63942 Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices

C. Safety Determination

Based on the very low level of

substance toxicity, relatively short

period of environmental fate and its

usage pattern, Mival exhibits very

minimal risk exposure both in dietary

and non-occupational exposures to

children.

D. International Tolerances

There are no Codex maximum residue

levels established for residues of Mival.

[FR Doc. 97–31549 Filed 12–2–97; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–780; FRL–5756–1]

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–780, must be

received on or before January 2, 1998.

ADDRESSES: By mail submit written

comments to: Public Information and

Records Integrity Branch, Information

Resources and Services Division

(7502C), 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: The

product manager listed in the table

below:

Product Manager Office location/telephone number Address

Joanne Miller (PM 23) ... Rm. 237, CM #2, 703–305–6224, e-mail:miller.joanne@epamail.epa.gov. 1921 Jefferson Davis Hwy, Arlington, VA

James Tompkins (PM

25).

Rm. 239, CM #2, 703–305–5697, e-mail: tompkins.james@epamail.epa.gov. 1921 Jefferson Davis Hwy, Arlington, VA.

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–780]

(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 number (insert docket

number) and appropriate petition

number. Electronic comments on notice

may be filed online at many Federal

Depository Libraries.

List of Subjects

Environmental protection,

Agricultural commodities, Feed

additives, Food additives, Pesticides

and pests, Reporting and recordkeeping

requirements.

Dated: November 21, 1997

Peter Caulkins,

Acting Director, Registration Division, Office

of Pesticide Programs.

Summaries of Petitions

Petitioner summaries of the pesticide

petitions are printed below as required

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

summaries of the petitions were

prepared by the petitioners and

represent the views of the petitioners.

EPA is publishing the petition

summaries verbatim without editing

them in any way. The petition summary

announces the availability of a

description of the analytical methods

available to EPA for the detection and

measurement of the pesticide chemical

residues or an explanation of why no

such method is needed.

1. Valent U.S.A. Corporation

PP 7F4873

EPA has received a pesticide petition

(PP 7F4873) from Valent U.S.A.

Corporation, 1333 N. California Blvd.,

Walnut Creek, CA 94596. proposing

pursuant to section 408(d) of the Federal

Food, Drug and Cosmetic Act, 21 U.S.C.

346a(d), to amend 40 CFR part 180 by

establishing a tolerance for residues of

clethodim in or on the raw agricultural

commodities tuberous and corm

vegetables (crop subgroup 1-C) at 1.0

parts per million (ppm), potato flakes/

granules at 2.0 ppm, sunflower seed at

5.0 ppm, sunflower meal at 10.0 ppm,

canola seed at 0.5 ppm, and canola meal

at 1.5 ppm. The crop subgroup 1-C

tolerance should replace the 0.5 ppm

tolerance that already exists for

clethodim in/or potato tubers which

was based on data from Canada. The
Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices 63943

proposed analytical method for these

commodities is EPA-RM-26D-3, a highperformance liquid chromatography

(HPLC) method. 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. Clethodim is

used for postemergent control of grasses

in a wide variety of crops including

cotton, soybeans, sugar beets, onions,

tomatoes, etc. Plant metabolism studies

have been performed in carrots,

soybeans, and cotton. Studies were

performed with clethodim radiolabeled

in the ring structure and in the side

chain to follow both parts of the

molecule.

The major metabolic pathway in

plants is initial sulfoxidation to form

clethodim sulfoxide followed by further

sulfoxidation to form clethodim sulfone;

elimination of the chloroallyloxy side

chain to give the imine sulfoxide and

sulfone; and hydroxylation to form the

5-OH sulfoxide and 5-OH sulfone.

Clethodim sulfoxide and clethodim

sulfone conjugates were also detected as

major or minor metabolites, depending

on plant species and subfractions. Once

cleaved from clethodim, the

chloroallyloxy moiety udergoes

extensive metabolism to eliminate the

chlorine atom and incorporate the threecarbon moieties into natural plant

components.

Based on these metabolism studies,

the residues of concern in crops are

clethodim and its metabolites

containing the cyclohexene moiety, and

their sulfoxides and sulfones.

2. Analytical method. Adequate

analytical methodology is available for

detecting and measuring levels of

clethodim and its metabolites in crops.

For most commodities, the primary

enforcement method is EPA-RM-26D-3,

an HPLC method capable of

distinguishing clethodim from the

structurally related herbicide

sethoxydim. However, for milk natural

interferences prevent adequate

quantitation of clethodim moieties and

the common-moiety method (RM-26B-2)

is the primary enforcement method with

EPA-RM-26D-3 as the secondary method

if needed to determine whether residues

are clethodim or sethoxydim. Both of

these methods have successfully

undergone petition method validations

at EPA.

3. Magnitude of residues. Clethodim

is the active ingredient in SELECT 2 EC

Herbicide (EPA Reg. No. 59639-3) and

SELECT Herbicide (also known as

PRISM and ENVOY Herbicides, EPA

Reg. No. 59639-78). Tolerances have

been established for residues in cotton,

soybean, sugar beet, onion (dry bulb),

and animal commodities, and tolerances

are expected soon for alfalfa, peanut,

dry bean, and tomato commodities. A

summary of available field residue data

for the pending tolerances on tuberous

and corm vegetables (crop subgroup 1-

C), sunflower, and canola commodities

is presented below.

In 17 field trials, potatoes were treated

with two post-emergent applications of

0.25 lb. a.i./A each, approximately 14–

days apart, and harvested approximately

30 days after the last application. Trials

were performed in EPA Regions 1, 2, 3,

5, 9, 10, and 11. Residues for potato

tuber samples ranged from < 0.1 ppm to

0.80 ppm total clethodim. The highest

average field trial (HAFT) residue was

0.775 ppm. The average residue value

for all trials, excluding samples less

than the limit of detection, was 0.42

ppm. Two processing studies were also

performed for potatoes. Residues were

found to concentrate in flakes, but not

wet peel or chips. The average

concentration factor for flakes was 2.4.

Since potato is the only representative

crop for crop subgroup 1-C per 40 CFR

180.41, these data support time-limited

tolerances of 1.0 ppm in tuberous and

corm vegetables (crop subgroup 1-C)

and 2.0 ppm in flakes/granules.

In 8 field trials, sunflowers were

treated with two post-emergent

applications of 0.25 lb. a.i./A each.

Sunflower seeds were harvested 56 to

72 days after the last application. Trials

were performed in EPA Regions 5, 7,

and 8. Residues for sunflower seed

samples ranged from 0.46 ppm to 4.4

ppm total clethodim. The highest

average field trial (HAFT) residue was

4.2 ppm. The average residue level was

1.6 ppm. A processing study was also

performed for sunflowers. Residues

were found to concentrate in meal, but

not in refined oil. The concentration

factor for meal was 2.1. These data

support tolerances of 5.0 ppm in

sunflower seed and 10.0 ppm in

sunflower meal.

In 18 field trials, canola or rape was

treated with one post-emergent

application of 0.11 to 0.32 lb. a.i./A and

harvested approximately 70 to 98 days

after the application. Most of the trials

were performed in Canada in growing

regions adjacent to the U.S. areas where

canola is grown. These data were used

to support a maximum residue level in

Canada and are being cited in order to

harmonize maximum residue levels

between the U.S. and Canada and

remove the existing trade barrier.

Residues in canola seed samples ranged

from < 0.05 ppm to 0.54 ppm. The

highest average field trial (HAFT)

residue was 0.505 ppm. The average

residue value for all trials, including

samples less than the limit of detection

at one-half the limit, was 0.162 ppm. A

processing study was also performed for

canola and residues were found to

concentrate in meal, but not in crude

oil. Since the highest residues were the

result of application rates higher than

those proposed for the U.S., these data

support tolerances of 0.5 ppm in canola

seed and 1.5 ppm in canola oil.

B. Toxicological Profile

1. Acute toxicity. Clethodim

Technical is slightly toxic to animals

following acute oral (Toxicity Category

III), dermal (Toxicity Category IV), or

inhalation exposure (Toxicity Category

IV under current guideline

interpretation). Clethodim is a moderate

eye irritant (Category III), a severe skin

irritant (Category II), and does not cause

skin sensitization in the modified

Buehler test in guinea pigs. In addition,

an acute oral no-observed effect level

(NOEL) has been determined in rats to

be 300 milligrams/kilograms (mg/kg).

Since this NOEL is significantly higher

than the lowest chronic NOEL of 1 mg/

kg/day, chronic exposures are expected

to be of the most concern and this

summary will focus on repeated

exposures.

2. Genotoxicty. Clethodim Technical

did not induce gene mutation in

microbial in vitro assays. A weak

response in an in vitro assay for

chromosome aberrations was not

confirmed when clethodim was tested

in an in vivo cytogenetics assay up to

the maximally tolerated dose level, nor

was the response observed in vitro using

technical material of a higher purity. No

evidence of unscheduled DNA synthesis

was seen following in vivo exposure up

to a dose level near the LD50 (1.5 g/kg).

This evidence indicates that clethodim

does not present a genetic hazard to

intact animal systems.

3. Reproductive and developmental

toxicity. No reproductive toxicity was

observed with Clethodim Technical at

feeding levels up to 2,500 ppm.

Developmental toxicity was observed in

two rodent species, but only at

maternally toxic dose levels. In rats, the

developmental NOEL was 300 mg/kg/

day while the maternal toxicity NOEL

was only 150 mg/kg/day. In rabbits, the

developmental NOEL was >300 mg/kg/

day and the maternal NOEL was only 25

mg/kg/day. Valent therefore does not
63944 Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices

consider clethodim to be a reproductive

or developmental hazard. These studies

also indicate that clethodim does not

adversely affect endocrine function.

4. Subchronic toxicity. High doses of

Clethodim Technical cause decreased

body weights, increased liver size

(increased weight and cell hypertrophy),

and anemia (decreased erythrocyte

counts, hemoglobin, or hematocrit) in

rats and dogs. No observable effect

levels have been determined to be 100

mg/kg/day for a 4-week dermal study in

rats, 200 to 1,000 ppm for 4- or 5-week

feeding studies in rats or mice, 500 ppm

in a 13-week feeding study in rats, and

25 mg/kg/day in a 90-day oral study in

dogs.

5. Chronic toxicity and oncogenicity.

In chronic studies conducted in rats,

mice, and dogs, compound-related

effects noted at high doses included

decreased body weight, increased liver

size (liver weight and hypertrophy), and

anemia (decreased hemoglobin,

hematocrit, and erythrocyte count).

Bone marrow hyperplasia was observed

in dogs at the highest dose tested. No

treatment-related increases in incidence

of neoplasms were observed in any

study. Chronic NOELs were 200 ppm for

an 18-month feeding study in mice and

500 ppm for a 24-month study in rats.

The lowest NOEL is from the 1-year oral

dog study and is 1 mg/kg/day clethodim

technical. Based on this study and a

100-fold safety factor, the reference dose

(RfD) for clethodim was determined to

be 0.01 mg/kg/day. Valent believes that

clethodim is not carcinogenic. These

studies also indicate that clethodim

does not adversely affect endocrine

function.

6. Animal metabolism. The in vivo

metabolism of clethodim in rats was

tested at a high dose (468 mg/kg), low

dose (4.4 mg/kg), and a low dose (4.8

mg/kg) following 14-days of treatment

with Clethodim Technical. A single oral

dose of [14C]-clethodim was given to

each rat and expired carbon dioxide and

excreta were collected over the next 2-

and 7-days, respectively, to determine

radiolabel recovery. Several organs and

tissues, and the remaining carcass, were

collected after sacrifice to determine

radiolabel recovery. In all treatment

groups, nearly all of the radiolabel was

eliminated in the urine (87-93%), feces

(9-17%), and carbon dioxide (0.5-1%)

and less than 1% of the dose was

recovered in the organs and tissues after

7- days.

Elimination was rapid as most of the

recovered dose was eliminated within

48 hours. The low dose groups

eliminated clethodim slightly faster

than the high dose group, and repeated

exposure to clethodim prior to

radiolabel dosing did not affect the rate

of elimination or distribution of

recovered radiolabel. There were no

apparent sex differences with respect to

elimination or distribution of

metabolites.

The primary excretory metabolites

were identified as clethodim sulfoxide

(48-63%), clethodim S-methyl sulfoxide

(6-12%), clethodim imine sulfoxide (7-

10%), and clethodim 5-hydroxy

sulfoxide (3-5%). Minor metabolites

included clethodim oxazole sulfoxide

(2-3%), clethodim trione sulfoxide (1%),

clethodim (1%), clethodim 5-hydroxy

sulfone (0.3-1%), clethodim sulfone

(0.1-1%), aromatic sulfone (0.2-0.7%),

and S-methyl sulfone (0-0.4%).

7. Dermal penetration. The dermal

penetration of SELECT 2 EC Herbicide,

the end-use product, was tested on

unabraded, shaved skin of rats. Single

doses of approximately 0.05, 0.5, and

5.0 mg of radiolabeled (14C-clethodim)

SELECT 2 EC Herbicide, were applied

topically to 10 cm2 sites on the dorsal

trunk. After 2, 10, or 24 hours, urine,

feces, volatiles, scrubbings of the skin,

skin at treatment site, blood, several

tissues, and the carcass were collected

and counted for radioactivity.

Clethodim was found to be slowly

absorbed through the skin in a timedependent manner. The percent of dose

absorbed increased with length of

exposure and decreased with increasing

dose. 10-hour absorption rates ranged

from 7.5% to 30.0%. Most of the

absorbed material was found in the

urine and carcass, and most of the

unabsorbed material was found in the

skin scrubbings indicating that material

was still on the skin surface.

8. Metabolite toxicology. 2 metabolites

of clethodim, clethodim imine sulfone

(RE-47719) and clethodim 5-hydroxy

sulfone (RE-51228), have been tested in

toxicity screening studies to evaluate

the potential impact of these metabolites

on the toxicity of clethodim. In general,

these metabolites were found to be less

toxic than Clethodim Technical for

acute and oral toxicity studies;

reproduction and teratology screening

studies; and several mutagenicity

studies.

C. Aggregate Exposure

1. Dietary exposure—i. Food.

Clethodim is approved for use in the

production of commercial agricultural

crops including cotton, soybeans, sugar

beets, and onions (dry bulb). Approval

is expected soon for several additional

crops. Dietary exposures are expected to

represent the major route of exposure to

the public. Since chronic exposures are

of more concern than acute exposures

for clethodim, this summary will focus

primarily on chronic issues. Chronic

dietary assessments for clethodim have

been conducted by the registrant for all

currently approved crops, all pending

crops, and the crops proposed in this

petition (tuberous and corm vegetables,

sunflower, and canola).

In Valent’s assessment, anticipated

residues were used for all crop and

animal commodities. Anticipated

residue levels were the mean levels

found in crop field trial data after

treatment with the maximum

recommended rate and harvested at

minimum allowable intervals. These

values are, therefore, slightly

conservative. An assessment was

performed assuming 100% of crop

treated (still conservative) as well as

assuming a more realistic percent of

crop treated based on market survey

data for existing uses or market

projections for proposed uses. Adjusting

for percent of crop treated is justified

because most of treated commodities are

combined in central locations and

broadly distributed to the public; none

of the clethodim tolerances or uses are

limited to specific regions in the U.S.;

and the primary concern is with chronic

dietary exposure which minimizes the

variance of single serving residues. The

results of these assessments are

summarized below in the Safety

Determination section and indicate that

chronic dietary exposures for existing

and proposed uses of clethodim are well

below the reference dose in either case.

ii. Drinking water. Since clethodim is

applied outdoors to growing agricultural

crops, the potential exists for clethodim

or its metabolites to leach into

groundwater. Drinking water, therefore,

represents a potential route of exposure

for clethodim and should be considered

in an aggregate exposure assessment.

Based on available studies used in

EPA’s assessment of environmental risk

for clethodim (memo from E. Brinson

Conerly dated June 26, 1990), clethodim

itself was classified as mobile in soil,

but very non-persistent, representing a

minimal groundwater concern.

Metabolites of clethodim were also

classified as mobile, but are slightly

more persistent (half-lives up to 30–

days versus up to 3-days for parent).

Regarding clethodim metabolites, the

Agency concluded that the ‘‘potential

for groundwater contamination may be

somewhat higher than for clethodim but

would still be expected to be relatively

low in most cases due to their

moderately low persistence’’.

There is no established Maximum

Concentration Level for residues of

clethodim in drinking water under the

Safe Drinking Water Act.
Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices 63945

Based on this information, Valent

believes that clethodim appears to

represent an insignificant risk for

exposure through drinking water.

2. Non-dietary exposure. Clethodim is

currently approved for the commercial

production of agricultural crops

including soybeans, cotton, sugar beets,

onions, and ornamental plants as well

as for use on non-crop areas. The new

uses proposed in this notice of filing are

all agricultural crops. While there is a

potential for clethodim to be used in

non-crop areas (e.g. around parks and

rights-of-way) where the public does

spend some time, the likelihood of

significant exposure is very small. First,

this grass herbicide cannot be sprayed

on lawns where the public does spend

significant amounts of time, but instead

must be used where there is no crop or

around ornamental plants that are

tolerant to the chemical. The public

does not spend significant amounts of

time in these areas. And second,

clethodim is not persistent in the

environment so the potential for public

exposure is short term. Therefore,

Valent believes that the potential for

non-occupational exposure to the

general public, other than through the

diet or drinking water, is insignificant.

D. Cumulative Effects

There is one other pesticide

compound registered in the United

States, sethoxydim, which is

structurally related to clethodim and

has similar effects on animals.

Sethoxydim is approved for use on a

variety of agricultural crops, in non-crop

areas, and around the home. This

chemical should be considered in an

aggregate exposure assessment along

with clethodim. Dietary exposure is

expected to represent the major route of

exposure for sethoxydim as well as for

clethodim.

The reference dose for sethoxydim is

0.09 mg/kg/day based on the 1–year dog

feeding study NOEL and a 100-fold

safety factor. This in on the same order

of magnitude as clethodim, 0.01 mg/kg/

day, which is also based on a 1–year dog

study and a 100-fold safety factor.

A discussion of the cumulative effects

from clethodim and sethoxydim

exposures is presented below in the

Safety Determination section.

E. Safety Determination

1. U.S. population. Using the dietary

exposure assessment procedures

described above for clethodim, chronic

dietary exposures resulting from

existing and proposed uses of clethodim

were compared to the reference dose

(RfD) of clethodim. In Valent’s

conservative assessment (using

anticipated residues and assuming

100% treated for all crops), exposure for

the U.S. population would occupy

13.6% of the RfD and non-nursing

infants (< 1–year) are most highly

exposed with total exposure occupying

32.3% of the RfD. Exposure to children

1 to 6 years old would occupy 27.1% of

the RfD. In Valent’s realistic analysis

(using anticipated residues and

estimated percent of crop treated for all

crops), exposure for the U.S. population

would occupy only 0.6% of the RfD and

non-nursing infants are still the highest

and would be at only 1.6% of the RfD.

For sethoxydim, recent EPA dietary

assessments have been performed in

conjunction with the extension of

several time-limited tolerances. In a

Final Rule published in the Federal

Register of April 11, 1997 (62 FR 17735)

(FRL-5598-7), EPA estimated that

exposure to all existing tolerances for

sethoxydim would occupy 36% of the

sethoxydim RfD for the U.S. population

and 72% of the RfD for the most

exposed subpopulation of children aged

1– to 6-years. The assumptions used

were conservative and the final rule

stated that ‘‘actual risks using more

realistic assumptions would likely

result in significantly lower risk

estimates.’’

Since clethodim and sethoxydim have

similar toxicological effects in

mammals, the contributions to the

individual reference doses may need to

be considered in an aggregate exposure

assessment. The EPA generally has no

concern for exposures below 100% 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.

Directly summing the results of the

conservative sethoxydim and the

conservative clethodim contributions to

RfD would be approaching 100%.

However, reliable information is not

available to indicate that directly

summing the percent of RfD for these

two chemicals is the most appropriate

thing to do. Since using realistic

assumptions for clethodim, including

adjustment for percent of crop treated,

result in large decreases in dietary risk

(about 20-fold) Valent expects that the

sethoxydim risk estimates would also be

reduced significantly. Therefore, Valent

believes that the cumulative chronic

dietary risk of sethoxydim and

clethodim is likely to be well below the

100% level for all population

subgroups.

Regarding drinking water exposures,

sethoxydim is similar to clethodim

representing a minimal risk for leaching

into groundwater due to its rapid

degradation in the environment. There

is no established Maximum

Concentration Level for residues of

sethoxydim in drinking water under the

Safe Drinking Water Act.

Regarding non-occupational

exposures, sethoxydim is registered for

use in non-crop areas and around the

home and may have some potential for

exposure to the general public.

However, as discussed for clethodim,

sethoxydim cannot be applied to grass

where public contact is expected and

sethoxydim is not persistent in the

environment. Valent therefore expects

that non-occupational exposures to the

public be minimal for sethoxydim.

In summary, dietary exposure for

clethodim and sethoxydim are each

expected to occupy less than 10% of

their RfD’s when anticipated residue

levels and percent of crop treated values

are considered. Exposures through the

drinking water or other nonoccupational routes are expected by

Valent to be minimal. Collectively,

Valent believes that the aggregate risks

associated with the uses of these two

chemicals is small and demonstrates a

reasonable certainty of no harm to the

public.

2. Infants and children. As discussed

above, dietary exposure for clethodim

and sethoxydim is greatest for children

ages 1–6-years or non-nursing infants

less than 1–year old. However, using a

realistic approach to estimating

exposures, exposures are expected to be

below 10% of the RfD for each chemical

even for infants and children. The

databases for clethodim and sethoxydim

are complete relative to current pre- and

post-natal toxicity testing requirements

including developmental toxicity

studies in two species and multigeneration reproduction studies in rats.

Reproduction and developmental effects

have been found in toxicology studies

for clethodim and sethoxydim, but the

effects were seen at levels that were also

maternally toxic. This indicates that

developing animals are not more

sensitive than adults. FQPA requires an

additional safety factor of up to 10 for

chemicals which represent special risks

to infants or children. Clethodim and

sethoxydim do not meet the criterion for

application of an additional safety factor

for infants and children. Valent believes

that this demonstrates a reasonable

certainty of no harm to children and

infants from the proposed uses of

clethodim.

F. International Tolerances

Although some have been proposed,

there are no Mexican or Codex

tolerances or maximum residue limits

established for clethodim on potatoes,

sunflower, or canola commodities. In
63946 Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices

Canada, there are maximum residue

limits established for potato tubers at

0.5 ppm and canola oil at 0.1 ppm. The

use rates proposed for the use on

tuberous and corm vegetables (crop

subgroup 1-C) may exceed the 0.5 ppm

level in tubers so a higher level is

necessary. In Canada, canola oil is the

only canola commodity considered for a

residue limit since this is the

commodity consumed by humans. In

the U.S., a tolerance is not being

proposed for the processed commodity

canola oil since concentration did not

occur in the processing study.

Consequently, residue in oil up to 0.5

ppm would be allowed in the U.S.

However, the residue data indicate that

residues in oil are not expected to

exceed 0.1 ppm and Valent does not

believe this would represent a barrier

against exporting U.S.-treated canola oil

into Canada.

2. Zeneca Ag Products

PP 6F4609

EPA has received a pesticide petition

(PP 6F4609) from Zeneca Ag Products,

1800 Concord Pike, P.O. Box 15458,

Wilmington, DE 19850. 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

diquat dibromide in or on the raw

agricultural commodity dried shelled

pea and bean (except soybean) subgroup

(seed) at 0.80 ppm. The proposed

analytical method is a

spectrophotometric method measuring

absorption following derivitisation of

the diquat with alkaline sodium

dithionite. EPA has determined that the

petition contains data or information

regarding the elements set forth in

section 408(d)(2) of the FFDCA;

however, EPA has not fully evaluated

the sufficiency of the submitted data at

this time or whether the data supports

granting of the petition. Additional data

may be needed before EPA rules on the

petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism

of diquat in plants is adequately

understood. The residue of concern in

plants is diquat per se. No further plant

metabolism data are necessary for this

proposed use.

2. Analytical method. The method of

analysis is a spectrophotometic method

measuring absorption following

derivitisation of the diquat with alkaline

sodium dithinoite.

3. Magnitude of residues. Dry Pea -

Six residue field trials were conducted

during 1994 in California, Idaho,

Oregon, Texas, and Washington. The

seed samples were analyzed for the

active ingredient diquat. Diquat residues

in dry pea seed ranged from 0.05 to 0.56

ppm.

Lentil - Five residue field trials were

conducted during 1994 in Idaho, North

Dakota, and Washington. The seed

samples were analyzed for the active

ingredient diquat. Diquat residues in

lentil seed ranged from < 0.05 to 0.54

ppm.

Dry Bean - Eight residue field trials

were conducted during 1994 in

California, Colorado, Idaho, Michigan,

Minnesota, North Dakota, Nebraska, and

New York. The bean seed were analyzed

for the active ingredient diquat. Diquat

residues were less than the limit of

quantitation (<0.05 ppm) in all the bean

seed samples.

B. Toxicological Profile

1. Acute toxicity. In studies using

laboratory animals, diquat dibromide

has been shown generally to be of

moderate toxicity. It can cause slight to

severe eye irritation and has been

placed in Toxicity Category II for acute

dermal eye irritation effects. It is slightly

acutely toxic by the oral and inhalation

routes and has been placed in Toxicity

Category III for these effects. Diquat

dibromide causes slight dermal

irritation and has been placed in

Toxicity Category IV for this effect. It is

not a skin sensitizer.

2. Genotoxicty. Diquat dibromide was

negative for mutagenicity in the

following test: 1 gene mutation (Ames),

2 structural chromosome aberration

(mouse micronucleus and dominant

lethal in mice) and 1 other genotoxic

effects (unscheduled DNA synthesis in

rat hepatocytes in vitro). Diquat was

positive in 1 gene mutation test (mouse

lymphoma cell assay) and in 1

chromosome aberration test (human

blood lymphocytes, depending on the

concentration of diquat dibromide and

the presence or absence of the metabolic

activation system). EPA has concluded

that Diquat does not appear to present

a mutagenicity concern in (in vivo)

studies and for heritable risk

considerations based on available

information.

3. Reproductive and developmental

toxicity. In a rat multigeneration study,

diquat was fed at dose levels equivalent

to 0, 16, 80 or 400/240 ppm of diquat

cation. There was evidence of toxicity in

both adults and offspring at 400/240

ppm diquat. A low incidence of toxicity

was seen at 80 ppm in the adult rats

only. Based on the findings, the NOEL

and LOEL for systemic toxicity are 16

ppm (0.8 mg/kg/day) and 80 ppm (4 mg/

kg/day), respectively, expressed as

diquat cation. The NOEL and LOEL for

reproductive toxicity are 80 ppm (4 mg/

kg/day) and 400/240 ppm (20/12 mg/kg/

day) respectively, expressed as diquat

cation.

In a developmental toxicity study in

rabbits, diquat dibromide was

administered by gavage at dose levels of

0, 1, 3, or 10 mg/kg/day. There was no

evidence to suggest that diquat was

teratogenic to the rabbit at any dose

level tested. Based on the findings, the

NOEL and LOEL for maternal toxicity

are 1 mg/kg/day and 3 mg/kg/day,

respectively, expressed as diquat cation.

The developmental toxicity NOEL and

LOEL are, respectively, 3 mg/kg/day and

10 mg/kg/day, expressed as diquat

cation.

In a developmental toxicity study in

the rat, diquat dibromide was

administered by oral gauge dose levels

of 0, 4, 12 or 40 mg/kg/day. Diquat was

not a rat teratogen at any of the dose

levels tested. Maternal toxicity and

foetotoxicity were in evidence at 40 mg/

kg/day with mild and transient maternal

toxicity persisting to the lowest dose

level tested (4 mg/kg/day). The

developmental toxicity NOEL and LOEL

are, respectively, 12 mg/kg/day and 40

mg/kg/day expressed as diquat cation.

4. Subchronic toxicity. A

supplemental subchronic dermal

toxicity study using rabbits exposed to

technical diquat dibromide at doses of

0, 20, 40, 80, or 160 mg/kg/day with a

toxicological NOEL and LOEL for

systemic toxicity, for both sexes, of 20

mg/kg/day and 40 mg/kg/day,

respectively.

A repeated dermal toxicity study

using rats exposed to technical diquat

dibromide at doses of 0, 5, 20, 40 or 80

mg/kg of body weight/day with a

toxicological NOEL and LOEL for

systemic toxicity, for both sexes, of 5

mg/kg/day and 20 mg/kg/day,

respectively.

An inhalation study using rats

resulted in increase in lung weight,

lung/body weight and lung/brain

weight, lung lesions, and mottling and

reddening of the lungs in females;

however, all effects except the latter

were reversible. A second inhalation

study using rats showed no effects on

any of the parameters examined at a

dose of 0.1 μg/l. Based on both studies

the NOEL and LOEL on inhalation

exposure are 0.1μg/L and 0.49 μg/L,

respectively.

5. Chronic toxicity.— i. 2–Year rat

study. - A chronic feeding

carcinogenicity study was conducted on

rats which were fed diets containing 0,

5, 15, 75 or 375 ppm of diquat cation.

The systemic NOEL for both sexes was

15 ppm (0.58 mg/kg/day for males and
Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices 63947

0.72 mg/kg/day for females, expressed

as diquat cation); and the systemic

LOEL was 75 ppm (2.91 mg/kg/day for

males and 3.64 mg/kg/day for females,

expressed as diquat cation).

ii. 1–Year dog study. - A chronic dog

study was conducted on beagles which

were fed diets containing 0, 0.5, 2.5, or

12.5 mg/kg/day, expressed as diquat

cation. The systemic NOEL for both

sexes was 0.5 mg/kg/day and systemic

LOEL was 2.5 mg/kg/day.

iii. 2–Year mice study. - A chronic

feeding/carcinogenicity study was

conducted on mice which were fed diets

containing 0,30,100 or 300 ppm,

expressed as diquat cation. The

systemic NOEL for both sexes was 30

ppm. The systemic LOEL was 100 ppm.

Zeneca believes that diquat was not

carcinogenic in this study.

The carcinogenic potential of diquat

dibromide was evaluated by the Health

Effects Division Reference Dose (RfD)/

Peer Review Committee on March 31,

1994. The Committee classified diquat

dibromide into Group E (evidence of

noncarcinogenicity for humans, based

on a lack of evidence of carcinogenicity

in acceptable studies with two animal

species, rat and mouse.

6. Animal metabolism. The

reregistration requirements for animal

metabolism are fulfilled. The qualitative

nature of the residue in animals is

adequately understood based on

acceptable poultry, ruminant, and fish

metabolism studies. There are no animal

feed items associated with this proposed

use. The diquat metabolism and

magnitude of residue in animals is not

germane to this petition.

7. Metabolite toxicology. The

qualitative nature of the residue in

plants is adequately understood based

on an acceptable potato metabolism

study and rat bioavailabilty study. The

terminal residue of concern in plants is

diquat per se. The qualitative nature of

the residue in animals is adequately

understood.

C. Aggregate Exposure

Diquat is a non-selective, contact

herbicide with both food and non-food

uses. As such, aggregate nonoccupational exposure would include

exposures resulting from consumption

of potential residues in food and water,

as well as from residue exposure

resulting from non-crop use around

trees, shrubs, lawns, walks, driveways,

etc. Thus, the possible human exposure

from food, drinking water and

residential uses has been assessed

below.

1. Dietary exposure— i. Food. Acute

dietary - The EPA did not identify an

acute toxicity endpoint of concern for

diquat in the Reregistration Eligibility

Decision (RED) document, and

determined that an acute dietary risk

assessment is not required for this

chemical.

ii. Chronic dietary. For purposes of

assessing the potential chronic dietary

exposure, Zeneca has estimated the

aggregate exposure based on Theoretical

Maximum Residue Contribution

(TMRC) for all existing tolerances and

the proposed tolerances of diquat on dry

beans and dry peas at 0.8 ppm. The

TMRC is obtained by multiplying the

tolerance level residues (existing and

proposed) by the consumption data

which estimates the amount of those

food products eaten by various

population subgroups. Exposure of

humans to residues could also result if

such residues are transferred to meat,

milk, poultry or eggs. The following

assumptions were used in conducting

this exposure assessment: 100% of the

crops were treated, the RAC residues

would be at the level of the tolerance,

and certain processed food residues

would be at anticipated (average) levels

based on processing studies. In

addition, residues of diquat in tap water

at the Maximum Contaminant Level

(MCL) of 0.02 ppm was included in the

dietary assessment. These conservative

assumptions result in a ‘‘worst-case’’

risk assessment and a significant

overestimate of actual human exposure.

An assessment was also performed

using Anticipated Residues

Contributions (ARC) derived from field

trial data for sorghum, soybeans,

potatoes, dry beans and peas. The ARC

assessment also included percent crop

treated data as cited in the July 1995

Diquat RED, as well as market

projections for dry beans and peas. The

resulting TMRC for the US population is

0.002946 mg/kg body weight/day

(58.9% of the RfD). For this same group,

the Anticipated Residue Contribution

(ARC) is 0.000711 mg/kg body weight/

day (14.2% RfD). For children ages 1 to

6 and non-nursing infants the TMRC

was 0.004571 mg/kg body-weight/day

(91.4% RfD) and 0.003620 mg/kg bodyweight/day (72.4% RfD), respectively.

For these same groups the ARC was

0.001513 mg/kg body-weight/day

(30.3% RfD) for children ages 1 to 6, and

0.002795 mg/kg body-weight/day

(55.9% RfD) for non-nursing infants.

None of the subgroups assessed

exceeded 100% of the RfD.

iii. Drinking water. In examining

aggregate exposure, FQPA directs EPA

to consider available information

concerning exposures from the pesticide

residue in food and all other nonoccupational exposures. The primary

non-food sources of exposure the

Agency looks at, include drinking water

(whether from groundwater or surface

water), is exposure through pesticide

use in gardens, lawns, etc (residential

uses).

The lifetime health advisory and

maximum contaminant level (MCL) set

by EPA for diquat are the same and

given as 0.02 parts per million (ppm) as

required under the Drinking Water

Regulations under the Safe Drinking

Water Act. Drinking water which meets

the EPA standard is associated with

little to no risk and should be

considered safe. Inclusion of MCL level

residues of diquat in water in the

dietary assessment demonstrated a safe

exposure level to all subgroups in the

US population. The Agency no longer

establishes tolerances for residues in

potable water; the tolerance for diquat

dibromide has been replaced with a

designated maximum contaminant level

goal (MCLG) of 0.02 ppm for residues of

diquat in potable water.

The primary route of environmental

dissipation of diquat is strong

adsorption to soil particles. Diquat does

not hydrolyse or photodegrade and is

resistant to microbial degradation under

aerobic and anaerobic conditions. There

were no major degradates isolated from

any of the environmental fate studies.

When used as an aquatic herbicide,

diquat is removed from the water

column by adsorption to soil sediments,

aquatic vegetation, and organic matter.

Adsorbed diquat is persistent and

immobile, and is not expected to be a

ground-water contaminant. The

environmental fate data base for diquat

is complete for reregistration of diquat

dibromide.

2. Non-dietary exposure. As a nonselective, contact herbicide, homeowner

use of diquat will consist primarily of

spot spraying of weeds around trees,

shrubs, walks, driveways, flower beds,

fence lines, etc. The potential for

exposure following application as a spot

treatment in residential gardens,

driveway edges, patios, etc. is low due

to the limited frequency and duration of

exposure. The exposures which would

result from the use of diquat are

determined to be of an intermittent

nature. Any exposures to diquat would

result from dermal exposure. These

exposures are not expected to pose any

acute toxicity concerns. Based on the

US EPA National Home and Garden

Pesticide Use Survey (RTI/5100/17-01F,

March 1992), the average homeowner is

expected to use non-selective herbicides

only about four times a year. Thus, these

exposure have not been factored into a

chronic exposure assessment. Also,

diquat has extremely low skin

permeation, is not volatile, presenting
63948 Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices

no inhalation risk, and has rapid and

strong binding characteristics to leaf

surfaces and soil. The Agency concludes

that non-occupational and non-dietary

exposure to diquat will not be

significant and has not been aggregated

with dietary exposures in estimating

chronic risk.

D. Cumulative Effects

The only other compound in the

bipyridilium chemical family is

paraquat dichloride. Since diquat

dibromide and paraquat dichloride have

different toxicological endpoints and

therefore do not have a common mode

of action, there is no need for an

assessment of cumulative effects.

E. Safety Determination

1. U.S. population. The proposed uses

utilize 58.9% of the RfD for the general

U.S. population, based on the

assumptions of 100% crop treated, MCL

level residues in tap water and all

residues at tolerance levels; 72.4% of

the RfD for non-nursing infants under 1-

year old, 19.6% of the RfD for nursing

infants under 1-year old; 91.4% of the

RfD for children 1-6 years old; and

71.5% of the RfD for children 7-12 years

old. An additional risk assessment for

residential uses is unnecessary because

there is no evidence for toxicological

concern via the dermal or inhalation

routes of exposure. Given diquat’s

strong binding characteristics, exposure

via drinking water is highly unlikely.

Zeneca concludes that there is

reasonable certainty that no harm will

occur from aggregate exposure to diquat.

2. Infants and children. FFCDA

section 408 provides that EPA shall

apply an additional ten fold margin of

exposure 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 exposure will be safe for infants and

children. EPA believes that reliable data

support using the standard margin of

exposure (usually 100 x for combined

inter- and intra-species variability) and

not the additional tenfold margin of

exposure when EPA has a complete data

base under existing guidelines and

when the severity of the potential 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 of exposure.

Risk to infants and children was

determined by the use of a rat

multigeneration reproduction study and

developmental toxicity studies in

rabbits and rats. The reproduction study

provides information on potential

effects from exposure on the

reproductive capability of mating

parents and on systemic toxicity. The

developmental studies provide

information on the potential for adverse

effects from exposure on the developing

organism during prenatal development.

The toxicological data base for

evaluating pre- and post-natal toxicity

for diquat is considered to be complete.

In the rat reproduction study, systemic

toxicity to the mating parents was

observed at 4 and 20/12 mg diquat

cation/kg body weight/day, and

reproductive effects in the form of

decreased pups per litter and decreased

body weight gain were seen at 20/12

mg/kg/day. Given that the effects seen

in the pups and litters were at doses that

clearly affected the parents at this dose

level and below, diquat is considered

not to affect reproductive performance

without significantly compromising the

health of the parental animals.

Developmental effects in the rat and

rabbit studies, including decreased body

weights, kidney and liver effects, and

delayed ossification, were only observed

at the highest doses tested and are

considered to be related to the

significant maternal toxicity exhibited at

these dose levels. There was no

evidence in these studies that diquat

caused teratogenic effects.

Furthermore, the RfD is currently

based on effects seen at 0.5 mg/kg/day

in the dog. Effects seen at maternally

toxic doses in the rat developmental

study were 80 times higher, and in the

rabbit study were 20 times higher than

the level on which the RfD is based.

Thus, Zeneca does not believe the

effects seen in these studies are of such

a concern to require an additional safety

factor. Accordingly, Zeneca concludes

that the RfD has an adequate margin of

protection for infants and children and

there is reasonable certainty that no

harm will occur to infants and children

from aggregate exposure to diquat.

F. International Tolerances

Codex lists diquat cation in dry beans

and peas at 0.2 ppm. Diquat is listed in

Canada in beans and peas at 0.1 ppm.

There are no Mexican maximum residue

limits for diquat on dry beans or peas.

3. E.I. DuPont de Nemours and Co., Inc.

PP 7F4849

EPA has received a pesticide petition

(PP 7F4849) from E.I. DuPont de

Nemours and Co., Inc. (DuPont), Barley

Mill Plaza, P.O. Box 80083, Wilmington,

DE 19880-0038. 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 for

azafenidin, 2-[2,4-dichloro-5-(2-

propynyloxy) phenyl]-5,6,7,8-

tetrahydro-1,2,4-triazolo [4,3-a] pyridin3(2H)-1 in or on the raw agricultural

commodities of the crop grouping of

citrus, grapes, sugarcane and sugarcane

molasses. The proposed analytical

method involves homogenization,

filtration, partition and cleanup with

analysis by gas chromatography using

mass selective detection. 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 qualitative

nature of the residues of azafenidin in

citrus, grapes and sugarcane is

adequately understood for the purposes

of registration. Metabolic pathways in

grapefruit, grapes and sugarcane are

similar, consisting of rapid Odealkylation and production of

hydroxyl derivatives, with subsequent

formation of glucuronide and sulfate.

2. Analytical method. The proposed

analytical method involves

homogenization, filtration, partition and

cleanup with analysis by gas

chromatography using mass selective

detection.

3. Magnitude of residues. DuPont

proposes establishing tolerances for

residues azafenidin, 2-[2,4-dichloro-5-

(2-propynyloxy)phenyl]-5,6,7,8-

tetrahydro-1,2,4-triazolo[4,3-a]pyridin3(2H)-1 (Milestone*) in or on the

agricultural commodities of the crop

grouping of citrus at 0.1 ppm, grapes at

0.02 ppm, sugarcane at 0.02 ppm and

sugarcane molasses at 0.1 ppm .

B. Toxicological Profile

1. Acute toxicity. Technical

azafenidin has been placed in acute

toxicology category III based on overall

results from several studies. Results

from the following studies indicate

toxicology category III: acute dermal

toxicity (LD50 > 2,000kg; rabbits) and

eye irritation (effects reversible within

72 hours; rabbits). Acute oral toxicity

(LD50 > 5,000 mg/kg; rats), acute

inhalation toxicity (LC50 > 5.4 mg/L,

rats) and skin irritation (slight effects

resolved within 48 hours; rabbits)

results were assigned toxicology

category IV. Technical azafenidin is not

a dermal sensitizer.

An acute neurotoxicity study was

conducted in rats administered
Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices 63949

azafenidin via gavage at 0, 100, 300 or

900 mg/kg. Azafenidin was not

neurotoxic at any dose. The systemic

NOEL was 100 mg/kg for males and

females based on reduced food

consumption and body weights at 300

mg/kg and above.

2. Genotoxicty. Technical azafenidin

was negative for genotoxicity in a

battery of in vitro and in vivo tests.

These tests included the following:

mutagenicity in bacterial (Ames test)

and mammalian (CHO/HGPRT assay)

cells; in vitro cytogenetics

(chromosomal aberration in human

lymphocytes); in vivo cytogenetics (bone

marrow micronucleus assay in mice);

and unscheduled DNA synthesis in rat

primary hepatocytes.

3. Reproductive and developmental

toxicity. A 2-generation reproduction

study was conducted in rats with

dietary technical azafenidin

concentrations of 0, 5, 30, 180 or 1,080

ppm. The NOEL was 30 ppm (1.7 to 2.8

mg/kg/day for P1 and F1 males and

females and their offspring). This was

based on the following effects at 180

ppm (10.1 to 17.8 mg/kg/day for P1 and

F1 males and females and/or their

offspring): slight reductions in mean

body weights for F1 males and females;

reductions in mean gestation body

weight gain and implantation efficiency;

slightly increased gestation lengths;

decreased offspring survival, body

weights and other indices of offspring

health; and increased incidence of

diarrhea among F1 parental males.

A developmental study was

conducted in rats administered

technical azafenidin by gavage at 0, 3,

8, 16 or 24 mg/kg/day. Azafenidin was

not teratogenic. The NOEL was 16 mg/

kg/day based on the following

observations at 24 mg/kg/day: reduced

maternal body weight, increased

resorptions, reductions in litter size and

fetal weights and increased sternebral

variations. The maternal effects

consisted of transient body weight

reductions; however, the nature of these

effects suggested that fetal resorptions

contributed to these weight reductions.

A developmental study was

conducted in rabbits administered

technical azafenidin by gavage at 0, 12,

36, 100 or 300 mg/kg/day. Azafenidin

was not teratogenic. The NOELs for

maternal and offspring toxicity were 12

and 100 mg/kg/day, respectively. The

maternal NOEL was based on reduced

body weight at 36 and 100 mg/kg/day

and mortality at higher doses. Excessive

maternal toxicity at 300 mg/kg/day

precluded a Crop field trial residue data

from citrus, grape and sugarcane studies

show that the proposed tolerances on

these commodities will not be exceeded

when Milestone* is used as directed.

Assessment of developmental effects at

this level. However, the developmental

NOEL was considered to be 100 mg/kg/

day since there were no indications of

fetal toxicity up to and including this

dose level.

4. Subchronic toxicity. A 90–day

study in mice was conducted at dietary

concentrations of 0, 50, 300, 900 or

1,500 ppm. The NOEL was 300 ppm

(47.2 and 65.8 mg/kg/day for male and

female mice, respectively). This was

based on reduced body weight gain in

males and microcytic and hypochromic

anemia in males and females at 900

ppm (or 144 and 192 mg/kg/day for

males and females, respectively).

Technical azafenidin was

administered in the diets of rats at 0, 50,

300, 900 or 1,500 ppm for 90 days. The

NOEL was 300 ppm (24.2 and 28.2 mg/

kg/day for male and female rats,

respectively). This was based on

methemoglobinemia and microcytic and

hypochromic anemia in males and

females at 900 ppm (or 71.9 and 83.8

mg/kg/day for male and female rats,

respectively).

Dogs were administered technical

azafenidin in their diets at 0, 10, 60, 120

or 240 ppm for 90–days. The NOEL was

10 ppm (0.34 and 0.33 mg/kg/day for

males and females, respectively). This

was based on enlarged hepatocytes and

increased serum alkaline phosphatase

and alanine aminotransferase activities

at 60 ppm (2.02 and 2.13 mg/kg/day for

male and female dogs, respectively).

A 90–day subchronic neurotoxicity

study was conducted in rats at 0, 50,

750 or 1,500 ppm. There were no

neurological effects observed in this

study. The NOEL for systemic toxicity

was 50 ppm (3.0 mg/kg/day) and 750

ppm (54.5 mg/kg/day) for male and

female rats, respectively. These were

based on reduced food consumption

and body weights and increased

incidences of clinical signs of toxicity at

the higher doses.

A 28–day dermal study was

conducted in rats at 0, 80, 400 or 1,000

mg/kg/day. There was no dermal

irritation or systemic toxicity among

males or females at the highest dose

tested. The NOEL was > 1,000 mg/kg/

day.

5. Chronic toxicity. An 18–month

mouse study was conducted with

dietary concentrations of 0, 10, 30, 300

or 900 ppm technical azafenidin. This

product was not oncogenic in mice. The

systemic NOEL was 300 ppm (39.8 and

54.1 mg/kg/day for males and females,

respectively). This was based on

hepatotoxicity among males and

reduced body weights and food

efficiency among females at 900 ppm (or

122 and 163 mg/kg/day for males and

females, respectively).

A 2–year chronic toxicity/

oncogenicity study was conducted in

rats fed diets that contained 0, 5, 15, 30,

300 or 900 ppm technical azafenidin.

This product was not oncogenic in rats.

The systemic NOEL was 300 ppm (12.1

and 16.4 mg/kg/day males and females,

respectively). The NOEL was defined by

microcytic, hypochromic and hemolytic

anemia and mortality at 900 (or 35.2 and

50.2 mg/kg/day for male and female

rats, respectively).

Technical azafenidin was

administered for 1–year to dogs at

dietary concentrations of 0, 5, 10, 120

and 360 ppm. The NOEL was 10 ppm

(0.30 mg/kg/day for males and females).

This was based on observations of

altered hepatocyte morphology,

hydropic degeneration and elevated

alanine aminotransferase and alkaline

phosphatase at 30 ppm (0.86 and 0.87

mg/kg/day for male and female dogs,

respectively) and above.

6. Animal metabolism. The

metabolism of azafenidin in animals (rat

and goat) is adequately understood and

is similar among the species evaluated.

Azafenidin was readily absorbed

following oral administration,

extensively metabolized and rapidly

eliminated in the urine and feces. The

terminal elimination half-life in plasma

was 40 hours in rats. Less than 1% of

the administered dose was present in rat

tissues at 120 hours. There were no

volatile metabolites of azafenidin. The

major metabolic pathways in the rat and

goat consisted of rapid O-dealkylation

and production of hydroxyl derivatives,

subsequent formation of glucuronide

and sulfate conjugates and elimination

of these conjugates in feces and urine.

There was no evidence of accumulation

of azafenidin or its metabolites in the

tissues of either species or in the goat’s

milk.

7. Metabolite toxicology. There is no

evidence that the metabolites of

azafenidin identified in animal or plant

metabolism studies are of any

toxicological significance. The existing

metabolism studies indicate that the

metabolites formed are unlikely to

accumulate in humans or in animals

that may be exposed to these residues in

the diet. The fact that no quantifiable

residues were found in edible portions

of treated crops further indicates that

exposures to and accumulation of

metabolites are unlikely.

C. Aggregate Exposure

1. Food—i. Acute dietary exposure.

Since there were no acute affects

appropriate for assessment of the

general population, the NOEL of 16 mg/
63950 Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices

kg/day from the rat developmental

toxicity study was used to assess acute

dietary risk for females 13–years of age

and older. Exposures were estimated

using the DEEM computer software

(version 5.03b, Novigen Sciences, Inc,

1997). The proposed azafenidin

tolerances for the raw agricultural

commodities and processed fractions

that were used in the calculations

included: grapes, 0.02 ppm; citrus, 0.1

ppm; and sugarcane - 0.02 ppm for cane

sugar and 0.1 ppm for molasses. The

following exposures indicate margins of

exposure > 11,000 at the 95th percentile

and provides a reasonable certainty that

no harm to the individual or the

developing child will occur under these

conservative exposure assumptions (i.e.,

all labeled crops are treated, residues

are present at the proposed tolerances

and there is no reduction of residues

prior to consumption of these food

commodities).

Subpopulations

Exposure -

95th Percentile (mg/

kg/day)

MOEa

13+/Pregnant;

Not Nursing.

0.000868 86,800

13+/Nursing ..... 0.001384 11,561

13 - 19/ Not

Pregnant; Not

Nursing.

0.001119 14,561

20+/Not Pregnant; Not

Nursing.

0.000832 0.19,231

13 - 50 Years .. 0.000938 17,056

a MOE - Margin of Exposure = NOEL from

rat developmental study (16 mg/kg/day) divided by the 95th percentile exposure.

ii.Chronic dietary exposure. A

Reference Dose (RfD) of 0.003 mg/kg/

day has been proposed based on the

NOEL from the most sensitive chronic

study (NOEL of 0.3 mg/kg/day from the

1–year dog study) and applying a 100-

fold uncertainty factor. General and

subpopulation exposures were

estimated using the DEEM computer

software (version 5.03b, Novigen

Sciences, Inc, 1997). The following

proposed azafenidin tolerances for the

raw agricultural commodities and

processed fractions were used in the

calculations: grapes, 0.02 ppm; citrus,

0.1 ppm; and sugarcane - 0.02 ppm for

cane sugar and 0.1 ppm for molasses.

Exposure assessments assumed 100% of

the crops were treated with azafenidin,

that residues were present at the

tolerance level and that no residues

were removed prior to consumption of

treated crops. These assessments

indicated adequate margins of exposure

for all subpopulations and that only

21% or less of the RfD was utilized by

any group. For example, the TMRCs

were 0.000237 mg/kg/day (7.9% RfD)

for the general population and 0.000619

mg/kg/day (20.6% RfD) for the

subpopulation with the highest

potential exposure, children ages 1

through 6 years.

2. Drinking water. Other potential

dietary sources of exposure of the

general population to pesticides are

residues in drinking water. There is no

Maximum Contaminant Level

established for residues of azafendidin.

The petitioner is reporting to the

Environmental Fate and Groundwater

Branch of EPA (EFGWB) the interim

results of a prospective groundwater

monitoring study conducted at a highly

vulnerable site. Based on the

preliminary results of this study the

petitioner does not anticipate residues

of azafenidin in drinking water and

exposure from this route is unlikely.

However, given that less than 21% of

the RfD is attained by the TMRC for the

population subgroup with the highest

theoretical dietary exposure (children 1-

6 years of age), there is ample allowance

for safe exposure to azafenidin via

drinking water should it ever be

detected.

3. Non-dietary exposure. Azafenidin

is proposed for use in weed control in

selective non-food crop situations

including certain temperate woody

crops, and in non-crop situations

including industrial sites and

unimproved turf areas. Azafenidin is

not be used in on residential temperate

woody plantings, or on lawns,

walkways, driveways, tennis courts, golf

courses, athletic fields, commercial sod

operations, or other high maintenance

fine turf grass areas, or similar areas.

Any non-occupational exposure to

azafenidin is likely to be negligible.

C. Cumulative Effects

The herbicidal activity of azafenidin

is due to its inhibition of an enzyme

involved with synthesis of the

porphyrin precursors of chlorophyll,

protoporphyrinogen oxidase. Mammals

utilize this enzyme in the synthesis of

heme. Although there are other

herbicides that also inhibit this enzyme,

there is no reliable information that

would indicate or suggest that

azafenidin has any toxic effects on

mammals that would be cumulative

with those of any other chemicals. In

addition there is no valid methodology

for combining the risks of adverse

effects of overexposures to these

compounds.

D. Safety Determination

1. U.S. population. Based on the

completeness and reliability of this

azafenidin toxicology database and

using the conservative aggregate

exposure assumptions presented earlier,

it has been concluded that azafenidin

products may be used with a reasonable

certainty of no harm relative to

exposures from food and drinking

water. A chronic RfD of 0.003 mg/kg/

day has been proposed from the NOEL

of the most sensitive chronic dietary

study and the use of a 100-fold

uncertainty factor. The TMRC

determined for proposed tolerances in

citrus, grapes and sugar cane utilized

only 7.9% of the RfD (an exposure of

0.000237 mg/kg/day). Although there

was no data to accurately assess

potential exposures through drinking

water, the small fraction of the RfD

utilized for food by the general and

subpopulations indicate that is unlikely

that aggregate exposures will exceed

acceptable limits. In addition, the use

patterns and physical chemical

properties of azafenidin suggest that the

potential for significant concentrations

in drinking water are remote. It has been

concluded that the aggregate exposure

for the proposed tolerances on citrus,

grapes and sugar cane provide a

reasonable certainty of no harm to the

general population. Because of effects

observed in the rat developmental

toxicology study, an acute safety

determination based on margins of

exposure was calculated from the NOEL

of 16 mg/kg/day. The subpopulation

potentially at risk was considered to be

females 13–years of age and older.

However, based on the MOEs presented

previously of >11,000 at the 95th

exposure percentile, it was concluded

that these potential dietary exposures

represented a reasonable certainty of no

harm for this group. An MOE of 100 or

greater is generally considered

protective.

2. Infants and children. In assessing

the potential for additional sensitivity of

infants and children to residues of

azafenidin, data from the previously

discussed developmental and

multigeneration reproductive toxicity

studies were considered. Developmental

studies are designed to evaluate adverse

effects on the developing organism

resulting from pesticide exposure

during pre-natal development.

Reproduction studies provide

information relating to reproductive and

other effects on adults and offspring

from pre-natal and post-natal exposures

to the pesticide. The rat reproduction

and developmental studies indicated

developmental effects in this species at

exposures that produced minimal

maternal effects. A clear dose-response

and developmental NOEL has been

defined for these effects. FFDCA section
Federal Register / Vol. 62, No. 232 / Wednesday, December 3, 1997 / Notices 63951

408 provides that EPA may apply an

additional uncertainty 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. The additional uncertainty

factor may increase the MOE from the

usual 100- up to 1,000-fold. Based on

current toxicological data requirements,

the database for azafenidin relative to

pre- and post-natal effects for children

is complete. In addition, the NOEL of

0.3 mg/kg/day in the 1–year dog study

and upon which the RfD is based is

much lower than the NOELs defined in

the reproduction and developmental

toxicology studies. Conservative

assumptions utilized to estimate

aggregate dietary exposures of infants

and children to azafenidin (0.000619

mg/kg/day) demonstrated that only

20.6% of the RfD was utilized for the

proposed tolerances. Based on these

exposure estimates and the fact that

MOEs in excess of 1,000-fold exist

relative to the NOELs in the rat

reproduction study (NOEL = 1.7 mg/kg/

day and MOE = 2,746) and the rat

developmental toxicity study (NOEL =

16 mg/kg/day and MOE = 25,848), the

extra 10-fold uncertainty factor is not

warranted for these groups. Therefore, it

may be concluded that there is

reasonable certainty that no harm will

result to infants and children from

aggregate exposures to azafenidin].

E. International Tolerances

There are no established Canadian,

Mexican or Codex MRLs for azafenidin.

Compatibility is not a problem.

[FR Doc. 97–31542 Filed 12–2–97; 8:45 am]

BILLING CODE 6560–50–F

FEDERAL COMMUNICATIONS

COMMISSION

[Report No. 2240]

Petitions for Reconsideration and

Clarification of Action in Rulemaking

Proceedings

November 28, 1997.

Petitions for reconsideration and

clarification have been filed in the

Commission’s rulemaking proceedings

listed in this Public Notice and

published pursuant to 47 CFR Section

1.429(e). The full text of these

documents are available for viewing and

copying in Room 239, 1919 M Street,

N.W., Washington, D.C. or may be

purchased from the Commission’s copy

contractor, ITS, Inc. (202) 857–3800.

Oppositions to these petitions must be

filed December 18, 1997. See Section

1.4(b)(1) of the Commission’s rule (47

CFR 1.4(b)(1)). Replies to an opposition

must be filed within 10 days after the

time for filing oppositions has expired.

Subject: Investigation of Special

Access Tariffs of Local Exchange

Carriers (CC Docket No. 85–166, Phase

I).

Number of Petitions Filed: 1.

Subject: Amendments of Parts 73 and

74 of the Commission’s Rules To Permit

Certain Minor Changes in Broadcast

Facilities Without a Construction Permit

(MM Docket No. 96–58).

Number of Petitions Filed: 4.

Subject: Anthony T. Easton (WT

Docket No. 97–199).

Number of Petitions Filed: 1.

Federal Communications Commission.

Magalie Roman Salas,

Secretary.

[FR Doc. 97–31592 Filed 12–2–97; 8:45 am]

BILLING CODE 6712–01–M

FEDERAL MARITIME COMMISSION

Notice of Agreement(s) Filed

The Commission hereby gives notice

of the filing of the following

agreement(s) under the Shipping Act of

1984.

Interested parties can review or obtain

copies of agreements at the Washington,

DC offices of the Commission, 800

North Capitol Street, NW., Room 962.

Interested parties may submit comments

on an agreement to the Secretary,

Federal Maritime Commission,

Washington, DC 20573, within 10 days

of the date this notice appears in the

Federal Register.

Agreement No.: 202–010689–068.

Title: Transpacific Westbound Rate

Agreement (‘‘TWRA’’).

Parties:

American President Lines, Ltd.

Hapag-Lloyd Container Linie GmbH

Kawasaki Kisen Kaisha, Ltd.

A.P. Moller-Maersk Line

Mitsui O.S.K. Lines, Ltd.

Neptune Orient Lines, Ltd.

Nippon Yusen Kaisha Line

Orient Overseas Container Line, Inc.

P&O Nedlloyd Limited

P&O Nedlloyd Lijnen, B.V.

Sea-Land Service, Inc.

Synopsis: The proposed modification

authorizes the parties to consider and

act upon proposals and

recommendations of the Equipment

Interchange Discussion Agreement

(FMC Agreement No. 202–011284)

with respect to activities within the

scope of the TWRA agreement.

Dated: November 26, 1997.

By Order of the Federal Maritime

Commission.

Joseph C. Polking,

Secretary.

[FR Doc. 97–31670 Filed 12–2–97; 8:45 am]

BILLING CODE 6730–01–M

FEDERAL MARITIME COMMISSION

Request for Additional Information

Agreement No.: 203–011075–041

Title: Central America Discussion

Agreement

Parties:

Concorde Shipping, Inc.

Global Reefer Carriers Ltd.

Dole Fresh Fruit

King Ocean Central America, S.A.

Crowley American Transport, Inc.

Seaboard Marine, Ltd.

A.P. Moller-Maersk Line

Sea-Land Service, Inc.

NPR, Inc.

Synopsis: Notice is hereby given that the

Federal Maritime Commission,

pursuant to section 6(d) of the

Shipping Act of 1984 (46 U.S.C. app.

1701–1720), has requested additional

information from the parties to the

Agreement as required by the Act.

This action extends the review period

as provided in section 6(c) of the Act

Dated: November 28, 1997.

By Order of the Federal Maritime

Commission.

Joseph C. Polking,

Secretary.

[FR Doc. 97–31671 Filed 12–2–97; 8:45 am]

BILLING CODE 6730–01–M

FEDERAL RESERVE SYSTEM

Change in Bank Control Notices;

Acquisitions of Shares of Banks or

Bank Holding Companies

The notificants listed below have

applied under the Change in Bank

Control Act (12 U.S.C. 1817(j)) and §

225.41 of the Board’s Regulation Y (12

CFR 225.41) to acquire a bank or bank

holding company. The factors that are

considered in acting on the notices are

set forth in paragraph 7 of the Act (12

U.S.C. 1817(j)(7)).

The notices are available for

immediate inspection at the Federal

Reserve Bank indicated. The notices

also will be available for inspection at

the offices of the Board of Governors.

Interested persons may express their

views in writing to the Reserve Bank

indicated for that notice or to the offices

of the Board of Governors. Comments

must be received not later than

December 16, 1997.