Federal Register / Vol. 60, No. 60 / Wednesday, March 29, 1995 / Proposed Rules 16111

Guidelines to the Regulatory Flexibility

Act of 1980, as shown above. Further

information on the initial RFA is

available in the background information

package (see SUPPLEMENTARY

INFORMATION section near the beginning

of this preamble).

G. Miscellaneous

In accordance with section 117 of the

Act, publication of this proposal was

preceded by consultation with

appropriate advisory committees,

independent experts, and Federal

departments and agencies. The

Administrator will welcome comments

on all aspects of the proposed

regulation, including health, economic

and technical issues, and on the

proposed test methods.

This regulation will be reviewed 8

years from the date of promulgation.

This review will include an assessment

of such factors as evaluation of the

residual health and environmental risks,

any overlap with other programs, the

existence of alternative methods,

enforceability, improvements in

emission control technology and health

data, and the recordkeeping and

reporting requirements.

List of Subjects in 40 CFR Part 63

Environmental protection, Air

pollution control, Hazardous

substances, Reporting and

recordkeeping requirements.

Dated: March 15, 1995.

Carol M. Browner,

Administrator.

[FR Doc. 95–7066 Filed 3–28–95; 8:45 am]

BILLING CODE 6560–50–P

40 CFR Part 180

[PP 3F4233/P609; FRL–4944–7]

RIN 2070–AC18

Bromoxynil; Pesticide Tolerance

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: This document proposes a

tolerance for residues of the herbicide

bromoxynil (3,5-dibromo-4-

hydroxybenzonitrile), resulting from the

application of its octanoic and

heptanoic acid esters. The proposal

would amend the tolerance in or on the

raw agricultural commodity (RAC)

cottonseed (transgenic BXN varieties

only) at 0.04 part per million (ppm).

Rhone-Poulenc AG Co. submitted

petitions requesting EPA to establish the

maximum permissible residue of the

herbicide in or on transgenic

cottonseed.

DATES: Written comments, identified by

the document control number, [PP

3F4233/P609], must be received on or

before April 28, 1995.

ADDRESSES: By mail, submit comments

to: Public Docket and Freedom of

Information Section, Field Operations

Division (7506C), Office of Pesticide

Programs, Environmental Protection

Agency, 401 M St., SW., Washington,

DC 20460. In person bring comments to:

Rm. 1132, CM #2, 1921 Jefferson Davis

Hwy., Arlington, VA 22202.

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). Information so marked 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 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays.

FOR FURTHER INFORMATION CONTACT: By

mail: Robert J. Taylor, Product Manager

(PM) 25, Registration Division (7505C),

Environmental Protection Agency, 401

M. St., SW., Washington, DC 20460.

Office location and telephone number:

Rm., 241, CM #2, 1921 Jefferson Davis

Hwy., Arlington, VA 22202, (703)-305-

6800; e-mail:

Taylor.Robert@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA

issued a notice, published in the

Federal Register of October 21, 1993 (58

FR 54354), announcing that the RhonePoulenc AG Co., P.O. Box 12014, 2 T.W.

Alexander Drive, Research Triangle

Park, NC 27709, had submitted a

pesticide petition, PP 3F4233, to EPA

proposing to amend 40 CFR 180.324 by

establishing a regulation to permit the

residues of the herbicide bromoxynil

(3,5-dibromo-4-hydroxybenzonitrile)

resulting from the application of its

octanoic and heptanoic acid esters in or

on the raw agricultural commodity

(RAC) transgenic cottonseed at 0.04

ppm. There were no comments or

requests for referral to an advisory

committee received in response to the

notice of filing.

The data submitted in the petition

and other relevant material have been

evaluated. The toxicology data listed

below were considered in support of

this tolerance. Based on bridging

studies, the Agency has determined that

bromoxynil octanoate and bromoxynil

heptanoate are toxicologically

equivalent. For this reason, studies

using the bromoxynil phenol are

accepted in fulfillment of studies

required for bromoxynil octanoate and

bromoxynil heptanoate.

Phenol technical-grade bromoxynil

1. Several acute toxicology studies

were performed, placing technical-grade

bromoxynil in toxicity Category II.

2. An acute oral toxicity study in rats

resulted in LD50 = 81 mg/kg (males) and

LD50 = 93 mg/kg (females).

3. A 2-year combined feeding/

carcinogenicity study was conducted

with rats administered (oral) dosages of

0, 60, 190, or 600 ppm (0, 2.6, 8.2, or

28 mg/kg/day in males; 0, 3.3, 11.0, or

41 mg/kg/day in females) bromoxynil

phenol in the diet. In males the noobserved-effect-level (NOEL) for

systemic toxicity is 2.6 mg/kg/day, and

the lowest-effect-level (LEL) is 8.2 mg/

kg/day. In females, the NOEL is 3.3 mg/

kg/day, and the lowest-effect-level (LEL)

is 11.0 mg/kg/day. This study did not

demonstrate any increase in tumor

incidences in either male or female rats.

This study has not been considered by

the RfD committee. The RfD was set

based on the NOEL from the

supplementary rat study (see item #4).

4. A 2-year combined feeding/

carcinogenicity study was conducted

with rats administered bromoxynil

phenol in the diet at dose levels of 0, 10,

30, or 100 ppm (0, 0.5, 1.5, or 5 mg/kg/

day). In both males and females, the

NOEL and LOEL for systemic toxicity

was 5 mg/kg/day and >5 mg/kg/day,

respectively. At the highest dose tested,

increased liver weights were observed at

12 months, but not at 24 months. This

study was considered negative for

carcinogenicity. This study is

considered supplementary. The RfD is

based on this study and an uncertainty

factor of 300 rather than 100 was used

since the study is supplementary.

5. A 1-year oral study was conducted

with dogs administered bromoxynil

phenol at dose levels of 0, 0.1, 0.3, 1.5,

or 7.5 mg/kg/day in capsules. The NOEL

is 0.3 mg/kg/day and the LEL is 1.5 mg/

kg/day in both males and females.

6. An 18-month carcinogenicity study

was conducted with mice administered

bromoxynil phenol at dose levels of 0,

10, 30, or 100 ppm (0, 1.3, 3.9, or 13 mg/

kg/day) in the diet. For males, doserelated increases in hyperplastic

nodules and liver adenomas/carcinomas

were observed which were statistically

significant at the 13-mg/kg/day dose

level. Increased relative liver weights
16112 Federal Register / Vol. 60, No. 60 / Wednesday, March 29, 1995 / Proposed Rules

were also observed. In females,

increased absolute liver weights and

relative liver and kidney weights were

observed. The study was considered

negative for carcinogenicity for females.

7. A developmental toxicity study was

conducted with rats administered

(orally) bromoxynil phenol at dose

levels of 0, 4, 12.5, or 40 mg/kg/day. The

maternal NOEL and LEL are 12.5 mg/kg/

day and 40 mg/kg/day, respectively. The

developmental NOEL and LEL are 4 mg/

kg/day and 12.5 mg/kg/day,

respectively.

8. A developmental toxicity study was

conducted with rats administered

(orally) bromoxynil phenol at dose

levels of 0, 5, 15, or 35 mg/kg/day. The

maternal NOEL and LEL are 5 mg/kg/

day and 15 mg/kg/day, respectively. The

fetotoxicity and developmental NOEL

and LEL are less than 5 mg/kg/day and

5 mg/kg/day, respectively.

9. A developmental toxicity study was

conducted with rats administered

(orally) bromoxynil phenol at dose

levels of 0, 1.7, 5, or 15 mg/kg/day. The

maternal NOEL and LEL is 5 mg/kg/day

and 15 mg/kg/day, respectively. The

developmental NOEL and LEL are 5 mg/

kg/day and 15 mg/kg/day, respectively.

10. A developmental toxicity study

was conducted with rabbits

administered (orally) bromoxynil

phenol at dose levels of 0, 15, 30, or 60

mg/kg/day. The maternal NOEL and

LEL are 15 mg/kg/day and 30 mg/kg/

day, respectively. The developmental

NOEL and LEL are less than 15 mg/kg/

day and 15 mg/kg/day, respectively.

11. A developmental toxicity study

was conducted with mice administered

(orally) bromoxynil phenol at dose

levels of 0, 11, 32, or 96 mg/kg/day. The

maternal NOEL and LEL are 11 mg/kg/

day and 32 mg/kg/day, respectively. The

developmental NOEL and LEL are 32

mg/kg/day and 96 mg/kg/day,

respectively.

12. A reproduction study was

conducted with rats administered

(orally) bromoxynil phenol at dose

levels of 0, 0.8, 4, or 21 mg/kg/day in

the diet. The systemic adult rat NOEL is

4 mg/kg/day, and the LEL is 21 mg/kg/

day. The reproductive NOEL is 21 mg/

kg/day, and the LEL is greater than 21

mg/kg/day. The postnatal

developmental NOEL is 4 mg/kg/day,

and the LEL is 21 mg/kg/day.

13. A reproduction study was

conducted with rats administered

(orally) bromoxynil phenol at dose

levels of 0, 1.5, 5, or 15 mg/kg/day in

the diet. The systemic adult rat NOEL is

1.5 mg/kg/day (tentative), and the LEL

is 5 mg/kg/day (tentative). The

reproductive NOEL is 15 mg/kg/day,

and the LEL is greater than 15 mg/kg/

day. The offspring developmental NOEL

is 5 mg/kg/day, and the LEL is 15 mg/

kg/day.

14. Mutagenicity data included

unscheduled DNA synthesis study—rat

primary hepatocytes (negative); in vitro

transformation assay—mouse cells

(negative); sister chromosomal exchange

study—CHO cells (negative); forward

mutation study—mouse lymphoma cells

(negative without activation and

positive with activation); DNA repair

test—E. coli (positive); in vitro

chromosomal aberration (negative

without activation and positive with

activation); two separate micronucleus

assays (both negative); forward

mutation—CHO cells (negative); and

Ames study Salmonella typhimurium

(negative with and without activation).

Heptanoate technical-grade bromoxynil

1. Several acute toxicology studies

were performed, placing technical-grade

bromoxynil in toxicity Category II.

2. An acute oral toxicity study in rats

resulted in LD50 = 362 mg/kg (males)

and LD50 = 292 mg/kg (females).

3. A general metabolism study was

conducted with rats, and the results

were similar when a single low dose (2

mg/kg), a single high dose (20 mg/kg) or

a low dose (2 mg/kg/day) administered

for 14 consecutive days were

administered. Bromoxynil heptanoate is

rapidly absorbed and widely distributed

in most tissues. The highest

concentrations were found in the blood,

plasma, liver, kidney, and thyroid.

Higher tissue concentrations were found

in females than in males. Excretion was

more rapid in males. Most of the

radioactivity was excreted in the urine,

mostly in the form of bromoxynil

phenol. Bromoxynil phenol and

bromoxynil heptanoate were present in

the feces. There was no significant

retention in tissues after 7 days.

Essentially, bromoxynil heptanoate was

metabolized to bromoxynil phenol via

ester hydrolysis.

Octanoate technical-grade bromoxynil

1. Several acute toxicology studies

were performed, placing technical-grade

bromoxynil in toxicity Category II.

2. An acute oral toxicity study in rats

resulted in LD50 = 400 mg/kg (males)

and LD50 = 238 mg/kg (females).

3. A 13-week oral study was

conducted with rats administered

bromoxynil octanoate at dose levels of

0, 150, 600, or 1,100 ppm (0, 11, 45, or

91 mg/kg/day in males; 0, 13, 55, or 111

mg/kg/day in females) in the diet. This

is equivalent to 0, 8, 31, or 63 mg/kg/

day in males; 0, 9, 38, or 77 mg/kg/day

in females of bromoxynil phenol. The

NOEL and LEL in males are 31 mg/kg/

day and 63 mg/kg/day, respectively. In

females, the NOEL and LEL are 9 mg/

kg/day and 38 mg/kg/day, respectively.

4. A developmental toxicity study was

conducted with rats administered

(orally) bromoxynil octanoate at dose

levels of 0, 2.4, 7.3, or 21.8 mg/kg/day.

This is equivalent to 0, 1.7, 5, or 15 mg/

kg/day of bromoxynil phenol. The

maternal NOEL and LEL are 5 mg/kg/

day and 15 mg/kg/day, respectively. The

developmental NOEL and LEL are 5 mg/

kg/day and 15 mg/kg/day, respectively.

5. Mutagenicity data included the

following: the Ames study—Salmonella

typhimurium (negative with and

without activation); micronucleus assay

(negative); and unscheduled DNA

synthesis—rat primary hepatocytes

(negative).

Carcinogenicity Peer Review

Committee/SAP

The Scientific Advisory Panel met on

June 25, 1992, to review the scientific

issues regarding the Carcinogenicity

Peer Review Committee’s classification

of bromoxynil as a Group C carcinogen

and recommended that a low- dose

extrapolation model, applied to the

experimental animal tumor data, be

used for quantification (Q1*) of human

risk. The Panel felt that a Group D

classification was more consistent with

the existing data base. The SAP

concluded that the available data did

not provide sufficient evidence to

classify bromoxynil as Group C and

recommended a Group D classification

pending completion of the ongoing

mouse carcinogenicity study. The SAP

further recommended that the mouse

study be extended beyond 18 months

(e.g., 24 months) if survival was

adequate and that contemporary

historical control data be made available

at the time of evaluation.

After the SAP meeting the

Carcinogenicity Peer Review Committee

met on July 29, 1992, to further discuss

and evaluate the weight-of-the-evidence

on bromoxynil with particular reference

to its carcinogenic potential. The Peer

Review Committee (PRC) concluded

that the classification of bromoxynil as

a Group C, possible human carcinogen,

should be maintained and

recommended that for the purpose of

risk characterization the Reference Dose

(RfD) methodology should be used at

this time. The PRC also placed a

condition on the decision to defer

utilization of a Q1*. The condition was

that additional uses should not be

granted prior to analysis of the new

mouse study. The PRC agreed that the

results of the new mouse cancer study

were critical to the ultimate

classification and dose-response
Federal Register / Vol. 60, No. 60 / Wednesday, March 29, 1995 / Proposed Rules 16113

assessment. Since the conditional

registration involves a new use, HED

has determined that it is prudent to

apply the Q1* to existing data.

Nature of the Residue and Analytical

Method

The nature of the residue in

transgenic cotton is considered to be

adequately understood. The primary

bromoxynil metabolite in transgenic

cotton is 3,5-dibromo-4-hydroxybenzoic

acid (DBHA). DBHA is only a major

metabolite in/on bromoxynil treated

transgenic cotton. For the purposes of a

time-limited tolerance, only the parent

compound will be regulated as in 40

CFR 180.324. This interim decision is

based on the minimal risk resulting

from total residues of the parent and

metabolite in cottonseed contributing

only about 1/1000th to the total dietary

exposure from all registered uses of

bromoxynil.

Adequate methodology is available for

enforcement purposes, based upon

methods for the parent compound. The

method is a modified version of Method

I in the Pesticide Analytical Manual

(PAM), Vol. II. The method involves

sample reflux in methanolic KOH,

partitioning with ether/hexane,

concentration of the organic phase,

derivatization with diazomethane and

analysis by GC. The limit of detection

(LOD) for this method is 0.02 ppm.

The nature of the residue in

ruminants and poultry is considered to

be adequately understood. Any

secondary residues occurring in the fat,

meat, and meat byproducts of cattle,

goats, horses, poultry, and sheep will be

covered by existing tolerances.

Risk Assessment

The reference dose (RfD) (acceptable

daily intake (ADI)) for bromoxynil is

calculated to be 0.02 mg/kg body

weight/day based on a 2-year rat chronic

feeding study with a NOEL of 5.0 mg/

kg bwt/day and a safety factor of 300.

The theoretical maximum residue

contribution (TMRC) for published

tolerances is 0.450 ug/kg bwt/day or

2.25% of the RfD for the overall U.S.

population. The use on transgenic

cotton would contribute less than

0.0004 ug/kg bwt/day representing

approximately 1/1000 of the total

dietary exposure to bromoxynil residue.

This analysis comparing the dietary

exposure from bromoxynil to the

noncarcinogenic chronic effects results

in a negligible chronic risk.

Although the new mouse study has

been received, a full review by the

Agency has not been completed at this

time. Therefore, an estimate of the

upper-bound carcinogenic risk has been

estimated based on published tolerances

and the previously determined upper

bound potency factor (Q1* = 4.1 X 10-1

(mg/kg/day)-1). The resulting upperbound cancer risk was found to be 2 X

10-4. An additional cancer risk as a

result of the use of bromoxynil on

transgenic BXN cotton would be 2 X

10-7, which is incrementally

insignificant. The 10-4 risk includes the

assumption that residues were present

in or on every commodity at tolerance

level and that one hundred percent of

the acreage for every commodity was

treated with bromoxynil. Thus, this

cancer risk should be viewed as an

unrealistic ‘‘worst case’’ estimate. The

risk resulting from the use of

bromoxynil on transgenic cotton alone

will be negligible.

Based on the above information cited,

the Agency has determined that the

establishment of the tolerance by

amending 40 CFR part 180 will protect

the public health. Therefore, the

tolerance is established as set forth

below.

The tolerance will expire on April 1,

1997. Based upon the evaluation of a

mouse carcinogenicity study currently

under review and submission of an

analytical method, residue data and

livestock metabolism study on the

metabolite, the Agency will determine

whether establishing permanent

tolerances is appropriate. Residues

remaining in or on the raw agricultural

commodity after expiration of this

tolerance will not be considered

actionable if the pesticide is legally

applied during the term, and in

accordance with the provisions of the

conditional registration.

Any person who has registered or

submitted an application for registration

of a pesticide, under the Federal

Insecticide, Fungicide, and Rodenticide

Act (FIFRA) as amended, which

contains any of the ingredients listed

herein, may request within 30 days after

publication of this document in the

Federal Register that this rulemaking

proposal be referred to an Advisory

Committee in accordance with section

408(e) of the Federal Food, Drug, and

Cosmetic Act.

Interested persons are invited to

submit written comments on the

proposed regulation. Comments must

bear a notation indicating the document

control number [PP 8F3671/609]. All

written comments filed in response to

this petition will be available in the

Public Response and Program Resources

Branch, at the address given above from

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

Friday, except legal holidays.

The Office of Management and Budget

has exempted this regulation from

section 3 of Executive Order 12866.

Pursuant to requirements of the

Regulatory Flexibility Act (Pub. L. 96-

354, 94 Stat. 1164, 5 U.S.C. 601-612),

the Administrator has determined that

regulations establishing new tolerances

or raising tolerance levels or

establishing exemptions from tolerance

requirements do not have a significant

economic impact on a substantial

number of small entities. A certification

statement to this effect was published in

the Federal Register of May 4, 1981 (46

FR 24950).

List of Subjects in 40 CFR Part 180

Environmental protection,

Administrative practice and procedure,

Agricultural commodities, Pesticides

and pests, Reporting and recordkeeping

requirements.

Dated: March 23, 1995.

Daniel M. Barolo,

Director, Office of Pesticide Programs.

Therefore, it is proposed that part 180

be amended as follows:

PART 180—[AMENDED]

1. The authority citation for part 180

continues to read as follows:

Authority: 21 U.S.C. 346a and 371.

2. In § 180.324, by adding new

paragraph (d), to read as follows:

§ 180.324 Bromoxynil; tolerances for

residues.

* * * * *

(d) Tolerances are established for

residues of the herbicide bromoxynil

(3,5-dibromo-4-hydroxybenzonitrile)

resulting from application of its

octanoic and heptanoic acid esters in or

on the following raw agricultural

commodity:
16114 Federal Register / Vol. 60, No. 60 / Wednesday, March 29, 1995 / Proposed Rules

Commodity Parts per million Expiration date

Cottonseed (transgenic BXN varieties only) .................. 0.04 ........................................... April 1, 1997

[FR Doc. 95–7714 Filed 3–28–95; 8:45 am]

BILLING CODE 6560–50–F