant Quarantine Program (Department of

Agriculture-Animal and Plant Health

Inspection Service-7 CFR part 301).

D. Cumulative Effects

Zeneca will submit information for

EPA to consider concerning potential

cumulative effects of tefluthrin

consistent with the schedule established

by EPA on August 4, 1997 (62 FR 42020)

(FRL–5734–6) and other EPA

publications pursuant to the FQPA. At

this time, Zeneca cannot make a

determination, based on available and

reliable information, that tefluthrin and

other substances that may have a

common mechanism of toxicity would

have cumulative effects. Therefore, for

purposes of this request it is appropriate

only to consider the potential risks of

tefluthrin in an aggregate exposure

assessment.

E. Safety Determination

1. U.S. population. EPA recently

reviewed all of the toxicity end points

for the synthetic pyrethroids. Based on

this review EPA concluded that the

chronic RfD is 0.005 mg/kg/day. This

RfD is based on a 1–year dog feeding

study with a NOEL of 0.5 mg/kg/day for

ataxia, and a 100–fold uncertainty

factor. In addition, EPA derived an

acute NOEL of 0.5 mg/kg/day for use in

acute dietary risk assessment. This

NOEL is based on the 1–year dog

feeding study in which increased

incidence of tremors in both sexes of

dogs was observed on the first day of

dosing.

Using these RfD’s and EPA’s standard

default assumptions (i.e. tolerance level

residues and 100 percent market share),

Zeneca assessed the potential acute and

chronic dietary risk to the general U.S.

population and 22 subpopulations.

These analyses are considered ‘‘worstcase’’, and the results concluded that for

the U.S. population, uses were 0.000021

mg/kg/day (0.4 of the RfD). The acute

MOE’s at the 95th, 99th, and 99.9th

percentile were 5.195, 2,449, and 1,091

respectively. The most highly exposed

population subgroup (children ages one

to six), utilizes 1.0 percent of the

chronic RfD, and the acute dietary

MOE’s at the 95th, 99th, and 99.9th

percentiles were 2,436, 1,342, and 738,

respectively. These assessments indicate

a reasonable certainty that no harm will

result from aggregate exposure to

residues.

2. Infants and children. Section 408 of

the FFDCA provides that EPA shall

apply an additional 10–fold margin of

safety for infants and children in the

case of threshold effects to account for

pre– and post-natal toxicity and the

completeness of the database unless

EPA determines that a different margin

of safety will be safe for infants and

children. EPA generally defines the

level of appreciable risk as exposure

that is greater than 1⁄100 of the NOEL in

the animal study appropriate to the

particular risk assessment. This 100–

fold uncertainty (safety) factor/margin of

exposure is designed to account for

combined inter- and intra-species

variability. EPA believes that reliable

data support using the standard 100–

fold margin/factor, not the additional

10–fold margin/factor, when EPA has a

complete database under existing

guidelines and when the severity of the

effect in infants and children or the

potency or unusual toxic properties of a

compound do not raise concerns

regarding the adequacy of the standard

margin/factor.

In assessing the potential for

additional sensitivity of infants and

children to residues of tefluthrin, EPA

considered the data from oral

developmental toxicity studies in the rat

and rabbit, as well as data from a multigeneration reproduction study in the rat.

The developmental toxicity studies are

designed to evaluate adverse effects in

the developing organism resulting from

pesticide exposure during prenatal

development in the mothers.

Reproduction studies provide

information relating to effects from

exposure to the pesticide on the

reproductive capability of mating

animals and data on systemic toxicity.

3. Pre-natal effects. In a rat

developmental study delayed

ossification was noted in the highest

dose group (5 mg/kg/day), along with

significant maternal toxicity (decreased

bwt). The developmental NOEL for this

study was established at 3 mg/kg/day.

However, the effects observed were

most likely a secondary effect resulting

from maternal stress.

In a developmental toxicity study in

rabbits given gavage doses of 0, 3, 6, and

12 mg/kg/day the maternal NOEL is 3

mg/kg/day, and the developmental

NOEL is > 12 mg/kg/day. No

developmental effects were observed

under the conditions of the study.

4. Post-natal effects. In a rat multigeneration reproduction study

conducted at 0, 15, 50, and 250 ppm

with tefluthrin in the diet, a

reproductive NOEL was established at

50 ppm (3.4 mg/kg/day), based on

reduced pup weight and litter size

observed at 250 ppm (12.5 mg/kg/day).

Parental toxicity (in the form of

abnormal, sprayed, or high-stepping

gait) was also observed at 250 ppm.

Thus, the effects observed in offspring at

250 ppm is considered to be secondary

to maternal toxicity.

In EPA’s review of the toxicity

endpoints for tefluthrin they concluded

that the data on developmental and

reproductive toxicity tests do not

indicate any increased pre- or post-natal

sensitivity. Therefore, EPA concluded

that reliable data support use of a 100–

fold safety factor, and additional 10–

fold safety factor is not needed. This

aggregate assessment of tefluthrin

clearly demonstrates that there is no

harm for all population groups.

F. International Tolerances

There are no Codex Maximum

Residue Levels (MRL’s) established for

tefluthrin. (John Hebert)

10. Zeneca Ag Products

PPs 7F3560, 7H5543, 7F3488, 1F3952,

1H5607, 1F3992, 2F4109, 2F4100,

2F4114, 1F3985, and 6F4769

EPA has received a request from

Zeneca Ag Products, 1800 Concord Pike,

P.O. Box 15458, Wilmington, Delaware

19850–5458, proposing pursuant to

section 408(d) of the Federal Food, Drug

and Cosmetic Act (FFDCA), 21 U.S.C.

346a(d), to amend 40 CFR 180.438 by

removing the time limitation for

tolerances established for residues of

lambda-cyhalothrin and its epimer in or

on the following crops and

commodities: broccoli at 0.4 ppm;
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50365

cabbage at 0.4 ppm; cattle, fat at 3.0

ppm; cattle, meat at 0.2 ppm; cattle,

meat and meat by-products (mbyp) at

0.2 ppm; corn, grain (field and pop) at

0.05 ppm; corn, fodder at 1.0 ppm; corn,

forage at 6.0 ppm; corn, sweet (k+kwhr)

at 0.05 ppm; cottonseed at 0.05 ppm;

dry bulb onion at 0.1 ppm; eggs at 0.01

ppm; garlic at 0.1 ppm; goats, fat at 3.0

ppm; goats, meat at 0.2 ppm; goats,

mbyp at 0.2 ppm, hogs, fat at 3.0 ppm;

hogs, meat at 0.2 ppm; hogs, mbyp at 0.2

ppm; horses, fat at 3.0 ppm; horses,

meat at 0.2 ppm; horses, mbyp at 0.2

ppm; lettuce, head at 2.0 ppm; milk, fat

(reflecting 0.2 ppm in whole milk) at 5.0

ppm; peanuts at 0.05 ppm; peanuts,

hulls at 0.05 ppm; poultry, fat at 0.01

ppm; poultry, meat at 0.01 ppm;

poultry, mbyp at 0.01 ppm; rice, grain

at 1.0 ppm; rice, hulls at 5.0 ppm; rice,

straw at 1.8 ppm; sheep, fat at 3.0 ppm;

sheep, meat at 0.2 ppm; sheep, mbyp at

0.2 ppm; soybeans at 0.01 ppm;

sorghum, grain at 0.02 ppm; sorghum,

grain dust at 1.5 ppm; sunflower, seeds

at 0.2 ppm; sunflower, forage at 0.2

ppm; tomatoes at 0.1 ppm; wheat, grain

at 0.05 ppm; wheat, forage at 2.0 ppm;

wheat, hay at 2.0 ppm; wheat, straw at

2.0 ppm; wheat, grain dust at 2.0 ppm;

corn, grain flour at 0.15 ppm; sunflower,

oil at 0.30 ppm; sunflower, hulls at 0.50

ppm; tomato pomace (dry or wet) at 6.0

ppm; and wheat, bran at 0.2 ppm. The

IUPAC name for lambda-cyhalothrin is

a 1:1 mixture of (S)-alpha-cyano-3-

phenoxybenzyl-(Z)-(1R,3R)-3-(2-chloro3,3,3-trifluoroprop-1-enyl)-2,2-

dimethylcyclopropanecarboxylate and

(R)-alpha-cyano-3-phenoxybenzyl-(Z)-

(1S,3S)-3-(2-chloro-3,3,3-trifluoroprop1-enyl)-2,2-

dimethylcyclopropanecarboxylate and

the epimer of lambda-cyhalothrin is a

1:1 mixture of (S)-alpha-cyano-3-

phenoxybenzyl-(Z)-(1S,3S)-3-(2-chloro3,3,3-trifluoroprop-1-enyl)-2,2-

dimethylcyclopropanecarboxylate and

(R)-alpha-cyano-3-phenoxybenzyl-(Z)-

(1R,3R)-3-(2-chloro-3,3,3-trifluoroprop1-enyl)-2,2-

dimethylcyclopropanecarboxylate.

These tolerances were originally

requested in Pesticide Petition Numbers

7F3560, 7H5543, 7F3488, 1F3952,

1H5607, 1F3992, 2F4109, 2F4100,

2F4114, 1F3985, and 6F4769. EPA has

determined that the petitions 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 the request.

Additional data may be needed before

EPA rules on the request.

A. Residue Chemistry

1. Plant metabolism.The metabolism

of lambda-cyhalothrin has been studied

in cotton, soybean, cabbage and wheat

plants. The studies show that the

metabolism generally follows that of

other pyrethroid insecticides. The ester

linkage is cleaved to form

cyclopropanecarboxylic acids and the

corresponding phenoxybenzyl alcohol.

Overall the studies show that

unchanged lambda-cyhalothrin is the

principal constituent of the residue on

edible portions of these crops.

2. Analytical method. An adequate

analytical method (gas liquid

chromatography with an electron

capture detector) is available for

enforcement purposes.

3. Magnitude of residues. Field

residue trials, meeting EPA study

requirements, have been conducted for

each crop in this petition. These data

have previously been reviewed and

classified by the Agency as supportive

of these tolerances.

B. Toxicological Profile

The following toxicity studies have

been conducted to support this request.

1. Acute toxicity. Acute toxicity

studies with the technical grade of the

active ingredient lambda-cyahothrin:

oral LD50 in the rat of 79 millgrams/

kilogram (mg/kg) (males) and 56 mg/kg

(females), dermal LD50 in the rat of 632

mg/kg (males) and 696 mg/kg females,

primary eye irritation study showed

mild irritation and primary dermal

irritation study showed no irritation.

2. Genotoxicty. The following

genotoxicity tests were all negative: a

gene mutation assay (Ames), a mouse

micronucleus assay, an in-vitro

cytogenetics assay, and a gene mutation

study in mouse lymphoma cells.

3. Reproductive and developmental

toxicity. A three-generation

reproduction study in rats fed diets

containing 0, 10, 30, and 100 ppm with

no developmental toxicity observed at

100 ppm, the highest dose tested. The

maternal NOEL and LOEL for the study

are established at 30 (1.5 mg/kg/day)

and 100 ppm (5 mg/kg/day),

respectively, based upon decreased

parental body weight gain. The

reproductive NOEL and LOEL are

established at 30 (1.5 mg/kg/day) and

100 ppm (5 mg/kg/day), respectively,

based on decreased pup weight gain

during weaning.

A developmental toxicity study was

conducted in rats given gavage doses of

0, 5, 10, and 15 mg/kg/day with no

developmental toxicity observed under

the conditions of the study. The

developmental NOEL is greater than 15

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

maternal NOEL and LOEL are

established at 10 and 15 mg/kg/day,

respectively, based on reduced body

weight gain.

A developmental toxicity study was

conducted in rabbits given gavage doses

of 0, 3, 10, and 30 mg/kg/day with no

developmental toxicity observed under

the conditions of the study. The

maternal NOEL and LOEL are

established at 10 and 30 mg/kg/day,

respectively based on decreased body

weight gain. The developmental NOEL

is greater than 30 mg/kg/day, the highest

dose tested.

4. Subchronic toxicity. A 90–day

feeding study in rats fed doses of 0, 10,

50 and 250 ppm with a NOEL of 50 ppm

and a LOEL of 250 ppm based on body

weight gain reduction.

A study where lambda-cyhalothrin in

olive oil was applied to the skin of rats

for 21 successive days at dose rates of

1, 10, or 100 (reduced to 50 after 2–3

applications) mg/kg/day. A NOEL of 10

mg/kg/day is based on clinical signs of

slight general toxicity at 50 mg/kg/day.

5. Chronic toxicity. A 12–month

feeding study was conducted in dogs

fed dose (by capsule) levels of 0, 0.1,

0.5, 3.5 mg/kg/day with a NOEL of 0.1

mg/kg/day. The LOEL for this study is

established at 0.5 mg/kg/day based upon

clinical signs of neurotoxicity.

A 24–month chronic feeding/

carcinogenicity study was conducted

with rats fed diets containing 0, 10, 50,

and 250 ppm. The NOEL was

established at 50 ppm and LOEL at 250

ppm based on reduced body weight

gain. There were no carcinogenic effects

observed under the conditions of the

study.

A carcinogenicity study was

conducted in mice fed dose levels of 0,

20, 100, or 500 ppm (0, 3, 15, or 75 mg/

kg/day) in the diet for 2 years. A

systemic NOEL was established at 100

ppm and systemic LOEL at 500 ppm

based on decreased body weight gain in

males throughout the study at 500 ppm.

The Agency has classified lambdacyhalothrin as a Group D carcinogen

(not classifiable due to an equivocal

finding in this study). It is Zeneca’s

position that no treatment-related

carcinogenic effects were observed

under the conditions of the study.

6. Animal metabolism. Metabolism

studies in rats demonstrated that

distribution patterns and excretion rates

in multiple oral dose studies are similar

to single-dose studies. Accumulation of

unchanged compound in fat upon

chronic administration shows slow

elimination. Otherwise, lambdacyhalothrin was rapidly metabolized

and excreted. The metabolism of
50366 Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices

lambda-cyhalothrin in livestock has

been studied in the goat, chicken, and

cow. Unchanged lambda-cyhalothrin is

the major residue component of

toxicological concern in meat and milk.

Human metabolism of lambdacyhalothrin was assessed by

administering 5 mg lambda-cyhalothrin

orally to six male volunteers (average

dose was 0.06 mg/kg) and dermally at

20 mg/800 cm2 to five volunteers. No

adverse effects were noted in the

individuals given an oral dose, and only

mild signs of parasthesia were noted in

individuals receiving a dermal dose.

Absorption by these two routes of

exposure were determined by analysis

of urinary metabolites. An average

amount of 59% of the oral dose was

absorbed. Dermal absorption was

extremely low, and estimated to be

0.12% (range 0.04–0.19%).

7. Metabolite toxicology. The Agency

has previously determined that the

metabolites of lambda-cyhalothrin are

not of toxicological concern and need

not be included in the tolerance

expression. Given this determination, it

is concluded that there is no need to

discuss metabolite toxicity.

8. Endocrine disruption. EPA is

required to develop a screening program

to determine whether certain substances

(including all pesticides and inerts)

‘‘may have an effect in humans that is

similar to an effect produced by a

naturally occurring estrogen, or such

other endocrine effect***.’’ The Agency

is currently working with interested

stakeholders, including other

government agencies, public interest

groups, industry and research scientists

in developing a screening and testing

program and a priority setting scheme to

implement this program. Congress has

allowed 3 years from the passage of

FQPA (August 3, 1999) to implement

this program. At that time, EPA may

require further testing of this active

ingredient and end use products for

endocrine disrupter effects.

C. Aggregate Exposure

Zeneca has conducted an aggregate

exposure assessment for lambdacyhalothrin. This assessment included

exposures resulting from agricultural

crop use and non-dietary residential

use.

1. Dietary exposure. For the purposes

of assessing the potential chronic

dietary exposure for all existing and

pending tolerances for lambdacyhalothrin, Zeneca has utilized

available information on anticipated

residues (FDA monitoring data, average

field trial residues and processing data)

and percent crop treated. For the acute

dietary assessment, a Monte Carlo

modeling was used to estimate

exposure.

2. Food. The Agency has stated that

the acute dietary risk assessment for

lambda-cyhalothrin should be based on

a toxicological NOEL from a 1–year dog

study. Zeneca disagrees with EPA’s

selection of a multiple-dose

toxicological endpoint (0.5 mg/kg) for

the acute dietary risk assessment, and

have requested the Agency to base the

acute dietary NOEL on single-dose

effects. Acute risk, by EPA definition,

results from 1–day consumption of food

and water, and reflects toxicity which

could be expressed following a single

oral exposure to pesticide residues.

Therefore, an appropriate NOEL must be

based on effects noted after a single

dose, even if the endpoint is selected

from a repeat dose study, such as a 1–

year dog. Nonetheless, sufficient

margins of exposure are achieved at

percentiles of exposure up to and

including the 99.9th percentile based on

the Agency’s NOEL of 0.5 mg/kg.

Based on the Agency’s selected acute

toxicity endpoint of 0.5 mg/kg bw day,

the acute dietary MOE for the most

highly exposed population subgroup

was children 1–6 years old. The MOEs

were 658 at the 95th percentile, 248 at

the 99th percentile, and 132 at the

99.9th percentile. EPA concludes that

there is a reasonable certainty of no

harm for a MOE of 100 or greater.

Therefore, the acute dietary risk

assessment for lambda-cyhalothrin

clearly indicates a reasonable certainty

of no harm. The assessment of chronic

dietary exposure was estimated to be

5.0% of the chronic reference dose (RfD)

for the overall U.S. population. The RfD

for lambda-cyhalothrin, 0.001 mg/kg bw

/day, is based on the NOEL of 0.1 mg/

kg from the 1–year dog study and an

Uncertainty Factor of 100. For the most

exposed subgroup, children 1–6 years

old, the exposure was estimated to be

0.000159 mg/kg bw/day, or 15.9% of the

RfD. Since EPA generally has no

concern for exposures below 100

percent of the RfD, there is a reasonable

certainty that no harm will result from

chronic dietary exposure to lambdacyhalothrin residues.

3. Drinking water. Laboratory and

field data have demonstrated that

lambda-cyhalothrin and its degradates

are immobile in soil and will not leach

into ground water. Other data show that

lambda-cyhalothrin is virtually

insoluble in water and extremely

lipophilic. As a result, residues reaching

surface waters from field runoff will

quickly adsorb to sediment particles and

be partitioned from the water column.

Together these data indicate that

residues are not expected in drinking

water.

A screening evaluation of leaching

potential of a typical pyrethroid was

conducted using EPA’s Pesticide Root

Zone Model (PRZM3). Based on this

screening assessment, the potential

concentrations of a pyrethorid in ground

water at depths of 1 and 2 meters are

essentially zero (< 0.001 parts per

billion (ppb)). Surface water

concentrations for pyrethroids were

estimated using PRZM3 and Exposure

Analysis Modeling System (EXAMS)

using standard EPA cotton runoff and

Mississippi pond scenarios. The

maximum concentration predicted in

the simulated pond was 0.052 ppb.

Concentrations in actual drinking water

would be much lower than the levels

predicted in the hypothetical, small,

stagnant farm pond model since

drinking water derived from surface

water would normally be treated before

consumption. Based on these analyses,

the contribution of water to the dietary

risk estimate is negligible.

4. Non-dietary exposure. Other

potential sources of exposure are from

non-occupational sources such as

structural pest control and ornamental

plant and lawn use of lambdacyhalothrin. In its review of toxicity

endpoints for assessing risks for lambdacyhalothrin, the Agency concluded that

the most appropriate endpoint for nondietary risk assessment is 10 mg/kg bw/

day based on the NOEL from the 21–day

dermal toxicity study. Exposure was

estimated using available market use

information and surrogate indoor

exposure data. The resulting MOEs were

15,000 for the U.S. population, 7,000 for

non-nursing infants and 7,200 for

children 1–6 years old. The aggregate

risk assessment of combined exposures

from chronic dietary, drinking water

and non-dietary residential sources has

been conducted. The resulting MOEs are

14,000 for the U.S. Population, 6,500 for

non-nursing infants and 6,500 for

children 1–6 years old. EPA concludes

that there is a reasonable certainty of no

harm for MOE of 100 or greater.

Therefore, the non-dietary and overall

aggregate risk assessments for lambdacyhalothrin clearly indicates a

reasonable certainty of no harm.

D. Cumulative Effects

Zeneca Ag Products will submit

information for EPA to consider

concerning potential cumulative effects

of lambda-cyhalothrin consistent with

the schedule established by EPA at 62

FR 42020 (August 4, 1997)(FRL–5734–6)

and other EPA publications pursuant to

the FQPA. At this time, Zeneca cannot

make a determination based on
Federal Register / Vol. 62, No. 186 / Thursday, September 25, 1997 / Notices 50367

available and reliable information that

lambda-cyhalothrin and other

substances that may have a common

mechanism of toxicity would have

cumulative effects. Therefore for

purposes of this request it is appropriate

only to consider the potential risks of

lambda-cyhalothrin in an aggregate

exposure assessment.

E. Safety Determination

The acceptable RfD based on a NOEL

of 0.1 mg/kg bw/day from the chronic

dog study and a safety factor of 100 is

0.001 mg/kg bw/day. A chronic dietary

exposure/risk assessment has been

performed for lambda-cyhalothrin using

the above RfD. Available information on

anticipated residues, monitoring data

and percent crop treated was

incorporated into the analysis to

estimate the Anticipated Residue

Contribution (ARC). The ARC is

generally considered a more realistic

estimate than an estimate based on

tolerance level residues.

1. U.S. population. The ARC from

established tolerances and the current

and pending actions are estimated to be

0.00005 mg/kg bw/day and utilize 5.0

per cent of the RfD for the U.S.

population. For the acute dietary

assessment the MOEs at the 95th, 99th,

and 99.9th percentiles are 2074, 742,

and 237, respectively.

2. Infants and children. FFDCA

section 408 provides that EPA shall

apply an additional tenfold margin of

safety for infants and children in the

case of threshold effects to account for

pre- and post-natal toxicity and the

completeness of the database unless

EPA determines that a different margin

of safety will be safe for infants and

children. EPA generally defines the

level of appreciable risk as exposure

that is greater than 1/100 of the NOEL

in the animal study appropriate to the

particular risk assessment. This

hundredfold uncertainty (safety) factor/

margin of exposure is designed to

account for combined inter and

intraspecies variability. EPA believes

that reliable data support using the

standard hundredfold margin/factor and

not the additional tenfold margin/factor

when EPA has a complete database

under existing guidelines and when the

severity of the effect in infants and

children or the potency or unusual toxic

properties of a compound do not raise

concerns regarding the adequacy of the

standard margin/factor.

In assessing the potential for

additional sensitivity of infants and

children to residues of lambdacyhalothrin, EPA considered the data

from oral developmental toxicity studies

in the rat and rabbit, as well as data

from a multi-generation reproduction

study in the rat. The developmental

toxicity studies are designed to evaluate

adverse effects in the developing

organism resulting from pesticide

exposure during prenatal development

in the mothers. Reproduction studies

provide information relating to effects

from exposure to the pesticide on the

reproductive capability of mating

animals and data on systemic toxicity.

i. Pre-natal effects. A developmental

toxicity study in rats given gavage doses

of 0, 5, 10, and 15 mg/kg/day with no

developmental toxicity observed under

the conditions of the study. The

developmental NOEL is greater than 15

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

maternal NOEL and LOEL are

established at 10 and 15 mg/kg/day,

respectively, based on reduced body

weight gain.

A developmental toxicity study in

rabbits given gavage doses of 0, 3, 10,

and 30 mg/kg/day with no

developmental toxicity observed under

the conditions of the study. The

maternal NOEL and LOEL are

established at 10 and 30 mg/kg/day,

respectively based on decreased body

weight gain. The developmental NOEL

is greater than 30 mg/kg/day, the highest

dose tested.

ii. Post-natal effects. A threegeneration reproduction study in rats

fed diets containing 0, 10, 30, and 100

ppm with no developmental toxicity

observed at 100 ppm, the highest dose

tested. The maternal NOEL and LOEL

for the study are established at 30 (1.5

mg/kg/day) and 100 ppm (5 mg/kg/day),

respectively, based upon decreased

parental body weight gain. The

reproductive NOEL and LOEL are

established at 30 (1.5 mg/kg/day) and

100 ppm (5 mg/kg/day), respectively,

based on decreased pup weight gain

during weaning.

In EPA’s review of the toxicity

endpoints for lambda-cyhalothrin they

concluded that the data on

developmental and reproductive

toxicity tests do not indicate any

increased pre- or post-natal sensitivity.

Therefore, EPA concluded that reliable

data support use of a hundredfold safety

factor and that an additional tenfold

safety factor is not needed.

Based on this information the ARC for

children 1-6 years old, and non-nursing

infants (subgroups most highly exposed)

utilizes 0.000159 mg/kg bw/day (15.9%

of the RfD) and 0.000101 mg/kg bw/day

(10.1% of the RfD), respectively.

Generally speaking, the Agency has no

cause for concern if anticipated residues

contribution for all published and

proposed tolerances is less than the RfD.

For the acute dietary assessment the

MOEs at the 95th, 99th, and 99.9th

percentiles are 658, 248, and 132,

respectively for children 1–6 years old.

For non-nursing infants the MOEs at the

95th, 99th and 99.9th percentiles are

710, 316, and 152, respectively.

F. International Tolerances

There are Codex maximum residue

levels established for residues of

cyhalothrin, as the sum of all isomers,

in or on the following crops and

commodities: pome fruits at 0.2 ppm;

cabbage, head at 0.2 ppm; potatoes at

0.02 ppm; cotton seed at 0.02 ppm;

cotton seed oil, crude at 0.02 ppm; and

cotton seed oil, edible at 0.02 ppm.

(Adam Heyward)

[FR Doc. 97–25499 Filed 9–22–97; 3:06 pm]

BILLING CODE 6560–50–F

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September 19, 1997.

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following information collection(s), as

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information on the respondents,

including the use of automated

collection techniques or other forms of

information technology.

DATES: Written comments should be

submitted on or before October 27,

1997. If you anticipate that you will be

submitting comments, but find it

difficult to do so within the period of