### 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 ofthe Toxic Substances Control Act (TSCA), EPA is proposing that manufacturers and processors ofcresols test these chemicals for carcinogenicity, mutagenicity, teratogenicity, reproductive effects, neurotoxicity, skin sensitization and subchronic toxicity. The testing being proposed will be performed according t6protocols adopted by theAgency. 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 ofcresols

as priority candidates fortesting. DATES: Submit written comments on or before September 9, 1983. Ifpersons 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 ofthis preamble. ADDRESS: Submit written comments in triplicate to: TSCA PublicInformation Office (TS-793), Office ofPesticide 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) ofTSCA (Pub.L. 94-469, 90 Stat. 2003 etseq.;15 U.S.C. 2601 et seq.) established an Interagency Testing Committee (ITO) to recommend to EPA

a list ofchemicals to be considered for testing under section 4(a) ofthe Act. The ITC iay designate substances on the list for priority consideration for requiring testing by EPA.

The ITC designated cresols for priority consideration inits 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. TheITC 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 ofcresols 

### produced in the United States. Itwas estimated in the ITC's report that the U.S.production ofcresols in 1975 was about90 million pounds. The ITC also reported an annual release rate of approximately 45million pounds. In addition,the ITC was concerned that themanufacture and use ofcresolcontaining products could result in substantial occupational exposure and 

### high general population exposure.

Under section 4(a)(1) ofTSCA, EPA mustrequire testing ofa chemical substance to develop health or environmental data ifthe Agency finds that:

(A) (i) the manufacture, distribution in commerce, processing, use, or disposal of achemical substance or mixture, or that any cohbination of such activities, may present an unreasonable risk ofinjury tohealth 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 suchsubstance 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- ablybe 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 ofevidence approach in making a section 4(a)(1)(A)(i) finding in which both exposure and toxicity information are considered tomake the finding that the chemical may present an unreasonable *risk.For the section 4(a)(1)(B)(i) finding, EPA considers onlyproduction, exposure and release information to determine ifthere 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 ifexisting 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 testingwhich 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'inEPA's first and second proposed testrules as published in the Federal Register ofJuly 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 bymanufacturers of cresols under the TSCA section 8(a) Preliminary Assessment Information Rule (40 CFR Part 712]; health and safety studies 

### submitted bythe 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 

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described in thispreamble and the accompanying technical support document,EPA isproposing 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 notbe required. However, due to the absence ofchronic toxicity data for fish and invertebrates in freshwater and saltwater systems, EPA is soliciting comments on the needfor additional environmental effects testing.By these actions, EPA is responding to theITC's designation of cresols fortesting consideration.
II.Cresols
A. Profile

Cresols (C 7

### 1-IsO) is a chemical category consisting ofthree cresol isomers; ortho-cresol(o-cresol),metacresol (m-cresol), andpars-cresol(pcresol). Cresols arecommercially available as individual isomers oras mixtures. Approximately, 172-200 million pounds ofcresols are either produced in orimported into theUnited States each year.The EPAToxic Substances Inventory records that approximately 72million pounds of0- cresol; 32million pounds ofm-cresol and62 million pounds ofp-cresol were produced in the United States in 1977.

Cresols are used as wire enamel solvents and as organic intermediates in the manufacture ofphenolic resins and phosphate esters. Additional usesof either individual isomers or mixtures are in the production ofseveral herbicides,

as cleaning compounds and disinfectants, and in ore flotation.

B.Findings

The EPA is basing its proposed testing

onthe authority ofsection 4(a)(1)(B) of TSCA. Additionally, for mutagenicity and oncogenicity, theAgency is basing this proposal on the authority ofsection 4(a)(1)(A).

EPA finds that each of thethree 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 ofthis exposure in the areas of carcinogenic, mutagenic, teratogenic, reproductive, neurotoxic, skin sensitivity, and subchronic health effects.These findings are based onthe 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 ofcresols is estimated to be approximately 169 million pounds, with another 17 

### million pounds impbrted into theUnited States each year.Each ofthe three cresol isomers isindividually produced in substantial'quantities. Ofthe total 169 million pounds produced domestically, 43 percent iso-cresol, 37 percent ispcresol 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 ofthese citedhuman health effects fromwhich 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 willresult in a loss to society ofthe benefits of cresols because theAgency's economic evaluation has shown that the economic impact oftesting these substances willbe minimal.

- In addition, EPA has found that (a) there is evidence ofpotential 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 ofcresols 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 testing EPA will determine i testing is needed based upon public comments.

In addition, the Agency has concluded that thefollowing 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 skincorrosivity. The Agency has also concluded that available information is sufficient to evaluate the chemical fate and bioconcentration potential ofcresols, andtherefore no further testing in these areas is being proposed at this time.

With respect to environmental
concerns, theAgency finds that the release of cresols to the environment is high. About 3.5 million pounds per year

are released to the atmosphere, while theestimated annualrelease ofcresols

as solid wastes is 4.2million pounds. The aqueous compartment mayreceive

asmuch as 11.2million pounds per year from dispersed useofcleaning compounds. It is estimated that about 80 percent ofthat volume is discharged to sewage treatment plants and willbe biodegraded resulting in an expected annual release ofas much as 2.8 million pounds ofcresols to naturalwaters.

While there is no existing chronic aquatic effects data forcresols, the Agency believes that information exists which allows EPA to reasonably predict that exposure ofaqdatic organisms to cresols should not cause chroniceffects. Therefore, the Agency has made a preliminaryjudgment that no additional environmental effects testing is needed atthis time. Thisjudgment is based on monitoring informationwhich indicates .thatthe ambient concentrations of cresols found in aquatic systems are expected to be minimal and will not be acutely toxic to aquatic organisms based on existingdata foracute effects. In addition, analyses have been conducted for cresols usingEPA's Exposure Analsysis Modeling Systems (EXAMS) and the Environmental Partitioning Model (ENPART). The results ofEXAMS andENPART, 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 ofdischarge, 0.0014 mg/L-five miles frompoint of discharge, and finally 0.00094 mg/L--30 milesfrom point ofdischarge. These numbers reflect the concentration levels that would be expected in the winter months, when microbial degradation rates would be thelowest, and with maximum effluent discharge rates.

Therefore, while the ITC recommended testingfor environmental effects, theAgency'may be ableto reasonably predict that levels ofcresols 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 willbe 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 beinstrumental in assisting the Agency in evaluating its decision not to propose environmental effects testing for cresols. If, after thepublic comments

are reviewed and evaluated, and the Agency is convinced that itspreliminary decision is inappropriate forcresols, thexi the Agency will require, in the final rule for cresols, that environmental effects testing beperformed.

In that event, the environmental effects testing shall be performed for the purpose ofdeveloping data on the chronic toxicity ofcresols 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 inrainbow trout, freshwater invertebrate chronic test inDaphniasp., saltwater vertebrate early life stage in Menidia sp., and saltwater invertebrate chronic inMysid 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 ofcresols to the soil, thisroute ofenvironmental
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 topersist in the atmosphere because (1)cresols have low estimated half-lives ofless than 1 day; (2) they are sensitive to photolysis; and (3)the water solubility ofcresols may be expected to

cause transport ofcresols 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 willbe tested in the subchronic toxicity, teratogenicity, reproductive effects, neurotoxicity, and skin sensitization studies.However, some ofthe cresol isomers have previously been tested in individual mutagenicity tests included in theproposed battery.Therefore, in some instances, not alloftheisomers will be tested in each mutagenicity test.The test substance(s) in the oncogenicity bioassays willbe determined from the results obtained in theproposed mutagenicity test battery asfurther explained in section 7.4ofthe Cresols Support Document.

Each isomer has exhibited different chemical and toxicological properties in previous testing. EPAhas determined that because ofthese 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 tobe the test substance in theprescribed 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 hasbeen proposed for cresols, with testing endpoints that could result in oncogenicity bioassays for individual cresol isomers. This proposed tiered mutagenicity testing scheme hasbeen designed specifically for cresols. Ithas been conceived to

serve both as an indicator ofmutagenic 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, EPAfinds that the proposed mutagenicity testing scheme is

an appropriate and scientifically valid first testingtier 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 ofthe entire mutagenicity testbattery, each of the three cresol isomers produce only negative results, thereby not triggering any 2-year bioassays, then a mixture ofthe three isomers shall be tested in a full 2-year oncogenicity bioassay. Ifthe mutagenicity tests on individual isomers

are negative, the rulewill 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 isomericmixture 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 ofthe individual isomers, the isomers will be initially screened as the potential bioassay test substances, prior to any testing ofan isomeric mixture.

D.Persons Requiredto Test

Section4(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 ifthe findings are based on manufacturing, ("manufacture" is defined in section 3(7) ofTSCA to include "import"). Processors are required to test ifthe findings are based on processing. Both manufacturers and processors are required to test ifthe exposures giving rise to the potential risk occur during

use, distribution, or disposal. Because EPA has found that the manufacturing, processing, and use ofcresols give rise
to exposures that may lead to an unreasonable risk, EPAis proposing that
persons who manufacture or process, or who intend to manufacture orprocess these chemicals at any time from the effective date ofthis test rule to the end of the reimbursement period be subject
to the rule. The end ofthe reimbursement period, ordinarily willbe 5years 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 rulemust individually conduct testing. Section 4(b)(3)(A) ofTSCA provides that EPA permit two or more manufacturers or processors who are subject to a testrule
to designate one such person ora 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.DevelopmentandAdoption of Study Plans

EPAproposed generic test methodology requirements (generic test standards) for various health effects in the Federal Register ofMay 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 

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forproviding test standards for TSCA 

### section 4 test rules and issued generic test methodology guidelines to replace previously proposed generic test methodology requirements. (Seethe Federal Register ofMarch 26, 1982;47 

### FR 13012.) The Health Effects Guidelines have beenpublished bythe 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 forindividual chemicals, specifying thehealth orenvironmental effects characteristics for which test data are to be developed and the reporting requirements. InPhase II, following promulgation ofa test rule, those persons subject to therule willbe required to develop study plans forthe development ofdata pertaining to the effects and characteristics specified in therule. 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 forHazard Evaluation: Human and Domestic Animals, published byNTIS under publication number PB 83-153916.

Sponsors must submit their study 

### plans to EPA within90 days from the effective dateofthetest rule. After an opportunity forpublic comment, EPA will issue a final rule adopting the study plans asproposed 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 ofthe 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 ofannouncing the carcinogenicity test ifit is needed, the Agency will publish an announcement in the Federal Register announcing the receipt of the mutagenicity data, the results ofthe testing and the need for the carcinogenicity testing, and the particular test substance. This Notice will therl start the portion ofthe rule requiring carcinogenicity testing. Persons subject to therule will follow the existing mechanisms for submission ofstudy 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, thetests tobe performed, and the test standards which would apply to the specific tests. After receiving comments on all aspects ofthe rule, EPA would promulgate the final rule. Once the final rule was in effect, manufacturers and processors subject to therule would be required to announce theirintention to test orapply 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 Irather than being submitted by test sponsors in phase II. EPA believes such a change would be appropriate in light ofits experience in rulemaking under section 4 and would be likely to speed theprocess 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 ofthe 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 ofthese protocols and could, ifdesired, propose alternative protocols.

IfEPA 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.ExemptionProcedures

Within 30 days after the effective date ofthe final rule, each cresol manufacturer or group ofcresol manufacturers must either (1)notify EPA that itintends to conduct or sponsor testing and to submit study plans forthe required tests, or (2) apply foran exemption on a beliefthat testing will be performed by others. Study plans
mustbe submitted 90 days after the effective date of thisrule. Ifno manufacturer notifiesEPA ofits intent
to sponsor testing, EPAwill 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 ofcresols 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 ofthe 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. Ifthe substance manufactured contains more than one cresol isomer, then the percent isomer composition or range ofpercent isomer composition should be given.

EPA proposed exemption procedures for section 4 testrules in the Federal Register ofJuly 18, 1980 (45FR 48512). EPA intends to issue these procedures

as a final rule shortly. Ifthere are significant changes in the exemption procedures, EPA may allow a short period ofsupplementary comment on the cresols proposals.

G. ReportingRequirements

EPA is proposing that all data be reported in accordance with the EPA GLP Standards to appear in 40 CFR Part 792. EPAhas reviewed public comment

on theproposed GLP Standards and is

now developing final GLP standards. I I| II I I 31815

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The final GLP Standards will apply to this rule.

EPA is required byTSCA section 4(b)(1)(C) to specify thetime 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 ifEPA changes its policy as described in section E, above.

TSCA section 145(b) governs Agency disclosure ofall test data submitted pursuant to section ofTSCA. Upon receipt ofdata required by this rule, the Agency will publish a notice ofreceipt in the Federal Register as required by section 4(d).

L. EnforcementProvisions

Section 15(1) ofTSCA makesit unlawful for any person to fail or refuse to comply with any rule ororder issued under section 4. Section 15(3) ofTSCA 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 ofrecords required by the Act or any regulation issuedunder TSCA. The Agency considers that failure to comply with any aspect ofa section 4 rulemay be judged to be a violation ofsections 15(1) and 15(3) of TSCA.

Additionally, TSCA section 15(4) makes it unlawful forany 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 ormixtures 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 isheld 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 ofthe EPA for the
purpose ofdetermining 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 ofTSCA may be subject to criminal and civil liability. Persons who submit materially misleading or false information in connection with the requirement ofany provision ofthis rule may be subject to penalties calculated

as ifthey 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 ofup to $25,000 per day for each violation. Each day of operation in violation may constitute a separate violation. (Thiswould also be applicable
to manufacturers orprocessors who fail
to submit a letter ofintent to perform testing oran exemptionrequest and who continue manufacturing or processing after the deadlines for such submissions. Knowing or willful violations could lead
to the imposition ofcriminal penalties of
up to $25,000 for each day ofviolation and imprisonment for up to one year. Other remedies are available to EPA under sections 7 and 17 ofTSCA, such

as seeking an injunction to restrain violations ofTSCA 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 ofTSCA. EPA nay,at its discretion, proceed against individuals as well as companies themselves. In particular, this includes individuals who report false information orwho cause it to be reported. In addition, the submission of false, fictitious, orfraudulent statements is a violation under 18 U.S.C. 1001.

. Issues forPublicComment
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 ofthe fact that the ITCrecommended carcinogenicity testing for cresols. Does the mutagenicity scheme, as designed, serve the purpose ofscreening the three isomers forpotential 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 ofthe three cresol isomers

was tested. The results ofthe 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. Inthe
event that the cresol isomers, when tested individually, produce negative results in all ofthe assays in the full mutagenicity testing sheme, no oncogenicity bioassays would be triggered for any ofthe cresol isomers. 

### The present testing scheme isdesigned

so that positive results in any ofthe six mutagenicity assays, for any individual isomers would trigger a 2-year oncogenicity bioassay for that isomer. However, thecresol mixture did produce positive results in some ofthese

same tests.TheAgency is proposing to require that an isomeric mixture of cresols be tested in a 2-year oncogenicity bioassay if allthe individual isomers producenegative results in themutageicity testing scheme.

However, cresols are commercially processed into a wide variety of mixtures, composed oftwo or three isomers in anynumber ofproportional combinations with each other andwith other chemicals. Therefore, the Agency is requesting comments onthe suitable
test substance in atwo-year oncogenicity bioassay. What would be a representational isomeric mixture which could serve as a test substance,in the event that none ofthe individual cresol isomers trigger atwo-year bioassay in the mutagenicity testing screen?

3.The ITC recommended that cresols -betested for chronic effects in fish and other aquatic organisms. TheAgency believes that there is substantial release and exposure to the environment by cresols, andhas tentatively concluded that there is sufficient information which, when evaluated, allows the Agency to reasonably predict that cresols do notpose either an acute ora chronic aquatic toxicityhazard. This information upon which theevaluation

wasbased, includes ambient concentrations predicted through computermodels, available acute toxicitydata, monitoring data, and knownbioconcentration, 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 ofthe discharge. Further, the Agency believes that given this ratio there is a low likelihood ofchronic effects. However, the Agency acknowledges that it does nothave an absolute assurance that chronic toxicity could not occur.Ifcomment convinces EPA that it cannotreasonably predict that cresols will notbe chronically toxic at known or projected concentration levels, itwould require freshwater and saltwater chronic tests on aquatic vertebrates {rainbow,trout andMenidia sp.) and a chronic toxicity study on aquatic invertebrates (Daphnia sp. and Mysid shrimp). The Agency recognizes that data, particularly those obtained 

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## / 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 ofProposed Rule

To assess the potential economic impact ofthis proposed rule, EPA has prepared a Level Ieconomic evaluation that examines the costs ofthe required testing and analyzes fourmarket characteristics ofthe chemical: (1) Demand sensitivity, (2)cost characteristics, f3) industry structure, and (4) market expectations.

The Level Ianalysis of cresols, which estimates a total testing cost offrom $800,000 for the minimum set oftests 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 forcresols.

2.The production ofcoproducts to cresols would mitigate thepotential for impact ofincremental test costs.

3.The relative magnitude of thetest
cost is minor, i.e., on an annualized unit
cost basis, the upper end ofthe cost range is equivalent to$0.012 perpound 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 foro-cresol, 0.6 percent for cresylic acid, and 1.0 percent for all other cresols.

4. Demand in most ofthe 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 forcresols.

IV. Availability ofTest Facilities and Personnel

Section 4(b)(1) requires EPA to consider "the reasonably foreseeable availability ofthe facilities and personnel needed to perform the'testing required under the rule." Therefore, EPA conducted a study to assess the availability oftest facilities and personnel tohandle the additional demand fortesting services created by section 4 test rules and test programs negotiated with industry inplace 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 thatthere will be available

resources to perform the testingin 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, fortest rules. EPA has determined that voluntary preparation ofan EIS isnot appropriate forregulations issued under section 4 ofTSCA. Forfurther discussion ofEPA's EIS policies, see the preamble to theAgency's rules for compliance with NEPA published in the Federal Register ofNovember 6, 1979 (44 FR 64174).

VI. Public Meetings

Ifpersons wish to present comments

on thisproposed rule toEPA 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 ofwritten comments, so thatissues 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. (Operator-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 thepublic do not wish to make oral comments.

The Agency will transcribe the meeting and include the written transcript in thepublic record. Participants are invited, but not required, to submit copiesof their
statements priorto oron the day ofthe meeting. All such written materials will become part ofEPA'srecord for this rulemaking.

VII. PublicRecord

EPA 'hasestablished a public record forthis rulemaking docket number [OPTS-42033] which is available for inspection in the OPTS Reading Room from 8:00a.m. to 4:00 p.m., Monday through Friday, except legal holidays in Rm.E-107, 401 M St. SW., Washington, 

### D.C. Thisrecord includes thebasic information the Agency considered in developing this proposal, and appropriate Federal Register notices. TheAgency will supplement therecord with additional information as it is received. This record includes the following information:

(1)FederalRegister notices pertaining to this rule consisting of:

(a] Notice ofproposed rule on cresols. (b)Notice containing the ITC designation ofcresols to thePriority List (42 FR 55026, October 12, 1977).

(c)Notices relating to EPA's health effects testguidelines and EPA Good Laboratory Practice Standards.

(d) Notice ofproposed rule'on exemption policy and procedures.

(e)Notice ofproposed 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 oftelephone conversations.

(c)Meeting summaries. (d)Reports-published and unpublished factual materials, including contractors' reports.
VIII. Classification ofRule

UnderExecutive Order 12291, EPA mustjudge:whether a regulation is "Major" and, therefore, subject to the requirement ofa Regulatory Impact Analysis. Theregulation for these chemical substances is notmajor because it does notmeet any ofthe criteria setforth in section 1(b) ofthe Order. First,the actual annual costof thetesting prescribed for cresols is less than$1.3 million over the testingand reimbursement period, Second,because the costofthe required testing willbe distributed over a large production volume, therule willhave only very minor effects (lessthan 2.1 percent a year)onproducers' costs or users' prices for this chemical. Finally,taking into account the nature ofthe market for this substance, thelow level of costs involved, and the expected nature of the mechanisms for sharing the costs ofthe required testing, EPA concludes that there willbe no significant adverse economicimpact ofany type as a result ofthisrule.

This proposed regulation was submitted to theOffice ofManagement 31817

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

and Budget (OMB) forreview 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, (15U.S.C. 601, etseq., Pub. L.96-354, September 19, 1980), EPA is certifying that this test rule, ifpromulgated, will
not have a significant impact on a substantial number of small businesses forthe following reasons:

1.Small processors will not perform testing themselves, or will not participate in the organization ofthe testing effort.

2.Small processors will experience only minor costs in securing exemption from testing requirements.

3.Small processors are unlikely tobe affected by reimbursement requirements.

X. Paperwork Reduction Act

The Paperwork Reduction Act of1980 (44 U.S.C. 3501 etseq.) authorizes the Director ofOMB to review certain information collection requests by Federal agencies. The test rule proposed in this notice, ifpromulgated, could result in the submission ofseveral types of information related to the required testing, including study plans and final reports for each testrequired by persons sponsoring the tests. Forthe reasons set forth in the Federal Register ofJune 5, 1981 (46 FR 30315), EPA believes that the
testrule 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-SpecificChemical Testing §799.1250 ortho-Cresol (o-cresol), metacresol (m-cresol) and para-cresol (p-cresol).

(a) Identificationoftestsubstance.(1) o-Cresol (CAS No. 95-48-7), m-cresol (CAS No. 108-39-4), andp-cresol (CAS No. 106-44-5), each shall be tested in accordance with this part.

(2) o-Cresol, m-cresol andp-cresol of
at least 99 percent purity shall be used

as the test substances in all tests.

(b) Personsrequired to test.(1)All
persons who manufacture orintend to manufacture any cresol isomer or any mixture of cresol isomers from the effective date ofthis 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 ofthis 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 ofthis rule, each manufacturer of cresols must notify EPA by letter ofan intent either to submit a proposed study plan or to be exempted from testing for each test or study required in thisrule.

(3)If manufacturers submit study plans, conduct testing, and submit data in a satisfactory manner, processors will be given an automatic exemption by EPA. Ifmanufacturers fail to submit study plans, all persons who process or intend to process cresols from the effective date ofthis 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 thisPart or be in violation of thisrule.

(c) Studyplans-(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 theEPA 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 ofstudy plans should be prepared and submitted bypersons who are jointly sponsoring testing.

(ii) If, by the date specified in paragraph (b)(2) ofthis 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. Ifno manufacturer promptly decides to submit a study plan and conduct testing, EPAwill publish a Federal Register notice ofthis 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 willperform testing must submit proposed study plans on orbefore 90 days after publication ofsuch a notice.

(iii) Manufacturers which do not notify EPA oftheir intent, either to submit a proposed study plan or to be exempted from testing for each test or study required in thisrule, will be considered in violation ofthe rule beginning on the 31st day after the effective date ofthe rule. Manufacturers who indicate they will perform testing and which do not submit proposed study plans on orbefore 90 days after the effective date of thisrule will be considered in violation ofthe rule beginning on the 91st day after the effective date of thisrule. 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 ofthe notice described in paragraph (c)(2)(ii) ofthis section.

(iv) Ifno 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 thisrule 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 testrequirements of that rule to be covered by the study plan.

(B)(1) The names and addresses ofthe
test sponsors.

(2)The names and addresses of the responsible administrative officials and project manager(s) in theprincipal 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 ofthe testing facility(ies) including responsible administrative officials and project manager(s) responsible for this testing.

(hi] Briefsummaries ofthe training and experience ofeach 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 

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## / 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) ofexposure; a description ofdiet to be used and its
source, including nutrients and contaminants and their concentrations; for in vitrotest systems, a description of culture medium and its source; and a summary ofexpected spontaneous chronic disease (includingtumors), genealogy, and life span.

(E) Schedule for initiation and completion ofmajor phases oflong term tests; schedule for submission -of interim
progress and finalreports toEPA.

(ii)Information given under paragraph (c)(3)(i)(B)(4) ofthis section is not required in proposed study plans ifthe information isnot available at the time ofsubmission however, the information
mustbe submitted before-the initiation oftesting.

(4)Adoption Upon receipt of proposed studyplans, EPAwill 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 willprovide an opportunity for an oral presentation on the request ofany person. EPA may extend the comment period ifit appears from the nature of the issues raised byEPA'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 willbecome the test standards by which the study willbe conducted.

(5) Modificationofstudyplansduring conductofstudy-(i)Application.Any
test sponsor who wishes to modify the adopted study plan for any test required under this rulemust submit an application in accordance with this section. Application formodification shall be made inwriting orby 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) ifEPA believes that

an immediate modification to a study plan is necessary in order to preserve the accuracy ofan on-going study or (B) ifEPA determinesthat amodification clearly does not pose any significant substantive issues.EPA will notifythe
sponsor ofthe Agency's approval or disapproval. When the Agency approves

a modification, it willpublish a notice in the Federal Register indicating that the study plan has beenmodified.

(d) Healtheffects testing--1) Subchronicinhalation toxicity--4i) Requiredtesting.Ninety-day subchronic inhalation toxicity testing shall be conducted with a-,m-, and p-cresol, individually.

(ii) Studyplans.Forguidance 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 fromthe 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) Mutageniceffects-Chromosomal aberrations-(i) Requiredtesting.-(A) In vitrocytogenetic§ tests shall be conducted with o-,m- andp-cresol, individually.

.

(B) An in viva cytogenetics test shall be conducted for each isomer which produces a-negativeresult in the in vitro cytogenetics test.

(C) A dominant lethal assay shall be conducted for each isomerwhich produces a positive result in either the in vitroor 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)Studyplans.Forguidance 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 TestGuidelines for Genetic Toxicology, and the FIFRA Pesticide Registration Guidelines; Proposed Data Requirements for Hazard Evaluation: Human and Domestic Animals, published by NTIS (PB82- 153916).

(3)Mutageniceffects-Gene Mutation-(i)Requiredtesting.{A) a DNA damage assay shall be conducted with m- cresol only.

'(B) Sister chromatid exchange (SCE)
assays shall be conducted withm- and p-cresol, individually. (C) Gene mutationin cells in culture
assays shall be conducted with m- and p-cresol, individually.

,(D) A second gene mutationin 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 byparagraph (d)(3)(D) ofthis section, coupled with positive results in both the DNA damage and SCE assays.

(E)a- andp-Cresol shall be tested in a Drosophilasex-linked recessive lethal (SLRL) test. A DrosophipSLRL test'also shall be conducted form-cresol if it produces a positive result in the DNA damage assay, SCE assay oreither gene mutation in cells in culture assay. '



### (F) A mouse specific locus assay shall be conducted with each isomer which produces apositive result in the DrosophilaSLRL. (G)Further testing forgene mutations is not required for anyisomer which produces a negativeresult in the DrosophilaSLRL. (H)Further testingfor gene mutations is not required for any isomer which produces a negative result in the second
gene mutation in cells in culture assay.

(ii) Studyplans.For guidance in preparing study plans,it is recommended that theTSCA 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) MutagenicEffects-Cellular Transformation-(iRequiredtesting. (A) Balb/c 3T3 cellular transformation
tests performed without metabolic activation shall be conducted with mandp-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 

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

in the cellular transformation test without activation.

(2)

### Ifthemethod ofmetabolic activationin the cell transformation assay with activation, forthe individual cresol isomers, is by feeder layers using rathepatocytes, then an equimixture of the three isomers shall also be tested under these conditions.

(C)A confirmatory tumor formation in vivo assay shallbe 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 anegative result in the cellular transformation test with activation or in the confirmatory tumor formation in vivo assay.

(ii)Studyplans.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 ofthe Literature; A Report of theUSEPA's Gene-Tox Program.MutationResearch 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 ofthe 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 invivo tests. A twoyear oncogenicity bioassay shall be conducted with a mixture of

### o-,m-, and 

### p-cresol, ifafter the completion ofthe entire mutagenicity test battery, each of the three isomers produce only negative results, thereby not triggering any 2-year bioassays for individual isomers. (ii)Studyplans.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 (PB83-153916).

(6) Teratogenicity-(i) Required testing.Teratogenicity studies shall be conducted with 

### o-,m-, andp-cresol, individually.

(ii)Studyplans.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 (PB82-232984), 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) Reproductiveeffects-(i)Required testing.Two-generation reproductive effects studies shall be conducted with


### a-,m-, andp-cresol, individually. Inhalation shall be the route of administration ofthe test substances in these studies.

(ii) Studyplans.For guidance in preparing study plans, it is recommended that the TSCA Health Effects Test Guidelines for Specific Organ/Tissue Toxicity-Reproduction/ FertilityEffects, 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-, andp-cresol, individually.

(B) A motor activity test shall be conducted with 

### a-,m-, andp-cresol, individually.

(C) A functional observation battery shall be conducted with 

### a-,m-, andpcresol, individually.

(ii)Studyplans.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) Studyplans.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 theFIFRA Pesticide Registration Guidelines; Prop6sed Data Requirements for Hazard Evaluation: Human and Domestic Animals, published by NTIS (PB83-153916).

[FRDoc. 83-18570 Filed 7-8-83; 8:45am]
BILLING CODE 6560-50-M 

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