Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

ENVIRONMENTAL PROTECTION

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 799

[OPTS-42033; BH-FRL 2341-2]

Cresols; Proposed Test Rule

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: Under section 4 of the Toxic

Substances Control Act (TSCA), EPA is

proposing that manufacturers and

processors of cresols test these

chemicals for carcinogenicity,

mutagenicity, teratogenicity,

reproductive effects, neurotoxicity, skin

sensitization and subchronic toxicity.

The testing being proposed will be

performed according t6 protocols

adopted by the Agency. EPA is not

proposing to require any additional

erlvironmental effects testing at this

time. However, EPA is also soliciting

public comments on the decision not to

propose environmental effects testing

for cresols. This notice constitutes EPA's

response to the Interagency Testing

Committee's (ITC) designation of cresols

as priority candidates for testing.

DATES: Submit written comments on or

before September 9, 1983. If persons

request an opportunity for oral comment

by August 25, 1983, EPA will hold a

public meeting on September 26, 1983,

on this rule in Washington, D.C. For

further information on arranging to

speak at the meeting see unit VI of this

preamble.

ADDRESS: Submit written comments in

triplicate to: TSCA Public Information

Office (TS-793), Office of Pesticide and

Toxic Substances, Environmental

Protection Agency, Rm. E-108, 401 M St.

SW., Washington, D.C. 20460.

Include the document control number

[OPTS-42032] on all submissions.

FOR FURTHER INFORMATION CONTACT:

Jack P. McCarthy, Director, TSCA

Assistance Office (TS-799), Office of

Toxic Substances, Rm. E-545, 401 M St.

SW., Washington, D.C. 20460, Toll Free:

(800-424-9065], In Washington, D.C.:

(554-1404), Outgide the USA: (Operator202-554-1404).

SUPPLEMENTARY INFORMATION:

I. Introduction

Section 4(e) of TSCA (Pub. L. 94-469,

90 Stat. 2003 et seq.; 15 U.S.C. 2601 et

seq.) established an Interagency Testing

Committee (ITO) to recommend to EPA

a list of chemicals to be considered for

testing under section 4(a) of the Act. The

ITC iay designate substances on the

list for priority consideration for

requiring testing by EPA.

The ITC designated cresols for

priority consideration in its Initial

Report, published in the Federal Register

on October 12, 1977 (42 FR 55026). The

ITC recommended that industry test

cresols for the following health effects:

carcinogenicity, mutagenicity,

teratogenicity and other chronic effects.

The ITC also recommended testing for

environmental effects, specifically

chronic effects in fish and other aquatic

organisms.

The ITC's recommendations were

based on the large volume of cresols

produced in the United States. It was

estimated in the ITC's report that the

U.S. production of cresols in 1975 was

about 90 million pounds. The ITC also

reported an annual release rate of

approximately 45 million pounds. In

addition, the ITC was concerned that

the manufacture and use of cresolcontaining products could result in

substantial occupational exposure and

high general population exposure.

Under section 4(a)(1) of TSCA, EPA

must require testing of a chemical

substance to develop health or

environmental data if the Agency finds

that:

(A) (i) the manufacture, distribution in commerce, processing, use, or disposal of a chemical substance or mixture, or that

any cohbination of such activities, may present an unreasonable

risk of injury to health or the environment,

(ii) there are insufficient data and experience upon which the

effects of such manufacture, distribution in commerce, processing,

use, or disposal of such substance or mixture or of any combination of such activities on health or the environment can reasonably be determined or predicted, and

(iii) testing of such substance or mixture with respect to sucheffects is necessary to develop such data; or (B) (i) a chemical substance or mixture is or will be producedin substantial quantities, and (I) it enters or may reasonably be

anticipated to enter the environment in substantial quantities or (II) there is or may be significant or substantial human exposure

to such substance or mixture,

(ii) there are insufficient data and experience upon which the

effects of the manufacture, distribution in commerce, processing,

use, or disposal of such substance or mixture or of any combination of such activities on health or the environment can reason- ably be determined or predicted, and

(iii) testing of such substance or mixture with respect to such

effects is necessary to develop such data.

EPA uses a weight of evidence

approach in making a section

4(a)(1)(A)(i) finding in which both

exposure and toxicity information are

considered to make the finding that the

chemical may present an unreasonable

*risk. For the section 4(a)(1)(B)(i) finding,

EPA considers only production,

exposure and release information to

determine if there is substantial ,

exposure. or release. For the findings

under both section 4(a)(1)(A)(ii) and

4(a)(1)(B)(ii), EPA examines toxicity and

fate studies to determine if existing

information is adequate to determine or

reasonably predict the effects of human

exposure to or environmental release of

the chemical. In making the third finding

that testing is necessary, EPA considers

whether any ongoing testing will satisfy

the information needs for the chemical

and whether testing which the Agency

might require would be capable of

developing the necessary information.

EPA's process for determining when

these findings can be made is described

in detail'in EPA's first and second

proposed test rules as published in the

Federal Register of July 18, 1980 (45 FR

48528) and June 5, 1981 (46 FR 30300).

The section 4(a)(1)(A) finding is

discussed in 45 FR 48528, and the

section 4(a)(1)(B) finding is discussed in

46 FR 30300.

In evaluating the ITC's testing

recommendations concerning cresols,

EPA considered all available relevant

information including the following:

Information presented in the ITC's

report recommending testing

consideration; production volume, use,

exposure, and release information

reported by manufacturers of cresols

under the TSCA section 8(a) Preliminary

Assessment Information Rule (40 CFR

Part 712]; health and safety studies

submitted by the manufacturers of

cresols under the TSCA section 8(d)

Health and Safety Data Reporting Rule

(40 CFR Part 716); and published and

unpublished data available to the

Agency. Based on its evaluation, as

31812
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

described in this preamble and the

accompanying technical support

document, EPA is proposing health

effects testing requirements for cresols

under section 4(a)(1)(A) and 4(a)(1)(B).

EPA tentatively has determined that

additional environmental effects testing

should not be required. However, due to

the absence of chronic toxicity data for

fish and invertebrates in freshwater and

saltwater systems, EPA is soliciting

comments on the need for additional

environmental effects testing. By these

actions, EPA is responding to the ITC's

designation of cresols for testing

consideration.

II. Cresols

A. Profile

Cresols (C71-IsO) is a chemical

category consisting of three cresol

isomers; ortho-cresol (o-cresol), metacresol (m-cresol), and pars-cresol (pcresol). Cresols are commercially

available as individual isomers or as

mixtures. Approximately, 172-200

million pounds of cresols are either

produced in or imported into the United

States each year. The EPA Toxic

Substances Inventory records that

approximately 72 million pounds of 0-

cresol; 32 million pounds of m-cresol

and 62 million pounds of p-cresol were

produced in the United States in 1977.

Cresols are used as wire enamel

solvents and as organic intermediates in

the manufacture of phenolic resins and

phosphate esters. Additional uses of

either individual isomers or mixtures are

in the production of several herbicides,

as cleaning compounds and

disinfectants, and in ore flotation.

B. Findings

The EPA is basing its proposed testing

on the authority of section 4(a)(1)(B) of

TSCA. Additionally, for mutagenicity

and oncogenicity, the Agency is basing

this proposal on the authority of section

4(a)(1)(A).

EPA finds that each of the three cresol

isomers is manufactured, processed, and

used in substantial quantities, which

may result in substantial human

exposure. Furthermore, EPA finds that

there are insufficient data available to

either reasonably determine or predict

the result of this exposure in the areas of

carcinogenic, mutagenic, teratogenic,

reproductive, neurotoxic, skin

sensitivity, and subchronic health

effects. These findings are based on the

following information:

1. There are substantial amounts of

cresols produced in or imported into the

United States each year. The annual

U.S. production volume of cresols is

estimated to be approximately 169

million pounds, with another 17 million

pounds impbrted into the United States

each year. Each of the three cresol

isomers is individually produced in

substantial'quantities. Of the total 169

million pounds produced domestically,

43 percent is o-cresol, 37 percent is pcresol and 20 percent is m-cresol.

2. Estimates indicate that between

600,000 and 1.2 million people are

exposed to cresols each year via

manufacturing, processing and/or use

activities.

3. EPA finds that there are insufficient

data on all of these cited human health

effects from which to reasonably

determined or predict the result of

exposure to cresols, and that testing of

cresols for these effects is necesiary to

develop such data.

4. EPA does not believe that the rule

will result in a loss to society of the

benefits of cresols because the Agency's

economic evaluation has shown that the

economic impact of testing these

substances will be minimal.

- In addition, EPA has found that (a)

there is evidence of potential

unreasonable human health risks from

mutagenic and carcinogenic effects

resulting from the manufacture,

processing and use activities associated

with cresols, and that while there are

existing data which support this belief

with respect to these effects, (b) these

existing data are inadequate to

reasonably predict or determine the

effects of these exposures to cresols,

and (c) testing is necessary for these

effects. Therefore, EPA believes that

requiring testing of cresols for

mutagenicity and carcinogenicity can

also be based upon'section 4(a](l)(A) of

TSCA.

The analyses on which the above

findings are based, are presented in the

Cresols Support Document which is

available from the TSCA Assistance

Office (TAO). The ITC

recommendations and EPA's proposed

testing requirements are summarized in

the following tables:

ITC EPA Effect recommen- proposed

dation testing

Skin sensitization .................... - X

Chronic effects ......................... x <

Mutagenicity ................................ x X

Carcinogenicity7 ........................ X X

Teratogenicity .......................... x X

Reproductive effects ................. X

Neurotoxecity ........................... X X

Environmental effects ................. x

Subcthronic proposed in lieu of full chronic. RTest substance(s) to be selected based on mutagenicity

testingEPA will determine i testing is needed based upon public comments.

In addition, the Agency has concluded

that the following human'health effects

are adequately characterized and,

therefore, that no further testing should

be required at this time: Acute toxicity

(lethality); acute skin and eye irritation,

and skin corrosivity. The Agency has

also concluded that available

information is sufficient to evaluate the

chemical fate and bioconcentration

potential of cresols, and therefore no

further testing in these areas is being

proposed at this time.

With respect to environmental

concerns, the Agency finds that the

release of cresols to the environment is

high. About 3.5 million pounds per year

are released to the atmosphere, while

the estimated annual release of cresols

as solid wastes is 4.2 million pounds.

The aqueous compartment may receive

as much as 11.2 million pounds per year

from dispersed use of cleaning

compounds. It is estimated that about 80

percent of that volume is discharged to

sewage treatment plants and will be

biodegraded resulting in an expected

annual release of as much as 2.8 million

pounds of cresols to natural waters.

While there is no existing chronic

aquatic effects data for cresols, the

Agency believes that information exists

which allows EPA to reasonably predict

that exposure of aqdatic organisms to

cresols should not cause chronic effects.

Therefore, the Agency has made a

preliminary judgment that no additional

environmental effects testing is needed

at this time. This judgment is based on

monitoring information which indicates

.that the ambient concentrations of

cresols found in aquatic systems are

expected to be minimal and will not be

acutely toxic to aquatic organisms

based on existing data for acute effects.

In addition, analyses have been

conducted for cresols using EPA's

Exposure Analsysis Modeling Systems

(EXAMS) and the Environmental

Partitioning Model (ENPART). The

results of EXAMS and ENPART, using

actual discharge and flow rates from a

cresols manufacturing plant, indicate

that the expected concentrations of

cresols, after treatment, will be 0.0016

mg/L-one mile from point of discharge,

0.0014 mg/L-five miles from point of

discharge, and finally 0.00094 mg/L--30

miles from point of discharge. These

numbers reflect the concentration levels

that would be expected in the winter

months, when microbial degradation

rates would be the lowest, and with

maximum effluent discharge rates.

Therefore, while the ITC

recommended testing for environmental

effects, the Agency'may be able to

reasonably predict that levels of cresols

may not cause chronic effects. However,

this preliminary decision not to propose

31813
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

environmental effects testing for cresols

is one for which further input by

interested parties will be particularly

helpful to the Agency. Therefore, EPA is

soliciting public comment on the need

for chronic toxicity data generation.

The public comments received in

response to this Federal Register notice

will be instrumental in assisting the

Agency in evaluating its decision not to

propose environmental effects testing

for cresols. If, after the public comments

are reviewed and evaluated, and the

Agency is convinced that its preliminary

decision is inappropriate for cresols,

thexi the Agency will require, in the final

rule for cresols, that environmental

effects testing be performed.

In that event, the environmental

effects testing shall be performed for the

purpose of developing data on the

chronic toxicity of cresols to aquatic

organisms in saltwater and freshwater

systems. The following environmental

effects studies would be included as

required testing in the final rule:

Freshwater vertebrate early life stage

testing in rainbow trout, freshwater

invertebrate chronic test in Daphnia sp.,

saltwater vertebrate early life stage in

Menidia sp., and saltwater invertebrate

chronic in Mysid shrimp.

The Agency has determined that

sufficient information does exist for

acute toxicity and that no additional

acute testing is needed. In addition, the

Agency has determined that while there

is substantial release of cresols to the

soil, this route of environmental

exposure is not expected to be a

problem. Cresols are readily

biodegraded by soil microflora and are mobile in soils. Therefore, cresols will

not persist in soils and will probably be

leached, due to their water solubility

into the aquatic environment where they

will be acted upon by degrading

microorganisms. The Agency has also

determined that cresols released to the

atmosphere are not expected to create

an exposure problem. Cresols are not

expected to persist in the atmosphere

because (1) cresols have low estimated

half-lives of less than 1 day; (2) they are

sensitive to photolysis; and (3) the water

solubility of cresols may be expected to

cause transport of cresols from the

atmosphere to the soil or aqueous

'environment.

C. Test Substance

EPA is proposing for the subchronic

toxicity, mutagenicity, carcinogenicity,

teratogenicity, reproductive effects,

neurotoxicity, and skin sensitization

testing that o-cresol, m-cresol and/orpcresol of at least 99 percent purity shall

be used as the test substance(s).

Each individual isomer will be tested

in the subchronic toxicity,

teratogenicity, reproductive effects,

neurotoxicity, and skin sensitization

studies. However, some of the cresol

isomers have previously been tested in

individual mutagenicity tests included in

the proposed battery. Therefore, in some

instances, not all of the isomers will be

tested in each mutagenicity test. The

test substance(s) in the oncogenicity

bioassays will be determined from the

results obtained in the proposed

mutagenicity test battery as further

explained in section 7.4 of the Cresols

Support Document.

Each isomer has exhibited different

chemical and toxicological properties in

previous testing. EPA has determined

that because of these differences, one of

the cresol isomers could not

satisfactorily be tested in all the

proposed testing as a representative of

all three.

Furthermore, it is not generally

acceptable for an equimolar mixture of

the three cresol isomers to be the test

substance in the prescribed health

effects testing. The Agency is primarily

interested in the health effects

attributable to individual cresol isomers.

With regard to mutagenic and

carcinogenic effects, a mutagenicity

testing battery has been proposed for

cresols, with testing endpoints that

could result in oncogenicity bioassays

for individual cresol isomers. This

proposed tiered mutagenicity testing

scheme has been designed specifically

for cresols. It has been conceived to

serve both as an indicator of mutagenic

potential, an ITC concern, and also as a

procedure to identify the test

substance(s) to be used in any

subsequent oncogenicity testing. While

the ITC recommended carcinogenicity

testing for cresols, EPA finds that the

proposed mutagenicity testing scheme is

an appropriate and scientifically valid

first testing tier in screening for -

oncogenicity.

Several testing endpoints in this

mutagenicity battery could result in

oncogenicity bioassays for individual

cresol isomers. However, if, after the

completion of the entire mutagenicity

test battery, each of the three cresol

isomers produce only negative results,

thereby not triggering any 2-year

bioassays, then a mixture of the three

isomers shall be tested in a full 2-year

oncogenicity bioassay. If the

mutagenicity tests on individual isomers

are negative, the rule will require that a

mixture be tested. EPA requests

comments on the appropriate

composition for such a mixture. The

decision to propose an oncogenicity

bioassay for isomeric mixture is based

on the fact that, in previous'

mutagenicity testing, an equimixture of

the three cresol isomers has tiad positive

results. However, as the Agency is

primarily interested in the health effects

of the individual isomers, the isomers

will be initially screened as the potential

bioassay test substances, prior to any

testing of an isomeric mixture.

D. Persons Required to Test

Section 4(b)(3)(B) specifies that the

activities for which the Administrator

makes section 4(a) findings

(manufacture, processing, distribution,

use and/or disposal) determines who

bears the responsibility for testing.

Manufacturers are required to test if the

findings are based on manufacturing,

("manufacture" is defined in section 3(7)

of TSCA to include "import").

Processors are required to test if the

findings are based on processing. Both

manufacturers and processors are

required to test if the exposures giving

rise to the potential risk occur during

use, distribution, or disposal. Because

EPA has found that the manufacturing,

processing, and use of cresols give rise

to exposures that may lead to an

unreasonable risk, EPA is proposing that

persons who manufacture or process, or

who intend to manufacture or process

these chemicals at any time from the

effective date of this test rule to the end

of the reimbursement period be subject

to the rule. The end of the

reimbursement period, ordinarily will be

5 years after the last final report is

submitted. As discussed in Unit II.F,

EPA expects that manufacturers will

conduct testing and that processors will

ordinarily be exempted from testing.

'Because TSCA contains provisions to

.avoid duplicative testing, not every

person subject to this rule must

individually conduct testing. Section

4(b)(3)(A) of TSCA provides that EPA

permit two or more manufacturers or

processors who are subject to a test rule

to designate one such person or a

qualified third person to conduct these

tests and submit data on their behalf.

Section 4(c) provides that any person

required to test may apply to EPA for an

exemption from that requirement.

E. Development and Adoption of Study

Plans

EPA proposed generic test

methodology requirements (generic test

standards) for various health effects in

the Federal Register of May 9, 1979 (44

FR 27334) and July 26, 1979 (44 FR

44054). In response to concerns about

rigid generic test methodology

requirements, EPA-changed its approach

31814
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

for providing test standards for TSCA

section 4 test rules and issued generic

test methodology guidelines to replace

previously proposed generic test

methodology requirements. (See the

Federal Register of March 26, 1982; 47

FR 13012.) The Health Effects Guidelines

have been published by the National

Technical Information Service (NTIS)

under publication number PB 82-232984.

Good Laboratory Practice (GLP)

standards will continue to be

promulgated as generic requirements.

Under the new approach, test rule

development will be a two-phase

process. In Phase I, test rules will be

promulgated for individual chemicals,

specifying the health or environmental

effects characteristics for which test

data are to be developed and the

reporting requirements. In Phase II,

following promulgation of a test rule,

those persons subject to the rule will be

required to develop study plans for the

development of data pertaining to the

effects and chara cteristics specified in

the rule. For guidance in preparing study

plans, it is recommended that the TSCA

Health Effects Test Guidelines,

published by NTIS (PS 82-232984), be

consulted. Additional guidance may be

obtained from the Organization for

Economic Cooperation and

Development (OECD) Test Guidelines

and the Federal Insecticide, Fungicide,

and Rodenticide Act (FIFRA) Pesticide

Registration Guidelines; Proposed Data

Requirements for Hazard Evaluation:

Human and Domestic Animals,

published by NTIS under publication

number PB 83-153916.

Sponsors must submit their study

plans to EPA within 90 days from the

effective date of the test rule. After an

opportunity for public comment, EPA

will issue a final rule adopting the study

plans as proposed or modified. The

approved and adopted study plans will

become the enforceable test

requirements and will serve as the

chemical specific test standards for the

test rule. Testing will also be subject to

EPA's generic GLP standards.

Modification to the adopted study plans

can be made only with EPA approval.

EPA intends to issue a procedural rule

which will set out the details of the twophase rulemaking process. That

procedural rule will apply to the test

rule for cresols and all other test rules.

Information on this proposed procedure

appears in the July 18, 1980 Federal

Register (45 FR 48512), which describes

the proposed exemption policy and

procedures, in March 26, 1982 Federal

Register (47 FR 10312) which provides

the policy statement on the test rules

development process and in the

proposed test rule for

diethylenetriamine, see the April 29,

1982 Federal Register (47 FR 18390). The

final procedural rule will be issued

before the cresols rule is promulgated.If

there are significant changes in the final

procedural rule, EPA may allow a short

period of supplementary comment on

the cresols proposal.

For the purposes of announcing the

carcinogenicity test if it is needed, the

Agency will publish an announcement in

the Federal Register announcing the

receipt of the mutagenicity data, the

results of the testing and the need for

the carcinogenicity testing, and the

particular test substance. This Notice

will therl start the portion of the rule

requiring carcinogenicity testing.

Persons subject to the rule will follow

the existing mechanisms for submission

of study plans within the allowed time.

EPA has been reevaluating this twophase rulemaking process with a view to

improving its efficiency. The Agency is

considering a modification as follows.

EPA would conduct its rulemaking in a

single phase. The proposed test rule

would contain all the necessary

elements: The basis for the testing

decision, who must test, the tests to be

performed, and the test standards which

would apply to the specific tests. After

receiving comments on all aspects of the

rule, EPA would promulgate the final

rule. Once the final rule was in effect,

manufacturers and processors subject to

the rule would be required to announce

their intention to test or apply for

exemption.

The key difference between this

modified approach and current twophase approach is that the protocols

which would become the test standards

for the required tests would be proposed

by EPA in phase I rather than being

submitted by test sponsors in phase II.

EPA believes such a change would be

appropriate in light of its experience in

rulemaking under section 4 and would

be likely to speed the process for

adopting test rules. To implement this

approach EPA is considering proposing

that testers be able to choose to perform

the required tests under any of the

appropriate protocols in the FIFRA

guidelines, OECD guidelines, and TSCA

.guidelines. During the comment period,

interested persons would be able to

comnuent on the details of these

protocols and could, if desired, propose

alternative protocols.

If EPA decides to take this modified

approach, the Agency will publish later

this year supplementary proposls for

cresols and other recent proposed test

rules setting out protocols which would

be the test standards, and seeking

comment on those protocols. EPA

believes these supplementary proposals

would result in final test rules faster

than under the current two-phase

process.

EPA solicits comments on this

proposed modification-of the test rules

process.

F. Exemption Procedures

Within 30 days after the effective date

of the final rule, each cresol

manufacturer or group of cresol

manufacturers must either (1) notify

EPA that it intends to conduct or

sponsor testing and to submit study

plans for the required tests, or (2) apply

for an exemption on a belief that testing

will be performed by others. Study plans

must be submitted 90 days after the

effective date of this rule. If no

manufacturer notifies EPA of its intent

to sponsor testing, EPA will inform

manufacturers that their exemptions will

not be granted and will give them an

opportunity to submit study plans in

compliance with this rule.

Processors of cresols will not be

required to apply for an exemption,

submit study plans or conduct testing

unless manufacturers do not submit

study plans and conduct testing, EPA

will issue a notice in the Federal

Register requiring processors to submit

notices of intent to test or apply for an

exemption, submit study plans and

conduct testing.-No exemptions will be

granted until a study plan for each of the

required tests is received and approved.

EPA has determined that the three

cresol isomers are not equivalent

because each isomer has exhibited

different chemical and toxicological

properties in previous testing. In

applying for an exemption,

manufacturers must state which isomer

or isomers they manufacture. If the

substance manufactured contains more

than one cresol isomer, then the percent

isomer composition or range of percent

isomer composition should be given.

EPA proposed exemption procedures

for section 4 test rules in the Federal

Register of July 18, 1980 (45 FR 48512).

EPA intends to issue these procedures

as a final rule shortly. If there are

significant changes in the exemption

procedures, EPA may allow a short

period of supplementary comment on

the cresols proposals.

G. Reporting Requirements

EPA is proposing that all data be

reported in accordance with the EPA

GLP Standards to appear in 40 CFR Part

792. EPA has reviewed public comment

on the proposed GLP Standards and is

now developing final GLP standards.

I I| II I I

31815
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

The final GLP Standards will apply to

this rule.

EPA is required by TSCA section

4(b)(1)(C) to specify the time period

during which persons subject to a test

rule must submit testdata. These

deadlines will be established in the

Phase II rulemaking in which study

plans are approved, or in a subsequent

FR notice if EPA changes its policy as

described in section E, above.

TSCA section 145(b) governs Agency

disclosure of all test data submitted

pursuant to section of TSCA. Upon

receipt of data required by this rule, the

Agency will publish a notice of receipt

in the Federal Register as required by

section 4(d).

L. Enforcement Provisions

Section 15(1) of TSCA makes it

unlawful for any person to fail or refuse

to comply with any rule or order issued

under section 4. Section 15(3) of TSCA

makes it unlawful for any person to fail

or refuse to (1) establish or maintain

records, (2) submit reports, notices, or

other information, or (3) permit access to

or copying of records required by the

Act or any regulation issued under

TSCA. The Agency considers that

failure to comply with any aspect of a

section 4 rule may be judged to be a violation of sections 15(1) and 15(3) of

TSCA. Additionally, TSCA section 15(4)

makes it unlawful for any person to fail

or refuse to permit entry or inspection as

required by section 11. Section 11

applies to any "establishment, facility,

or other premises in which chemical

substances or mixtures are manufactured, processed, stored; or held

before or after their distribution in

commerce * * ". The Agency considers a testing facility to be a place where-the

chemical is held or stored and,

therefore, subject to inspection.

Laboratory audits/inspections will be

conducted periodically in accordance

with the procedures outlined in TSCA

section 11 by only designated

representatives of the EPA for the

purpose of determining compliance with

any final rule for cresols. These

inspections may be conducted for

purposes which verification that testing

as begun, that schedules are being met,

that reports accurately reflect the

underlying raw data and interpretations

and evaluations thereof, and that the

studies are being conducted according

to TSCA standards and the test

standards established in the Phase II

rule.

Violators of TSCA may be subject to

criminal and civil liability. Persons who

submit materially misleading or false

information in connection with the

requirement of any provision of this rule

may be subject to penalties calculated

as if they never submitted their data.

Under the penalty provision of section

16,of TSCA, any person who violates

section 15 could be subject to a civil

penalty of up to $25,000 per day for each

violation. Each day of operation in

violation may constitute a separate

violation. (This would also be applicable

to manufacturers or processors who fail

to submit a letter of intent to perform

testing or an exemption request and who

continue manufacturing or processing

after the deadlines for such submissions.

Knowing or willful violations could lead

to the imposition of criminal penalties of

up to $25,000 for each day of violation

and imprisonment for up to one year.

Other remedies are available to EPA

under sections 7 and 17 of TSCA, such

as seeking an injunction to restrain

violations of TSCA section 4 and the

seizure of chemical substances

manufacture or processed in violation of

the rule.

Individuals, as well as corporations,

could be subject to enforcement actions.

Section 15 and 16 of TSCA apply to "any

person" who violates various provisions

of TSCA. EPA nay, at its discretion,

proceed against individuals as well as

companies themselves. In particular,

this includes individuals who report

false information or who cause it to be

reported. In addition, the submission of

false, fictitious, or fraudulent statements

is a violation under 18 U.S.C. 1001.

. Issues for Public Comment

1. The Agency has proposed a

mutagenicity testing scheme with testing

endpoints that could result in

oncogenicity bioassays for individual

cresol isomers. The Agency is requesting

comments on the tiered testing approach

for cresols, in light of the fact that the

ITC recommended carcinogenicity

testing for cresols. Does the

mutagenicity scheme, as designed, serve

the purpose of screening the three

isomers for potential oncogenicity? Does

a negative result for an isomer in the

mutagenicity screen reasonably

eliminate the need to require a full

bioassay for that isomer?

2. In previous mutagenicity assays, an equimixture of the three cresol isomers

was tested. The results of the

equimixture in the unscheduled DNA

synthesis assay, the mouse lymphoma

assay, the sister chromatid exchange

assay and the cell transformation, with

activation, assay were positive. In the

event that the cresol isomers, when

tested individually, produce negative

results in all of the assays in the full

mutagenicity testing sheme, no

oncogenicity bioassays would be

triggered for any of the cresol isomers.

The present testing scheme is designed

so that positive results in any of the six

mutagenicity assays, for any individual

isomers would trigger a 2-year

oncogenicity bioassay for that isomer.

However, the cresol mixture did

produce positive results in some of these

same tests. The Agency is proposing to

require that an isomeric mixture of

cresols be tested in a 2-year

oncogenicity bioassay if all the

individual isomers produce negative

results in the mutageicity testing

scheme.

However, cresols are commercially

processed into a wide variety of

mixtures, composed of two or three

isomers in any number of proportional

combinations with each other and with

other chemicals. Therefore, the Agency

is requesting comments on the suitable

test substance in a two-year

oncogenicity bioassay. What would be a

representational isomeric mixture which

could serve as a test substance, in the

event that none of the individual cresol

isomers trigger a two-year bioassay in

the mutagenicity testing screen?

3. The ITC recommended that cresols

-be tested for chronic effects in fish and

other aquatic organisms. The Agency

believes that there is substantial release

and exposure to the environment by

cresols, and has tentatively concluded

that there is sufficient information

which, when evaluated, allows the

Agency to reasonably predict that

cresols do not pose either an acute or a

chronic aquatic toxicity hazard. This

information upon which the evaluation

was based, includes ambient

concentrations predicted through

computer models, available acute

toxicity data, monitoring data, and

known bioconcentration, biodegradation

and persistence values.

The Agency in this proposed rule has

an acute toxicity to ambient

concentration ratio of over 10,000 at a

point approximately 30 miles

downstream of the discharge. Further,

the Agency believes that given this ratio

there is a low likelihood of chronic

effects. However, the Agency

acknowledges that it does not have an

absolute assurance that chronic toxicity

could not occur. If comment convinces

EPA that it cannot reasonably predict

that cresols will not be chronically toxic

at known or projected concentration

levels, it would require freshwater and

saltwater chronic tests on aquatic

vertebrates {rainbow, trout and Menidia

sp.) and a chronic toxicity study on

aquatic invertebrates (Daphnia sp. and

Mysid shrimp). The Agency recognizes

that data, particularly those obtained

31816
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

from predictive modeling, are open to

many different interpretations.

Therefore, the Agency is soliciting

comments on the amount and. type of -

data which the Agency should have

before making a decision that this data

allows it to reasonably predict that

effects will not occur.

III. Economic Analysis of Proposed Rule

To assess the potential economic

impact of this proposed rule, EPA has

prepared a Level I economic evaluation

that examines the costs of the required

testing and analyzes four market

characteristics of the chemical: (1)

Demand sensitivity, (2) cost

characteristics, f3) industry structure,

and (4) market expectations.

The Level I analysis of cresols, which

estimates a total testing cost of from

$800,000 for the minimum set of tests to

$5 million for the maximum set of tests,

indicates that the potential for adverse

economic effects due to the estimated

testing costs is low. This conclusion is

based on the following observations:

1. Stable or moderate growth is

expected in most markets for cresols.

2. The production of coproducts to

cresols would mitigate the potential for

impact of incremental test costs.

3. The relative magnitude of the test

cost is minor, i.e., on an annualized unit

cost basis, the upper end of the cost

range is equivalent to $0.012 per pound

for o-cresol and for the mixed cresols

(m-cresol and p-cresbl) the cost is $0.009

per pound. This represents 2.1 percent of

price for o-cresol, 0.6 percent for cresylic

acid, and 1.0 percent for all other

cresols.

4. Demand in most of the markets

does not appear very sensitive to small

increases in price.

Because the Level I analysis indicates

very little potential for an adverse

economic impact, EPA has determined

that a more comprehensive and detailed

Level II economic evaluation is not

needed for cresols.

IV. Availability of Test Facilities and

Personnel

Section 4(b)(1) requires EPA to

consider "the reasonably foreseeable

availability of the facilities and

personnel needed to perform the'testing

required under the rule." Therefore, EPA

conducted a study to assess the

availability of test facilities and

personnel to handle the additional

demand for testing services created by

section 4 test rules and test programs

negotiated with industry in place of

rulemaking. Copies of the study,

"Chemical Testing Industry- Profile of

Toxicological Testing, October, 1981,"

can be obtained from NTIS, under

publication number PB 82-140773.

On the basis of this study, the Agency

believes that there will be available

resources to perform the testing in this

proposed rule.

V. Environmental Impact Statement

EPA is not required to prepare

Environmental Impact Statements (EIS),

under the National Environmental Policy

Act (NEPA), 41 U.S.C. 4321, for test

rules. EPA has determined that

voluntary preparation of an EIS is not

appropriate for regulations issued under

section 4 of TSCA. For further

discussion of EPA's EIS policies, see the

preamble to the Agency's rules for

compliance with NEPA published in the

Federal Register of November 6, 1979 (44

FR 64174).

VI. Public Meetings

If persons wish to present comments

on this proposed rule to EPA officials

who are directly responsible for

developing the rule and supporting

analyses, EPA will hold a public meeting

on September 26, 1983, in Washington,

D.C. This meeting is scheduled after the

deadline for :submission of written

comments, so that issues raised in the

written comments can be. discussed by

EPA and the-public commenters.

Information on the exact time and place

of the meeting is available from the

TSCA Assistance 'Office (TAO), Toll

Free: (800-424-9065). In Washington,

D.C.: (554-1404). Outside the U.S.A.

(Op erator-202-554-1404).

Persons who wish to attend or present

comments at the meeting should call the

TAO by August 25, 1983. While the

meeting will be open to the public,

active participation will be limited to

those persons who arranged to present

comments and to designated EPA

participants. Attendees should call the

TAO before making travel plans

because the meeting will not be held if

members of the public do not wish to

make oral comments.

The Agency will transcribe the

meeting and include the written

transcript in the public record.

Participants are invited, but not

required, to submit copies of their

statements prior to or on the day of the

meeting. All such written materials will

become part of EPA's record for this

rulemaking.

VII. Public Record

EPA 'has established a public record

for this rulemaking docket number

[OPTS-42033] which is available for

inspection in the OPTS Reading Room

from 8:00 a.m. to 4:00 p.m., Monday

through Friday, except legal holidays in

Rm. E-107, 401 M St. SW., Washington,

D.C. This record includes the basic

information the Agency considered in

developing this proposal, and

appropriate Federal Register notices.

The Agency will supplement the record

with additional information as it is

received. This record includes the

following information:

(1) Federal Register notices pertaining

to this rule consisting of:

(a] Notice of proposed rule on cresols.

(b) Notice containing the ITC

designation of cresols to the Priority List

(42 FR 55026, October 12, 1977).

(c) Notices relating to EPA's health

effects test guidelines and EPA Good

Laboratory Practice Standards.

(d) Notice of proposed rule'on

exemption policy and procedures.

(e) Notice of proposed rulemaking on

reimbursement policy and procedures.

(2) Support Documents: consisting of:

(a) Cresols support document.

(b) Economic analysis support

document.

(c) Human exposure assessment

support document.

(3] Communications before proposal

consisting of:

(a) Written public and intra-agency

memoranda and comments.

(b) Summaries of telephone

conversations.

(c) Meeting summaries.

(d) Reports-published and

unpublished factual materials, including

contractors' reports.

VIII. Classification of Rule

Under Executive Order 12291, EPA

must judge: whether a regulation is

"Major" and, therefore, subject to the

requirement of a Regulatory Impact

Analysis. The regulation for these

chemical substances is not major

because it does not meet any of the

criteria set forth in section 1(b) of the

Order. First, the actual annual cost of

the testing prescribed for cresols is less

than $1.3 million over the testing and

reimbursement period, Second, because

the cost of the required testing will be

distributed over a large production

volume, the rule will have only very

minor effects (less than 2.1 percent a

year) on producers' costs or users' prices

for this chemical. Finally, taking into

account the nature of the market for this

substance, the low level of costs

involved, and the expected nature of the

mechanisms for sharing the costs of the

required testing, EPA concludes that

there will be no significant adverse

economic impact of any type as a result

of this rule.

This proposed regulation was

submitted to the Office of Management

31817
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

and Budget (OMB) for review as

required by Executive Order 12291. Any

comments from OMB to EPA, and any

EPA response to those comments, are

included in the public record.

IX. Regulatory Flexibility Act

Under the Regulatory Flexibility Act,

(15 U.S.C. 601, et seq., Pub. L. 96-354,

September 19, 1980), EPA is certifying

that this test rule, if promulgated, will

not have a significant impact on a

substantial number of small businesses

for the following reasons:

1. Small processors will not perform

testing themselves, or will not

participate in the organization of the

testing effort.

2. Small processors will experience

only minor costs in securing exemption

from testing requirements.

3. Small processors are unlikely to be

affected by reimbursement

requirements.

X. Paperwork Reduction Act

The Paperwork Reduction Act of 1980

(44 U.S.C. 3501 et seq.) authorizes the

Director of OMB to review certain

information collection requests by

Federal agencies. The test rule proposed

in this notice, if promulgated, could

result in the submission of several types

of information related to the required

testing, including study plans and final

reports for each test required by persons

sponsoring the tests. For the reasons set

forth in the Federal Register of June 5,

1981 (46 FR 30315), EPA believes that the

test rule contained in this notice does

not cohstitute an information collection

request as defined in the Paperwork

Reduction Act.

(Sec. 4, TSCA (Pub. L. 94-469, 90 Stat, 2003, 15

U.S.C. 2601))

List of Subjects in 40 CFR Part 799

Testing, Environmental protection,

Hazardous material, Chemicals.

Dated: June 30, 1983.

William D. Ruckelshaus,

Administrator.

PART 799-IDENTIFICATION OF

SPECIFIC CHEMICAL SUBSTANCES

TESTING REQUIREMENTS

Therefore, it is proposed that a new

§ 799.1250 be added to the proposed Part

799 to read as follows:

Subpart A-[Reserved]

Subpart B-Specific Chemical Testing

§ 799.1250 ortho-Cresol (o-cresol), metacresol (m-cresol) and para-cresol (p-cresol).

(a) Identification of test substance. (1)

o-Cresol (CAS No. 95-48-7), m-cresol

(CAS No. 108-39-4), and p-cresol (CAS

No. 106-44-5), each shall be tested in

accordance with this part.

(2) o-Cresol, m-cresol and p-cresol of

at least 99 percent purity shall be used

as the test substances in all tests.

(b) Persons required to test. (1) All

persons who manufacture or intend to

manufacture any cresol isomer or any

mixture of cresol isomers from the

effective date of this rule to the end of

the reimbursement period shall submit

study plans, as specified by 40 CFR Part

770, and conduct tests and submit data

as specified by this part.

(2) Any person subject to the

requirements of this section may apply

to EPA for an exemption from study

plan submission, testing and data

submission. No later than 30 days after

the effective date of this rule, each

manufacturer of cresols must notify EPA

by letter of an intent either to submit a

proposed study plan or to be exempted

from testing for each test or study

required in this rule.

(3) If manufacturers submit study

plans, conduct testing, and submit data

in a satisfactory manner, processors will

be given an automatic exemption by

EPA. If manufacturers fail to submit

study plans, all persons who process or

intend to process cresols from the

effective date of this rule to the end of

the reimbursement period shall be

directed in a special Federal Register

notice to submit study plans and to

conduct tests and submit data as

specified by this Part or be in violation

of this rule.

(c) Study plans-(1) Testing. Testing

shall be performed using a study plan

submitted and approved in accordance

with 40 CFR Part 770. All data must be

developed and reported in accordance

with the EPA Good Laboratory Practice

(GLP) standards in accordance with 40

CFR Part 792. Laboratories conducting

testing under this rule must adhere to

the EPA GLP standards published by the

Agency.

(2) Submission. (i) Manufacturers of

cresols who indicate they will perform

testing must submit proposed study

plans on or before 90 days after the

effective date of this rule. Only one set

of study plans should be prepared and

submitted by persons who are jointly

sponsoring testing.

(ii) If, by the date specified in

paragraph (b)(2) of this section, no letter

of intent to submit a proposed study

plan is submitted by a manufacturer for

a test or study required by this rule, EPA

will so notify the manufacturers of

cresols. If no manufacturer promptly

decides to submit a study plan and

conduct testing, EPA will publish a

Federal Register notice of this fact and

then (A) no later than 30 days after

publication of such a notice, each

processor must notify EPA by letter of

its intent either to submit a proposed

study plan for each test or study that

will not be covered by manufacturers'

study plans or to be exempted from

testing and (B) processors who indicate

they will perform testing must submit

proposed study plans on or before 90

days after publication of such a notice.

(iii) Manufacturers which do not

notify EPA of their intent, either to

submit a proposed study plan or to be

exempted from testing for each test or

study required in this rule, will be

considered in violation of the rule

beginning on the 31st day after the

effective date of the rule. Manufacturers

who indicate they will perform testing

and which do not submit proposed study

plans on or before 90 days after the

effective date of this rule will be

considered in violation of the rule

beginning on the 91st day after the

effective date of this rule. Each

processor who fails to submit a letter of

intent to submit a study plan or to

request an exemption when required

will also be considered in violation of

this rulebeginning on the 31st day after

publication of the notice described in

paragraph (c)(2)(ii) of this section.

(iv) If no study plan is proposed for

each test or study required in this rule,

every manufacturer.and every processor

of such chemicals will be in violation of

this rule beginning on the 91st day after

the publication of the notice described

in paragraph (c)(2)(ii) of this section

until such a study plan is submitted by

an appropriate sponsor.

(3) Content. (i) All study plans are

required to contain the following

information: (A) Identity of the test rule

and the specific test requirements of

that rule to be covered by the study

plan.

(B)(1) The names and addresses of the

test sponsors.

(2) The names and addresses of the

responsible administrative officials and

project manager(s) in the principal

sponsor's organization.

(3) The name, address and telephone

number of the appropriate individual(s)

for oral and written communications

with EPA.

(4)(JI The name and address of the

testing facility(ies) including responsible

administrative officials and project

manager(s) responsible for this testing.

(hi] Brief summaries of the training

and experience of each professional

involved in the study including study

director, veterinarian(s), toxicologist(s),

pathologist(s) and laboratory assistants.

(C) Identity and data on the

substances being tested including

31818
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

appropriate physical constants, spectral

data, chemical analysis and stability

under test and storage conditions.

(D) Study protocols, including

rationale for: species-strain selection;

dose selection (and supporting data);

route(s) or method(s) of exposure; a

description of diet to be used and its

source, including nutrients and

contaminants and their concentrations;

for in vitro test systems, a description of

culture medium and its source; and a

summary of expected spontaneous

chronic disease (including tumors),

genealogy, and life span.

(E) Schedule for initiation and

completion of major phases of long term

tests; schedule for submission -of interim

progress and final reports to EPA.

(ii) Information given under paragraph

(c)(3)(i)(B)(4) of this section is not

required in proposed study plans if the

information is not available at the time

of submission however, the information

must be submitted before- the initiation

of testing.

(4) Adoption Upon receipt of

proposed study plans, EPA will publish

in the Federal Register a notice

requesting comments on the ability of

the study plans to ensure that data from

the tests are reliable and adequate. EPA

will provide a 45-day comment period,

and will provide an opportunity for an oral presentation on the request of any

person. EPA may extend the comment

period if it appears from the nature of

the issues raised by EPA's review or

public comment that further comment is

warranted. Following the close of the

comment period, EPA will publish a

final rule adopting the study plans as

proposed or modified which will become

the test standards by which the study

will be conducted.

(5) Modification of study plans during

conduct of study-(i) Application. Any

test sponsor who wishes to modify the

adopted study plan for any test required

under this rule must submit an

application in accordance with this

section. Application for modification

shall be made in writing or by phone to

the Chief Test Rules Development

Branch, with written confirmation to

follow within 10 working days.

Applications must explain why the

modification is necessary.

(ii) Adoptibn. To the extend feasible,

EPA will seek comment on all

significant substantive changes in study

plans. EPA will issue a notice in the

Federal Register requesting comments

on requested modifications in

accordance with section 4(b)(5) of

TSCA. However, EPA will act on the

requested modification without seeking

public comment (A) if EPA believes that

an immediate modification to a study

plan is necessary in order to preserve

the accuracy of an on-going study or (B)

if EPA determines that a modification

clearly does not pose any significant

substantive issues. EPA will notify the

sponsor of the Agency's approval or

disapproval. When the Agency approves

a modification, it will publish a notice in

the Federal Register indicating that the

study plan has been modified.

(d) Health effects testing--1)

Subchronic inhalation toxicity--4i)

Required testing. Ninety-day subchronic

inhalation toxicity testing shall be

conducted with a-, m-, and p-cresol,

individually.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the Toxic Substances

Control Act (TSCA) Health Effects Test

Guidelines for Subchronic Exposure,

Inhalation Toxicity, published by the

National Technical Information Service

(NITS) under publication number PB-82-

232984, be consulted. Additional

guidance may be obtained from the

organization for Economic Cooperation

and Development (OECD) Test

Guidelines for Health Effects and the

Federal Insecticide. Fungicide, and

Rodenticide Act (FIFRA) Pesticide

Registration Guidelines; Proposed Data

Requirements for Hazard Evaluation:

Human and Domestic Animals,

published by NTIS under publication

number PB 83-153916.

(2) Mutagenic effects-Chromosomal

aberrations-(i) Required testing.-(A)

In vitro cytogenetic§ tests shall be

conducted with o-, m- and p-cresol,

individually. .

(B) An in viva cytogenetics test shall

be conducted for each isomer which

produces a -negative result in the in vitro

cytogenetics test.

(C) A dominant lethal assay shall be

conducted for each isomer which

produces a positive result in either the

in vitro or the in viva cytogenetics test.

(D) A heritable translocation assay

shall be conducted with each isomer

which produces a positive result in the

dominant lethal assay.

(E) Further testing for chromosomal

aberrations is not required for any

isomer which produces a negative result

in the in viva cytogenetics test or the

dominant lethal assay.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for

Chromosomal Effects, published by

NTIS (PB 82-232984), be consulted.

Additional guidance ntay be obtained

from the OECD Test Guidelines for

Genetic Toxicology, and the FIFRA

Pesticide Registration Guidelines;

Proposed Data Requirements for Hazard

Evaluation: Human and Domestic

Animals, published by NTIS (PB 82-

153916).

(3) Mutagenic effects-Gene

Mutation-(i) Required testing. {A) a

DNA damage assay shall be conducted

with m- cresol only.

'(B) Sister chromatid exchange (SCE)

assays shall be conducted with m- and

p-cresol, individually.

(C) Gene mutation in cells in culture

assays shall be conducted with m- and

p-cresol, individually.

,(D) A second gene mutation in cells in

culture assay, using a different cell line

from-that used in the first assay, shall be

conducted for each isomer which

produces a negative result in the first

gene mutation in cells in culture assay,

specified by paragraph (d)(3)(D) of this

section, coupled with positive results in

both the DNA damage and SCE assays.

(E) a- and p-Cresol shall be tested in a

Drosophila sex-linked recessive lethal

(SLRL) test. A Drosophip SLRL test'also

shall be conducted for m-cresol if it

produces a positive result in the DNA

damage assay, SCE assay or either gene

mutation in cells in culture assay. '

(F) A mouse specific locus assay shall

be conducted with each isomer which

produces a positive result in the

Drosophila SLRL.

(G) Further testing for gene mutations

is not required for any isomer which

produces a negative result in the

Drosophila SLRL.

(H) Further testing for gene mutations

is not required for any isomer which

produces a negative result in the second

gene mutation in cells in culture assay.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for Gene

Mutations and DNA Effects, published

by NTIS (PB 82-232984), be consulted.

Additional guidance may be obtained

from the OECD Test Guidelines for

Genetic Toxicology and the FIFRA

Pesticide Registration Guidelines;

Proposed Data Requirements for Hazard

Evaluation: Human and Domestic

Animals, published by NTIS (PB 83-

153916).

(4) Mutagenic Effects-Cellular

Transformation-(i Required testing.

(A) Balb/c 3T3 cellular transformation

tests performed without metabolic

activation shall be conducted with mand p-cresol, individually.

(B)(1) o-Cresol shall be tested in the

cellular transformation test with

activation. A Balb/c 3T3 cellular

transformation test with metabolic

activation shall be conducted with each

isomer which produces a negative result

31819
Federal Register / Vol. 48, No. 133 / Monday, July 11, 1983 / Proposed Rules

in the cellular transformation test

without activation.

(2) If the method of metabolic

activation in the cell transformation

assay with activation, for the individual

cresol isomers, is by feeder layers using

rat hepatocytes, then an equimixture of

the three isomers shall also be tested

under these conditions.

(C) A confirmatory tumor formation in

vivo assay shall be performed with each

isomer which produces a positive result

in the cellular transformation test

without activation or with activation.

(D) Further testing for cell

transformations is not necessary for any

isomer which produces a negative result

in the cellular transformation test with

activation or in the confirmatory tumor

formation in vivo assay.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the following paper

be consulted: Heidelberger, et al. 1983.

Cell Transformption by Chemical

Agents; A Review and Analysis of the

Literature; A Report of the USEPA's

Gene-Tox Program. Mutation Research

Vol. 114, pp. 283-385.

(5) Carcinogenicity-(i) Required

testing. A two-year oncogenicity

bioassay shall be conducted with each

isomer which produces a positive result

in any one of the following tests: in vitro

cytogenetics test, in viva cytogenetiis

test, first gene mutation in cells in

culture assay, second gene mutation in

cells in culture assay, Drosophila SLRL

and cell transformation confirmatory

tumor formation in vivo tests. A twoyear oncogenicity bioassay shall be

conducted with a mixture of o-, m-, and

p-cresol, if after the completion of the

entire mutagenicity test battery, each of

the three isomers produce only negative

results, thereby not triggering any 2-year

bioassays for individual isomers.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Guidelines for Chronic

Exposure-Oncogenicity, published by

NTIS (PB 82-232984), be consulted.

Additional guidance may be obtained

from the OECD Test Guidelines for

Health Effects, and the FIFRA Pesticide

Registration Guidelines: Proposed Data

Requirements for Hazard Evaluation:

Human and Domestic Animals,

published by NTIS (PB 83-153916).

(6) Teratogenicity-(i) Required

testing. Teratogenicity studies shall be

conducted with o-, m-, and p-cresol,

individually.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for Specific

Organ/Tissue Toxicity-Teratogenicity,

published by NTIS (PB 82-232984), be

consulted. Additional guidance may be

obtained from the OECD Test

Guidelines for Health Effects, and the

FIFRA Pesticide Registration Guidelines;

Proposed Data Requirements for Hazard

Evaluation: Human and Domestic

Animals, published by NTIS (PB 83-

153916).

. (7) Reproductive effects-(i) Required

testing. Two-generation reproductive

effects studies shall be conducted with

a-, m-, and p-cresol, individually.

Inhalation shall be the route of

administration of the test substances in

these studies.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for Specific

Organ/Tissue Toxicity-Reproduction/

Fertility Effects, published by NTIS (PB

82-232984), be consulted. Additional

guidance may be obtained from the

FIFRA Pesticide Registration Guidelines;

Proposed Data Requirements for Hazard

Evaluation: Human and Domestic

Animals, published by NTIS (PB 83-

153916).

(8) Neurotoxicity-(i) Required

testing. The following neurotoxicity test

battery shall be performed following

subchronic inhalation exposure.

(A) A neuropathology test shall be

conducted with o-, m-, and p-cresol,

individually.

(B) A motor activity test shall be

conducted with a-, m-, and p-cresol,

individually.

(C) A functional observation battery

shall be conducted with a-, m-, andpcresol, individually.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for

Neurotoxicity, published by NTIS (PB

82-232984), be consulted. Additional

guidance may be obtained from the

FIFRA Pesticide Registration Guidelines;

Proposed Data Requirements for Hazard

Evaluation: Human and Domestic

Animals, published by NTIS (PB 83-

153916).

(9) Skin sensitization-(i) Required

testing. Skin sensitization studies shall

be conducted with a-, m-, and p-cresol,

individually.

(ii) Study plans. For guidance in

preparing study plans, it is

recommended that the TSCA Health

Effects Test Guidelines for Dermal.

Sensitization, published by NTIS (PB 82-

232984), be consulted. Additional

guidance may be obtained from the

OECD Test Guidelines for Health

Effects, and the FIFRA Pesticide

Registration Guidelines; Prop6sed Data

Requirements for Hazard Evaluation:

Human and Domestic Animals,

published by NTIS (PB 83-153916).

[FR Doc. 83-18570 Filed 7-8-83; 8:45 am]

BILLING CODE 6560-50-M

31820