Federal Register / Vol. 60, No. 11 / Wednesday, January 18, 1995 / Proposed Rules 3607

Rule 71.2 Storage of Reactive Organic

Compound Liquids (Adopted 9/26/89)

Rule 71.3 Transfer of Reactive Organic

Compound Liquids (Adopted 6/16/92)

Rule 71.4 Petroleum Sumps, Pits, Ponds,

and Well Cellars (Adopted 6/8/93)

Rule 72 New Source Performance Standards

(NSPS) (Adopted 6/28/94)

Rule 74 Specific Source Standards

(Adopted 7/6/76)

Rule 74.1 Abrasive Blasting (Adopted 11/

12/91)

Rule 74.2 Architectural Coatings (Adopted

08/11/92)

Rule 74.6 Surface Cleaning and Degreasing

(Adopted 5/8/90)

Rule 74.6.1 Cold Cleaning Operations

(Adopted 9/12/89)

Rule 74.6.2 Batch Loaded Vapor Degreasing

Operations (Adopted 9/12/89)

Rule 74.7 Fugitive Emissions of Reactive

Organic Compounds at Petroleum

Refineries and Chemical Plants (Adopted

1/10/89)

Rule 74.8 Refinery Vacuum Producing

Systems, Waste-water Separators and

Process Turnarounds (Adopted 7/5/83)

Rule 74.9 Stationary Internal Combustion

Engines (Adopted 12/21/93)

Rule 74.10 Components at Crude Oil

Production Facilities and Natural Gas

Production and Processing Facilities

(Adopted 6/16/92)

Rule 74.11 Natural Gas-Fired Residential

Water Heaters-Control of NOX (Adopted

4/9/85)

Rule 74.12 Surface Coating of Metal Parts

and Products (Adopted 11/17/92)

Rule 74.15 Boilers, Steam Generators and

Process Heaters (5MM BTUs and greater)

(Adopted 12/3/91)

Rule 74.15.1 Boilers, Steam Generators and

Process Heaters (1–5MM BTUs)

(Adopted 5/11/93)

Rule 74.16 Oil Field Drilling Operations

(Adopted 1/8/91)

Rule 74.20 Adhesives and Sealants

(Adopted 6/8/93)

Rule 74.24 Marine Coating Operations

(Adopted 3/8/94)

Rule 74.28 Asphalt Roofing Operations

(Adopted 5/10/94)

Rule 74.30 Wood Products Coatings

(Adopted 5/17/94)

Rule 75 Circumvention (Adopted 11/27/78)

Appendix IV–A Soap Bubble Tests

(Adopted 12/86)

Rule 100 Analytical Methods (Adopted 7/

18/72)

Rule 101 Sampling and Testing Facilities

(Adopted 5/23/72)

Rule 102 Source Tests (Adopted 11/21/78)

Rule 103 Stack Monitoring (Adopted 6/4/

91)

Rule 154 Stage 1 Episode Actions (Adopted

9/17/91)

Rule 155 Stage 2 Episode Actions (Adopted

9/17/91)

Rule 156 Stage 3 Episode Actions (Adopted

9/17/91)

Rule 158 Source Abatement Plans (Adopted

9/17/91)

Rule 159 Traffic Abatement Procedures

(Adopted 9/17/91)

* * * * *

[FR Doc. 95–1185 Filed 1–17–95; 8:45 am]

BILLING CODE 6050–50–P

40 CFR Part 185

[OPP–300360; FRL–4910–8]

RIN 2070–AC18

Acephate, Triadimefon, Iprodione, and

Imazalil; Revocation of Food Additive

Regulations

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA is proposing to revoke

food additive regulations for the

pesticides acephate, triadimefon (1-(4-

chlorophenoxy)-3,3-dimethyl-1-(1H1,2,4-triazol-1-yl)-2-butanone),

iprodione, and imazalil, which EPA has

determined ‘‘induce cancer’’ within the

meaning of the Delaney clause of

section 409 of the Federal Food, Drug

and Cosmetic Act (FFDCA). As a result

of a 1992 court decision regarding the

Delaney clause, EPA has initiated the

process of revoking those section 409

tolerances for pesticides found to

‘‘induce cancer.’’ This proposed rule is

the second in a series of proposals to

revoke affected regulations under

section 409 of the FFDCA.

DATES: Written comments, identified by

the document control number [OPP300360], must be received on or before

April 18, 1995.

ADDRESSES: By mail, submit comments

to: Public Response Section, Field

Operations Division (7506C), Office of

Pesticide Programs, Environmental

Protection Agency, 401 M St., SW.,

Washington, DC 20460. In person, bring

comments to: OPP Docket, Public

Information Branch, Field Operations

Division, Rm. 1132, Crystal Mall #2,

1921 Jefferson Davis Hwy., Arlington,

VA. The telephone number for the OPP

docket is (703)-305-5805.

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’’ (or

CBI). Information so marked will not be

disclosed except in accordance with

procedures set forth in 40 CFR part 2

and in section 10 of the Federal

Insecticide, Fungicide and Rodenticide

Act (FIFRA). For questions related to

disclosure of materials, contact the OPP

Docket at the telephone number given

above. 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 the OPP Docket, Rm. 1132

at the Virginia address given above,

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

Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By

mail: Niloufar Nazmi or Lisa Nisenson,

Special Review and Reregistration

Division (7508W), Environmental

Protection Agency, 401 M St. SW.,

Washington, DC, 20460. Office location

and telephone number: Crystal Station

#1, 2800 Crystal Drive, Arlington, VA.

Telephone 703-308-8010.

SUPPLEMENTARY INFORMATION:

I. Introduction

A. Statutory Background

The Federal Food, Drug and Cosmetic

Act (FFDCA) (21 U.S.C. 301 et seq.)

authorizes the establishment of

maximum permissible levels of

pesticides in foods, which are referred

to as ‘‘tolerances’’ (21 U.S.C. 346a, 348).

Without such a tolerance or an

exemption from a tolerance, a food

containing a pesticide residue is

‘‘adulterated’’ under section 402 of the

FFDCA and may not be legally moved

in interstate commerce (21 U.S.C. 342).

Monitoring and enforcement of

pesticide residues are carried out by the

U.S. Food and Drug Administration

(FDA) and the United States Department

of Agriculture (USDA).

The FFDCA governs tolerances for

raw agricultural commodities (RACs)

and processed foods separately. For

pesticide residues in or on RACs, EPA

establishes tolerances, or exemptions

from tolerances when appropriate,

under section 408. In processed foods,

food additive regulations setting

maximum permissible levels of

pesticide residues are established under

section 409. Section 409 tolerances are

needed, however, only for certain

pesticide residues in processed food.

Under section 402(a)(2) of the FFDCA,

no section 409 tolerance is required if

any pesticide residue in a processed

food is equal to or below the tolerance

for that pesticide in or on the RAC from

which it was derived and all other

conditions of section 402(a)(2) are met.

This exemption in section 402(a)(2) is

commonly referred to as the ‘‘flowthrough’’ provision because it allows the

section 408 raw food tolerance to flow

through to the processed food form.

Thus, a section 409 tolerance is

necessary to prevent foods from being

deemed adulterated when the

concentration of the pesticide residue in

a processed food is greater than the

tolerance prescribed for the RAC, or if
3608 Federal Register / Vol. 60, No. 11 / Wednesday, January 18, 1995 / Proposed Rules

the processed food itself is treated or

comes in contact with a pesticide.

If a food additive regulation must be

established, section 409 of the FFDCA

requires that the use of the pesticide

will be ‘‘safe’’ (21 U.S.C. 348(c)(3)).

Relevant factors in this safety

determination include: (1) the probable

consumption of the pesticide or its

metabolites; (2) the cumulative effect of

the pesticide in the diet of man or

animals, taking into account any related

substances in the diet; and (3)

appropriate safety factors to relate the

animal data to the human risk

evaluation. Section 409 also contains

the Delaney clause, which specifically

provides that, with little exception, ‘‘no

additive shall be deemed safe if it has

been found to induce cancer when

ingested by man or animal’’ (21 U.S.C.

348(c)(3)).

Before a pesticide may be sold or

distributed, it must be registered under

the Federal Insecticide, Fungicide and

Rodenticide Act (FIFRA). To qualify for

registration, a pesticide must, among

other things, perform its intended

function without causing ‘‘unreasonable

adverse effects on the environment’’ (7

U.S.C. 136a(c)(5)). The term

‘‘unreasonable adverse effects on the

environment’’ is defined as ‘‘any

unreasonable risk to man or the

environment taking into account the

economic, social and environmental

costs and benefits of the use of any

pesticide’’ (7 U.S.C. 136(bb)).

B. Regulatory Background

On May 25, 1989, the State of

California, the Natural Resources

Defense Council, Public Citizen, the

AFL-CIO, and several individuals filed

a petition requesting that EPA revoke

several food additive regulations and

challenging EPA’s de minimis

interpretation of the Delaney clause.

The petition, which sought a ‘‘zero-risk’’

interpretation of the Delaney clause,

requested that EPA revoke certain food

additive regulations. The petitioners

argued that these food additive

regulations should be revoked because

they violate the Delaney clause.

EPA responded to the petition by

revoking certain food additive

regulations, but retained several others

on the grounds that the Delaney clause

provides an exception for pesticide

residues posing de minimis risk; EPA

denied the petition for the food additive

regulations determined to fall under this

exception.

EPA’s response was challenged by the

petitioners in the U.S. Court of Appeals,

Ninth Circuit. On July 8, 1992, the court

ruled in Les v. Reilly, 968 F.2d 985 (9th

Cir.), cert. denied, 113 S.Ct. 1361 (1993),

that the Delaney clause barred the

establishment of a food additive

regulation for pesticides which ‘‘induce

cancer’’ no matter how infinitesimal the

risk.

On July 14, 1993, EPA issued a

revised response to the petition taking

into account the court’s ruling. That

revised response granted the original

petition and revoked the food additive

regulations named in the petition. The

food additive regulations for two of the

four affected pesticides, benomyl and

trifluralin, have been reinstated pending

judicial review by the Court of Appeals,

District of Columbia Circuit, of several

registrants’ challenge to the revocation.

In implementing the court’s decision

in Les v. Reilly, EPA has taken steps to

identify and revoke all section 409

tolerances for pesticides which have

been found to ‘‘induce cancer.’’ EPA has

issued two lists of pesticide uses which

would likely be affected by the court’s

decision. The first list contains affected

food and feed additive regulations, and

the second identifies uses for pesticides

that have either been found to induce

cancer or are likely to be so classified

where data show a food or feed additive

regulation needs to be established. Both

lists have been updated to reflect

changes in data reviews and other

regulatory actions (see 59 FR 14980,

March 30, 1994). The first proposed

revocation, which included 26 food

additive regulations for seven pesticides

classified as ‘‘B’’, probable human

carcinogens or ‘‘C’’, possible human

carcinogens subject to quantification by

a linear low-dose extrapolation model,

was published in the Federal Register of

July 1, 1994 (59 FR 33941).

II. Proposed Revocation of Section 409

Tolerances Which are Inconsistent with

the Delaney Clause

EPA intends to revoke all food and

feed additive regulations which are

inconsistent with the Delaney clause.

This notice proposes revocation of all

food additive regulations published in

the March 30, 1994 Federal Register

notice which have not previously been

proposed for revocation. EPA expects to

publish additional proposed revocations

for feed additive regulations in the near

future.

A. Basis for Proposing Revocation

As a result of the court’s 1992

decision, the only issue to be considered

for these proposed revocations is

whether acephate, triadimefon, imazalil,

and iprodione qualify under the

Delaney clause as having been ‘‘found to

induce cancer when ingested by man or

animals, or it is found, after tests which

are appropriate for the evaluation of the

safety of food additives, to induce

cancer in man or animal.’’ 21 U.S.C.

348(c)(3)(A). If EPA finds they are

human or animal carcinogens within the

meaning of the Delaney clause, the food

additive regulations must be revoked.

In construing the ‘‘induce cancer’’

standard as to animals, EPA follows a

weight-of-the-evidence approach which

is guided, where appropriate, by the

principles in EPA’s Cancer Assessment

Guidelines. In regard to animal

carcinogenicity, EPA, in general,

interprets ‘‘induces cancer’’ to mean:

The carcinogenicity of a substance in

animals is established when administration

in adequately designed and conducted study

or studies results in an increase in the

incidence of one or more types of malignant

(or, where appropriate, benign or a

combination of benign and malignant)

neoplasms in treated animals compared to

untreated animals maintained under

identical conditions except for exposure to

the test compound. Determination that the

incidence of neoplasms increases as the

result of exposure to the test compound

requires a full biological, pathological, and

statistical evaluation. Statistics assist in

evaluating the biological significance of the

observed responses, but a conclusion on

carcinogenicity is not determined on the

basis of statistics alone. Under this approach,

a substance may be found to ‘‘induce cancer’’

in animals despite the fact that increased

tumor incidence occurs only at high doses,

or that only benign tumors occur, and despite

negative results in other animal feeding

studies. (See 58 FR 37863, July 14, 1993; 53

FR 41108, October 19, 1988; and 52 FR

49577, December 31, 1987).

Acephate, triadimefon, imazalil, and

iprodione all qualify as animal

carcinogens under this test.

Summarized below is the information

supporting EPA’s determination that

these pesticides ‘‘induce cancer.’’ Full

copies of each of these reviews and

other references in this notice are

available in the OPP Docket, the

location of which is given under

‘‘ADDRESSES’’ above.

Acephate

After a full evaluation of all the data

and supporting information regarding

animal carcinogenicity, EPA has

concluded that exposure to acephate

results in the induction of malignant

hepatocellular carcinomas in female CD1 mice.

Male and female CD-1 mice were fed

0, 50, 250, or 1,000 parts per million

(ppm) of acephate for 105 weeks.

Although fewer low-dose and mid-dose

female mice survived to the end of the

study compared with controls, the

survival of the highest dose tested

(HDT) female mice and all male mice

was higher than that with the controls.

Decreases in body weight gain ranged
Federal Register / Vol. 60, No. 11 / Wednesday, January 18, 1995 / Proposed Rules 3609

from 8 to 11 percent for males and 6 to

14 percent for females at the mid-dose,

and about 24 percent for males and

29percent for females at the HDT. Doserelated increasing levels of liver

toxicity, including regenerative changes,

were observed. In the female mice at the

HDT, the incidence of malignant

hepatocellular carcinomas and

hyperplastic nodules was significantly

increased in comparison with controls.

The increased incidence of carcinomas

exceeds the testing laboratory’s

historical control range. There were no

increases in tumors in the two lower

dosed female groups or any of the male

groups.

Male and female Charles River (CD)

Sprague-Dawley rats were fed 0, 5, 50,

and 700 ppm of acephate for 28 months.

There was no dose-related effect on

mortality, although there was significant

cholinesterase inhibition in the midand high-dose male and female rats.

There was a 4 to 8 percent weight loss

in the HDT males.

Acephate has been tested in a wide

array of genotoxicity assays. The

evidence indicates that acephate

produced positive responses in gene

mutation in vitro assays with

Salmonella, E. coli, and S. cerevisiae.

Acephate has been reported to produce

mutations in mouse lymphoma cells,

sister chromatid exchanges (SCEs) in

Chinese hamster ovary (CHO) cells, and

mitotic recombination in

Saccharomyces. Several in vivo assays

for SCEs and cytogenetic endpoints

have been negative.

Based on this information regarding

animal carcinogenicity, the Agency

concludes that exposure to acephate

results in the induction of malignant

hepatocellular carcinomas in female CD1 mice. The incidence exceeded the

historical control range of the testing

laboratory. There is evidence that

acephate is genotoxic based on in vitro

studies, but this activity may be difficult

to detect in vivo. The relevance of these

data to an evaluation of acephate’s

potential for human carcinogenicity is

discussed in the Peer Review document

of Acephate (May 8, 1985).

Triadimefon

After a full evaluation of all the data

and supporting information regarding

animal carcinogenicity, EPA has

concluded that exposure to triadimefon

results in the induction of

hepatocellular adenomas in both male

and female NMRI mice. Male and

female NMRI mice were fed 0, 50, 300,

or 1,800 ppm of triadimefon for 21

months. At the HDT, the incidence of

hepatocellular adenomas was increased

in both male and female mice by pairwise comparison between the HDT and

controls. A positive dose-related

significant trend for adenomas was

found in both sexes. The incidence of

hepatocellular adenomas for each sex

exceeded the testing laboratory’s

historical control range for adenomas in

NMRI mice.

In another study, male and female

CF1-W74 mice were fed 0, 50, 300, or

1,800 ppm of triadimefon for 24 months.

The HDT was considered appropriate

for assessing carcinogenicity based on

increased hematological changes;

statistically significant increases in liver

weights accompanied by

histopathological changes and weight

gains at the HDT were significantly

lower than in controls.

Initially, the tumor profile was

thought to provide no indication that

triadimefon had an influence on total

tumor incidence, on the number of mice

with tumors or on incidence of single

tumor types; however, the pathology

report indicated that more mice had

hyperplastic liver nodules at the HDT

than mice in the other treated groups or

the controls. The Peer Review

Committee recommended that in light of

the NMRI study results outlined above,

and that the original analysis of the

study results was performed before the

current criteria were put into place, the

liver nodules should be re-read with

updated criteria.

The new histopathological

information for the CF1-W74 mouse

study was submitted subsequent to the

completion of the latest Triadimefon

Peer Review document. Only a small

number of slides were available for

reexamination, and the results were

deemed inconclusive. However, they are

suggestive of an effect on tumor

incidence in the liver and are consistent

with the findings in the NMRI study

that the liver is a principal site for

tumor induction. Lesions which were

originally classified as hyperplastic or

regenerative nodules were reclassified

as either hepatocellular adenomas or

carcinomas. In males, 3, 3, 2, and 3

adenomas and 1, 4, 4, and 4 carcinomas

were found out of 6, 8, 7, and 13 liver

samples examined at doses of 0, 50, 300,

and 1,800 ppm, respectively. This

suggests that triadimefon may

contribute to the induction of liver

tumors and there may be a carcinoma

component.

In a 104-week study, male and female

Wistar rats were fed 0, 50, 300, or 1,800

ppm of triadimefon. Triadimefon

induced a positive dose-related trend in

the incidence of thyroid follicular cell

adenomas/adenomas multiple in male

Wistar rats. Positive dose-related trends

were achieved in both sexes for

combined incidences of thyroid

follicular cell cystic hyperplasia and

adenomas/adenomas multiple.

Hepatocellular adenomas are

considered to be evidence of cancer

because hepatocellular adenomas can

progress to hepatocellular carcinomas.

Malignancy (carcinoma) implies a more

extensive disease process. Thus,

hepatocellular adenomas represent an

earlier stage than carcinomas in the

progression of cancer induction. This is

one of the major reasons that the

National Toxicology Program (NTP) has

used to justify combining these two

tumor types for an overall analysis of

carcinogenicity (in addition to analyzing

them separately). For triadimefon, the

possible progression to carcinoma was

suggested in the CF1-W74 mouse study

and is strongly supported by carcinoma

induction in close structural analogues,

e.g., etaconazole, uniconazole,

cyproconazole, tebuconazole, and

fenbuconazole.

Based on the above data and

supporting information regarding

animal carcinogenicity, it is concluded

that exposure to triadimefon results in

the induction of hepatocellular

adenomas in both male and female

NMRI mice. A positive dose-related

significant trend for adenomas was also

found in both sexes. This conclusion is

bolstered by the extensive structural

activity support from closely

structurally related triazole compounds

tested in many mouse studies that

showed increased incidences of not

only adenomas but carcinomas as well.

It is also noted that although the

analysis was inconclusive, there was a

carcinoma response by triadimefon in

the CF1-W74 mouse study. In addition,

triadimefon induced a positive doserelated trend in the incidence of thyroid

follicular cell adenomas/adenomas

multiple in male Wistar rats. Positive

dose-related trends were achieved in

both sexes for combined incidences of

thyroid follicular cell cystic hyperplasia

and adenomas/adenomas multiple.

The relevance of these data to an

evaluation of triadimefon’s potential for

human carcinogenicity is discussed in

the Peer Review document of

Triadimefon (September 26, 1990).

Iprodione

After a full evaluation of the data and

supporting information regarding

animal carcinogenicity, EPA concludes

that exposure to iprodione resulted in

an increased incidence of hepatocellular

malignant carcinomas in male mice and

combined hepatocellular adenomas/

carcinomas in both sexes of mice,

ovarian lutenomas in female mice, and
3610 Federal Register / Vol. 60, No. 11 / Wednesday, January 18, 1995 / Proposed Rules

testicular interstitial cell tumors in male

rats.

Iprodione was administered to CD-1

mice (50/sex/group) at levels of 0, 160,

800, or 1,400 ppm for at least 99 weeks

(or until the 52-week interim sacrifice of

15 additional mice/sex/group). At the

terminal sacrifice, there was a

significantly increased incidence of

benign and malignant liver cell tumors

in both sexes compared to the control.

Analysis indicates that male mice had

significant difference in the pair-wise

comparisons of the 1,400-ppm dose

group with the controls for liver

adenomas, carcinomas and combined

adenomas and/or carcinomas. Female

mice had significant increasing trends

in liver adenomas, carcinomas, and

combined adenomas and/or carcinomas.

All males in all dose groups (including

concurrent controls) displayed a higher

incidence of carcinomas than observed

in historical controls. Although there

was no increase in the incidence of

testicular tumors in the male mice, there

was a dose-related increase in the

incidence of interstitial cell hyperplasia

at the 800- and 1,400-ppm dose levels.

In female mice, iprodione was

associated with significant dose-related

increasing trends in liver adenomas,

carcinomas and combined adenomas

and/or carcinomas; there were

significant differences in pair-wise

comparisons with the high-dose level

with controls for liver adenomas and

combined adenomas and/or carcinomas.

The increased incidences of

hepatocellular tumors at the 1,400-ppm

level generally exceeded the available

historical control data for these tumor

types in mice of this strain.

Additionally, iprodione was associated

with a significant increasing trend in

ovarian lutenomas, and there was a

significant difference in the pair-wise

comparison of the 1,400-ppm dose

group with the control group and

historical controls. EPA considers the

dose levels used in this study to be

adequate for testing the carcinogenicity

of iprodione in mice.

Iprodione was administered in the

diet to 60 Sprague-Dawley rats/sex/

group for 2 years at dose levels of 0, 150,

300, or 1,600 ppm. There was a 52-week

interim sacrifice of 10 additional rats/

sex/group. At the interim sacrifice,

males at the high-dose level displayed

an increase in the incidence of lesions

in the adrenals, and there was an

increase in the incidence of

centrilobular hepatocyte enlargement in

males at the 300 and 600 dose levels;

females displayed an increased

incidence of centrilobular hepatocyte

enlargement at the highest dose tested.

In male rats fed iprodione for 2 years,

there was a significant dose-related

increasing trend and a significant

difference in the pair-wise comparison

of the 1,600-ppm dose group with the

controls for testicular interstitial cell

benign tumors. The incidence of both

unilateral and bilateral benign

interstitial cell tumors was increased at

this dose level compared to historical

control data. In addition to the

neoplastic lesions, interstitial cell

hyperplasia in the testes, reduced

spermatozoa in the epididymis, and

absent/empty secretory colloid cells or

reduced secretion in the seminal

vesicles were observed at the 300- and

1,600-ppm dose levels. Atrophy of the

seminiferous tubules in the testes, with

atrophy of the prostate and absence of

spermatozoa in the epididymis, were

observed at 1,600 ppm. Centrilobular

hepatocyte enlargement was increased

in males at the high-dose level. Adrenal

lesions were observed in both sexes at

the 300- and 1,600- ppm dose levels,

although males displayed more lesions

than females.

In females rats fed iprodione at the

high-dose level for 2 years, there were

no significant compound-related tumors

observed, although there was an

increased incidence of tubular

hyperplasia in the ovaries and increased

sciatic nerve fiber degeneration

compared to the controls. The dose

levels chosen for this study were

considered appropriate for assessing the

carcinogenicity of iprodione in rats.

Iprodione is structurally related to

vinclozolin and procymidone.

Procymidone has been associated with

the appearance of tumors in both sexes

in the reproductive organs and the liver,

but did not have mutagenic activity in

several tests. Vinclozolin, which is

currently being tested for its

carcinogenic potential, has been

associated with adverse effects on the

reproductive organs and liver. With the

exception of the mouse lymphoma

(forward mutation) assay, vinclozalin

was negative for mutagenicity. In

mutagenicity studies, iprodione was not

mutagenic in the Ames assay, the CHO/

HGPRT mammalian cell forwarded

mutation assay, the in vitro

chromosome aberration assay in CHO

cells, the in vitro sister chromatid

exchange assay in CHO cells and the

dominant-lethal test in mice. However,

iprodione was positive in the Bacillus

subtilis assay for DNA damage without

metabolic activation.

Imazalil

After a full evaluation of the data and

supporting information regarding

animal carcinogenicity, EPA concludes

that exposure to imazalil is associated

with an increased incidence of

adenomas and combined adenomas/

adenocarcinomas of the livers of male

Swiss mice and with a significant doserelated increasing trend in

hepatocellular adenomas and combined

adenomas and/or carcinomas.

Imazalil base was administered in the

diet to groups of 50 male and 50 female

Swiss mice and treated for 100 to 101

weeks at levels of 0, 50, 200, or 600

ppm. Male mice had a significant doserelated increasing trends in

hepatocellular adenomas and/or

carcinomas. There was a significant

difference in the pair-wise comparison

of the 200-ppm dose group with the

controls for hepatocellular adenomas.

There were also significant differences

in the pair-wise comparisons of the 600-

ppm dose group with the controls for

hepatocellular adenomas and combined

adenomas and/or carcinomas. EPA has

concluded that the malignant carcinoma

response at the 600-ppm dose level was

biologically relevant and related to

imazalil exposure despite the lack of

pair-wise statistical significance

compared to controls. There was over a

doubling of the concurrent control

incidence and a positive trend for

carcinomas. The male carcinoma

incidence was also outside the historical

control data provided by the submitting

company. It was noted that about 50%

of the significantly positive combined

incidence was contributed by

carcinomas. Also, there appears to be a

progression towards malignancy across

the dose groups.

Female mice had significant doserelated increasing trends in

hepatocellular adenomas and combined

adenomas and/or carcinomas. There

were no significant differences in the

pair-wise comparisons of the dosed

groups with the controls.

Nonneoplastic changes in the liver

were also observed in male mice at all

dose levels. At the 200-ppm level, males

had a significant increase in the

incidence of focal cellular changes, large

vacuoles, and swollen sinusoidal cells

in the liver. At the highest dose tested,

males also had a significantly increased

incidence of pigmentation in the

sinusoidal cells of the liver and focal

cellular changes in the pancreas,

increased absolute and relative liver

weight, and decreased body weight and

body weight gain. Female mice did not

exhibit any cellular changes in the liver,

although there was some effect on body

weight at the 600-ppm dose and slight

increases in liver weights at the highest

dose tested as well.

There is extensive structure-activity

relationship (SAR) support for the
Federal Register / Vol. 60, No. 11 / Wednesday, January 18, 1995 / Proposed Rules 3611

tumor response associated with

imazalil. Closely related compounds

with the chlorinated benzene moiety,

e.g., etaconazole, cyproconazole,

tebuconazole, induced hepatocellular

adenomas, and malignant carcinomas in

both sexes of several strains of mice.

The mutagenicity data for imazalil did

not indicate genotoxic activity;

however, a data gap was identified and

additional testing is required.

B. Proposed Food Additive Revocations

Acephate. EPA is proposing to revoke

the food additive regulation of 0.02 ppm

for the combined residues of acephate

(O,S-dimethyl

acetylphosphoramidothioate) and its

cholinesterase-inhibiting metabolite,

methamidophos, set to cover use of the

pesticide in food-handling

establishments. This food additive

regulation is codified at 40 CFR185.100.

EPA is proposing to revoke this food

additive regulation because the Agency

has determined that acephate induces

cancer in animals. Thus, the regulation

violates the Delaney clause in section

409 of the FFDCA.

Triadimefon. EPA is proposing to

revoke the food additive regulations for

triadimefon (1-(4-chlorophenoxy)-3,3-

dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-

butanone) and its metabolite beta-(4-

chlorophenoxy)-alpha-(1,1-

dimethylethyl)-1H-1,2,4triazole-1-

ethanol set to cover residues in or on

milled fractions of barley (except flour)

and milled fractions of wheat (except

flour). The food additive regulations,

which are codified at 40 CFR 185.800,

are set at 4 ppm. EPA is proposing to

revoke these food additive regulations

because the Agency has determined that

triadimefon induces cancer in animals.

Thus, the regulations violate the

Delaney clause in section 409 of the

FFDCA.

Iprodione. EPA is proposing to revoke

the food additive regulations for

iprodione [3-(3,5-dichlorophenyl)-N-(1-

methylethyl)-2,4-dioxo-1-

imidazolidinecarboxamide], its isomer

[3-(1-methyl-ethyl)-N-(3,5-

dichlorophenyl)-2,4-dioxo-1-

imidazolidinecarboxamide], and its

metabolite [3-(3,5-dichlorophenyl)-2,4-

dioxo-1-imidazolidinecarboxamide] set

to cover residues in dried ginseng at 4

ppm and raisins at 300 ppm. The food

additive regulations for iprodione are

codified at 40 CFR 185.3750. EPA is

proposing to revoke these food additive

regulations because the Agency has

determined that iprodione induces

cancer in animals. Thus, the regulation

violates the Delaney clause in section

409 of the FFDCA.

Imazalil. EPA is proposing to revoke

the food additive regulation for imazalil

set to cover residues of the fungicide

imazalil 1-[2-(2,4-dichlorophenyl)-2-(2-

propenyloxy)ethyl]-1H-imidazole and

its metabolite 1-(2,4-dichlorophenyl)-2-

(1H-imidazole-1-yl)-1-ethanol in citrus

oil at a level of 25 ppm. This food

additive regulation is codified at 40 CFR

185.3650. EPA is proposing to revoke

this food additive regulation because the

Agency has determined that imazalil

induces cancer in animals, and thus

violates the Delaney clause in section

409 of the FFDCA.

III. Consideration of Comments

Any interested person may submit

comments on this proposed action on or

before April 18, 1995 at the address

given in the section above entitled

‘‘ADDRESSES.’’ Before issuing final

actions, EPA will consider all relevant

comments. Comments should be limited

only to the pesticides and food additive

regulations subject to this proposed

notice. After consideration of

comments, EPA will issue a final order

determining whether revocation of the

regulations is appropriate and making a

final finding on whether these

pesticides induce cancer within the

meaning of the Delaney clause. Such

order will be subject to objections

pursuant to section 409(f) (21 U.S.C.

348(f)). Failure to file an objection

within the appointed period will

constitute waiver of the right to raise

issues resolved in the order in future

proceedings.

IV. Executive Order 12866

Since this proposed action is being

taken under the Delaney clause, which

requires the Agency to act without

considering the costs or benefits of the

action, the Agency has not completed an

evaluation of the economic impacts of

this particular action. Nevertheless,

pursuant to an agreement between EPA

and OMB, this action was submitted to

OMB for an informal 10-day review. As

required by the Executive Order, any

comments or changes made in response

to OMB suggestions or

recommendations have been

documented in the public record. In

addition, the Agency welcomes any

comments and information regarding

the impacts of this proposed action.

These could contribute to an analysis of

the impacts of similar future actions.

V. Regulatory Flexibility Act

The Regulatory Flexibility Act of 1980

(Pub. L. 96-354; 94 Stat. 1164, 5 U.S.C.

601 et seq.) requires EPA to analyze

regulatory options to assess the

economic impact on small businesses,

small governments, and small

organizations. As explained above, the

Agency is compelled to take this action

without regard to the economic impacts.

Again, EPA welcomes any information

on impacts to small businesses,

governments, and organizations.

VI. Paperwork Reduction Act

This order does not contain any

information collection requirements

subject to review by Office of

Management and Budget under the

Paperwork Reduction Act of 1980, 44

U.S.C. 3501 et seq.

List of Subjects in 40 CFR Part 185

Environmental protection,

Administrative practice and procedure,

Agricultural commodities, Food

additives, Pesticides and pests,

Recording and recordkeeping

requirements.

Dated: January 10, 1995.

Lynn R. Goldman,

Assistant Administrator for Prevention,

Pesticides and Toxic Substances.

Therefore, it is proposed that 40 CFR

part 185 be amended as follows:

PART 185—[AMENDED]

1. The authority citation for part 185

continues to read as follows:

Authority: 2l U.S.C. 346a and 348.

§ 185.100 [Removed]

2. By removing § 185.100.

§ 185.800 [Removed]

3. By removing § 185.800.

§ 185.3650 [Removed]

4. By removing § 185.3650.

§ 185.3750 [Removed]

5. By removing § 185.3750

[FR Doc. 95–1062 Filed 1–17–95; 8:45 am]

BILLING CODE 6560–50–F

40 CFR Part 180

[OPP–300375; FRL–4926–6]

RIN 2070–AC18

Oryzalin; Revocation of Tolerances

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA is proposing to revoke

tolerances for residues of the herbicide

oryzalin in or on various raw

agricultural commodities. EPA is taking

this action because registered uses of

oryzalin for cottonseed, barley grain,