33400 Federal Register / Vol. 54, No. 155 / Monday, August 14, 1989 / Rules and Regulations'

ENVIRONMENTAL PROTECTION
AGENCY

40 CFR Parts 795and 799

[OPTS-42100B; FRL-3627-4]

TrIbutyl Phosphate; Final Test Rule

AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule.

SUMMARY: EPA is issuing a final testrule under section 4 of the Toxic Substances Control Act (TSCA) requiring manufacturers and processors of tributyl phosphate (TBP, CAS No. 126-73-8) to perform testing for health effects (oncogenicity, neurotoxicity, reproductive and developmental toxicity, mutagenicity, dermal sensitization, and oral/dermal pharmacokinetics), environmental effects (acute effects on algae, fish and aquatic invertebrates, and triggered chronic effects on fish and aquatic invertebrates and sediment bioassay), and chemical fate (vaporpressure, Koc, and hydrolysis rate). This rule is in response to the TSCA Interagency Testing Committee's (ITC) designation ofTBP for priority health effects, chemical fate, and environmental effects testing.
DATES: This rule shall become effective

on September 27, 1989. Forpurposes of judicial review, in accordance with 40 CFR 23.5, this rule shallbe promulgated
at 1 p.m. eastern fstandard or daylight

as appropriate) time on August 28, 1989. The incororation byreference in this rule is approved by the Director of the Federal Register as ofSeptember27, 1989.
FOR FURTHER iNFORMATION CONTACT: Michael M. Stahl, Director, TSCA Assistance Office (TS-799), Office of Toxic Substances, Room EB-44, 401 M Street SW., Washington, DC 20460, (202) 554-1404, TDD (202) 554-0551.
SUPPLEMENTARY INFORMATION: EPA is promulgating a final test rule under section 4(a) ofTSCA requiring health effects, environmental effects and chemical fate testing ofTBP.

I.Introduction

A. Test Rule Development UnderTSCA

This final rule is part of the overall implementation ofsection 4 ofTSCA (Pub. L. 94-469, 90 Stat. 2003 et seq., 15 U.S.C. 2601 et seq.), which authorizes EPA to require the development of data relevant to assessing the risk to health and the environment posed by exposure to particular chemical substances or mixtures (chemicals). Under section 4(a) ofTSCA, EPA must require testing ofa chemical to develop data ifthe Administrator makes certain findings as described in TSCA under section 4(a)(1)(A) or (B). Detailed discussions ofthe statutory section 4 findings are provided in the EPA's first and second proposed test rules published in the Federal Register's of July 18, 1980 (45FR 48510) and luneS, 1981 (46FR 30300).

B. Regulatory listory

The ITC recommended TBP with intent-to-designate in its eighteenth report published in the Federal Register ofMay 19, 1986 (51 FR 18368), and designated TBP for priority testing consideration in its nineteenth report published in the Federal Register of November 16, 1986 (51 FR 41417). In response to this designation, EPA issued

a proposed test rule in the Federal Register ofNovember 12 1987 (52 FR 43346) which would require that manufacturers and processors ofTBP test the chemical for various health and environmental effects, under sections 4(a)(1)(A) and (B) of TSCA.

II. Response to Comments

EPA received written comments on the TBP proposed test rule from the Tributyl Phosphate Task Force (TBPTF ofthe Synthetic Organic Chemical Manufacturers Association (SOCMA) on January 12, 1988 (Ref. 1). The TBPTF also requested a public meeting ontheir
comments which was held on April 7. 1988. The comments received by EPAin response to the proposed rule for TBP

are given below.
A.Exposwie
1.TBPTFexposure survey.The TBPTF commented that the exposure information available to EPA was insufficient to support a finding of significant or substantial human exposure since the data were merely suggestive. The TBPTF proposed to do

an industry-wide.survey ofU.S. sites distributing, processing, and using TSP and products containing TBP to determine the uses, use conditions, and potential worker exposure associated with TBP. EPA agreed to consider the study results in its deliberations for a final rule. TBPTF commissioned Temple, Barker, Sloane, Inc., to conduct and validate the survey. On April 7, 1988, the TBPTF presented EPA with the first part ofa report, "1987 U.S Survey ofTributyl Phosphate Users, Potential Exposure and Safety Procedures" (Ref.2). The report did not contain an estimate ofthe number ofworkers potentially exposed
to aircraft hydraulic fluid, a product that
accounts for a major part ofTBPusage (89percent by volume). After a public meeting with the TBPTF, EPA granted TBPTF a brief period to estimate the numbers and extent ofpotential worker
exposure to aircraft hydraulic fluid containing TBP from survey and additional data. On July 11, 1988, TBPTF submitted a report to EPA on estimated
exposure to TBP-containing aircraft hydraulic fluid (Ref.3).

The TBPTF reported that the greatest number ofworkers potentially exposed

was in the use ofaircraft hydraulic fluid. The three primary uses include aircraft manufacturing, hydraulic system component manufacturing, and commercial airline operations (passenger and freight). The TBPTF reported each type ofuser exposure in
terms ofestimated numbers of employees potentially exposed on an infrequent basis (less than once per week for less than one hour) and on a

more frequent or routine basis. On the basis ofconfidential discussions with
two major aircraft manufacturers, TBPTF estimates that 740 workers in this industry may be infrequently exposed to fluid, and 241 workers may be frequently exposed to hydraulic fluid containing TBP. On the basis ofsurvey responses from aircraft component manufacturers, the TBPTF estimates that 176 employees in this industry may be frequently exposed to aircraft hydraulic fluid containing TBP, and 411 employees
maybe infrequently exposed. On the basis of confidential estimates by one of the major airlines, TBPTF estimates that 2,200 employees in this industry are routinely exposed to aircraft hydraulic fluid containing TBP and approximately 43,000 aircraft mechanics at some time oould be exposed to aircraft hydraulic fluid. The activities potentially causing
exposure include: Venting ofpressurized systems at service sites, removal and repair ofcomponents, and testing and inspection ofcomponents. Aircraft manufacturers report that they require mechanics to use protective equipment (gloves, aprons, sleeve shields, goggles/ face shields).

In the survey, the other two types of hydraulic fluid users report these and other methods ofprotection. However, the survey report indicates that in practice, aircraft mechanics only take minimal precautions to prevent contact

even though they are aware ofthe irritating properties ofhydraulic fluid. Also, according to the survey, aircraft mechanics do not wear protective gloves.

Survey respondents reported that 100 distributor workers for 296 worker-hours per -yearand 200 processor workers forFederal Register 

## I Vol', 54,, No. 155, / Monday, August 14, i989 / Rules and Regulations

108,358 worker-hours per year have direct exposure to TBP.

Anestimated total of245 distributor workers (estimatedfrom survey respondents andnon-respondents) are potentially exposed for 502 workerhours per year according to the survey. An estimated total of345 processor workers (estimated from survey respondents and non-respondents) are potentially exposed for 183,382 workerhours per year.

Other uses ofTBP involve partially enclosed or open operations, and the concentration ofTBPin these products is under 10 percent Of these miscellaneous uses,paint spraying operations represent the most likely
exposure potential, but spray booths are often used and the paint is used only by original equipment manufacturers, suggesting that exposure is limited to manufacturing use.

2.EPA 'sresponseto TBPTFs
exposuresurvey.EPA reviewed the exposure survey performed by the TBPTF and finds the conclusions regarding potential occupational
exposure to TBP tobe reasonable. EPA has concerns about the completeness and accuracy of the survey but these do
not interfere with the adequacy of the study forpresent purposes (Refs. 4 and 5). The survey results simplyconfirm EPA's earlier conclusion that potential human exposure toTBP is substantial.

B. Testing

. 1. Genotoxicity. TheTBPTF commented that studies ofgene mutation in mammalian cells.in culture and in vivocytogenetics, specifically the

mouse micronucleus test, should be conducted to determine potential clastogenic effects, and that aprogram review ofthe entire genotoxicity data base should precede any considerations for further genotoxicity testing.

EPA agrees that a study ofgene mutationin somatic cells in culture is necessary as an early tier teset for gene mutation effects ofTBP. However, EPA believes that an in vitro mammalian cytogenetics test and invivo mammalian bone marrow cytogenetics chromosomal analysis test are necessary early tier tests for cytogenetics effects. EPA isreviewing the mouse micronucleus test as a potential alternative teat for cytogenetic effects in future test rules.

2. Pharmacokinetics. The TBPTF commented that the rat oral and dermal absorption, distribution and excretion pharmacokinetics, andoral metabolism studies should be performed as proposed. However, the TBPTF recommended dermal absorption testing in the pig (mini-pig or weanling swine) rather than theguinea pig,because pig skinis a better model forhuman skin than guinea pig skin.

EPA has reviewed the evidence the TBPTF has submitted to support testing the pig over the guinea pig and EPA agrees that the pig (mini-pigorweanling pig) is an acceptable substitute testing modelfor the guinea pig for dermal absoprption testing (Refa. 6 through 9).

3. Oncogenicity. The TBPTF commented that, because potential worker exposure issignificant only by the dermalroute asindicated by the exposure survey, a pilot 28-daydermal study in the ratshould be conducted first to evaluate thefeasibility of performing chronic efforts and oncogenicity studies by that route. The TBPTF believes thata decision regarding oncogenicity studies should be deferred pending results ofthe proposed pilotdermal studies and the completion ofpharmacokinetics studies.

EPA reported in theproposed rule that the available data suggest TBPmay have oncogenic potential. EPAis requiring an oncogenicity study by the oralroutebecause the comparative oral/dermalpharmacokinetics data will allow analysis of effects related to differences in route ofadministration. Protocol design fordermal bioassays present manyproblems including: Selection ofappropriate species; estimation and demonstration of absorbed versus applied dose, criteria fordefining the maximumtolerated dose, e.g., whetherbased on skin or systemic effects. EPA is assessingthe literature on this subject and has sponsored 'a workshop on dermal carcinogenesis bioassay problems and protocol development. In thenear future EPAhopes to publish a generic protocol fordermal bioassays andpublish guidelines on when testing should be done by that route.

4.Dermalsensitization. TBPTF commented that additional dermal sensitization testing is unnecessary because a mixture containing TBP has been tested in a human study and no sensitization occurred.TBPTF believes that ifTBP were a sensitizer some reaction would have occurred and results of (any)human study should take precedence over those obtained in animal (guined pig) studies (Ref 1].

EPA is requiring a dermal sensitization study because photosensitization was not evaluated in the available human study, and the exact TBP concentration inthe test mixture wasunknown and mayhave been toolow (reportedas "less thanf25 percent") to have elicited a reaction

5,Developmentaltoxicity.TBPTF comments that because the exposure survey indicates there is insignificant exposure potential for women ofchildbearing age andbecause ofirritant warning properties and low exposure levels, developmental toxicity testing should not be required.

Forpurposes ofrequiring testing under section 4ofTSCA, EPA is not, required to take into account genderspecific exposure patterns in its deliberations. EPA does not assume that gender-specific exposure patters will persist. Because there is a potential for substantial human exposure to TBP, developmental toxicity testingis required.

6.Reproductivetoxicity.TBPTF comments that reproductive testing should be triggered bymore general indications ofreproductive toxicity such

as invivo genotoxicity tests (Drosophila and in vivo cytogenetics) because there

are very low levels ofexposure ofboth males and females to TBP. In addition. two long-term studies, an 18-week study by Laham et al. and a 13-week study by FMC, showed no effect ongonadal tissues.

While EPA recognizes that there are situations where short-term tests may be appropriate to screen forreproductive effects, EPAdoes not agree that in the present situation the invivo genotoxicity tests are adequate to

screen for the reproductive toxicity of
TBP. And although the two studies mentioned by TBPTF do not show reproductive effects, they are not acequate by themselves to determine whether TBP hasreproductive toxicity. It is well documented that there are effects on reproduction that are not detectable by simplehistopathological analysis, i.e. effects on reproductive performance, hormones, outcomes of pregnancy, growth and maturation of offspring postnatally. Therefore testing specific for reproductive toxicity is required.

7. Neurotoxicity. The TBPTF suggested a tiered approach consisting ofan acute functional observational battery andmotor activity screen to be followed by a subchronic behavioral evaluation ifrequired after program reveiw. The TBPTF commented that neurotoxicity testing shouldbeby the dermal route ifthisroute proves feasible from the results ofthe 28-day study. The TBPTF believes that because available studies conclusively showthat TBP is not a delayed neurotoxicant (organophosphorus induced delayed neurotoxicity (OPIDNJisthe primary mechanism bywhich organophosphates
act directly on the nerves) a further

concern for neuropathy is unwarranted 

### 3340133402 Federal Register 

### / Vol. 54, No. 155 / Monday, August 14, 1989 / Rules and Regulations

and requirements forin situ perfusion should be removed from the test rule.

EPAdoes not agree with TBPTF's tiered approach. Both acute and subchronic tests are necessary because EPA is concerned about acute effects as well as the potential effects following repeated exposure. EPA encourages use of the relevant route ofadministration when possible. Although the dermal route of administration is theoretically acceptable, there are a number of practical problems which must be addressed before a dermal study would be acceptable. First, there must be a demonstration that a sufficient dose of the compound can be absorbed to produce neurobehavioral changes. Without such a high dose level effect, negative results would not be conclusive. Second, dermal application may interefere with satisfactory interpretation ofneurobehavioral information. Dermal application can

serve as a stress inducer and produce alterations in various neurobehavioral parameters. To account for this possible confounding effect itwould be necessary to use a positive control which can also be applied dermally (e.g., acrylamide). Because these problems have not been addressed, neurotoxicity testing by the oral route is required.

EPA believes that, although available studies indicate that under the conditions tested, TBP does not produce organophosphorus-induced delayed neuropathy (OPIDN), other available literature provides evidence of neurobehavioral changes following exposure to TBP, and a standard battery oftests is still indicated (Refs. 10 through 13).

8.Environmentaleffects.The TBPTF commented thatEPA's proposed environmental effects testing is generally reasonable and supportable. TBPTF raised the following points.First, TBPargued that the chronicityratio of 24- to 96-hour LC50 forfish and certain aquatic invertebrates (e.g., Gammorus)

or the ratio ofthe 24- to 48-hour LC50 for daphnid of2or greater is extremely stringent and shouldbe modified. Second, TBPTF believes there is no clear need forplant translocation tests because there is no or low level exposure for this environment, as TBP is shown to be readily biodegradable in the OECD screening test, by semicontinuous activated sludge, in a river die-away testand in ultimate biodegradation. Third, with respect to specific guidelines, the TBPTF believes that ascertaining whether the test material is in solution does not require analysis ofboth the total and filtered concentrations ofthe testmaterial. The concentration in only a filtered sample should be required except in the algal test, where measurements ofthe amount of test material associated with the algal cells is required. Centrifuging the samples is better because filtration may trap TBPin the filter medium. Requiring analysis ofboth total and filtered or centrifuged test medium will double analysis costs without any real need. Fourth; the time allotted (9 months) for the completion ofthe flow-through acute
tests may not be adequate. Flow-through
tests with analytical measurement of
test solutions tend to experience more problems than simple static tests; 12 months from official notification to final report would be a more reasonable estimate.

EPA does,not agree with the TBPTF that the chronicity ratio for fish and invertebrates is too stringent because historical data confirm the predictive capability ofthis decision criterion. EPA
agrees with TBPTF that the plant translocation test is unnecessary and EPAis not requiring this test because human exposure fromplant dietary uptake does not appear to be ofconcern. EPA-is considering whether it should
propose the early seedling growth test to determine the toxicity ofTBP to plants. EPA does not agree that only the filtered sample should require analysis and supports the testing guidelines which require analysis ofboth total and filtered samples. Testing both the total and filtered samples is necessary to know how much dissolved test substance is available during aquatic toxicity tests. EPA is not requiring that both the total and dissolved chemical be measured for every sample. Ifthe dissolved test substance being measured is consistently greater than or equal to 80 percent of total measured test substance, for all test substance concentrations, then it isnecessary to

measure only the dissolved or total test substance not both. EPA does not agree with TBPTF that 9 months is inadequate
to conduct acute flow-though testing because the TBPTF does not provide adequate evidence to the contrary.

C.EconomicIssues

1. Comment: The TBPTF has estimated the cost ofthe tisting program at about $2.4 million. The information to be developed by the testing program is
not a capital asset; and therefore the
cost involved must be treated as current expenses. Using the EPA estimated production volume range of6 to 9 million pounds during an approximate 2-
year test program, the cost ofthe testing proposed per pound would be $0.15 and $0.20 per pound ofTBPproduced. TBPTF does not believe this is an inconsequential amount.

Response:EPA's estimate ofthe test cost is between $1.3 million and $1.7 million. TBPTF's estimate ofthe oncogenicity testis roughly double EPA's estimate, and accounts for the largest portion of the difference. Some of the other estimates submitted by the TBPTFrange from 2to almost 10 times greater than EPA's estimates.

EPA has developed detailed test cost information for each test included in the rule. TBPTF has provided no such information nor any documentation regarding their testcost estimates. In addition, TBPTFhas not addressed the method usedby EPA to estimate test, cost or any of the detailed estimates. Without any such information, EPA
cannot address the estimates provided by TBPTF.

Also,TBPTF confuses the procedures used todetermine reimbursement for testing costs under section 4 of'TSCA with the analysis used to determine economic impacts ofthe rule. TBPTF looks at the accounting method used to pay for the costs associated with testing, while EPA's economic analysis employs
costrecovery analysis to estimate the likelihood ofadverse economic impact. In the economic analysis, test costs are annualized over the assumed market life ofthe product to estimate the amount which firms will have to increase price ofthe product to recover the costs associated with testing. This estimate of product price increase, as explained in the economic analysis, is used as an indicator ofthe potential for adverse economic impact.EPA's analysis method is fully explained in the economic analysis document accompanying theproposed rule'

2. Comment:Domestic TBP, and TBPbased end-use products, effectively compete in the international market. Aircraft hydraulic fluids containing TBP

are used by every major airline in the free world, and more than one-half of the fluid produced domestically is exported. While these fluids are currently only available from domestic
sources, excessive testing requirements and associated costs can only encourage the entry ofnon-domestic suppliers, thus placing an unfair competitive burden on domestic manufacturers and processors ofTBP.

Response:As the TBPTF has indicated, fluids containing TBP are used by every-major commercial airline in the free world and there are onlyU.S.

sources ofthese fluids. TBPTFhas not demonstrated that a price increase of1.4 percent to 2.0 percent to cover the costs oftesting will be a great enoughFederal Register / Vol. 54, No. 155 

### 1 Monday, August 14, 1989 / Rules and Regulations

incentive forcompanies outside of the U.S. to begin production ofTBP. In addition, any person who begins to import TBP from the effective date ofthe rule through thereimbursement period would also be subject to the testrule and therefore would be subject to reimbursement ofthe test costs.

3.Comnient" TBPTFcomments further that conclusions regarding the burden of testing, which are based on fixed assumptions in the inexact field of economic theory, mustbe seriously and thoroughly evaluated. The ability to pass through costs under conditions of inelastic demand and stable market conditions may be true but dramatically increased costs at only someproducers

or processors creates unstable conditions from both supply and consumption dynamics. In aworld-wide market, domestic producers and processors ofTBP could be placed at an unfair disadvantage. Even ifdomestic suppliers were able to pass through costs to domestic customers, it is less likely that such pass-through could be successful inforeign markets, putting a double burden on thedomestic marketplace. It iseconomically more prudent and more realistic to assume demand forTBP to be elastic with little probability ofincreasing price enough to

cover costs oftestingin areasonable time.These increased costs, under such assumptions, will directly impact the profitability ofTBPproduction and may ultimately eliminate one ormore producers, oreven the product, from the market.

Response:TBPTFhas not demonstrated that an increase inprice of1.4 percent to .0 percent qualifies as "dramatically increased costs". Moreover, asthe TBPTFhas indicated, there are no,foreign sources ofTBPcontaining fluids. As a result, all producers ofTBPwould incur these increased costs.EPA has not been able to identify any viable substitutes for TBP in its largest use. Producers ofTBP * should be able topass along the costof testing to all ofthese customers and not justto domestic customers.
III. Final,Test Rule

EPA is basing its final health and environmental effects testing for TBPon the authority ofsections 4(a)[1) (A)and (B) ofTSCA.
A. Fidings

Under section 4(a)}f)(A), EPA finds that the manufacturing, processing, distribution, use, and disposal ofTBPin aircraft hydraulic fluid and otheruses may present an unreasonable riskof adverse oncogenic effects,neurotoxic effects, and dermal sensitization. These findings are based on the available toxicity data discussed inUnit II ofthis preamble and in Unit II.F. ofthe preamble to the proposed rule (52 FR 43346).

Under section 4(a)l})(B), EPA finds that TBP is produced in substantial quantities and that there is ormay be substantial human exposure to TBP in its manufacture, processing, distribution.
use, and disposal. The estimated 1985 production capacity ofTBP is 6 to9 million poundsperyear (Ref. 14). Potentially 43,000 aircraft mechanics and another roughly 3000 aircraft industry employees at some time could beexposed to aircraft hydraulic fluid containing TSP (Ref.3). The exposure of mechanics is mainlydermal exposure from removing and repairing components, ventingpressurized systems at service sites, and the testing and visual andmanual inspection of components. Thereis also potential of mainly dermal exposure toTBP of approximately 500 TBPmanufacturing, processing, and distribution workers from suchoperations as handling, transfer and packaging ofproducts, equipmentrepair, cleaning equipment and spill cleanups. Thereis also potential limited dermal exposure to

users ofother TBP-containing products (lessthan 10 percent concentration representing in total 28 percent ofTBP volume) including use in original equipment, paints and coatings, inks. leather finishing, liquid fluorescent * penetrant, sewage treatment, vinyl floor finish for commercial and industrial applications, and stripping agents.

Under section 4[a)B1)fB. EPA finds that TBP is produced in substantial quantities, and that it enters or may reasonably beanticipated to enterthe environment in substantial quantities as
a result ofits manufacture, processing, distribution, use,and disposal as indicated by its presence in surface' water, sediment and groundwater. As stated in the proposed rule, TBPis expected to enter theenvironment as a result ofwastewater release from sites where itis madeorused and from leachate releases from landfills (see. Unit H.D. ofthe proposed rule). EPA believes that the low concentrations of TBP detected inorreleased to the environment at numerous and widely dispersed locations suggest that thetotal. releaseis,substantial undersection 4(a)(1)(BkofTSCA. 1.Healtheffects.EPA finds that the available data forinsufficient to reasonably determine orpredict the oncogenicity, neurotoxicity, dermal sensitization, developmental toxicity, reproductive and fertility effects, mutagenicity, and oral/dermal pharmacokinetics ofTBP resulting from exposure during manufacturing, processing, distribution, use, and disposal.EPA finds that testing is necessary to develop these data. EPA believes that the data resulting from this testing will be relevant to a determination as to whether the manufacturing, processing, distribution,
use, or disposal ofTBP does ordoes not present an unreasonable riskofinjury to human health.

2.Environmentaleffects andchemical fate.EPA believes that, for chemicals thathave substantial production and substantial environmental release, reliable data should be developed to

assess theirtoxicity andpersistence. Available data are insufficient to reasonably determine orpredict TBP's acute toxicity to algae, fish, and aquatic invertebrates, and chronic toxicity to fish and aquatic invertebrates (free swimming and in sediment). Available data are insufficient to reasonably determine or predict TBP's vapor pressure data at 250C, Koc, and hydrolysis rate. Vapor pressure data at 25"Care needed to estimate a reliable Henry's Law Constant (Hc) for TBP. Data on Koc are needed to estimate the sorption ofTBP to soil and sediments. -Finally, hydrolysis.rate data, which complement the available biodegradation data, are needed to estimate the persistence ofTPB in aquatic systems. EPA finds thattesting is necessary to develop environmental effects data and chemical fate data, and believes that the data resulting from these testrequirements will be relevant to adetermination that the manufacturing, processing, use and disposal ofTBP does or does not present

an unreasonable riskofinjury to the environment.
B.RequiredTesting, Test Standardsand ReportingRequirements

On the basis ofthesefindings EPA is requiring that chemical fate, environmental effects and health effects testingbe conducted forTBP in accordance with specific test guidelines set forthin 40 CFRparts 796, 797 and 798, or other published test methods as specified in this testrule as listed in the following table. 3340333404 Federal Register / Vol. 54, No. 155 / Monday, August 14, 1989 / Rules and Regulations

REQUIRED TESTING, TEST STANDARDS, AND REPORTING REQUIREMENTS FOR TRIBUTYL PHOSPHATE

Reporting iNueri (- Test Test standard 40 CFR citation deadline for n er
final rule1 mo) reports required

Chemical fate:
Vapor pressure....................................................................................................... § 796.1950

................................................................................ 6 0 Hydrolysis rate at 25 °C

........................................................................................ §796.3500

................................................................................ 6 0 Sediment and soil adsorption Isotherm

............................................................... §796.2750

........... ...................................... ................. 9 0 Environmental effects: Gamm arid acute toxity

........................................................................................... §795.120

................. ............................................................ 9 0 Selenastrum acute toxicity

.................................................................................... §797.1050

................................................................................ . 9 0 Rainbow trout acute toxicity

.................................................................................. §797.1400

................................................................................ 9 0 Daphnid acute toxicity

....................... ...................................................... ............. §797.1300

............................................... ........................ :

..... 9 0 Daphnid chronic toxicity

......................................................................................... §797.1330

................................................................................ 21 1 Fish early life stage
................................................................................................ §797.1600

................................................................................ 21 1 Sediment invertebrate bioassay

............................................................................ Adamset al.

(Ref. 15)

............................................................. 21 1 Health effects: Oral/dermal pharmacokinetics

.............................................................................. §798.228

................................................................................. 12 1 Oncogenicity

............................................................................................................ §798.3300

....................................... . ....................................... 53 8 Reproduction and fertility effects (oral)

............................................................... §798.4700

................................................................................. 29 4 Developm ental toxicity (oral)

................................................................................. §798.4900

................................................................................ 12 1 Dermal sensitization

............................................................................................... 0§ 798.4100

................................................................................ 6 Functional observation battery (acute and subchronic)

.................................... §798.6050

................................................................................ 18 2
Motor activity (acuteand subchronic)

................................................................. §798.6200

................................................................................ 18 2 Neuropathology

.............................................................................................. §798.6400

................................................................................ 18 2
Mammalian cells in

culture

.................................................................................... §798.5300

................................................................................ 10 1 Drosophila sex-linked recessive lethal

................................................................ §798.5275

................................................................................ 22 1 In

vitro cytogenetics

............................................................................................... §798.5375

................................................................................ 10 1 In

vivo cytogenetics

................................................................................................ §798.5385

................................................................................ 24 1
Dominant lethal ssay ........................................................................................... §798.5450

................................................................................ 36 5 Heritable translocation assay ................................................................................ §798.5460:

.............................................................................. 225 3
'Number of months after effective date, except as indicated.

2 Figure indicates the reporting deadline, in months, calculated from the date of notification of the test sponsor by certified letter or FEDERAL REGISTER notice that following public review of all the existing data for TBP, the Agency has determined that required testing must be performed.

Although the major occupational exposure route for TBPis dermal, EPA is requiring that testing for oncogenicity, neurotoxicity, development toxicity, reproductive and fertility effects shall'be by the oral route because (1)the skin irritating effects ofTBP could confound the results ofdermal testing, (2)existing supporting studies have been done by the oral route, and (3)there are technical problems conducting dermal tests. EPA is also requiring oral/dermal pharmacokinetics. EPA is specifying that the Sprague-Dawley rat be used for both oncogenicity and pharmacokinetics testing because existing data presented in the proposed rule show this species to be sensitive to TBP.

EPA requires that all data developed under this rule be reported in accordance with its TSCA Good Laboratory Practice (GLP] Standards, in 40 CFR part 792.

In accordance with 40 CFR part 790, under single-phase rulemaking procedures, test sponsors are required to submit individual study plans at least 45 days before initiation ofeach test.

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 test data. Final testing requirements, test standards and reporting requirements forthis TBP test rule are summarized in the preceding table. Interim progress reports for the tests shall be provided to EPA at 6- month intervals after the effective date ofthis rule until the final report is submitted to EPA.

TSCA section 14(b) governs EPA disclosure ofall test data submitted pursuant to section 4 ofTSCA. Upon receipt ofdata required by this rule, EPA will publish a notice ofreceipt in the Federal Register as required by section 4(d).

Persons who export a chemical which is subject to a section 4 test rule are subject to the export reporting requirements ofsection 12(b) ofTSCA. Final regulations interpreting the requirements ofsection 12(b) are in 40 CFR part 707. In brief, as ofthe effective date ofthis test rule, an exporter ofTBP
must report toEPA the first annual export or intended export ofTBP to each country. EPA will notify the foreign country concerning the test rule for TPB.

For the purpose ofthis test rule,these guidelines are the test standards that
must be met by the test sponsors. The
route ofadministration ofTBP for all
tests shall be oral unless otherwise specified. Data resulting from these tests will assist EPA in conducting health and environmental risk assessments for TBP. The TSCA test guidelines, proposed modifications, and other .citedtest guidelines discussed in the following paragraphs in III.B. specify generally accepted minimal conditions for determining toxicities and properties of substances such as TBP to which human and aquatic life are expected to be exposed. Conducting the required studies in accordance with these TSCA guidelines will help ensure that the test results are reliable and adequate.

The oral/dermal pharmacokinetics
testguideline in the proposed rule has been revised based upon public
comments and is promulgated as §795.228 Oral/dermal pharmacokinetics test.

EPA periodically reviews the TSCA Test Guidelines, according to the process described at 47 FR 41857 (September 22, 1982).

1.Healtheffects.The neurotoxicity testing required will consist of an acute and'subchronic functional observation battery specified in §798.6050, as modified in §799.4360(c)(1)(i)(A)(2), an acute and subchronic motor activity test specified in §798.6200, as modified in §799.4360(c)(1)(i)(B)(2), and a subchronic neuropathologic evaluation of tissues perfused in situ specified in §798.6400, as modified in §799.4360(c)(1)(i)(C)(2).

To assess the developmental effects of TBP, EPA is requiring'that testing be conducted by gavage according to §798.4900, as modified in §799.4360(c)(2)(i)(B).Federal Register / Vol. 54, No. 155 / Monday, August 14, 1989 / Rules and Regulations

To assess the reproductive and fertility effects ofTBP, EPA is requiring that testingbe conducted according to §798.4700, as modified in §799.4360(c)(3)(i){B) (i)(B).

To assess the mutagenic effects of TBP, EPA is requring that testingbe conducted in tiers. First-tier testing will consist ofthe detection ofgene mutation in somatic cells inculture using the test guideline §798.5300, an in vitro mammalian cytogenetics testusing the test guideline in §798.5375, and an in vivo mammalian bone marrow cytogenetics chromosomal analysis test using the testguideline in §798.5385, as modified in §799.4360(c)(5)(i)(B)(2). Unless the results ofthe gene mutation in somatic cells in culture are negative, a sex-linked recessive lethal test in Drosophilamelanogaster will be required. Second-tier testing will consist ofa sex-linked recessive lethal assay in Drosophilamelanogaster using the test guideline in §798.5275, as modified in §799.4360(c)(4)(i)(B)(2), and a rodent dominant lethal test using the test guideline in §798.5450; third-tier testing will consist ofa rodent heritable translocation test using the test guidelines in §798.5460, and as modified in §799.4360(c)(5)(i)(D)(2).

In the proposed rule,EPA would have required third-tier testing consisting of a
mouse visible specific locus testusing the test guideline in §798.5200 as modified. Positive results in the sexlinked recessive lethal test may have triggered the requirement for conducting

a mouse visible specific locus (MVSL) test. EPA believes that the MVSL may benecessary, when these lower-tier tests are positive, to establish definitively whether a substance is capable ofeliciting heritable gene mutations. Under the approach proposed, EPA would have considered the positive results in the lower-tier tests in a public program review, together with other relevant information, during which interested persons would be able to give their views to EPA. If, after the review, EPA had determined that the MVSL was still appropriate, EPA would have notified the test sponsors by letter orFederal Register notice that they must conduct the test. If EPA had determined that the testwas
no longer necessary, EPA would have amended the rule to delete the test requirement.

The final test rule for TBP includes requirements to conduct the lower-tier tests for gene mutation. However, EPA is not promulgating the requirement for the MVSL forTBP at this time. EPAhas based its proposal to require the MVSL, in part, on information and assumptions about the cost ofconducting the test and the availability oflaboratories capable ofperforming the test. The information and assumptions have since proven to be incorrect. Accordingly, EPA is in the process ofreexamining the MVSL requirement for all those chemical substances for which the MVSL has been required orproposed tobe required. In particular, EPA is reviewing whether any laboratories are available to perform the MVSL for industry in accordance with the TSCA Good Laboratory Practice Standards at 40 CFR part 792 and the cost ofsuch testing, EPAis also reviewing possible alternative tests to the MVSL for which costs may be lower or laboratory availability may be more certain.

EPA has published a notice in the Federal Register concerning the MVSL for TBP and other substances subject to proposed and final TSCA section 4 test rules (53 FR 51897). This notice provides up-to-date information on the cost of MVSL testing, availability of laboratories to perform the MVSL, and possible alternative tests to the MVSL together with their costs and laboratory availability. Thenotice also addresses EPA's intentions about any changes to the MVSL requirements in the various test rules and provides an opportunity for public comment. If, after this proposed rule is finalized and ifafter lower tier mutagenicity testing ofTBP, EPA concludes that the MVSL is appropriate for TBP, EPAwill amend this rule to include the MVSL requirements with any appropriate modifications.

Should the gene mutation in somatic cells testprove negative, no further gene-mutation tests will be required. If the sex-linked recessive lethal testis negative, no further gene-mutation test will be required ofTAP.

If the results ofthe in vitro mammalian cytogenetics test are negative, an in vivo mammalian bone

marrow cytogenetics, chromosomal analysis test will be required. Unless the results ofthe in vivo test are negative, a rodent dominant lethal testwill be required. A positive result in the rodent dominant lethal testwill tr'iggerthe requirement that a heritable translocation test be conducted. Should the invivo mammalian cytogenetics test results provenegative, no further chromosomal effects testing will be required. Ifthe dominant lethal test is negative, no further chromosomal effects testing will be required forTBP.

Under this final rule, ifthe result of the second-tier rodent dominant lethal test is positive, EPA will hold apublic program review before industry will be required to initiate the third-tier heritable translocation test.The public will participate in this program review either by submitting written comments

or commenting during a public meeting. A request forpublic comment or notification ofpublic meeting will be published in the Federal Register. Should EPA determine, from the available weight ofevidence, that proceeding to the heritable translocation test is no longer warranted, EPA will propose to repeal this testing requirement and, after public comment, issue a final amendment to rescind this requirement. EPA will notify the test sponsors by certified letter or Federal Register notice, following the public program review ofall the then-existing data for TBP, ifthe heritable translocation testmust be performed. EPAwill also conduct internal program reviews ofthe reports ofthe gene mutations in somatic cells in culture assay, the in vitro mammalian bone

marrow cytogenetics test, and the in vivo mammalian bone marrow cytogenetics test and other available mutagenicity data to evaluate whether the sex-linked recessive lethal and the rodent dominant lethal tests have been triggered.

For a more detailed discussion of mutagenicity tiered testing and public program review procedures, see EPA's final testrule for the C9 aromatic hydrocarbon fraction published in the Federal Register ofMay 17, 1985 (50 FR 20662).

To assess the oncogenic effects of TBP, EPA is requiring that testingbe conducted according to §798.3300 in Sprague-Dawley rats and in mice via the oralroute ofadministration.

To assess the dermal sensitization effects ofTBP, EPAis requiring that testingbe conducted according to §798.4100.

To compare the oral route of administration ofTBP in §798.3300 and the dermal route, in §798.4100 which is thought to be a primary route ofhuman exposure, EPA is requiring an oral/ dermal pharmacokinetic test with TBP to examine absorption, distribution, metabolism, and excretion. EPA is requiring that testing be conducted according to §798.7485. The decision to require most testing ofTBP by the oral route is based on the results ofdermal irritation tests showing TBP effects to range from irritating to corrosive (Unit II.F.1. ofpreamble to proposed rule). Moreover, dermal application ofthe corrosive TBPcould stress the test animals, which may distort test results. TBP is well tolerated by the oral route (Unit II.F. ofpreamble to proposed rule). 3340533406 Federal Register / Vol. 54, No.. 155 / Monday,. August 14, 1989 

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EPA is not requiring the renal effects
test recommended by the ITC.Acute and subacute oral studies by Mitomo et al. (Ref.16) showed kidney tubule damage in rats and mice. However, two oral subchronic rats studies ofg0 days and 126 days showed no kidney damage

even at dosages higher than the Mitomo studies (Refs. 17 and 18). EPAbelieves that there are adequate data available
to assess the effects ofTBPon kidney tubules.

2.Environmental effects. EPA is requiring the following environmental effects testing to determine the toxicity ofTBP to an alga, a fish, and aquatic invertebrates: (1)Selenastrum capricornutum, in accordance with § 797.1050 as modified in § 799.4360(d)(1)(i)(B); (2) rainbow trout in accordance with § 797.1400, as modified in §799.4360(d](2)(i](B); (3) daphnids in accordance with §797.1300, and as modified in § 799.4360(d)(3)i)(B); and (4)gammarids in accordance with §795.120, as modified in §799.4360(d)(4)(i)(B. Only one test species, rainbow trout, is required for the fish acute toxicity testbecause an acute test for the fathead minnow is available and adequate in combination with the testing required for the rainbow
trout for purposes ofassessing the acute toxicity ofTBP offish (see Unit 1.G.]. All the acute aquatic toxicity data from these tests will be used to determine whether chronic aquatic testing is
necessary according to the testing scheme presented in the following figure:

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