Federal Register / Vol. 65, No. 86 / Wednesday, May 3, 2000 / Notices 25721

encoding this protein and its regulatory

regions. ‘‘Regulatory regions’’ are the

genetic material that control the

expression of the genetic material

encoding the protein, such as

promoters, terminators and enhancers.

DNA is common to all forms of plant

and animal life and the Agency has

previously stated that they are not aware

of an instance where these nucleic acids

have been associated with toxic effects

related to their consumption as a

component of food. These ubiquitous

nucleic acids, as they appear in the

subject inert ingredient, have been

adequately characterized. Therefore, no

mammalian toxicity is anticipated from

dietary exposure to the genetic material

necessary for the production of the

subject inert plant pesticidal ingredient.

D. Aggregate Exposure

1. Dietary exposure—i. Food. The

functional activity of the GUS protein

has been thoroughly studied and the

protein is present in a number of

animals, plants and microbes.

Considering that GUS is already present

in both the environment and food, the

presence of the GUS protein in

transgenic plants is unlikely to pose

additional health concerns for humans

or animals. Additionally, the in vitro

digestive fate data demonstrate that the

protein is likely degraded by stomach

digestion prior to passage to the

intestinal tract. Finally, the GUS protein

is degraded upon heating and looses its

functional activity.

ii. Drinking water. Transfer of the

GUS protein to drinking water from

genetically modified crops is highly

unlikely given containment of the

protein in plant cells and natural

degradation upon plant senescence.

However, if it were to occur, the levels

would be insignificant compared to the

levels of GUS protein produced by

bacteria known to inhabit natural

waters.

2. Non-dietary exposure.

Occupational exposure is anticipated to

be minimal during handling, storage,

transportation or disposal of transgenic

plants containing the GUS protein, since

the protein is contained within the cells

of the plant. This containment also

results in a lack of volatilization or

movement.

E. Cumulative Exposure

GUS belongs to a category of nontoxic proteinaceous substances that are

not known to produce toxicological

effects. The presence of the GUS protein

in animals, plants and bacteria

demonstrated a history of safe

consumption of the protein in human

food and animal feed supplies. Because

there is no indication of mammalian

toxicity caused by the GUS protein,

there are no cumulative effects

expected.

F. Safety Determination

1. U.S. population. The toxicity

profile for the GUS protein indicates

essentially no risk from exposure to the

overall U.S. population. Therefore, there

is a reasonable certainty that no harm

will result from aggregate exposure of

the U.S. population, including infants

and children, to the GUS protein and

the genetic material necessary for its

production. This includes all

anticipated dietary exposures and all

other exposures for which there is

reliable information.

2. Infants and children. The

functional activity of this protein has

been thoroughly studied and the protein

is present in plants, animals and

microbes. Considering the widespread

exposure to GUS, additional food

sources containing the GUS protein are

unlikely to pose health concerns for

humans or animals, including infants

and children. This is supported by a

history of safe consumption of the GUS

protein naturally occurring in food and

confirmed by the lack of toxic effects in

an acute mouse gavage study.

G. Effects on the Immune and Endocrine

Systems

No instances are known or reported of

adverse reproductive or developmental

effects to humans, domestic animals or

wildlife as a result of exposure to the

GUS protein or the microbial source of

the uidA gene, Escherichia coli. The

functional activity of this protein has

been thoroughly studied and there is no

known toxicological activity associated

with this protein. Enzyme proteins are

not known to interact or bind directly

with the estrogen receptor, which would

be necessary to produce endocrine

effects. Further, there is little

opportunity for systematic absorption of

the GUS protein due to degradation

upon heating and by digestive enzymes.

H. Existing Tolerances

The registrant is not aware of any

tolerances established for residues of

GUS in raw agricultural commodities

and or processed food/feed.

I. International Tolerances

The registrant is not aware of any

Maximum Residue Levels (MRLs)

established for GUS by the Codex

Alimentarius Commission (CODEX).

[FR Doc. 00–11033 Filed 5–2–00; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–939; FRL–6555–9]

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 certain

pesticide chemicals in or on various

food commodities.

DATES: Comments, identified by docket

control number PF–939, must be

received on or before June 2, 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–939 in the subject

line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By

mail: William G. Sproat, Jr., Registration

Division (7505C), Office of Pesticide

Programs, Environmental Protection

Agency, Ariel Rios Bldg., 1200

Pennsylvania Ave., NW., Washington,

DC 20460; telephone number: (703)

308–8587; e-mail address:

Sproat.william@epamail.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:

CategoriesNAICS

codes

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

25722 Federal Register / Vol. 65, No. 86 / Wednesday, May 3, 2000 / Notices

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–

939. 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–939 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

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–939. 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: April 24, 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

represents the view 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.

Federal Register / Vol. 65, No. 86 / Wednesday, May 3, 2000 / Notices 25723

I. Elanco Animal Health, a Division of

Eli Lilly and Company

OF6115

EPA has received a pesticide petition

OF6115 from Elanco Animal Health, a

Division of Eli Lilly and Company, 2001

W. Main Street, Greenfield, IN 46140

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 spinosad in

or on the raw agricultural commodity

cattle meat, cattle meat by-products,

cattle fat, milk, and milk fat at 0.45,

2.25, 5.75, 0.75, and 8.0 parts per

million (ppm), respectively. 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 support granting of the petition.

Additional data may be needed before

EPA rules on the petition.

A. Residue Chemistry

1. Analytical method. There are two

practical methods immunoassay, high

performance liquid chromotography

(HPLC), for detecting (0.005 ppm) and

measuring (0.01 ppm) levels of spinosad

in or on food with a limit of detection

that allows for monitoring of food with

residues at or above the levels set for

these tolerances. The methods have had

successful method tryout in EPA’s

laboratories.

2. Magnitude of residues. A

magnitude of the residue study was

conducted in lactating dairy cattle after

dermal application of spinosad, where

spinosad residues were most

concentrated in fat (approx 1.3 ppm)

and were much lower in the other

edible tissues and milk (<0/75 ppm).

B. Toxicological Profile

1. Acute toxicity. Spinosad has low

acute toxicity. The rat oral LD50 is 3,738

milligrams/kilograms (mg/kg) for males

and >5,000 mg/kg for females, whereas

the mouse oral LD50 is >5,000 mg/kg.

The rabbit dermal LD50 is >5,000 mg/kg

and the rat inhalation LC50 is >5.18

milligrams/liter (mg/L) air. In addition,

spinosad is not a skin sensitizer in

guinea pigs and does not produce

significant dermal or ocular irritation in

rabbits. End use formulations of

spinosad that are water based

suspension concentrates have similar

low acute toxicity profiles.

2. Genotoxicity. Short-term assays for

genotoxicity consisting of a bacterial

reverse mutation assay (Ames test), an

in vitro assay for cytogenetic damage

using the Chinese hamster ovary (CHO)

cells, an in vitro mammalian gene

mutation assay using mouse lymphoma

cells, an in vitro assay for DNA damage

and repair in rat hepatocytes, and an in

vivo cytogenetic assay in the mouse

bone marrow (micronucleus test) have

been conducted with spinosad. These

studies show a lack of genotoxicity.

3. Reproductive and developmental

toxicity. Spinosad caused decreased

body weights in maternal rats given 200

mg/kg/day by gavage (highest dose

tested (HDT)). This was not

accompanied by either embryo toxicity,

fetal toxicity, or teratogenicity. The no

observed adverse effect levels (NOAELs)

for maternal and fetal toxicity in rats

were 50 and 200 mg/kg/day,

respectively. A teratology study in

rabbits showed that spinosad caused

decreased body weight gain and a few

abortions in maternal rabbits given 50

mg/kg/day (HDT). Maternal toxicity was

not accompanied by either embryo

toxicity, fetal toxicity, or teratogenicity.

The NOAELs for maternal and fetal

toxicity in rabbits were 10 and 50 mg/

kg/day, respectively. In a 2–generation

reproduction study in rats, parental

toxicity was observed in both males and

females given 100 mg/kg/day. Perinatal

effects (decreased litter size and pup

weight) at 100 mg/kg/day were

attributed to maternal toxicity. The

NOAEL for maternal and pup effects

was 10 mg/kg/day.

4. Subchronic toxicity. Spinosad was

evaluated in 13–week dietary studies

and showed NOAELs of 4.89 and 5.38

mg/kg/day in male and female dogs,

respectively; 6 and 8 mg/kg/day in male

and female mice, respectively; and 33.9

and 38.8 mg/kg/day in male and female

rats, respectively. No dermal irritation

or systemic toxicity occurred in a 21–

day repeated dose dermal toxicity study

in rabbits given 1,000 mg/kg/day.

5. Chronic toxicity. Based on chronic

testing with spinosad in the dog and the

rat, EPA has set a reference dose (RfD)

of 0.0268 mg/kg/day for spinosad. The

RfD has incorporated a 100–fold safety

factor to the NOAELs found in the

chronic dog study to account for

interspecies and intraspecies variation.

The NOAELs shown in the dog chronic

study were 2.68 and 2.72 mg/kg/day for

male and female dogs, respectively. The

NOAELs (systemic) shown in the rat

chronic/carcinogenicity/neurotoxicity

study were 9.5 and 12.0 mg/kg/day for

male and female rats, respectively.

Using the Guidelines for Carcinogen

Risk Assessment published September

24, 1986 (51 FR 33992), it is proposed

that spinosad be classified as Group E

for carcinogenicity (no evidence of

carcinogenicity) based on the results of

carcinogenicity studies in two species.

There was no evidence of

carcinogenicity in an 18–month mouse

feeding study and a 24–month rat

feeding study at all dosages tested. The

NOAELs shown in the mouse

oncogenicity study were 11.4 and 13.8

mg/kg/day for male and female mice,

respectively. A maximum tolerated dose

was achieved at the top dosage level

tested in both of these studies based on

excessive mortality. Thus, the doses

tested are adequate for identifying a

cancer risk. Accordingly, a cancer risk

assessment is not needed.

6. Animal metabolism. There were no

major differences in the bioavailability,

routes or rates of excretion, or

metabolism of spinosyn A and spinosyn

D following oral administration in rats.

Urine and fecal excretions were almost

completed in 48–hours post-dosing. In

addition, the routes and rates of

excretion were not affected by repeated

administration.

7. Metabolite toxicology. The residue

of concern for tolerance setting purposes

is the parent material (spinosyn A and

spinosyn D). Thus, there is no need to

address metabolite toxicity.

8. Endocrine disruption. There is no

evidence to suggest that spinosad has an

effect on any endocrine system.

C. Aggregate Exposure

1. Dietary exposure. For purposes of

assessing the potential dietary exposure

from the use of spinosad on cattle, and

existing registered uses on cotton, fruit,

and vegetable crops, a conservative

estimate of aggregate exposure is

determined by basing the theoretical

maximum residue concentration

(TMRC) on the proposed tolerance

levels for spinosad and assuming that

100% of the proposed and registered

uses on cattle and crops raised or grown

in the U.S. were treated with spinosad.

The TMRC is obtained by multiplying

the tolerance residue levels by the

consumption data which estimates the

amount of meat, crops and related

foodstuffs consumed by various

population subgroups. This

conservative use of a tolerance level and

100% of the cattle and crops are treated

with spinosad clearly results in an over

estimation of human exposure.

Using a more realistic analysis

anticipated residues can be evaluated

under a Tier II risk assessment taking

into account a conservative percent of

market share expected for the dermally

applied spinosad to cattle (Extinosad).

Assuming residues of spinosad in food

commodities at the tolerance levels for

commodities based on existing crop

uses, and a 35% market share for the

portion of the tolerance increasing in

25724 Federal Register / Vol. 65, No. 86 / Wednesday, May 3, 2000 / Notices

commodities due to the new dermal

application of spinosad to cattle, a Tier

II dietary risk assessment can be

calculated.

2. Drinking water. Another potential

source of dietary exposure are residues

in drinking water. Based on the

available environmental studies

conducted with spinosad which shows

little or no mobility in soil, there is no

anticipated exposure to residues of

spinosad in drinking water. In addition,

there is no established maximum

concentration level for residues of

spinosad in drinking water.

3. Non-dietary exposure. Spinosad is

being submitted in this application for

control of ectoparasites on cattle and

agricultural premises. Spinosad is

currently registered for use on a number

of crops including cotton and various

fruits and vegetables, all of which

involve applications of spinosad in an

agriculture environment. Spinosad is

also currently registered for outdoor use

on turf and ornamentals at low rates of

application (0.04 to 0.54 lb active

ingredent per acre) and indoor use for

drywood termite control extremely low

application rates with no occupant

exposure expected. Thus, the potential

for non-occupational exposure to the

general population is considered

negligible.

D. Cumulative Effects

The potential for cumulative effects of

spinosad and other substances that have

a common mechanism of toxicity is also

considered. In terms of insect control,

spinosad causes excitation of the insect

nervous system, leading to involuntary

muscle contractions, prostration with

tremors, and finally paralysis. These

effects are consistent with the activation

of nicotinic acetylcholine receptors by a

mechanism that is clearly novel and

unique among known insecticidal

compounds. Spinosad also has effects

on the gamma aminobatopic acid

(GABA) receptor function that may

contribute further to its insecticidal

activity. Based on results found in tests

with various mammalian species,

spinosad appears to have a mechanism

of toxicity like that of many amphiphilic

cationic compounds. There is no

reliable information to indicate that

toxic effects produced by spinosad

would be cumulative with those of any

other pesticide chemical. Thus it is

appropriate to consider only the

potential risks of spinosad in an

aggregate exposure assessment.

E. Safety Determination

1. U.S. population. Using the

conservative exposure assumptions and

the proposed RfD described above, the

aggregate exposure (based on food and

feed wherein potable water and nonoccupational exposure is expected to be

negligible) to spinosad use on cattle as

well as existing registered crop uses will

utilize 41.8% of the RfD for the U.S.

population. A more realistic estimate of

dietary exposure and risk relative to a

chronic toxicity endpoint is obtained if

market share percentage is applied to

the tolerance levels to yield anticipated

residue values. Inserting the anticipated

residue values as a result of the percent

market share, in place of tolerance

residue levels produces a more realistic,

but still conservative risk assessment.

Based on anticipated residues which

considers percent of market share in a

dietary risk analysis, the use of spinosad

on cattle and premises as well as

existing registered crop uses will utilize

36.9% of the RfD for the U.S.

population. EPA generally has no

concern for exposures below 100% of

the RfD because the RfD represents the

level at or below which daily aggregate

dietary exposure over a lifetime will not

pose appreciable risks to human health.

Thus, it is clear that there is reasonable

certainty that no harm will result from

aggregate exposure to spinosad residues

on all existing crop uses and the

pending animal uses.

2. Infants and children. In assessing

the potential for additional sensitivity of

infants and children to residues of

spinosad, data from developmental

toxicity studies in rats and rabbits and

a 2–generation reproduction study in

rats are considered. 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 effects from

exposure to the pesticide on the

reproductive capability and potential

systemic toxicity of mating animals and

on various parameters associated with

the well-being of pups.

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 prenatal

and postnatal toxicity and the

completeness of the data base. Based on

the current toxicological data

requirements, the data base for spinosad

relative to prenatal and postnatal effects

for children is complete. Further, for

spinosad, the NOAEL in the chronic

feeding study which was used to

calculate the RfD (0.027 mg/kg/day) is

already lower than the NOAELs from

the developmental studies in rats and

rabbits by a factor of more than 10–fold.

Concerning the reproduction study in

rats, the pup effects shown at the

highest dose tested were attributed to

maternal toxicity. Therefore, it is

concluded that an additional

uncertainty factor is not needed and that

the RfD at 0.027 mg/kg/day is

appropriate for assessing risk to infants

and children. In addition, EPA has

determined that the 10x factor to

account for enhanced sensitivity of

infants and children is not needed

because:

i. The data provided no indication of

increased susceptibility of rats or rabbits

to in utero and/or postnatal exposure to

spinosad. In the prenatal developmental

toxicity studies in rats and rabbits and

2–generation reproduction in rats,

effects in the offspring were observed

only at or below treatment levels which

resulted in evidence of parental toxicity.

ii. No neurotoxic signs have been

observed in any of the standard required

studies conducted.

iii. The toxicology data base is

complete and there are no data gaps.

Using the conservative exposure

assumptions previously described

(tolerance level residues), the percent

RfD utilized by the use of spinosad on

cattle and premises as well as existing

registered crop uses is 96.1% for

children 1–6 years old, the most

sensitive population subgroup. Based on

anticipated residues which considers a

percent of market share in a dietary risk

analysis, the use of spinosad on cattle

and premises as well as existing

registered crop uses will utilize 81.9%

of the RfD for the children 1–6 years

old. Thus, based on the completeness

and reliability of the toxicity data and

the conservative exposure assessment, it

is concluded that there is a reasonable

certainty that no harm will result to

infants and children from aggregate

exposure to spinosad residues on the

proposed crop uses, including all

existing crop uses.

F. International Tolerances

There are no Codex maximum residue

levels established for residues of

spinosad on any commodity.

[FR Doc. 00–10772 Filed 5–2–00; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[OPP–50867; FRL–6552–5]

Issuance of Experimental Use Permits

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: EPA has granted experimental

use permits (EUPs) to the following