Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices 38543

bodies of water. This expectation is

based on the rapid degradation of

cyprodinil and the recommended low

use rates that will further restrict the

amount of chemical available for

leaching or run-off.

2. Non-dietary exposure. Novartis

believes that the potential for nonoccupational exposure to the general

public is unlikely except for potential

residues in food crops discussed above.

The proposed uses for cyprodinil are for

agricultural crops and the product is not

used residentially in or around the

home.

D. Cumulative Effects

Consideration of a common

mechanism of toxicity is not appropriate

at this time since there is no information

to indicate that toxic effects produced

by cyprodinil would be cumulative with

those of any other chemicals.

Consequently, only the potential

exposure to cyprodinil is considered in

this risk assessment.

E. Safety Determination

1. U.S. population. For the U.S.

population (48 contiguous states)

chronic exposure was 11% of the RfD.

EPA usually has no concern for

exposures below 100% of the RfD

because the RfD represents the level at

or below which daily aggregate dietary

exposure over a lifetime will not pose

appreciable risks to human health.

Novartis concludes that there is a

reasonable certainty that no harm will

result from aggregate exposure to

cyprodinil.

2. Infants and children. Maximum

expected chronic exposure to cyprodinil

in the diets of the most sensitive subpopulations, for non-nursing infants

(<1–year old) and 31.1% of the RfD for

childern (1–6 years old) was calculated

to be 28.6% of the RfD.

F. International Tolerances

Codex maximum residue levels

(MRLs) have not been established for

residues.

[FR Doc. 00–15161 Filed 6–20–00; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–942; FRL–6557–3]

Notice of Filing a Pesticide Petition to

Establish a Tolerance for Certain

Pesticide Chemicals in or on Food

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of a pesticide petition

proposing the establishment of

regulations for residues of a certain

pesticide chemical in or on various food

commodities.

DATES: Comments, identified by docket

control number PF–942, must be

received on or before July 21, 2000.

ADDRESSES: Comments may be

submitted by mail, electronically, or in

person. Please follow the detailed

instructions for each method as

provided in Unit I.C. of the

‘‘SUPPLEMENTARY INFORMATION.’’

To ensure proper receipt by EPA, it is

imperative that you identify docket

control number PF–942 in the subject

line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By

mail: Richard J. Gebken, Registration

Support Branch, Registration Division

(7505C), Office of Pesticide Programs,

Environmental Protection Agency, Ariel

Rios Bldg., 1200 Pennsylvania Ave.,

NW., Washington, DC 20460; telephone

number: (703) 305–6701; e-mail address:

gebken.richard@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if

you are an agricultural producer, food

manufacturer or pesticide manufacturer.

Potentially affected categories and

entities may include, but are not limited

to:

Categories NAICS Examples of potentially affected entities

Industry 111 Crop production

112 Animal production

311 Food manufacturing

32532 Pesticide manufacturing

This listing is not intended to be

exhaustive, but rather provides a guide

for readers regarding entities likely to be

affected by this action. Other types of

entities not listed in the table could also

be affected. The North American

Industrial Classification System

(NAICS) codes have been provided to

assist you and others in determining

whether or not this action might apply

to certain entities. If you have questions

regarding the applicability of this action

to a particular entity, consult the person

listed under ‘‘FOR FURTHER

INFORMATION CONTACT.’’

B. How Can I Get Additional

Information, Including Copies of this

Document and Other Related

Documents?

1. Electronically. You may obtain

electronic copies of this document, and

certain other related documents that

might be available electronically, from

the EPA Internet Home Page at http://

www.epa.gov/. To access this

document, on the Home Page select

‘‘Laws and Regulations’’ and then look

up the entry for this document under

the ‘‘Federal Register—Environmental

Documents.’’ You can also go directly to

the Federal Register listings at http://

www.epa.gov/fedrgstr/.

2. In person. The Agency has

established an official record for this

action under docket control number PF–

942. The official record consists of the

documents specifically referenced in

this action, any public comments

received during an applicable comment

period, and other information related to

this action, including any information

claimed as confidential business

information (CBI). This official record

includes the documents that are

physically located in the docket, as well

as the documents that are referenced in

those documents. The public version of

the official record does not include any

information claimed as CBI. The public

version of the official record, which

includes printed, paper versions of any

electronic comments submitted during

an applicable comment period, is

available for inspection in the Public

Information and Records Integrity

Branch (PIRIB), Rm. 119, Crystal Mall

#2, 1921 Jefferson Davis Highway,

Arlington, VA, from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays. The PIRIB telephone number

is (703) 305–5805.

C. How and to Whom Do I Submit

Comments?

You may submit comments through

the mail, in person, or electronically. To

ensure proper receipt by EPA, it is

imperative that you identify docket

control number PF–942 in the subject

line on the first page of your response.

1. By mail. Submit your comments to:

Public Information and Records

Integrity Branch (PIRIB), Information

Resources and Services Division

(7502C), Office of Pesticide Programs

(OPP), Environmental Protection

Agency, Ariel Rios Bldg., 1200

Pennsylvania Ave., NW., Washington,

DC 20460.

2. In person or by courier. Deliver

your comments to: Public Information

and Records Integrity Branch (PIRIB),

Information Resources and Services

38544 Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices

Division (7502C), Office of Pesticide

Programs (OPP), Environmental

Protection Agency, Rm. 119, Crystal

Mall #2, 1921 Jefferson Davis Highway,

Arlington, VA. The PIRIB is open from

8:30 a.m. to 4 p.m., Monday through

Friday, excluding legal holidays. The

PIRIB telephone number is (703) 305–

5805.

3. Electronically. You may submit

your comments electronically by e-mail

to: ‘‘opp-docket@epa.gov,’’ or you can

submit a computer disk as described

above. Do not submit any information

electronically that you consider to be

CBI. Avoid the use of special characters

and any form of encryption. Electronic

submissions will be accepted in

Wordperfect 6.1/8.0 or ASCII file

format. All comments in electronic form

must be identified by docket control

number PF–942. Electronic comments

may also be filed online at many Federal

Depository Libraries.

D. How Should I Handle CBI That I

Want to Submit to the Agency?

Do not submit any information

electronically that you consider to be

CBI. You may claim information that

you submit to EPA in response to this

document as CBI by marking any part or

all of that information as CBI.

Information so marked will not be

disclosed except in accordance with

procedures set forth in 40 CFR part 2.

In addition to one complete version of

the comment that includes any

information claimed as CBI, a copy of

the comment that does not contain the

information claimed as CBI must be

submitted for inclusion in the public

version of the official record.

Information not marked confidential

will be included in the public version

of the official record without prior

notice. If you have any questions about

CBI or the procedures for claiming CBI,

please consult the person identified

under ‘‘FOR FURTHER INFORMATION

CONTACT.’’

E. What Should I Consider as I Prepare

My Comments for EPA?

You may find the following

suggestions helpful for preparing your

comments:

1. Explain your views as clearly as

possible

2. Describe any assumptions that you

used.

3. Provide copies of any technical

information and/or data you used that

support your views.

4. If you estimate potential burden or

costs, explain how you arrived at the

estimate that you provide.

5. Provide specific examples to

illustrate your concerns.

6. Make sure to submit your

comments by the deadline in this

notice.

7. To ensure proper receipt by EPA,

be sure to identify the docket control

number assigned to this action in the

subject line on the first page of your

response. You may also provide the

name, date, and Federal Register

citation.

II. What Action is the Agency Taking?

EPA has received a pesticide petition

as follows proposing the establishment

and/or amendment of regulations for

residues of a certain pesticide chemical

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

this petition contains 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.

List of Subjects

Environmental protection,

Agricultural commodities, Feed

additives, Food additives, Pesticides

and pests, Reporting and recordkeeping

requirements.

Dated: June 7, 2000.

James Jones,

Director, Registration Division, Office of

Pesticide Programs.

Summary of Petition

The petitioner summary of the

pesticide petition is printed below as

required by section 408(d)(3) of the

FFDCA. The summary of the petition

was prepared by the petitioner and

represent the views of the petitioner.

EPA is publishing the petition summary

verbatim without editing it 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.

AgrEvo USA Company

0F6087

EPA has received a pesticide petition

[0F6087] from Aventis CropScience

(fomerly AgrEvo USA Company),

Aventis CropScience USA LP, 2, T.W.

Alexander Drive, Research Triangle

Park, NC 27709 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 establishing a tolerance for

residues of buprofezin in or on the

following raw agricultural commodities:

almonds, nutmeats at 0.05 part per

million (ppm); almonds, hulls, at 0.7

ppm; bananas at 0.1 ppm; the citrus

crop group, fruit, at 0.7 ppm; cotton

seed at 1.0 ppm; grapes at 0.4 ppm; and

tomatoes, fruit at 0.8 ppm; in or on the

following processed commodities: citrus

oil at 26 ppm; citrus pulp, dried, at 2.5

ppm; cotton gin by-products at 23 ppm;

and raisins at 1.0 ppm; and in or on the

following meat and milk commodities:

the fat, meat and meat byproducts of

cattle, goats, hogs, horses, and sheep at

0.05 ppm; and milk at 0.01 ppm. EPA

has determined that the petition

contains data or information regarding

the elements set forth in section

408(d)(2) of the FFDCA; however, EPA

has not fully evaluated the sufficiency

of the submitted data at this time or

whether the data supports granting of

the petition. Additional data may be

needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolic

profile of buprofezin has been

elucidated in a wide range of crops,

including tomatoes, lettuce, cotton, and

citrus. For convenience, buprofezin

metabolites are identified in this

document by an internal code, BF 1

through 13. Corresponding structures

are available in the tolerance petition. In

tomatoes, lettuce, and cotton unchanged

buprofezin was the only significant

residue. In citrus, although buprofezin

was a major component of the residue,

a chromatographically well-defined

region of radioactivity, clearly

associated with polar conjugates, was

observed. Mass spectrometry identified

the principal polar residue as a hexose

conjugate of BF4 (buprofezin

hydroxylated in the t-butyl group).

Although the conjugate was resistant to

enzyme hydrolysis, acid hydrolysis of

the polar fraction released

predominantly BF26 with minor

amounts of BF9 and BF12. The same

compounds were observed following

acid hydrolysis of a standard of BF4

clearly indicating that BF4 is the

conjugated metabolite existing in citrus.

Although only limited metabolism was

observed in lettuce and cotton, trace

levels of BF4/BF26, BF9 and BF12 were

observed indicating that the metabolic

pathway does not differ with plant

species. In the tomato study, which was

run prior to the citrus, cotton, and

metabolism studies, these trace level

metabolites were not specifically looked

for due to the high percentage of the

residue accounted for by the parent;

Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices 38545

they may however have existed in trace

amounts.

2. Analytical method—i. Background.

Metabolism studies on lettuce and

tomatoes have shown that the only

significant residue in these crops is

buprofezin. Development of the

analytical method took place in parallel

with the metabolism studies and the

method was designed to quantify two

metabolites (BF9 and BF12) in addition

to the parent compound. This method

was used for analysis of samples from

the field trials on all crops except citrus,

but for tolerance enforcement only the

parent compound is considered.

In the case of citrus, the conjugate of

another metabolite (BF4) was

significant, and intensive efforts were

made to include it in the analytical

method. The technical problems proved

to be very severe however and the effort

was abandoned. As in all other crops,

the parent compound is by far the

largest component of the residue and

this together with the aforementioned

metabolites (BF9 and BF12) were the

only residues quantified. The only

modification made to the method for

citrus was to add an amino column

cleanup to take out some of the coextractives unique to citrus.

ii. Data collection method. Samples

are extracted with acetone. The extracts

are filtered and the acetone removed by

rotary evaporation. The remaining

aqueous extract is acidified with

hydrochloric acid and partitioned with

hexane. The hexane is applied to a

Florisil column and the residues are

then eluted from the column with ether/

hexane (50/50). The acidic aqueous

phase is adjusted to pH 7 and

partitioned with ethyl acetate/hexane

(50/50). This organic extract is

combined with the eluate from the

Florisil column, evaporated to dryness,

taken up in toluene and analyzed by gas

chromatography (GC) with NP

detection. The limit of quantitation

(LOQ) of this method is 0.01 ppm in the

sample.

iii. Tolerance enforcement method.

The metabolism work and field sample

analyses indicated that the only

significant residue in treated crops was

buprofezin. Accordingly, the method

proposed for tolerance enforcement

quantifies only buprofezin. The method

is identical to the data collection

method except that the acid partition

step was omitted. The method was

validated by an independent laboratory

using lettuce, tomato, and cucumber as

the test matrices. Since the method used

for citrus differs so little from that used

for the other crops, no separate ILV was

performed for that method.

iv. Multiresidue methods. Buprofezin

was tested through protocols D and F

using tomatoes (a representative nonfatty food) and cottonseed (a

representative fatty food). Recoveries

were satisfactory such that the

multiresidue methods could be used for

tolerance enforcement or as

confirmatory methods.

v. Animal methods. Because of the

complexity of the metabolism picture in

ruminants, methods were developed to

separately quantify buprofezin and three

metabolites (BF02, BF12 and BF23) in

milk and cattle tissues. The methods

were validated to a LOQ of 0.01 ppm in

milk and to an LOQ of 0.05 ppm in

tissues. These methods were used to

analyze the samples from a cattle

feeding study. On completion of the

study, only buprofezin could be

detected in any of the samples and

accordingly, the method for

determination of buprofezin in milk and

tissues is proposed for tolerance

enforcement. This method was

validated at an external laboratory.

3. Magnitude of residues. Field trials

were conducted on almonds, bananas,

citrus, cotton, grapes, and tomatoes. In

all crops buprofezin was the principal

residue and in all crops except citrus, it

was the only residue. Decline trials

conducted in every crop demonstrated

that the residue declined with time. In

most cases, the residues declined

approximately 50% in 3 to 7 days. In

addition, processing studies were

performed on tomatoes, grapes, citrus,

and cotton. Residues concentrated

significantly in orange oil, dry orange

pulp, wet and dry tomato pomace, and

in raisins, Two different formulations

were used in the field trials, a 40SC and

a 70WP. Bridging trials demonstrated

that there was no difference in the

residues produced by these two

formulations.

i. Residues in tomatoes. Field grown

tomatoes were treated with sequential

applications of APPLAUD 40 SC or

APPLAUD 70 WP at the maximum and

the minimum application and

preharvest intervals. (This is twice the

seasonal maximum on the proposed

label.) A total of 20 sites were used,

distributed throughout the United

States.

In the samples collected 7 days after

treatment, the residues of buprofezin

ranged from 0.02 ppm to 0.64 ppm.

There was no apparent difference

between tomatoes treated with the

70WP formulation and those treated

with the 40SC formulation.

ii. Residues in processed tomato

commodities. Tomatoes at one trial site

in California were treated four times

with APPLAUD 40 SC at 2.4 times the

proposed maximum rate and at the

minimum application and preharvest

intervals. After the final application,

whole tomatoes were harvested and

processed into wet pomace, dry pomace,

juice, puree, and paste.

The results indicate that following

typical commercial processing of

APPLAUD 40 SC-treated tomatoes,

buprofezin residues concentrated

slightly in the processed commodity,

tomato paste, relative to the whole

unwashed tomatoes. Buprofezin was

detected in paste at 0.68 ppm. This

value represents a concentration factor

of 1.26x for paste; however this factor

does not trigger a separate tolerance for

paste. No concentration was observed

for buprofezin in the other processed

commodity, puree.

iii. Residues in almonds. Almonds at

6 sites in California were given a single

treatment of APPLAUD 70 WP at the

maximum application rate and

minimum application and preharvest

intervals. No residues above the LOQ

(0.05 ppm) were present in any of the

nut meat samples. The residues in the

hulls ranged from < 0.05 ppm to 0.55

ppm. Only buprofezin was detected.

iv. Residues in grapes. Trials were

conducted at 15 different sites, which

represent 5 major grape producing

regions within the United States.

APPLAUD was applied twice to

grapevines at the maximum application

rate and minimum application and

preharvest intervals.

Results showed that the residues for

parent buprofezin ranged between 0.01

ppm and 0.27 ppm.

v. Residues in processed grape

commodities. A single trial was

conducted in California representing a

major grape-producing region within the

United States. APPLAUD 70WP was

applied twice to grape vines at an

exaggerated (5x) rate at the minimum

application and preharvest intervals.

Samples of treated grapes were

harvested after the final application of

APPLAUD and were processed into

grape juice and raisins.

Buprofezin residues were observed to

concentrate (2.41x) in raisins relative to

those found in whole grapes. No

concentration was observed for any

analyte in grape juice.

vi. Residues in cotton. Trials were

conducted at 15 different sites that

represent 5 major cotton producing

regions within the United States.

APPLAUD 70WP was applied four times

to plots of cotton at the maximum

application rate, and minimum

application and preharvest intervals.

(This is twice the seasonal maximum on

the proposed label). Duplicate samples

of treated cottonseed were harvested

38546 Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices

after the final application of APPLAUD

and ginned at six sites to produce gin

trash.

Five of the six samples of gin trash

harvested 14 days after the last

application of APPLAUD had residues

which ranged between 2.38 ppm and

6.12 ppm. The sixth sample had a

residue of 22.52 ppm.

Residues in cottonseed at 14 days

after the last application ranged between

0.06 ppm and 0.82 ppm. Residues were

observed to decline significantly for the

two sites randomly selected to be used

to generate decline data.

vii. Residues in processed cotton

commodities. A single trial was

conducted in California representing a

major cotton-producing region within

the United States. APPLAUD 70WP was

applied four times to cotton plants at an

exaggerated (5x) rate, and minimum

application and preharvest interval.

Samples of treated cotton were

harvested after the final application of

APPLAUD and were processed into

cottonseed, cottonseed by-products (gin

trash), meal, hulls, crude oil, refined oil,

and soapstock.

Following typical commercial

processing of cotton treated with

APPLAUD 70WP, at an exaggerated rate,

buprofezin residues were observed to be

37.99x higher in gin trash relative to

those found in cottonseed. No

concentration was observed for

buprofezin in any other cottonseed

fraction.

viii. Residues in citrus. A total of 30

citrus trials were conducted throughout

the major citrus producing regions

within the United States. The trials

consisted of orange, grapefruit, and

lemon sites. APPLAUD 70WP was

applied twice to the citrus trees at the

maximum rate and minimum

application and preharvest intervals.

Duplicate samples of treated oranges

were harvested after the final

application of APPLAUD, including

samples taken to observe residue

decline.

The highest of the citrus residues

were found in grapefruit (2.20 ppm)

harvested 60 days after the last

application of APPLAUD. This result is

inconsistent with the rest of the samples

in the study and no explanation can be

offered for it. The 2.20 ppm result

appears to be an outlier and if it is

excluded the range of the grapefruit

results is < 0.01 to 0.11, which is

consistent with the other results in the

study. Residues in oranges ranged from

below 0.01 ppm to 0.47 ppm. Residues

in lemons ranged between 0.01 ppm and

0.51 ppm.

Residues in citrus declined with time

after the last application.

ix. Residues in processed citrus

commodities. A single trial was

conducted in California representing a

major citrus producing region within

the United States. APPLAUD 70WP was

applied twice to orange trees at an

exaggerated (5x) rate and minimum

application and preharvest intervals.

Samples of treated oranges were

harvested after the final application of

APPLAUD and were processed into

orange oil, juice and dry pomace.

Following typical commercial

processing of oranges treated with

APPLAUD 70WP at 5x the highest

recommended application rate,

buprofezin residue was detected and

observed to concentrate (43.34x) in

citrus oil relative to that found in whole

fruit. The maximum average detected

residue consisting of buprofezin was

observed in orange oil at 15.17 ppm.

Concentration was also observed for

buprofezin at 4.14x in dry pulp relative

to that found in the whole fruit. No

concentration was observed for any

analyte in orange juice.

x. Residues in bananas. Trials were

conducted at one site in Puerto Rico and

four sites on the island of Hawaii.

Bananas were treated with four foliar

applications of APPLAUD 70WP at the

maximum application rate and

minimum application and preharvest

intervals. One half of the bananas site

was protected with plastic bags and the

other half was not. Samples were

collected from both bagged and

unbagged bananas at normal harvest. At

one site, samples were also collected to

develop data for a decline curve.

Residues were determined in both

peeled and unpeeled bananas.

Residues of buprofezin ranged from <

0.01 ppm (the LOQ) to 0.077 ppm in the

1-day PHI bananas. Residues were

detected only in the unbagged, unpeeled

bananas, indicating that these are

strictly surface residues. No residues

were detected in/on any bagged bananas

nor in/on any peeled bananas.

xi. Residues in milk and meat. Twelve

Holstein dairy cows were randomly

assigned to four groups consisting of

three cows each. Following quarantine,

each cow was orally dosed twice daily

for 28 consecutive days with one gelatin

capsule containing a known amount of

buprofezin. The control (T-0) group

received capsules containing no

buprofezin. Cattle in the T-I group

received 119 mg of buprofezin per cow

per day. Cattle in the T-II group received

357 mg per cow per day, and cattle in

the T-III group, 1,190 mg per cow per

day. These doses are equivalent to

consumption of diets containing 0, 5,

15, and 50 ppm buprofezin (0, 1x, 3x,

and 10x the maximum theoretical

intake).

Milk was sampled on the day prior to

the first dosing (day 1), on the day of the

first dosing (day 1), and on days 2, 4, 7,

10, 14, 17, 21, 24, and 28. Cream and

skim milk samples were prepared from

whole milk collected on day 28. All

cows were sacrificed on day 29 within

24 hours of the last dose. Sub-samples

of muscle (hind-quarter), fat

(perinephric), liver, and kidney were

taken for analysis.

Milk and tissues were analyzed by

methods that separately quantify

buprofezin and the metabolites BF02,

BF12, and BF23. The methods were

validated to an LOQ of 0.01 ppm in milk

and 0.05 ppm in tissues.

No buprofezin-derived residues were

found in meat or milk commodities in

the ruminant feeding study at a feeding

level equivalent to the maximum

theoretical intake of buprofezin.

B. Toxicological Profile

An extensive battery of toxicology

studies has been conducted with

buprofezin. These studies have been

reviewed and summarized by the Joint

Meeting of the FAO Panel of Experts on

Pesticide Residues in Food and the

Environment and the WHO Expert

Group on Pesticide Residues (JMPR,

1991 and 1995). They have also been

reviewed by the USEPA as part of the

submission for an Experimental Use

Permit. Supplemental information on

several studies (acute dermal, acute

inhalation, chronic dog, rat

reproduction, and rat chronic toxicity/

oncogenicity study) is being submitted

with this petition. These studies

indicate that buprofezin has a relatively

low degree of toxicity, is neither

genotoxic nor oncogenic, and does not

cause any significant reproductive or

developmental effects. Thus, the use of

buprofezin on lettuce and cucurbits (as

well as on cotton (Arizona and

California) and citrus (California) under

the current section 18 emergency

exemptions) will not pose a significant

risk to human health.

1. Acute toxicity. The acute rat oral

LD50 for buprofezin was 1,635 mg/kg in

males and 2,015 mg/kg in females. The

acute rat dermal LD50 was ≥ 5,000 mg/

kg in both sexes. The 4-hour rat

inhalation LC50 was > 4.57 milligram/

liter (mg/L). Buprofezin was slightly

irritating to rabbit eyes and skin and did

not induce dermal sensitization in

guinea pigs.

2. Genotoxicty. No evidence of

genotoxicity was noted in a battery of in

vitro and in vivo studies. Studies

included Ames Salmonella and mouse

lymphoma gene mutation assays, a

Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices 38547

mouse micronucleus assay, an in vitro

human lymphocyte cytogenetics assay

and an in vitro rat hepatocyte

unscheduled DNA synthesis (UDS)

assay.

3. Reproductive and developmental

toxicity. A developmental toxicity study

was conducted in rats at dose levels of

0, 50, 200, or 800 mg/kg/day. The

(systemic) maternal no observed adverse

effect level (NOAEL) for this study was

200 mg/kg/day based on weight loss,

decreased food consumption, clinical

signs, increased resorption rate,

increased loss of entire litters and one

maternal death at 800 mg/kg/day. The

developmental (fetal) NOAEL was also

200 mg/kg/day based on reduced fetal

body weights and increased incidence

of delayed ossification at 800 mg/kg/

day. Slightly reduced ossification was

also noted at 200 mg/kg/day but this

was within historical control range and

thus not considered to be significant.

A developmental toxicity study was

conducted in rabbits at dose levels of 0,

10, 50, or 250 mg/kg/day. The maternal

(systemic) NOAEL was 50 mg/kg/day

based on decreased weight gain,

decreased food consumption and the

complete resorption of 2 litters at 250

mg/kg/day. No evidence of

developmental toxicity was noted;

therefore, the developmental (fetal)

NOAEL was 250 mg/kg/day, the highest

dose tested (HDT).

Two rat reproduction studies have

been conducted at dietary

concentrations of 0, 10, 100, or 1,000

ppm. One was a 2-generation study that

included a teratological evaluation. The

other was a 1-generation reproduction

study conducted to further evaluate

some possible changes noted in the first

study. Based on the results from both

studies, the parental NOAEL was 1,000

ppm HDT. There were no effects on any

reproductive parameters but pup

weights were decreased at 1,000 ppm.

Thus, the reproductive NOAEL was 100

ppm.

4. Subchronic toxicity. A 90-day

feeding study was conducted in rats at

dietary concentrations of 0, 40, 200,

1,000, or 5,000 ppm. Effects noted at

1,000 and/or 5,000 ppm included

decreased weight gain, clinical

pathology changes, increased liver and

thyroid weights, and gross and/or

microscopic evidence of liver, thyroid

and kidney lesions. Only marginal

effects, consisting of slightly reduced

feed intake and slightly decreased

glucose levels, were noted at 200 ppm.

Although the report conservatively

concluded the NOAEL to be 40 ppm, the

NOAEL was considered by the EPA to

be 200 ppm (15 mg/kg/day).

A 90-day study was conducted in

which beagle dogs were administered

buprofezin via capsule at dose levels of

0, 2, 10, 50, or 300 mg/kg/day. Effects

noted at 50, and/or 300 mg/kg/day

included various clinical signs of

toxicity, substantially decreased weight

gain, clinical pathology changes,

increased liver, kidney and thyroid

weights, and microscopic liver lesions.

The NOAEL was 10 mg/kg/day.

5. Chronic toxicity. A 2-year study

was conducted in which beagle dogs

were administered buprofezin via

capsule at dose levels of 0, 2, 20, or 200

mg/kg/day. Effects noted at 20 and/or

200 mg/kg/day included decreased

weight gain, clinical pathology changes,

increased liver and thyroid weights,

decreased liver function (measured by

BSP clearance) and microscopic liver

lesions. Although the report concluded

that the NOAEL for this study was 2 mg/

kg/day, marginal effects in females at 2

mg/kg/day were considered to be a

possible effect by the EPA reviewer

pending receipt of additional historical

control data. These data are being

submitted with this petition and will

establish that the dose of 2 mg/kg/day

is a NOAEL for this study.

A 2-year rat feeding study was

conducted at dietary concentrations of

0, 5, 20, 200, or 2,000 ppm. No evidence

of oncogenicity was noted at any dose

level. Effects noted at 2,000 ppm

included decreased weight gain,

increased liver and thyroid weights, and

an increased incidence of nonneoplastic liver and thyroid lesions. A

possible increase in thyroid lesions was

also noted at 200 ppm. According to the

EPA reviewer, the NOAEL for this study

was 200 ppm (10 mg/kg/day). However,

the conclusions of the original report

and a subsequent histopathological

reevaluation, not yet reviewed by the

Agency, indicate that the NOAEL

should be considered to be 20 ppm (1

mg/kg/day).

A 2-year mouse feeding study was

conducted at dietary concentrations of

0, 20, 200, 2,000, and 5,000 ppm. Effects

observed at 2,000 and/or 5,000 ppm

included decreased weight gain, minor

clinical pathology changes, increased

liver weights and an increased

incidence of non-neoplastic liver

lesions. Increased liver weights were

also noted at 200 ppm. Thus, the

NOAEL was considered to be 20 ppm

(1.8 mg/kg/day). There were slightly

increased incidences of liver tumors in

females at 5,000 ppm and of lung

tumors in males at 200 and 5,000 ppm.

The increased incidences of these

common tumors were not considered to

be treatment-related by either the study

director or EPA reviewer but the study

was referred to EPA Carcinogenicity

Peer Review Group for further

valuation.

6. Animal metabolism. The

metabolism of buprofezin has been

extensively studied in various species of

animals and fish. Buprofezin has several

groups that can metabolize in a variety

of ways thus potentially producing a

very large number of metabolites.

Indeed extensive metabolism to many

minor metabolites was observed in all

the animal species. Metabolism in fish

was, however, much more limited and

clearly defined. Although not all

metabolic intermediates have been

detected in all the species, the major

routes of metabolism have been

identified in animals and fish and a

consistent pattern is observed

throughout these species. The proposed

metabolic pathway was provided in the

tolerance petition. For convenience,

degradates are referred to by an internal

code: BF 1 through 13. Corresponding

chemical structures were provided in

the tolerance petition.

i. Metabolism in rats. The major

metabolite found in rat excreta was

parent buprofezin in addition to several

compounds formed after extensive

metabolism. Whereas plant metabolism

appeared restricted mainly to oxidation

of the tertiary butyl group, oxidation of

the butyl group and hydroxylation of

the phenyl ring were both observed in

rats. Oxidation of the t-butyl group

proceeded beyond an alcohol to an acid

and was accompanied by ring opening.

The most extensively metabolized

compound identified in rats was BF23

(acetylated p-aminophenol)

ii. Metabolism in ruminants and hens.

Residue levels were low (< 0.05 ppm) in

all ruminant and poultry tissues and

commodities, following treatment at

exaggerated rates (approximately 20x

and 7,500x the anticipated dietary

burden, respectively). The only

exceptions were cow liver (1.21 ppm),

cow kidney (0.41 ppm), hen liver (0.15

ppm), and egg yolk (0.11 ppm).

Extensive metabolism was observed in

both species with a large number of

minor metabolites being produced.

The principal metabolites identified

in the cow were BF2 and BF23

indicating that the major pathway of

degradation in ruminants is

hydroxylation of the phenyl ring

followed by opening and degradation of

the heterocyclic ring. The identification

of trace levels of BF13 confirms this

pathway. As in rats, BF23 was the most

extensively metabolized compound

identified. Trace levels of BF12 were

also detected. This indicates that the

parallel pathway of heterocyclic ring

opening without hydroxylation of the

38548 Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices

phenyl ring is also in operation.

Similarly in hens, the identified

metabolites were derived from

degradation of the heterocyclic ring

either with (BF13) or without (BF9 and

BF12) phenyl ring hydroxylation. No

single unidentified compound

accounted for more than 6% of the total

residue in any animal tissue or

commodity, with the exception of a

component comprising 8.7% of egg

white. The total residue in egg white

was, however, only 0.02 ppm even at

this highly exaggerated dose rate.

iii. Metabolism in fish. Analysis of

fish tissues, following a

bioaccumulation study, found a much

simpler metabolic profile. Buprofezin

was present in both edible and nonedible tissues, but the principle

metabolites were polar conjugates of

BF4. Trace levels of BF12 were also

detected.

7. Endocrine disruption. No special

studies have been conducted to

investigate the potential of buprofezin to

induce estrogenic or other endocrine

effects. 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. The only effect noted

on endocrine organs was an increased

incidence of follicular cell hypertrophy

and C-cell hyperplasia of the thyroid

gland in rats administered buprofezin at

dietary concentrations of 2,000 ppm for

24 months. Buprofezin also caused mild

to moderate hepatotoxic effects at this

dietary concentration. AgrEvo believes

that the effect on the thyroid most likely

resulted from increased turnover of T3/

T4 in the liver with a resultant rise in

TSH secretion (due to the

hepatotoxicity). The rat is known to be

much more susceptible than humans to

these effects due to the very rapid

turnover of thyroxine in the blood in

rats (12 hours vs. about 5-9 days in

humans). Therefore, the thyroid

pathological changes which have been

noted following administration of high

doses of buprofezin are considered to be

of minimal relevance to human risk

assessment, particularly considering the

low levels of buprofezin to which

humans are likely to be exposed.

C. Aggregate Exposure

Buprofezin is an insect growth

regulator, which is approved for use

under a section 18 emergency

exemption for control of red scale on

citrus in California. Section 18

applications are pending at EPA for the

control of whitefly on cotton in Arizona

and California, on cucurbits in Arizona,

and on tomatoes in Florida. Non-crop

uses of buprofezin are limited to an

Experimental Use Permit for use on

ornamentals in greenhouses, thus only

dietary exposures are being considered.

1. Dietary exposure—i. Food.

Potential dietary exposures from food

commodities under the proposed food

tolerances for buprofezin, including

those in the previously submitted

tolerance petition number 7F4923, were

estimated using the exposure I software

system (TAS, Inc.) and the 1977-78

Department of Agriculture (USDA)

consumption data. A single, worst-case

scenario was evaluated.

In this case, it was assumed that all

uses contained residues at the proposed

tolerance levels of: Leaf lettuce (13

ppm), head lettuce (5 ppm), the

cucurbits crop group (0.5 ppm),

almonds, nutmeats (0/05 ppm), bananas

(0.8 ppm), citrus (0.6 ppm), grapes (0.3

ppm), raisins (0.8 ppm), tomatoes (0.7

ppm), animal fat, meat and meat byproducts (0.05 ppm), and milk (0.01

ppm). This very worst-case scenario also

assumed 100% of the crop treated.

ii. Drinking water. Exposure to

buprofezin from drinking water is

expected to be negligible. The potential

for buprofezin to leach into ground

water was assessed in various laboratory

studies as well as terrestrial field

dissipation studies conducted in two

locations and in varying soil types. The

degradation of buprofezin occurs

rapidly with half-lives in soil ranging

from 22 to 59 days. No evidence of

leaching of parent or degradation

products was observed in aged leaching

or terrestrial field dissipation studies.

The major routes of degradation result

in mineralization to carbon dioxide and

the formation of ‘‘bound’’ residues.

Buprofezin tends to bind to the top

layers of soil with low mobility. The

Koc for most soils fell in the range

2,100-4,800. The solubility in water is

low (0.382 mg/L).

A screening evaluation of worst-case

shallow ground water concentrations

was conducted using EPA model SCI/

GROW. A number of uses were

compared and the results are

summarized in the following table:

Crop Annual application

rate (lbs./acre)

Aerobic half-life

(days) Koc Relative IntrinsicLeaching Potential

Screening Concentration in Ground water

(ppb)

Almonds 2 0.036

Citrus 4 41 a 3008b 0.811c 0.072

Grapes 1 0.018

Vegetables & cotton 076 0.014

a Average of laboratory aerobic soil metabolism studies b Average of all tested soils excluding one abnormally highly value (Koc = 18836) c Relative Intrinsic Leaching Potential = (log(t1/2 5))*(4-log(Koc + 5))

The potential exposure of buprofezin

in drinking water abstracted from

surface water was assessed using a Tier

2, modeling approach. PRZM was used

to generate potential runoff loads from

a standardized agricultural field (10-ha)

to a standardized aquatic system (1-ha

2-m deep pond) following application of

buprofezin to citrus (the maximum

proposed use rate for all crops). EXAMS

was used to estimate the exposure

concentration (EEC) in surface water.

The ‘‘once-in-10-year’’ exceedance

probability corresponded to a

concentration at 0.52 part per billion

(ppb). This value refers to the 56-day

average estimated concentration in a

farm pond draining agricultural land

and must be considered a gross overestimate of concentrations of buprofezin

at the point of drinking water

abstraction.

The calculated worst-case maximum

exposure of buprofezin in drinking

water (assuming consumption of 2 liters

per day) will be no more than 1.04 μg

per day. Exposure from drinking water

abstracted from ground water will be an

order of magnitude lower (> 0.14 g per

day). However, the contribution of any

such residues to the total dietary intake

of buprofezin will be negligible.

Federal Register / Vol. 65, No. 120 / Wednesday, June 21, 2000 / Notices 38549

2. Non-dietary exposure. There is a

current Experimental Use Permit (EUP)

for the use of buprofezin on ornamentals

in greenhouses. Exposure to the general

population would be minimal in this

use and thus was not considered.

D. Cumulative Effects

At the present time, there are

insufficient data available to allow

AgrEvo to properly evaluate the

potential for cumulative effects with

other pesticides to which an individual

may be exposed. For the purposes of

this assessment, therefore, AgrEvo has

assumed that buprofezin does not have

a common mechanism of toxicity with

any other registered pesticides.

Therefore, only exposure from

buprofezin is being addressed at this

time.

E. Safety Determination

The toxicity and residue data bases

for buprofezin are considered to be

valid, reliable and essentially complete.

The standard margin of safety approach

is considered appropriate to assess the

risk of adverse effects from exposure to

buprofezin for both acute and chronic

effects. EPA has adopted a temporary

reference dose (RfD) for buprofezin at

0.002 mg/kg/day. This RfD was based on

the systemic lowest effect level (LEL) of

2.0 mg/kg/day limit dose tested (LDT)

from a 2-year dog study and using a

1,000-fold uncertainty factor (UF). An

extra factor of 10 was added to the

standard 100 fold safety factor since the

RfD was based on a LEL (rather than a

NOAEL) and the data base lacked an

acceptable reproductive study.

Additional data have been submitted to

upgrade the reproduction study and to

support the lowest dose in the 2-year

dog study as a NOAEL. With the

upgrading of these studies, the critical

study for the establishment of a

permanent RfD would be the rat

chronic/oncogenicity study. The

NOAEL for this study is 1 mg/kg/day.

Applying a standard safety factor of 100

for this study, to account for

interspecies extrapolation and

intraspecies variation, would result in a

RfD of 0.01 mg/kg/day. It is this

proposed RfD which was used to assess

risk to the public.

1. U.S. population—i. Acute risk. EPA

has previously selected, in their

approval of the section 18 emergency

exemption use, a developmental

NOAEL of 200 mg/kg/day from a rat

developmental study for the acute

dietary endpoint. However, it appears

that this is an inappropriate acute

endpoint since the clinical effects noted

at the higher dose (800 mg/kg/day)

occurred only after at least 5 days of

dosing and the fetal effects (reduced

fetal body weight and delayed

ossification) are not likely to be due to

an acute (1-day) exposure.

Based on this assessment, AgrEvo has

not evaluated the risk from acute

exposure to any subgroup of the

population. Previously, EPA has

assessed the acute risk from use of

buprofezin on citrus and cotton to the

population subgroup of females 13+

years of age. Using the developmental

NOAEL of 200 mg/kg/day, the margin of

exposure (MOE), according to EPA

calculations, was 5,000 for this

subgroup.

ii. Chronic risk. Chronic dietary

exposures for the U.S. population as a

whole utilize 30% of the buprofezin RfD

in the worst-case scenario of 100% of

crop treated and all residues at the

proposed tolerance levels. There is

generally no concern for exposures

below 100% of the RfD since it

represents the level at or below which

no appreciable risks to human health is

posed. Therefore, there is reasonable

certainty that no harm would result to

the U.S. population from exposure to

buprofezin.

2. Infants and children. Data from rat

and rabbit developmental toxicity

studies and rat multigeneration

reproduction studies are generally used

to assess the potential for increased

sensitivity to infants and children. The

developmental toxicity studies are

designed to evaluate adverse effects on

the developing organism resulting from

pesticide exposure during prenatal

development. Reproduction studies

provide information relating to

reproductive and other effects on adults

and offspring from prenatal and

postnatal exposure to the pesticide.

No indication of increased sensitivity

to infants and children was noted in

either of the developmental studies.

However, in the reproduction studies,

the NOAEL for pups (100 ppm) was

lower than for adults (1,000 ppm).

Based on the intake of buprofezin in

pups up to 8 weeks of age, the RfD for

children, using a 1,000 fold safety

factor, would be 0.01 mg/kg/day. This is

the same RfD that is calculated for

chronic exposure utilizing the rat

chronic/oncogenicity study.

Evaluation of the dietary exposure to

infants and children was conducted

utilizing the same assumptions as for

the U.S. population as a whole. In the

worst-case scenario, assuming residues

at the proposed tolerance levels and

with no adjustment for the percent crop

treated, the dietary exposure for

children, 1–6 years, was 50% of the RfD.

There is generally no concern for

exposures below 100% of the RfD since

it represents the level at or below which

no appreciable risks to human health is

posed. Thus, there is a reasonable

certainty that no harm will result to the

most highly exposed population

subgroup, children between 1 and 6

years of age, from exposure to

buprofezin.

F. International Tolerances

Buprofezin was reviewed by the Joint

Meeting of the Food and Agriculture

Organization Panel of Experts on

Pesticide Residues in Food and the

Environment and the World Health

Organization Expert Group on Pesticide

Residues (JMPR) to establish Codex

maximum residue levels (MRLs) in

1991, 1995, and 1997. Permanent MRLs

were granted for cucumbers and

tomatoes and a temporary MRL was

granted for oranges as described below.

Additional residue trial data on oranges

will be available for the 1999 JMPR

meeting to determine if this MRL should

also be made permanent.

Commodity MRL

Cucumber 0.3 ppm

Tomato 0.5 ppm

Oranges, Sweet, Sour 0.3 ppm (temporary)

[FR Doc. 00–15382 Filed 6–20–00; 8:45 am]

BILLING CODE 6560–50–F