Federal Register / Vol. 61, No. 116 / Friday, June 14, 1996 / Proposed Rules 30197

savings association, you must not take

advantage of corporate opportunities

belonging to the savings association.

(b) A corporate opportunity belongs to

a savings association if:

(1) The opportunity is within the

corporate powers of a savings

association or a subsidiary of the

savings association; and

(2) The opportunity is of present or

potential practical advantage to the

savings association, either directly or

through its subsidiary.

PART 571—STATEMENTS OF POLICY

12. The authority citation for part 571

continues to read as follows:

Authority: 5 U.S.C. 552, 559; 12 U.S.C.

1462a, 1463, 1464.

§§ 571.4, 571.7, 571.9 [Removed]

13. Sections 571.4, 571.7 and 571.9

are removed.

Dated: May 29, 1996.

By the Office of Thrift Supervision.

Jonathan L. Fiechter,

Acting Director.

[FR Doc. 96–14000 Filed 6–13–96; 8:45 am]

BILLING CODE 6720–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. 94P–0341]

Medical Devices; Classification/

Reclassification of

Immunohistochemistry Reagents and

Kits

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

classify/reclassify

immunohistochemistry reagents and

kits (IHC’s) (in-vitro diagnostic devices)

into three classes depending on

intended use. These actions are being

taken under the Federal Food, Drug, and

Cosmetic Act (the act), as amended by

the Medical Device Amendments of

1976 (the 1976 amendments) and the

Safe Medical Devices Act of 1990 (the

SMDA). The intention of this proposal

is to regulate these pre- and post-1976

devices in a consistent fashion.

Therefore, FDA is proposing

classification or reclassification of these

products as applicable.

DATES: Submit written comments by

August 30, 1996.

ADDRESSES: Submit written comments

on the proposed rule to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857.

FOR FURTHER INFORMATION CONTACT: Max

Robinowitz, Center for Devices and

Radiological Health (HFZ–440), Food

and Drug Administration, 2098 Gaither

Rd., Rockville, MD, 20850–4011, 301–

594–1293, ext. 136, or FAX 301–594–

5941.

SUPPLEMENTARY INFORMATION:

I. Background

The act (21 U.S.C. 201 et seq.), as

amended by the 1976 amendments (Pub.

L. 94–295) and the SMDA (Pub. L. 101–

629), established a comprehensive

system for the regulation of medical

devices intended for human use.

Section 513 of the act (21 U.S.C. 360c)

established three categories (classes) of

devices, depending on the regulatory

controls needed to provide reasonable

assurance of their safety and

effectiveness. The three categories of

devices are: Class I (general controls),

class II (special controls), and class III

(premarket approval).

Under section 513 of the act (21

U.S.C. 360c), devices that were in

commercial distribution before May 28,

1976, the enactment date of the 1976

amendments, are classified after FDA

has: (1) Received a recommendation

from a device classification panel (an

FDA advisory committee); (2) published

the panel’s recommendations for

comment, along with a proposed

regulation classifying the device; and (3)

published a final regulation classifying

the device. A device that is first offered

in commercial distribution after May 28,

1976, and which FDA determines to be

substantially equivalent to a device

classified under this scheme, is

classified into the same class as the

device to which it is substantially

equivalent. The agency determines

whether new devices are substantially

equivalent to previously offered devices

by means of premarket notification

procedures in section 510(k) of the act

(21 U.S.C. 360 (k)) and part 807 of the

regulations (21 CFR 807). A device that

was not in commercial distribution

prior to May 28, 1976, and that has not

been found by FDA to be substantially

equivalent to a legally marketed device,

is classified automatically by statute

(section 513(f) of the act) into class III,

without any FDA rulemaking

proceeding.

The scope of products covered by this

proposal includes both pre-1976 devices

which have not been previously

classified as well as post-1976 devices

which are statutorily classified into

class III. The intention of this proposal

is to regulate these pre- and post-1976

devices in a consistent fashion.

Therefore, FDA is proposing

classification or reclassification of these

products, as applicable.

Fluorescent-labeled

immunohistochemistry in vitro

diagnostic devices (IHC’s) have been

used for patient diagnosis since the

early 1940’s and enzyme-linked IHC’s

have been used since the early 1970’s.

IHC’s, however, were not classified as a

part of the 1979 FDA classification

activities. In addition, new IHC’s have

been marketed for the first time since

the passage of the 1976 amendments.

When used in a standardized controlled

manner, IHC’s enhance the accuracy

and scope of surgical pathology, provide

objective data to histopathological

examination, and contribute to

improved patient care. IHC’s can

specifically and objectively demonstrate

the presence and distribution of

antigens that may be of use in narrowing

differential diagnoses. IHC results are

integrated by the user pathologist and

interpreted together with other types of

data used in pathological diagnostic

decisionmaking (Refs. 1 through 4).

Because pathologists, the principal

users of IHC’s, were concerned about

the regulation of IHC’s, the College of

American Pathologists, the American

Society of Clinical Pathologists, the

Association of Pathology Chairs, the

Biological Stain Commission, and the

Association of Directors of Anatomic

and Surgical Pathology requested a

review of the classification of IHC

reagents and submitted a Petition for

Classification of IHC’s as class II (special

controls) medical devices during the

summer of 1994. In response to this

petition, FDA convened the Panel to

consider classification/reclassification

of these devices.

II. Panel Recommendation

The Hematology and Pathology

Devices Panel (the Panel) met on

October 21, 1994, and made the

following recommendation regarding

the classification of five

Immunohistochemistry devices.

A. Identification

Immunohistochemistry test systems

(IHC’s) are in-vitro diagnostic devices

that consist of polyclonal or monoclonal

antibodies and ancillary reagents that

are used to identify, by immunological

techniques, antigens in specimens of

tissues or intact cells in cytologic

specimens. IHC’s are primary antibody

reagents that are labeled with

instructions for use and performance
30198 Federal Register / Vol. 61, No. 116 / Friday, June 14, 1996 / Proposed Rules

claims and packaged either prediluted

or concentrated (neat), or as kits

consisting of optimally-diluted primary

antibody combined with detector

systems. IHC’s identify antigens in

tissue or cell preparations using ligandspecific antibodies whose reactivity is

detected and marked by secondary

reagents that are recognized by

pathologists using light or electron

microscopes. Most IHC’s are adjunctive

to conventional histopathology and aid

in the qualitative identification of

antigens, thereby supplementing the

conventional hematoxylin and eosin

stains used in the diagnostic

classification of normal and abnormal

cells and tissues. Some IHC’s may

provide semi-quantitative or

quantitative information about the

antigen they identify in normal and

abnormal cells and tissues.

B. Recommended Classification of the

Hematology and Pathology Devices

Panel

Class II (special controls). The Panel

recommended that establishing special

controls for IHC devices should be a

high priority.

C. Summary of Reasons for

Recommendation

The Panel recommended that IHC

devices be classified into class II

(special controls) because they

perceived the need for special controls

for IHC’s that prescribe acceptable

sensitivity, specificity, stability,

accuracy and precision for these

devices, and thereby minimize the

possibility that these devices may

generate inaccurate diagnostic

information. Patients may be placed at

unnecessary risk when reliance upon

inaccurate diagnostic information

results in initiating inappropriate

therapies or withholding appropriate

therapies.

The Panel stated that general controls

for IHC’s would not provide sufficient

control over sensitivity, specificity,

stability, accuracy and precision of IHC

devices. The Panel stated that special

controls are needed to provide

reasonable assurance of the safety and

effectiveness of IHC devices and that

sufficient information is available to

establish these special controls. The

Panel recommended that manufacturers

of IHC devices should follow the FDA’s

Guidance for Submission of

Immunohistochemistry Applications

and that this guidance should serve as

a special control.

A major concern of the Panel was that

manufacturers of IHC devices should be

subject to current good manufacturing

practice (CGMP) inspections in a timely

manner to ensure safe, reliable, stable,

and consistent IHC products.

D. Summary of Data Upon Which the

Recommendation is Based

The Panel based its recommendation

on the Panel members’ personal

knowledge of, and clinical experience

with IHC devices, and presentations by

Panel members, manufacturers, other

interested parties, and FDA (Ref. 5).

E. Risks to Health

IHC in vitro diagnostic devices are

intended for use as diagnostic tools.

Risk to the patient may result from

misdiagnosis and initiation of

inappropriate therapies or withholding

of appropriate therapies based on the

results obtained with the IHC diagnostic

device. The degree of risk depends on

whether the product is used as an

adjunct to conventional

histopathological diagnostic techniques

or provides information that is used

independently of the usual diagnostic

process. The highest risk products are

those used as independent, stand-alone

diagnostic tests that are the sole or

major determinant for a medical

decision and cannot be confirmed by

conventional histopathologic techniques

or other diagnostic tests or clinical

procedures.

III. Proposed Classification/

Reclassification

Following the Hematology and

Pathology Devices Panel meeting, the

agency considered the Panel’s

recommendation. The agency agrees in

part and disagrees in part with the

Panel’s recommendation. FDA believes

that general class I controls are

sufficient to ensure safety and

effectiveness for those adjunctive IHC’s

that furnish information that may be

incorporated into the pathologist’s

histopathology or cytopathology report

but that is not reported directly to

clinicians. These general controls

include: (1) Existing labeling

requirements (21 CFR 809.10) for in

vitro devices, (2) compliance with good

manufacturing practices, (3) registration,

listing, and premarket notification

(510(k)), (4) recordkeeping and medical

device reporting (MDR), (5) restriction

to prescription use (21 CFR 801.109.)

Those IHC’s that provide pathologists

with adjunctive diagnostic information

that may be incorporated into the

pathologist’s report, but that is not

ordinarily reported to the clinician as an

independent finding, are therefore

proposed to be categorized as class I.

These IHC’s are used in adjunctive tests

to subclassify malignant tumors, but the

primary diagnosis of tumor (neoplasm)

and malignancy is made by

conventional histopathology using

nonimmunological histochemical stains

such as hematoxylin and eosin.

Examples of these IHC’s proposed for

class I are differentiation markers, such

as antikeratin antibodies.

The manufacturer (sponsor) of a class

I IHC would be required to provide a

premarket notification submission to

FDA, including data documenting

compliance with the labeling

requirements in § 809.10 (21 CFR

809.10). Such manufacturers or

sponsors may wish to follow the ‘‘FDA

Guidance for Submissions of

Immunochemistry Applications to

FDA’’ (Guidance), for the purpose of

documenting manufacturing. The FDA

Guidance provides details about data

that may be submitted to comply with

§ 809.10.

In considering whether to place any

adjunctive IHC’s into class I, FDA

focused on whether this level of

regulation is adequate for the protection

of public health. FDA considers the total

test performance for any in vitro

diagnostic device to be dependent on

the net results of preanalytic, analytic,

and postanalytic factors. For example,

variability in IHC results may be

introduced at every step including

collection and fixation of the specimen,

automated processing, embedding,

sectioning, staining of the final slide

preparation, and the microscopic

interpretation by the pathologist. FDA

regulation and review are directed at

ensuring that the manufacturer

characterizes, manufacturers, and labels

the IHC appropriately before it is

marketed for professional use. Ongoing

initiatives by professional organizations,

manufacturers, and FDA are directed at

ensuring that pre- and postanalytic, as

well as analytic procedures, are

properly performed. In the context of

these initiatives, FDA believes that class

I regulation will assure that these

adjunctive IHC’s are used safely and

effectively.

IHC’s that provide the pathologist

with adjunctive diagnostic information

that is ordinarily reported as

independent diagnostic information to

the ordering clinician are proposed to be

classified in class II. Examples are IHC’s

for immunologic detection and semiquantitative measurement of specific

ligand markers of proliferation, such as

Ki-67, or semi-quantitative

determination of other analytes, such as

hormone receptors, if they are reported

for their prognostic implications.

However, this classification does not

apply to estrogen and progesterone

receptors, which are in class III by

previous regulation, and which provide
Federal Register / Vol. 61, No. 116 / Friday, June 14, 1996 / Proposed Rules 30199

information that is the basis for

significant medical decisions

substantially independent of other

pathological tests. FDA is proposing that

class II IHC’s be subject to general

controls and to a special control: The

FDA Guidance for submissions of

Immunohistochemistry Applications to

FDA (the guidance) (Ref. 6). The agency

believes that the manufacturer/sponsor

can establish reasonable assurance of

the safety and effectiveness of a class II

IHC by providing valid scientific

evidence from sponsor-supported

studies, as described in the guidance, or

from the scientific literature. The

guidance was drafted with input from

the Biological Stain commission, the

Joint Council of Immunohistochemistry

Manufacturers, the College of American

Pathologists, the American Society of

Clinical Pathology, FDA, and comments

from the public. The guidance also will

provide information to aid the end-users

of IHC’s (pathologists and other

laboratorians) with recommendations

about appropriate positive and negative

control tissue sections (or cytologic

preparations) for each intended use of

the IHC. The guidance will also describe

the form and content for the package

insert of IHC’s and provide the sponsor

with detailed recommendations about

how to comply with § 809.10 (Ref. 6).

IHC’s that generate information that is

reported directly to the clinician to be

used as the basis for significant medical

decisions, and that either provide

information substantially independent

of other pathological (or

cytopathological) aspects of the

specimen or that have novel claims not

supported by current widely accepted

scientific pathophysiologic principles,

would be categorized as class III.

Examples of IHC’s FDA proposes to put

in class III are markers of clinically

significant genetic mutations in tissues

that are normal by conventional

histopathology.

IV. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Taylor, C. R., and Cote, R. C.,

‘‘Immunomicroscopy: A Diagnostic Tool for

the Surgical Pathologist,’’ 2d ed.,

Philadelphia, W. B. Saunders, 1994.

2. True, L. D. (ed)., Atlas of Diagnostic

Immunohistopathology, Philadelphia,

Lippincott, 1990.

3. Nadji, M., and Morales, A. R.,

‘‘Immunoperoxidase Techniques: A Practical

Approach to Tumor Diagnosis’’ Chicago,

American Society of Clinical Pathologists

Press, 1986.

4. Taylor, C. R., ‘‘Quality Assurance and

Standardization in Immunohistochemistry,’’

A Proposal for the Annual Meeting of the

Biological Stain Commission, June 1991,

Biotechnic & Histochemistry, 67:110–117,

1992.

5. Transcripts of the Hematology and

Pathology Devices Panel meeting, October 21,

1994.

6. FDA Guidance for Submission of

Immunohistochemistry Applications to the

FDA, FDA Center for Devices and Radiologic

Health, 1995, available through the Division

of Small Manufacturers’ Assistance (DSMA),

1–800–638–2041.

7. Taylor, C. R., et al., Report of the

Immunohistochemistry Steering Committee

of the Biological Stain Commission,

‘‘Proposed Format: Package Insert for

Immunohisto Chemistry Products,’’

Biotechnic & Histochemistry, 67:328–338,

1992.

V. Environmental Impact

The agency has determined under 21

CFR 25.24(e)(2) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

VI. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(Pub. L. 96–354). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The agency

believes that this proposed rule is

consistent with the regulatory

philosophy and principles identified in

the Executive Order. In addition, the

proposed rule is not a significant

regulatory action as defined by the

Executive Order and so is not subject to

review under the Executive Order.

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact of a rule on small

entities. Because the agency believes

only a small number of firms will be

affected by this rule when finalized, the

agency certifies that the proposed rule

will not have a significant economic

impact on a substantial number of small

entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is

required.

VII. Request for Comment

Interested persons may, on August 30,

1996 submit to the Dockets Management

Branch (address above) written

comments regarding this proposal. Two

copies of any comments are to be

submitted except that individuals may

submit one copy. Comments are to be

identified with the docket number

found in brackets in the heading of this

document. Received comments may be

seen in the office above between 9 a.m

and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 864

Blood, Medical devices, Packaging

and containers.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 864 be amended as follows:

PART 864—HEMATOLOGY AND

PATHOLOGY DEVICES

1. The authority citation for 21 CFR

part 864 continues to read as follows:

Authority: Secs. 501, 510, 513, 515, 520,

701 of the Federal Food, Drug, and Cosmetic

Act (21 U.S.C. 351, 360, 360c, 360e, 360j,

371).

2. Section 864.1860 is added to

subpart B to read as follows:

§ 864.1860 Immunohistochemistry

reagents and kits.

(a) Identification.

Immunohistochemistry test systems

(IHC’s) are in-vitro diagnostic devices

consisting of polyclonal or monoclonal

antibodies labeled with directions for

use and performance claims, which may

be packaged with ancillary reagents in

kits. Their intended use is to identify,

by immunological techniques, antigens

in tissues or cytologic specimens.

Similar devices intended for use with

flow cytometry devices are not IHC’s.

(b) Classification of

immunohistochemistry devices. (1)

Class I for IHC’s that provide the

pathologist with adjunctive diagnostic

information that may be incorporated

into the pathologist’s report, but that is

not ordinarily reported to the clinician

as an independent finding. These IHC’s

are used after the primary diagnosis of

tumor (neoplasm) and malignancy is

made by conventional histopathology

using nonimmunologic histochemical

stains such as hematoxylin and eosin.

Examples of class I IHC are

differentiation markers, such as keratin,

which are used in adjunctive tests to

subclassify malignant tumors.

(2) Class II for IHC’s that provide the

pathologist with adjunctive diagnostic

information that is ordinarily reported
30200 Federal Register / Vol. 61, No. 116 / Friday, June 14, 1996 / Proposed Rules

as independent diagnostic information

to the ordering clinician. Examples are

IHC’s for immunologic detection and

semi-quantitative measurement of

specific ligand markers of proliferation,

such as Ki-67, or semi-quantitative

determination of other analytes, such as

hormone receptors, if they are reported

for their prognostic implications.

However, this classification does not

apply to estrogen and progesterone

receptors that are classified as class III

devices.

(3) Class III for IHC’s that generate

information that is reported directly to

the clinician to be used as the basis for

significant medical decisions, and that

either provide information substantially

independent of other pathological (or

cytopathological) aspects of the

specimen or that have novel claims not

supported by current widely accepted

scientific pathophysiologic principles.

Examples are markers used to identify

clinically significant genetic mutations

in tissues that are normal by

conventional histopathologic

examination.

(c) Date PMA or notice of completion

of a PDP is required. No effective date

has been established for the requirement

for premarket approval for the devices

described in paragraph(b)(3) of this

section. See § 864.3 for effective dates of

requirement for premarket approval.

Dated: May 31, 1996.

D.B. Burlington,

Director, Center for Devices and Radiological

Health.

[FR Doc. 96–15140 Filed 6–13–96; 8:45 am]

BILLING CODE 4160–01–F

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 180

[PP 5E4573/P662; FRL–5375–1]

RIN 2070–AC18

Fenarimol; Pesticide Tolerance For

Residues in or on Filberts

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA proposes to establish a

tolerance for residues of the fungicide

fenarimol in or on the raw agricultural

commodity filberts. The proposed

regulation to establish a maximum

permissible level for residues of the

fungicide was requested in a petition

submitted by the Interregional Research

Project No. 4 (IR-4).

DATES: Comments, identified by the

docket number [PP 5E4573/P662], must

be received on or before July 15, 1996.

ADDRESSES: By mail, submit written

comments to: Public Response and

Program Resources Branch, 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 Highway, Arlington, VA

22202.

Comments and data may also be

submitted to OPP by sending electronic

mail (e-mail) to: oppdocket@epamail.epa.gov. Electronic

comments must be submitted as an

ASCII file avoiding the use of special

characters and any form of encryption.

Comments 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

[PP 5E4573/P662]. Electronic comments

on this proposed rule may be filed

online at many Federal Depository

Libraries. Additional information on

electronic submissions can be found in

the ‘‘SUPPLEMENTARY

INFORMATION’’ section of this

document.

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 Virginia

address given above, from 8 a .m. to 4:30

p.m., Monday through Friday, excluding

legal holidays.

FOR FURTHER INFORMATION CONTACT: By

mail: Hoyt L. Jamerson, Registration

Division (7505W), Office of Pesticide

Programs, Environmental Protection

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

20460. Office location and telephone

number: Sixth Floor, Crystal Station #1,

2800 Jefferson Davis Highway,

Arlington, VA 22202, (703) 308–8783; email: jamerson.hoyt@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: The

Interregional Research Project No. 4 (IR4), New Jersey Agricultural Experiment

Station, P.O. Box 231, Rutgers

University, New Brunswick, NJ 08903,

has submitted pesticide petition (PP)

5E4573 to EPA on behalf of the Oregon

Filbert Commission.

This petition requests that the

Administrator, pursuant to section

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

Cosmetic Act (FFDCA), 21 U.S.C.

346a(e), amend 40 CFR 180.421 by

establishing a tolerance for residues of

the fungicide fenarimol [alpha-(2-

chlorophenyl)-alpha-(4-chlorophenyl)-5-

pyrimidine methanol] in or on the raw

agricultural commodity filberts at 0.02

parts per million (ppm).

The scientific data submitted in the

petition and other relevant material

have been evaluated. The toxicological

data considered in support of the

proposed tolerance include:

1. A 1–year feeding study with dogs

fed diets containing 0, 1.25, 12.5, or 125

milligrams/kilogram (mg/kg)/day. The

no-observed-effects level (NOEL) for this

study is established at 12.5 mg/kg/day.

The high dose level (125 mg/kg/day)

caused increased serum alkaline

phosphatase, increased liver weights, an

increase in p-nitroanisole o-demethylase

activity, and mild hepatic bile stasis.

2. A 2–year chronic feeding/

carcinogenicity study in rats fed diets

containing concentrations of 0, 50, 130,

or 350 ppm (equivalent to 0, 2.5, 6.5, or

17.5 mg/kg/day) with a systemic NOEL

of 130 ppm (equivalent to 6.5 mg/kg/

day). An increase in fatty liver changes

was observed in rats fed diets

containing 350 ppm. There were no

carcinogenic effects observed under the

conditions of the study.

3. A second 2–year chronic feeding/

carcinogenicity study in rats fed diets

containing 0, 12.5, 25, or 50 ppm

(equivalent to 0, 0.63, 1.25, or 2.5 mg/

kg/day) with no systemic or

carcinogenic effects observed under the

conditions of the study.

4. A 2–year carcinogenicity study in

mice fed diets containing concentrations

of 0, 50, 170, or 600 ppm (equivalent to

0, 7, 24.3, or 85.7 mg/kg/day) with a

NOEL for systemic effects at 170 ppm.

An increase in fatty liver changes was

observed in mice at the 600 ppm dose

level. There were no carcinogenic efects

observed under the conditions of the

study.

5. A developmental toxicity study

with rabbits given oral doses of 0, 5, 10,

or 35 mg/kg/day with no developmental

toxicity observed under the conditions

of the study.

6. A developmental toxicity study

with rats given oral doses of 0, 5, 13, or

35 mg/kg/day demonstrated

hydronephrosis at 35 mg/kg/day. The

NOEL for developmental toxicity in this

study is established at 13 mg/kg/day.