### 57452 Federal Register / Vol. 48, No. 251 / Thursday, December 29, 1983 / Rules and Regulations.

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 799

[OPTS-42038; BH-FRL2458-1]
ArylPhosphates; Response to the Interagency Testing Committee

AGENCY: Environmental Protection Agency (EPA). ACTION: Advance Notice ofProposed Rulemaking.

SUMMARY: In the Second Report ofthe Interagency Testing Committee (ITC), transmitted to the Administrator ofthe EPA on April 10, 1978, the ITC designated the aryl phosphate category fortesting consideration. The manufacturers ofaryl phosphates are currently conducting a testing program that EPAbelieves will provide adequate data in some ofthe areas where the Agency believes testing is needed. For the remaining data gaps, the Agency is publishing this Advance Notice of Proposed Rulemaking (ANPR), which initiates rulemaking to require the testing which appears necessary to complete a preliminary assessment of the health and environmental effects of the aryl phosphates. This notice constitutes EPA's response to the ITC's designation of the aryl phosphates for testing consideration. EPA seeks
comment on its conclusions as to the need for further testing of the aryl phosphates and the submission of data, information and views on a number of issues listed in Unit IV under the Supplementary Information heading of thisNotice. DATE: All comments should be submitted on or before February 27, 1984. ADDRESS: Written comments should bear the document control number OPTS-42038 and should be submitted in triplicate to: TSCA Public Information Office (TS-793), Office ofPesticides and Toxic Substances, Environmental Protection Agency, Rm. E-108, 401 M St., SW., Washington, D.C. 20460.

The administrative record supporting this action is available for public inspection in Rm. E-107 at the above address from 8:00a.m. to 4:00p.m., Monday through Friday, except legal holidays.
FOR FURTHER INFORMATION CONTACT: Jack P.McCarthy, Director, TSCA Assistance Office (TS-799), Office of Toxic Substances, Environmental Protection Agency, Rm. E-543, 401 M St. SW., Washington, D.C. 20460, Toll Free: (800-424-9065), In Washington, D.C.: (554-1404), Outside the USA: (Operator202-554-1404). SUPPLEMENTARY INFORMATION:

1.BacKground

Section 4(a) ofthe Toxic Substances C',ntrol Act (TSCA) (Pub.L. 94-469, 90 Stat. 2003 etseq., 15 U.S.C. 2601 etseq.] authorizes the EPA to promulgate regulations requiring testing ofchemical substances and mixtures inorder to develop data relevant to determining the risks that such chemicals may present to health and the environment. Section 4(e) ofTSCA established an Interagency Testing Committee (ITC) to recommend
to the EPA a list of chemicals tobe considered for the promulgation of testing rules under section 4(a) ofthe Act.

On April 10, 1978, the ITC placed on its priority testing list a category of chemicals known as aryl phosphates (see 43 FR 16684, April 19, 1978). The ITCdefined "aryl phosphates" as phosphate esters ofphenol orofalkylsubstituted phenols. Tri-aryl and mixed alkyl-aryl esters are included, but trialkyl esters are excluded. The ITC recommended that the aryl phosphates 

### be considered fortesting for the following health effects: carcinogenicity, mutagenicity, teratogenicity and chronic effects (with special emphasis on neurotoxicity). In addition, the ITCalso recommended that a epidemiology study be considered because ofthelarge-scale production and potential for substantial occupational exposure to certain aryl phosphates. The ITC also recommended that the aryl phosphates be considered for environmental effects testing and expressed specific concern about the potential foraryl phosphates to persist in the aquatic environment, to bioaccumulate in aquatic species, and the potential effects ofaryl phosphates

on aquatic and terrestrial systems. This Advance Notice ofProposed Rulemaking provides EPA's response to the ITC's designation ofthe aryl phosphates as required byTSCA section 4(e).

Under section 4(a)(1) ofTSCA, the Administrator shall byrule require testing ofa chemical substance to develop appropriate test data ifthe Agency finds that:

(A) (i) the manufacture, distribution in commerce, proc- 

### essing,use, or disposal of a chemical substance or mixture, or that any combination of such activities, may present an unreasonable riskof injury to health or the environment,

(ii) there are insufficient data and experience upon which the effects of such manufacture, distribution in commerce, processing,
use, or disposal ofsuch 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 oY mixture with respect to such effects is necessary todevelop such data; or (B) (i) a chemical substance or mixture is or will be produced in substantial quantities, and (I) it enters or may reasonably be anticipated to enter the environment in substantial quantities or (II) there isor may be significant or substantial human exposure tosuch substanceor 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 reasonablybedetermined orpredicted, 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 to make the finding that the chemical may present an unreasonable risk. For the section 4(a)(1)(B)(i) finding, EPAconsiders only production,
exposure, and release information to determine ifthere is substantial production, significant or substantial
-exposure, and substantial release. Thus, while EPA can require testing for an effect under section 4(a)(1)(A) only if there isa suspicion ofa hazard, under section 4(a)(1)(B) EPA can require testing whether or not there are data suggesting adverse effects ifthe relevant 

### production, exposure, and release criteria are met.

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 reasonably determine or predict the effects ofhuman exposure to,

or environmental release of, the chemical. In making the third finding, that testingis necessary, EPA considers whether ongoing testingwill satisfy the information needs forthe chemical and whether testingwhich theAgency might require would be capable ofdeveloping thenecessary information.

EPA'sprocess for determining when these findings can be made is describedFederal Register 

### / Vol. 48, No. 251 / Thursday, December 29, 1983 / Proposed Rules

in detail in EPA's first and second proposed testrules as published in the Federal RegisterofJuly 18,1980 (45 FR 48528) and June 5,1981 (46FR 30300). The section 4(a)(1)(A) finding is discussed in 45FR48528, and the section4(a)(1)(B) finding isdiscussed in 46 FR 30300.

In evaluating the ITC's testing recommendations concerning aryl phosphates,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 ofaryl phosphates under the TSCA section 8(a) Preliminary Assessment Information Rule (40CFR Part 712); and published and upublished data available to the Agency, including information submitted under theTSCA section 8(d) Health and SafetyData ReportingRule (40CFR Part 716).

The nine aryl phosphates listedbelow havebeen specifically identified by industry asbeing constituents of commercial products currently in production.

1.TCP-Tricresyl phosphate, mixed isomers (tritolyl phosphate, CAS No. 1330-78-5).

2.TXP-Trixylenyl phosphate, mixed isomers (trixylyl phosphate, CAS No. 25155-23-1).

3.TPP-Triphenyl phosphate (CAS No. 115-86-6).

4.NPDP-Nonylphenyl diphenyl phosphate, mixed isomers (CAS No. 64532-97-4).

5.DBDP-Dimethylbenzylphenyl diphenyl phosphate, mixed isomers (alsoknown as cumylphenyl diphenyl phosphate, CAS No. 34364-42--6).

6.IPDP-sopropylphenyl diphenyl phosphate, mixed isomers (CAS No. 28109-99-8).

7.BPDP-Butylphenyl diphenyl phosphate, mixed isomers (CAS No. 34364-42-6).

8.IDPP-Isodecyl diphenyl phosphate (CAS No. 59800-46-3).

9.EHDP-2-Ethylhexyl diphenyl phosphate (CAS No. 1241-94-7).

11.Tentative EPA Decision andIssues

A. Developmentof Rulemaking
TheAgency has reviewed available data which indicate thathuman exposure to aryl phosphates as a category may be substantial; however, the ambiguous nature ofthe information available regarding changes in the production, use and subsequent human
exposure to aryl phosphates, and the lack ofreliable environmental monitoring data have prompted EPA to issue an Advance Notice ofProposed Rulemaking tANPR) for the aryl phosphates, rather than issue a proposed test rule. Should data be submitted which indicate thatexposure levels are biologically insignificant or that the number ofpeople exposed to the aryl phosphates is low, theAgency will reconsider its decision toproceed with this rulemaking action. EPA will, in the intervening period between publication ofthisANPR and inssuance ofa proposed section4(a) rule, attempt to refine the exposure data and reconsider its decisions in light ofany additional data that become available.

EPA, inpublishing thisANPR, wishes
to receive comment on its tentative basis for requiring testing, and on the tests the Agency believes necessary to

Chemical characterize the health and environmental effects ofthe aryl phosphates. The bases for the suggested findings, and for the test3 under consideration, are discussed below.

B.Preliminary Findings

1.Potentialhumanexposure.The Agency considers that publicly available information indicates that the nine aryl phosphates listed above may meet the criteria for a findingunder section4(a)[l(1)(i): that the chemicals

are produced in substantial quantities and that there is ormay be substantial human exposure (seeTable 1).

TABLE 1

1977 production (rit.lb.)I 1980 protected production (ril.lb.)i Used as plasticizer Used as hydraulic

fluid/ lubricant additive Nun
po expo

weoo

TCP

....................... 23 (1) X X TXP

..................................................................................... 15 (1) X X
TPP

....................................................................................... 16 10 X

...................... NP OP/DBSP

...................................................................... 13 15-20 X X IPDP

. . . . ... ......... ...... 28 30-40 X

.......................

BPDP

................................................... . ........................... 3 15-20 X X IDPP

..................................................................................... 10 15 X X EHDP

............................................... 3.................... 4.6 X X

Total

....................................... ............................. I II 100-140

........................ ................. .........

Refs. 42 and50. Re. 46. Confidential industry estimates show a substantial dropinproduction since1977. 'Reported jointly byindustry. Subject oregulation byFDAunder 40 CFRPart175,300; 380; 390; 176.170 and177.1210

Most human exposure to aryl phosphates occurs in the workplace. The ITCcited the 1972-74 National Occupational Hazard Survey (NOHS), published in 1977by the National Institute for Occupational Safety and Health (NIOSH) (Ref. 63), as one oftheir

reasons for recommending testingofthe aryl phosphates.

Aryl phosphates are used primarily as fire retardant plasticizers (36.5 million pounds in 1977), and ashydraulic fluids and lubricant additives (41.8 million pounds in 1977) (Ref. 42). Human
exposure to aryl phosphates occurs primarily during polyvinyl chloride (PVC)processing and hydraulic fluid

use.

About 90percent ofthe 36.5 million pounds ofaryl phosphates used as flame retardant plasticizers are used in the processing ofpolyvinyl chloride (Ref. 52). The remaining ten percent is usedin various other plastics. No major difference inexposure profile would be expected due to the particular type of polymer in which the arylphosphates

are used.Certain procedures used to manufacture PVC products, such as calendering, roll coating, film casting. and dip molding, may afford opportunities for exposure toplasticizer mists containing aryl phosphates (Ref. 42).

Fire resistant hydraulic fluids (excluding brake fluids) based on phosphate esters are used primarilyin applications where high temperature be of

rsons Sed in he kplace

187.709

3.105 7,631 2,893

603 531

N.A. 11.432

could pose a firehazard ifthe hydraulic system developed leakage.The steel and automotive industries account for 65-70 percent ofaryl phosphate hydraulic fluid uses (Ref.42). Leakage of fire resistant hydraulic fluids containing phosphate esters may expose workers in thebasic metals industries, the automotive industry, die casting operations and steel foundries, and military applications (Ref. 55). Evidence that such leakage isnot infrequent is provided by estimates that as much as 80 percent ofthe annual use of phosphate esters in hydraulic fluids may be for replacement oflosses (26.8 million pounds in 1977) (Ref.55).

NIOSH estimated in the 1972-74 National Occupational Hazard Survey (NOHS) thatup to two million workers
may be exposed to arly phosphates (Ref. 63). However, in the NOHS survey for the aryl phosphates, NIOSH made a "generic" estimate based on observations ofproducts in general use in the workplace which the surveyor speculated might contain aryl phosphates. EPAbelieves that,in this instance, this "generic" NIOSH methodology may haveoverestimated actual aryl phosphate exposure by at least a factor often (Ref. 60). EPA believes that more recent NIOSIHI estimates, based on actual observed use ofaryl phosphates and the presence in theworkplace oftradename products known to contain aryl phosphates, are 

### 5745357454 Federal Register / Vol. 48, No. 251 / Thursday, December 29, 1983 / Proposed Rules

more reliable, and has based its evaluation on those figures (Ref.46). The actual and tradename results ofthe
survey indicate substantial human
exposure to some aryl phosphates. However, itis not clear that theactual and tradename survey results provide

an accurate picture ofhuman exposure due to changes in themarket condition for aryl phosphates over thelast 5years (Table 1).

For instance, theproduction and use ofTCPreportedly has declined dramatically since the 1972-74 NOHS

was performed (Ref.54). This decline has occurred as aresult ofthegreater availability and economy ofsynthetic feedstocks and theintentional phase-out ofTCP fromcertain uses due tothe neurotoxicity ofits ortho isomer (TOCP).

Manufacturers ofTCPcite this decline

as evidence that exposure to TCP has also declined dramatically. Ifexposure has decreased as much as production, it would be more thanan order of magnitude lowerthan indicated bythe 1972 NOHS and may not be considered substantial by EPA. However, manufacturers ofTCP admit thattheir knowledge of some ofthe downstream

uses ofTCPis very limited and that it is possible that small amounts (several percent) ofTCPcould be added to various specialty lubricants or other similar products towhich a substantial number ofpersons might be exposed (Ref.54). The manufacturers believe that the health significance ofsuch
exposures would be minimal, buthave been unable todate tofully support this contention. Anew NIOSH survey is currently beingconducted; however, results willnot be available until at least 1984. The replacement ofTCP by synthetic feedstock-derived aryl phosphates also raises the concern that the 1972-74 NIOSH survey may underestimate exposure to IPDP, NPDP, DBDP; IDPP,BPDP, and EHDP. Ifcurrent exposure estimates forthese six aryl phosphates indicate substantial TSCAcovered exposure, EPAwould expect to make substantial exposure findings under section 4(a)(1)(B)(i) ofTSCA for each ofthese aryl phosphates. (Exposure due to uses regulated under theFederal Food, Drug and Cosmetic Actare not covered byTSCA).

With the possible exception ofTCP, significant direct consumer exposure is unlikely because other arylphosphates donot appear to be in consumer products except asplasticizers. Because ofthe tendency ofthe aryl phosphates
to remain bound within the polymer matrix, they are not expected toleach or volatilize fromplastics in which they are contained in sufficient quantities to

cause concern due to this mode of exposure (Ref.42). The NOHS lists a number ofproducts which contained TCPwhich might be expected tohave consumer as well as industrial uses (Ref. 46).

As discussed under Unit B.3. of this Notice, Environmental Release, aryl phosphates are quite insoluble in water and would be expected to adsorb strongly to sediments (Ref. 41). Thus,
any aryl phosphates released to the aquatic environment would be expected

to partition to sediments and would not likelyresult in directhuman exposure, such as in finished drinking water. However, the potential does exist for indirect human exposure as a result of aryl phosphates accumulating in sediment-bound organisms or organisms which filter-feed sediment and interstitial waters, which in turn may be consumed by humans as food (shrimps, clams, mussels, snails, etc.). The Agency has not seen any data which would suggest that significant exposure to aryl phosphates occurs via foods or drinking
water, however.

2.Adequacyofinformationandneed forhealtheffects testing.EPA has approached its analysis ofhuman health

concerns for the aryl phosphates from the standpoint ofboth potential unreasonable risk (section 4(a)(1)(A)) and substantial production and
exposure (section 4(a)(1)(B)). (See Table 2). The specificjustifications for each approach are discussed below.

TABLE 2.-SUMMARY OF TENTATIVE HEALTH

EFFECTS TESTING REQUIREMENTS

Effect Under a 4(a)(1)(A) Under a4(a)()(B) finding I finding 2

Chronic/subchronic.. No

............. All.' Mutagenicity

.............. IPDP 4

...................... AII.3'' Oncogenicity

.............. No

............................. Triggered.' Teratogenicity

............ TCP

.......................... AllexceptNPDP,

DBDP. TPP. Reproductive

. TCP............ All.' Neurotoxicity. PDP,' TXP,TCP POP,' TXP.TCP. Epidemiology

............. No 7

.......................... No.7

I"Maypresent anunreasonable risk"finding. 'Substantial production and substantial or significant human exposure finding. 3All arylphosphates meeting substantial production and exposure criteria. ' Ongoing industry testing meets testing needs of IPDP for gene mutations. If resultsare positive,EPA willpropose higher tiered testing ofIPDP topermit assessment ofmuta- genicrisk. Ifsubstantial production andexposure criteria are met for IPDP, EPAwillpropose chromosomal abberations testing ofIPDP. 'Testingrequirement dependent uponresults ofmutagenicityand subchronic testing. t Ongoing industry testing meets testing needs ofIPDP for neurotoxicity. EPAdoesnotbelieve a suitable study population canbe identified atthis time.

a. Chronictoxicity.Several subacute and subchronic studies have been conducted on various aryl phosphates, including TCP, TPP, DBDP, NPDP, and TXP (Refs. 17, 23, 44, 45, 47 and 51), but these are primarily oral neurotoxicity studies in the hen of28 days or less duration, and are not adequate to assess the organ-specific subchronic effects in mammals for these aryl phosphates. Concentrations reported to produce effects in the liver, kidneys, and adrenals ofrats resulting from inhalation for up to 90 daysranged from 450ppm to 50,000 ppm withtypical lowest effect levels reported at about 1,000 ppm (Ref. 47, 51). Although these results are consistent with the low acute toxicity of these compounds (Refs. 10, 23, and 49), the Agency believes that organ-specific studies of90-day duration (or longer) in at least one mammalian species are needed to adequately assess the subchronic effect of any aryl phosphate to which there is substantial human exposure, and would propose subchronic testing under section 4(a)(1)(B) for all such aryl phosphates. However, the data available to the Agency up to this time do not support testing under section 4(a)(1)(A) (potential unreasonable risk).

b.Mutagenicity.All of the nine commercial aryl phosphates have received some mutagenicity testing using the Ames assay (Refs. 18-22, 30 and 49). Negative results were obtained for all ofthe aryl phosphates tested with the exception ofIPDP. These assays are inadequate to completely characterize the mutagenic potential ofthe aryl phosphates, however, because theAmes
testis not generally recognized as a stopping point in the tier testing oflarge
exposure chemicals. Therefore, EPA is considering requiring thatTCP, TXP, TPP,NPDP, DBDP, BPDP, IDPP, and EHDP be tested under TSCA section 4(a)(1)(B) for specific-locus gene mutation in cells in culture, for DNA damage as evidenced by either unscheduled DNA synthesis or sister chromatid exchange (SCE) formation, and for their ability to induce chromosomal aberrations in cells in culture. However, with the exception of IPDP, the data available to theAgency do not support testing under section 4(a)(1)(A) at this time.

Test results on IPDPwere negative in theAmes test and negative without activation in the mouse mammalian cell
gene mutation testusing lymphoma cells (Ref. 49). However, IPDPresults were equivocal with activation in the mouse lymphoma test. As a result,EPA believes an additional confirmatory
gene mutation test is necessary forIPDP. Industry is conducting such a test which

was initiated in April 1983 (Ref. 62). For' this reason, EPA is not initiating section 4(a) rulemaking to require gene-mutation testing of IPDP at this time. Should the industry testing ofIPDP or other data reveal a need for further mutagenicity testing of IPDP (including chromosomal abberration) which industry is unwilling

to perform, EPA will reconsider the need for a section 4(a) test rule for mutagenicity for this substance. The protocol and design for the mutagenicity testing being conducted by industry are discussed in Unit III of this notice. If a substantial exposure finding is made for IPDP under section 4(a)(1)(B), the Agency would expect to propose chromosomal aberration testing.

c. Oncogenicity. EPAbelieves that human exposure to the aryl phosphates

### Federal Register / Vol. 48, No. 251 / Thursday, December 29, 1983 / Proposed Rules

may be substantial under section 4(a)(1)(B) by currently available information, but has not seen any data which would indicate that they may present an oncogenic risk under section 4(a)(1)(A). Therefore, for purposes of determining testing needs under TSCA section 4, the Agency believes that the mutagenicity testing outlined above. together with the organ-specific subchronic testing to be required for all aryl phosphates meeting substantial production and exposure criteria, provides a reasonable screening
program to determine which, ifany, of the aryl phosphates should be subjected
to lifetime oncogenicity bioassays in laboratory animals. In accordance with that assessment, such testing would be required only ifthe results ofthe mutagenicity testing are positive or if the toxicity shown in the organ-specific subchronic testing indicates a likelihood ofoncogenicity. However, EPA will continue to review this preliminary decision, and requests public comment

on the issue of utilizing mutagenicity testing as a screen for identifying candidates for oncogenicity testing. (See Unit IV.). The Agency's rationale for planning to require a test system which would trigger oncogenicity testing from

a mutagenicity test battery is based on a long history ofscientific investigation as to the correlation between mutagenicity and carcinogenicity (Ref.71).

Priorto the late 1960's and early 1970's, it was generally felt that there

was little or no correlation between mutagenicity and carcinogenicity. Few mutagens had been shown to be potent carcinogens, and carcinogens which had been tested for mutagenicity, primarily in microbial assays which lacked the capacity for metabolic activation, has been designated "nonmutagenic." As basic understanding of the metabolism of carcinogenic chemicals increased, it

was discovered that many carcinogens undergo metabolic activation to an ultimate carcinogenic moiety by mammalian enzyme systems. This discovery was followed by the development of an invivo system, the host-mediated assay, to test for potential mutagenicity (Ref. 72); and in vitrotesting ofreactive forms of carcinogenic chemicals (Refs.73-76) which resulted in a demonstration ofthe mutagenicity of many known carcinogens.

Whatever the mechanistic basic for the correlation between mutagenicity and carcinogenicity, there does appear to be an empirical correlation which is worth exploiting in the identification of potential carcinogens. The Agency currently believes that the correlations indicated by these data are sufficiently sound such that the carcinogenic potential ofa chemical may reasonably be predicted from the results ofa mutagenicity testing scheme for the
purposes ofsetting priorities for conducting oncogenicity bioassays under section 4 ofTSCA. The Agency requests public comment on this issue.

d. Terotogenicity.SOme data are available relating to the teratogenic potential oftriorthocresyl phosphate (TOCP), NPDP, DBDP, and TPP (Refs. 7, 44, 57, 58, 59). With the exception of TOCP, the results are sufficient to reasonably predict that these aryl phosphates do not act as potential teratogens. EPA therefore is not proposing to require teratogenicity testing on NPDP, DBDP and TPP.

The only available teratogenicity study on TCP (Ref. 59) does not adequately characterize the teratogenic potential ofTCPbecause the protocol design is invalid and only the ortho isomer (TOCP)was tested. This study

was intended as a preliminary study to examine the potential effects ofprenatal
exposure to TOCP on postnatal behavior. Therefore, TOCP was administered (at 500 and 750 mg/kg/ day) by gavage late in gestation (day 18 and 19) during the fetal period. The investigators reported that significant increases in abnormalities were not observed. This is not surprising, however, because the most susceptible period toinducing gross structural abnormalities is during the period of major organogenesis (day 15-16 in the rat), and not the fetal period (Ref.68). The Agency does not believe that the study provides reliable data upon which
to evaluate the teratogenic potential of TCP.

Concern for the possible teratogenicity ofTCPis supported by the suggestion that TOCPmay interfere with vitamin Emetabolism (see Unit II.B.2.e., Reproductive Effects, below); vitamin E deficiency during gestation produces severe and often lethal syndromes ofcongenital malformations in laboratory animals (Ref.7). Thus, the Agency intends to require teratogenicity testing ofTCPunder section 4(a)(1)(A) ofTSCA. Because the Agency lacks data

on the teratogenicity ofTXP, IPDP, BPDP, IDPP, and EHDP,it is considering proposing teratogenicity testing for these compounds under section 4(a)(1)(B) if there is substantial exposure to these compounds.

e.Reproductiveeffects. The reproductive effects of the aryl phosphates have not been adequately characterized. Therefore, the Agency is considering proposing reproductive effects testing under section 4(a)(1)((B) for all aryl phosphates for which there is substantial production and exposure. The only data available are for tricresyl phosphate (TCP) and are from a Russian study on the comparative gonadotropic effects oftricresol, phosphorous oxychloride, and tricresyl phosphate, and from a general toxicology study in which a species comparison was conducted.

The data from the Russian study (Ref. 69) indicated that inhalation exposure of
rats to the MAC (maximum allowable concentration) oftricresyl phosphate did
not cause any changes in the ovarian and estrus cycles. The actual concentration to which the animals were exposed was not included in the report.

In the general toxicology study conducted by Carpenter (Ref.6), some degree ofdegeneration ofseminiferous tubules was reported in three offour
testes examined from twelve dogs which had been exposed to 20 subcutaneous injections over a 4 to 5-week period ofa mixture ofphosphate esters ofcresols, xylenols, and other alkyl phenols (TCP). The dose levels at which these effects

were observed were not explicitly stated, but the doses administered to a total of 12 dogs ranged from 100 to 500 mg/kg/dose. The study also reported that several rabbits which had been exposed to the same mixture by gavage exhibited changes suggestive ofearly testicular degeneration, but these changes were not definitive enough to be conclusive. The dose levels at which these effects were observed were not clearly indicated, but the doses administered to the six animals ranged from 120 to 480 mg/kg/day for 2 to 14 days or a total dose of0.72 to 2.88 g/kg.

Because many of the toxicities observed following exposure to TCP

were similar to those reported resulting from vitamin E deficiency, and because the structure ofTCP appears to be similar to features oftocols possessing vitamin E activity, Carpenter suggested the 'ossibility that interference with vitamin E metabolism may be responsible for toxic effects observed following exposure toTCP (Ref.6).

In summary, these studies are inadequate to assess the reproductive effects of tricresyl phosphate. Some of the reasons are as follows: (1)The actual doses administered or at which adverse testicular effects were observed

were not clearly indicated; (2)the number ofanimals on test were either
too few ornot reported; (3)the duration ofexposure was either not reported or too short; (4)the dosing ofdogs which showed evidence of testicular degeneration wvas performed by 

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subcutaneous injection, which is not representative ofpotential human
exposure to TCP; and (5) neither study examined the effects on male and female reproductive performance, such

as mating behavior, conception, parturition, lactation, weaning, and on the growth and development of offspring.

IfTCP orTOCP, indeed, are vitamin E antagonists, theirpotential forinducing adverse reproductive effects should be ofconcern. Vitamin E is important in the maintenance ofnormal testicular function and iscritical in the normal development ofoffspring. Interference with vitamin E metabolism may result in serious adverse reproductive effects (Ref. 7). Therefore, the Agency is considering proposing under section 4(a)[1)(A) that a 2-generation reproductive study be conducted on TCP.

Although the Agency believes that evidence ofreproductive toxicity on one category member raises some suspicion ofthis hazard from the others, under 4(a)(1)(A) EPA would propose reproductive effects testing only onTCP at this time because of the weaknesses ofthe reproductive effects studies of TCP described above. Ifthe results of the study on TCPare positive, EPA then
proposes to trigger full reproductive effects testing under section 4(a)(1)(A) for all other category members.

f.Neurotoxicity. All nine aryl phosphates have been tested for acute toxicity by both oral and dermal routes (Refs. 1,4, 6, 25-28, 31-34,47, and 49) and the acute neurotoxicity ofcertain aryl phosphates (TCP,TXP, IPDP) is well documented (Refs. 33-37). With the exception ofsubchronic neurotoxicity of IPDP, TXP and TCP, all aryl phosphates have been adequately characterized with respect to neurotoxic potential (Refs. 2-4, 8-17, 24-28). In the case of IPDP, the Agency has concluded that acute testing was adequate to determine that the para and meta isomers are not potentially neurotoxic, and that ortho isomer is neurotoxic (Refs. 3, 8-11, 16, 23-27,36-38). FMC corporation has agreed to perform a 90-day subchronic neurotoxicity study ofcommercial IPDP

as discussed in Unit III ofthis notice. The results of this study will be sufficient to reasonably predict or determine the neurotoxicity ofIPDP.

The 2,3- and 2,4- isomers ofTXP have been shown to be neurotoxic, as well as the 2,4-2,4-3,5- and the 2,6-3,5-3,5- isomers (Refs. 33-37). EPA considers the existing studies on TXPinadequate to

assess the chronic neurotoxicity ofTXP because of the small numbers ofanimals tested, the limited duration ofexposure, and the low levels ofexposure to which 

### the testanimals were subjected. Because ofthe indications ofneurotoxic potential and lack ofadequate data, EPA expects to propose subchronic neurotoxicity testing ofa commercial mixture ofthe isomers ofTXPunder TSCA section 4(a)(1)(A).

TheAgency has concluded that, although data on the acute neurotoxicity ofTCP are adequate, available data on the chemical's subchronic neurotoxicity

are not. Some data do exist,but the studies reviewed by the Agency are studies on the hen of28-day duration (Refs. 17, 28), which are not sufficient to adequately assess the effects ofTCP

over time fora subchronic neurotoxic effect. Industry's 90-day subchronic neurotoxicity study in thehen on isopropylphenyl diphenylphosphate (IPDP) (seeUnit 1II. 2.) will use triorthocresyl phosphate (TOCP)as the positive control.The neurotoxic activity ofTCPhas been conclusively'linked to its ortho isomer,TOCP (Ref. 33). 

### Therefore, characterizing the subchronic neurotoxicity ofTOCP should allow EPA to reasonably predict the subchronic neurotoxicity ofTCPwhose TOCPcontent is known. However, the

use ofTOCPas a positive control in the ongoing IPDP study will involve only

onedose level; this will not permit the determination of a dose-response curve. Therefore, EPAexpects to propose under TSCA section 4(a)(1)(A) a 90-day subrhronic neurotoxicity study using three dose levels ofTOCP.Analytical data on each manufacturer's commercial TCP product will allow theAgency to

assess thepotential toxicity ofthe commercial TCP product relative to the content ofTOCP within thatproduct. In addition, because the available data are inadequate for assessing the neurotoxicity ofTXP and TCP, the Agency is considering proposing such testing under TSCA section 4(a)(1)(B) for these two aryl phosphates ifthe substantial production and exposure findings are met.

g.Epidemiology.EPA believes that an epidemiological study ofworkers exposed to aryl phosphates could potentially provide reliable data for evaluating thepotential riskof neurologic harm from such exposure. EPA attempted to define a suitable study population through extensive contractor efforts. Excessive problems in terms ofvalid cohortidentification

werepresented, however. Thenumber ofworkers involved in manufacturing is too smallto permit a valid study for the observation ofneurotoxic effects, and the number ofprocessors is so large as to present severe logistical problems. Further attempts to define a cohortwere not recommended bythe contractor (Ref. 53). Because ofthe difficulty in identifying a suitable study population, EPA has concluded that an epidemiological study is not feasible at this time and will not propose that an epidemiological study be undertaken.

3. Environmental release.In 1977 an estimated 26.8 million pounds ofaryl phosphates in hydraulic fluids were used to replace losses due to leakage frompumps, primarily in the heavy metal and automotive industries (Ref. 42). The fate ofsuch leakage may be
aqueous discharge, landfill, and/or reclamation. Typically, each hydraulic machine has a catch basin orother device to catch and retain any leaks from the machine. These "catchings" are collected in a sump where the "oil" is separated from the water. The "oil" is collected for disposal or forreclamation. The water is usually filtered and sent to the sewer. This water is sometimes pretreated on the site before it is sent to publicly-owned treatment works.Due to the hydraulic fluids' usage patterns and certain monitoring data, EPA believes that there may be substantial entry of the arylphosphates into the environment without treatment. (Refs. 39, 41, 48]. Because industries that use hydraulic fluid containing aryl phosphates are situated near both saltwater and freshwater environments, EPAbelieves thatrelease to both environments is possible. The manufacturers ofthe aryl phosphates question this conclusion. They state that it is unrealistic to assume that substantial amounts ofhydraulic fluid
enter natural aquatic systems without
treatment. In support oftheirposition, the aryl phosphates manufacturers submitted a monitoring study conducted by Monsanto which reported that there

was a negligible or nonexistent release ofaryl phosphates to the environment (Ref. 45). After careful review by EPA scientists, the Agency suggested that industry develop a new and more comprehensive monitoring and sampling protocol forthe aryl phosphates. EPA did not believe that the original data submitted were adequate to support industry's position oflittle orno environmental release. In the Agency's view, the study submitted contained too few sampling sites, was conducted in a number oflocations where the Agency considered detection ofaryl phosphates unlikely, and did not provide a level of detection sensitive enough to adequately characterize the presence and extent ofaryl phosphate contamination (Ref.29).

To resolve the uncertainty regarding the amount ofaryl phosphates released
to the environment and the levels ofaryl 

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phosphates in sediment and surface water, the Aryl Phosphate Industry Ad Hoc Committee agreed to conduct a monitoring study and submitted a monitoring protocol to EPA (Ref. 61). More recently, industry submitted the results of the completed aquatic monitoring study (Ref. 64).

Sample collection for this study began July 28, 1982, and the final report was received April 14, 1983 (Ref.64). The protocol provided for sampling of all aryl phosphates at 24 sites mutually selected by EPA and industry where aryl phosphates were likely to be detected (such as downstream from hydraulic fluid production plants), as well as areas inwhich aryl phosphates have never been monitored but might be present (innerharbor at Baltimore, Md.). In addition, a sampling site was designated downstream from a major landfill where aryl phosphate production wastes are known to be disposed and several pristine sites were also included. Water and sediment samples taken from these sites were analyzed according toprocedures set forth in Monsanto's Good Laboratory Practices Manual (Ref.43).

Monsanto proposed a detection limit of0.1 ppb for aryl phosphates inwater. This detection limit is below the maximum acceptable toxicant concentration (MATC) for the most toxic aryl phosphate (DBDP) to the most sensitive species (rainbow trout) viz., 0.8-1.4 ppb (Ref.45). For aryl phosphates in sediments, Monsanto noted that
current methodology would provide detection limits ranging from 30-200 ppb, and selected a detection limit ranging from 30-200 ppb, and selected a detection limit for aryl phosphates in sediment of100 ppb.

However, upon receipt ofthe results ofthe monitoring study, Agency scientists noted several discrepancies in the quality assurance, analytical method, and statistical treatment of the data obtained. The Agency concluded that the data were ambiguous in certain details ofstatistical treatment (such as unspecified degrees offreedom for each entry in the data tables), that the results ofthe sediment data were particularly suspect, thereby necessitating further analyses, and that the field spiked sediment data did not support the lowest observed detection limit (LOD) of 100 ppb, (Refs. 65, 66, 67), as industry and EPA had agreed to in developing the original study protocol and design. For these reasons, the Agency believes that the study can not be relied upon to show that aryl phosphates are not present in the environment at levels of concern, and seeks comment through this ANPR as to theAgency's interpretation and analysis ofthe industry environmental monitoring study for the aryl phosphates in water and sediment.

In contrast to the suspected fate of aryl phosphates in hydraulic fluids, release from plasticizeruse is predominantly as solid waste to landfills. The fate ofsuch disposal is uncertain, but leaching ofsubstantial quantities ofaryl phosphates to surface
waters or groundwater is unlikely because they adsorb strongly to soil, have low water solubility, and tend to remain in plastic materials (Refs. 41, 52).

The amount ofaryl phosphates released from other sources is relatively low in comparison with the amounts from hydraulic fluid and plasticizer uses. Wastes from lubricant additive and miscellaneous uses appear tobe promarily disposed ofas solid waste and are primarily directed to landfills (Ref. 42).

4.Environmentaleffects. Although a great deal ofenvironmental effects testing has been performed on the aryl phosphates, the environmental effects data base is not complete for all category members. For instance, a complete comparative toxicity data base for each aryl phosphate in a selected species isnot available, nor has industry provided sufficient information to validate the majority of the existing studies. Some chronic aquatic toxicity and bioconcentration data exist for all aryl phosphates except TCP andqXP, although acute data exist for these two compounds (Ref.45). Sufficient bioconcentration data exist to reasonably predict the bioconcentration potential ofthe aryl phosphates in fish, but not inbenthic organisms (Ref. 45). Chronic aquatic toxicity data for algae

or benthic organisms are generally lacking. The Agency and industry initially agreed that the toxicity data of the most toxic aryl phosphate (DBDP) to the most sensitive aquatic organism (rainbow trout) could be used to assess the risk ofthe aryl phosphate exposure to all organisms in the aquatic environment for those compounds for which data do not exist.Because DBDP

was significantly more toxic to aquatic organisms than any ofthe other category members that have been tested, the Agency believed that an assessment based upon use ofDBDP data would provide an ample margin of safety with respect to the potential hazard ofother aryl phosphates.

However, the Agency has concluded that because the sediment detection limits, the quality assurance methods, the statistical treatment ofthe data generated, and the subsequent reliability of the monitoring study submitted by Monsanto are inadequate, more data are necessary to assess the no-observedeffect level (NOEL) and the subsequent environmental risk ofaryl phosphates.

The Agency believes that these data

can best be supplied by field monitoring studies which can evaluate whether or not trace concentrations ofaryl phosphates are injurious to the environment. The most common approach used for such evaluations includes conducting acute and chronic toxicity tests with water, sediment, or soil collected from a contaminated area and a contiguous noncontaminated area. The presence ofthe contaminant(s) is the only known difference between these areas. Such studies can also be conducted in the field using a mobile testing unit. Such evaluations have also used in-stream cage toxicity and bioconcentration tests with fish and macroinvertebrates, and comparisons

- of: species diversity and abundance in
water column and sediments; of standing crop (biomass); ofecosystem processes such as photosynthesis/ respiration rates; and ofcolonization and decolonization ofnatural and artificial substrates. Such methods have been used by Monsanto, other chemical companies, the electric power industry, and others to test effluents. As such, the methods are considered by industry and the Agency to be readily available and standard practice (Ref. 70).

A further advantage ofthis testing approach over conventional laboratory testing is the ability of the tests to indicate the extent to which the toxicity ofthese nine aryl phosphates is additive with each other and is multiplicative (synergistic) with otherenvironmental contaminants such as malathion and parathion. It isknown that certain aryl phosphate compounds, when used as pesticides, exhibit this multiplicative effect in the presence ofcontaminants such as malathion and parathion, primarily due to the reactivity oftheir thiol groups (Refs. 77, 78). As such, the Agency is reexamining the adequacy of comparing the rainbow trout MATC for DBDP independently with the concentration ofeach aryl phosphate measured in the water column or calculated in the sediment interstitial
water togauge environmental risk potential (the "ester by ester" approach proposed by Monsanto (Refs. 65, 66, 67). To address thisuncertainty, the Agency intends to propose supplemental testing under section 4(a)(1)(B) ofTSCA, including tissue residue analysis ofbiota exposed to water and sediments collected from sites known to contain aryl phosphates at measurable levels. In 

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this manner, the additive or synergistic effect of the aryl phosphates with other environmental contaminants such as pesticides can be further elucidated.

Because ofthe soil adsorption characteristics of the aryl phosphates and their tendency to remain bound in landfill-disposed plastic wastes, it is unlikely that they would present significant direct exposures to terrestrial organisms (Refs. 42, 55). However, the recent disposal practices employing estuarine dredge spoils, river sludge and
stream tailings as sources offertilizer and soil adjuvants on crop lands and reclamation sites may provide a source ofsignificant exposure to terrestrial organisms. Therefore, EPA is considering initiating rulemaking under section 4(a)(1)(B) at this time to require testing for effects on terrestrial organisms. Having described these types of available field studies, the Agency seeks comments through this ANPR as to which ofthese testing methods would be most appropriate for assessing the environmental effects ofaryl phosphates.

III. Industry Testing

1.Mutagenicity.FMC Corporation has submitted protocols (Ref. 62) to characterize the mutagenic potential of isopropyhenyl diphenyl phosphate using the six-linked recessive lethal (SLRL) mutagen assay in D.melanogasterafter the method ofBrusick (Ref. 5). Accumulated evidence has shown this
test to be the most sensitive among different test systems in Dmelanogaster (Ref. 56). The test measures the frequency oflethal mutations in approximately one-fifth ofthe total
genome ofthe fly.Testing began in April 1983 and a final report should be available to EPA early in 1984. The protocol called for exposure of at least 200 adult male files to two dose levels of the test substance and use ofboth negative and positive controls. A commercial grade ofIPDP is being tested. This test is being performed concurrently with the subchronic neurotoxicity study described below. If the result ofthis test is negative, no further gene mutation testing will be proposed according to the standard TSCA section 4 mutagenicity testing
sequence. If the results are positive, EPA will propose additonal testing ofIPDP to permit assessment ofmutagenic risk.

2. Subchronicneurotoxicity.FMC Corporation is currently conducting a go-day subchronic neurotoxicity study in the hen to provide data on the neurotoxicity ofIPDP under the testing guidelines set forth fortesting under the Federal Insecticide, Fungicide, and Rodenticide Act (43 FR 37374) which specify negative and positive controls and three dose levels. Triorthocresyl phosphate is being used as the positive control. The hen was selected as the test species because there are entensive background data on the hen and studies indicate that hens and humans have similar sensitivities to neurotoxic organophosphates (Refs. 38, 40). The birds will be examineddaily for signs of ataxia. At the conclusion ofthe 90-day period, the birds will be sacrificed and examined histologically for neural lesions.

3. Other pro visionsoftesting agreements.Industry has agreed to adhere to the proposed TSCA Good Laboratory Practice Standards published by the Agency, (44 FR 27334, May 9, 1979, 45 FR 77332, Nov. 21, 1980) and has agreed to permit laboratory audit inspections in accordance with the procudures outlined in TSCA section 11,
at the request of authorized representatives ofthe EPA. These inspections may be conducted for
purposes which include verification that testing has begun, that schedules are being met, that reports accurately reflect the raw data, and that the studies are being conducted with adequate quality

assurance procedures.

In addition, industry has agreed that all raw data, documentation, records, protocols, specimens, and reports generated as a result ofa study will be retained as specified in the proposed TSCA Good Laboratory Practice Standards published by the Agency and will be made available during an inspection or submitted to EPA if requested by EPA orits authorized representative.

Industry has agreed that TSCA section 14(b)(1)(a)(ii) governs Agency disclosure ofall test data submitted pursuant to these studies.

4. Timingoftesting.Industry began both the proposed 90-day subchronic neurotoxicity and mutagenicity tests of April 1, 1983. Final reports will be submitted toEPA within 12 months of study initiation for subchronic neurotoxicity, and within 9 months for mutagenicity.

IV. Issues forComment

1.One ofthe reasons given for the decline inproduction ofTCP, the aryl phosphate indicated by the 1972-74 NOlIS to be ofgreatest exposure concern, is the substitution ofaryl phosphates made from synthetic feedstocks. This may mean that the
exposure to aryl phosphates made from synthetic feedstocks is considerably greater than the 1973-74 NIOSH survey indicates. How many persons are exposed to these aryl phosphates and 

### what is thenature ofthe exposures? Are any new uses expected for any ofthese substances? What is theprojected market growth rate for these substances

over the next five years?Did any notable changes occur in the production volume oftheindividual substances

over the last five years?

2.EPAexpects to propose a 90-day subchronic neurotoxicity study for TCP, using 3dose levels.EPA favors testing TOCP. Will the analytical data received from the manufacturers ofcommercial TCPrelative to the TOCPcontent of their commercial product, when combined with theresults ofEPA's proposed 90-day subchronic neurotoxicity study using 3dose levels ofTOCP, enable theAgency to reasonably determine orpredict the neurotoxicity ofa TCP commercial product?

3.Should subchronic neurotoxicity testing ofTXP be required based upon indications that certain TXP isomers are acutely neurotoxic and the potential for TXPexposure through use in consumer products?

4. Do data implicate only TOCP as responsible for the suggested reproductive and teratogenic effects of TCP? Should individual TCPisomers be tested separately? Dothe existing data forTOCP provide sufficient evidence to indicate that the other aryl phosphates might cause teratogenic orreproductive effects?

5.Ifthere is substantial human exposure to a number ofaryl phosphates, considerable testingwould be necessary tocharacterize thetoxicity ofeach individual aryl phosphate. Is there away to reduce this testing burden bytesting a subset ofthe aryl phosphates, eitherby forming subcategories ofsimilar aryl phosphates

or bytesting a subset which spans the structural spectrum ofthe aryl phosphates category?

6.EPAbelieves themonitoring studies performed by Moftsanto were inadequate to demonstrate that aryl phosphates are not presentin the environment at levels which may present a risk to aquatic life. EPA seeks comment on the criteria upon which the Agency based its evaluation of the results ofthemonitoring study, such as the detection limit sensitivity, quality

assurance evaluation, location and selection ofsampling sites, statistical treatment ofthe data obtained, analytical method, and the interpretation ofthe results.

7.Because monitoring data alone will not allow the calculation ofa noobserved-effect level (NOEL), the Agency is considering issuing a site57458

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specific test protocol foraquatic environmental effects testing for the aryl phosphates which would employ water and sediment actually taken from designated sampling sites, with tissue sample analysis for aquatic and benthic organisms cultured in these media. Is this approach appropriate or should standard ecotoxicity testing protocols be used to fill in missing information? If site-specific testingis performed, which organisms should be cultured in orderto best quantify the levels ofaryl phosphates inwater and sediment? Should ecotoxicity testing for terrestrial organisms be proposed, in addition to aquatic toxicity testing, in order to more accurately evaluate the effect ofaryl phosphates on the environment?

8. Should oncogenicity testing ofthe substantial exposure aryl phosphates be required onlyifthe selected mutagenicity tests produce non-negative results, or should oncogenicity testing of these compounds be required immediately on the basis ofTSCA section 4(a)(1)(B) findings?

VI. References

(1)Aizenshtadt, vs. 1969. Toxicology ofvat residue oftricresylphosphate. Sb. Nauch. Tr. Kulbyshev. Nauch-Issled.Inst. 68, 92-93.

(2) Aldridge WN. 1954. Tricresylphosphate andcholinesterase. Biochem

### J.56:185-9.

(3) Aldridge WN, Barnes JM. 1961. Neurotoxic and biochemical properties of

some triarylphosphates. Biochem. Pharmacol. 6:177-188.

(4) BondyHF et al. 1960.A study on the
acute toxicity ofthe triaryl phosphates used

as plasticizers. Brit. 1.Industri. Med. 17:190- 200.

(5) Brusick,D. J.1980.Principles ofGenetic Toxicity.Plenum Press, New York, NY.

(6) Carpenter, HM,et al.1959. Toxicology ofa triarylphosphate oil. 1.Experimental toxicology. A.M.A. Arch. Ind.Health. 20:234-
252.

(7) Draper. HH,James, MF. andJohnson. BC. 1952. Tri-o-cresyl phosphate as a vitamin E antagonist in the lamb and rat.Fed. Proc.

1.204. (8) FMC. 1969a. January 8. Subacute oral neurotoxicity study ofMP-600.

(9) FMC. 1969b. January 8. Subacute oral neurotoxicity study ofKronitex 200.

(10) FMC. 1976. January 29. Acute toxicity screening tests Kronitex 50: synthetic triaryl phosphate, ICD/T-76-014. TRDB-0780-003.

(11) FMC. 1977a. September 15. Oral neurotoxicity study ofKronitex 200 B. ICG/ T-77-110.

(12) FMC. 1977b. May 5. Oral and dermal neurotoxicity study ofKronitex TXP.ICD/T77-062.

(13) FMC. 1977c. June 13. Oral neurotoxicity study ofKronitex 50. ICG/T-77-079.

(14) FMC. 1977d. June 13. Oral neurotoxicity study ofKronitex 100.ICG/T77-080.

(15) FMC. 1977e. September 15. Oral neurotoxicity study ofKronitex 200. ICG/T77-109. (16) FMC. 1977f. June 13. Oral neurotoxicity study ofKronitex 300. ICG/T-77-081.

(17) FMC. 1977g. May 5. Oral and dermal neurotoxicity ofKronitex TCP. ICG/T-77- 061.

(18) FMC. 1978a. November 17. Mutagenicity screening test: Salmonella/ microsomal assay ofKronitex TCP (C--8824- 29). ICGIT-78--151. TRDB 0780-005.

(19) FMC. 1978b. November 15. Mutagenicity screening test: Salmonellal microsomal assay ofKronitex TXP (C-8U4- 23). ICG/T-78-147. TRDB 0780-005.

(20) FMC. 1978c. January 9. Kronitex 20013. Mutagenicity screening test: Salmonellal microsomal assay (Ames test). ICG/T-78- 008. TRDB 0780-005.

(21) FMC. 1978d. October 13.Mutagenicity screening test: Salmonella/microsomal assay of trixylenyl phosphate ester (MP-600). Lot #77-1. ICG/T-78-114. TRDB 0780-005.

(22) FMC. 1978e. January 9. Kronitex 100B. Mutagenicity screening test: Salmonellal microsomal assay (Ames test). ICG/T-78- 005.TRDB 0780-005.

(23) FMC. 1978L April 24, 1978. Oral neurotoxicity ofKronitex TXP.#FCC7/79333. (Unpublished Report)

(24) FMC. 1979a. April 24, 1979. Oral toxicity ofMP 600. #FCC7/79332. (Unpublished Report)

(25) FMC. 1979b. April 24. 1979. Oral neurotoxicity of Kronitex 50.#FCC7/79331. (Unpublished Report)

(26) FMC. 1979c. April 24.1979. Oral neurotoxicity ofKronitex 100. ;tFCC7/79329. (Unpublished Report)

(27) FMC. 1979d. May 3, 1979. Oral neurotoxicity ofKronitex 200. &FCC7/79330. (Unpublished Report)

(28) FMC. 1979e. August 14, 1979. Oral neurotoxicity ofKronitex TCP 5479-78a. (Unpublished Report)

(29) USEPA. 1982. February 5. Memo from Kevin McCormack to aryl phosphates docket file. Minutes ofDecember 8, 1981. meeting with industry concerning monitoring protocol design.

(30) lanna P], Dyer KF. 1975a. Mutagenicity oforganophosphorous compounds in bacteria and Drosophila. Mutat. Res. 28:405-420.

(31) Hegyvary C., Csalay L., 1963. Endocrinological aspects ofpoisoning with tri-o-cresyl phosphate. Endokrinologie 44,62- 67.

(32) Henschler D. 1958.Die TrikresylphosphatvergiftuAg: Experimentelle Klarung vonProblemen der Atiologie and Pathogenese. Klin.Wschr. 36, 663-674.

(33) Henschler D, Bayer HH. 1958. Toxikologische Untersuchungen uber Triphenylphosphate und Triaryl phosphate

aus Mischunger homologer Phenole. NaunynSchemedebergs Arch. exp. Path. Pharmak. 233,512-517.

(34) Henschler D. 195.9. Beziehungen zwische chemischer Strucktur und Lahmungswirkung von Triarylphosphaten. Naunyn-Schmedeberg Arch. Exp. Path. Pharmak. 237, 459-472.

(35) Hine CH., et al. 1956. The neurotoxicity and anticholinesterase properties ofsome substituted phenyl phosphates.J.Pharmacol. Exp.Therap. 116,227-236.

(36) Johnson MK. 1975a. The delayed neuropathy caused by some organophosphorus esters: mechanism and challenge. CRC Critical Reviews in Toxicology pp. 289-316.

(37) Johnson MK. 1975b. Organophosphorous esters causing delayed neurotoxic effect. Arch. Toxicol. 34, 259-288.

(38) Johnson MK. 1975c. Structure-activity relationships for substrates and inhibitorsof hen brain neurotoxic esterase. Biochem. Pharmacol. 24:747-805.

(39) Lombardo P.Egry 1.1979. Identification and gas liquid chromatographic determination of arylphosphate residues in environmental samples. J.Assoc. Off.Anal. Chem. 62:47-51.

(40) Lotti M, Johnson MK. 1978. Neurotoxicity oforganophosphorus pesticides: predictions can bebased on in vitrostudies with hen and human enzymes. Arch. Toxicol. 41:215-221.

(41) Mayer FL, Adams WI, Finley MT, Michael PR,Mehrle PM, and Saeger VW. 1980. Phosphate ester hydraulic fluids: an aquaticenvironmental assessment ofPydraul 50E and 115E. Presented at ASTM Aquatic Symposium and submitted to EPA by Monsanto on March 6, 1980.

(42) Midwest Research Institute. 1979. May 15. Assessment ofthe need for limitation on triaryl and trialkylaryl phosphates. Draft Final Report, EPA Contract No.68--01-4313 (MRI Project No. 4309-L).

(43) Monsanto. 1979a. Good Laboratory Practices Manual.

(44) Monsanto. 1979b. Dec. 14 Letter toDr. Carol Mapes from Monsanto with enclosuies. TRDB 0780-010.

(45) Monsanto. 1981. August 7 letterfrom William J.Adams to Steven D. Newburg-Rinn with enclosures.

(46)NIOSH. 1980. August. Quarterly hazard
summary report.

(47) Saito C., et al. 1974 Tests ofthe subacute toxicity oftricresylphosphate (TCPI inrats. Oyo Yakuri 8:107-118.

(48) Sheaffer KK. 1977. November 14. Chief Aquatic Field Services Unit, Pennsylvania Department ofEnvironmental Resources. Toxicity ofaryl phosphates found in Kishacoquillas Creek, Pennsylvania. (Letter
toPH Howard, Syracuse Research Corporation).

(49) Stauffer Chemical Company. 1979. December 17.Toxicology data summaries and test protocols for stauffer Chemical Company aryl phosphates, i.e.. t-butyl phenyl diphenyl phosphates, tricresyl phosphate, trixylenyl phosphate, mixed tri-aryl phosphate, and isopropyl phenyl diphenyl phosphate. TRDB 0780-009.

(50) Stauffer Chemical Company. 1980. Projected aryl phosphate production estimates for 1980.

(51) Sutton WL et al. 1960. Studies on the industrial hygiene and toxicology of triphenyl phosphate, Arch. Environ. Health. 1:33-58.

(52) Touchette NW. 1978. Plasticizers. Modern Plastics Encylopedia. 1978-1979. 55(IOA):212

(53) USEPA. 1981. Sept. 28.Memo from Jason Toth to Irwin Baumel. Recommendations concerning aryl phosphates and implementation ofsection 4

test rules. 

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(54) USEPA. 1982. May 27. Personal communication between Kevin B. McCormack (EPA) and Harold K. Latourette (FMC Corporation). (Constitutes Confidential Business Information.)

(55) Versar Inc.1980. Untitled draft report

on aryl phosphates. Washington, D.C.: Office ofToxic Substances, U.S. Environmental Protection Agency, Contract No. 068-01-5791.

(56) Wurgler FE, Sobels FH, Vogel E. 1977. Drosophilaas assay system for detecting genetic changes. In: Handbook of mutagenicity test procedures. Kilbey BJ, et al. eds. Amsterdam: Elsevier/North Holland Biomedical Press, pp.335-373.

(57) Cavanaugh JB. 1983. Peripheral neuropathy caused by toxic agents. Crit. Rev. Toxicol. 2,365-417.

(58)McLaughlin J,Marliac JP, Verret MI, MutchlerMK, Fitzhugh OG, Garth, 0. 1963. The injection ofchemicals into the yolk sac offertile eggs prior to incubation as a toxicity
test.Toxicol. Appl. Pharmacol. 5:760-771.

(59)Mele JM, Jensh RP. 1977. Teratogenic effects oforally administered tri-o/cresyl phosphate on Wistar albino rats. Teratol. 15:32A.

(60)USEPA. 1982. September. Personal Communication between Kevin B. McCormack (EPA) and David Sundin (NIOSH), Cincinnati, Ohio.

(61) Monsanto. 1982. Phosphate ester surveillance sample collection method. Report No. ES-82-M-1. Project No. 43-000- 760.26. Dated January 28, 1982.

(62)FMC. 1981a. Protocols for sex-linked recessive lethal mutagenicity test in Drosphila melonogasterand subchronic neurotoxicity testin thehen. Letter from Tito Casieri (FMC) to Steven D. Newburg-Rinn (TRDB) with enclosures. Dated November 24, 1981.

(63) National Occupational Hazard Survey (NOHS) Vol. II.1977 DHEW (NIOSH) Pub. NO. 77-213.

(64) Final report ofthe 1982 industry-EPA phosphate ester aquatic surveillance
program. April 14, 1983. Submitted by Monsanto Company.

(65) USEPA. 1983. May 31. Memo to Steven D. Newburg-Rinn, from James Gilford. Review of aryl phosphates monitoring report.

(66) USEPA. 1983. May 18. Memo to Steven D. Newburg-Rinn from Joseph Carra. Review ofaryl phosphates sampling and analysis results.

(67) USEPA. 1983. June 13. Memo to Robert Boothfrom Denis L. Foerst. Review offinal report of the 1982industry-EPA Phosphate Ester Aquatic Survelliance Program.

(68) USEPA. 1982. Oct. 28. Memo to Joseph J.Merenda from Irwin Baumel. TCP testing needs.

(69) Pashkova, GH. 1973. Comparative evaluation and general toxic effect of tricresol, phosphorous oxychloride, and tricresyl phosphate. Vopr. Gig. Tr.Profpatol Toksikol Proizvod Ispol's Fosforog Plastif 1975, 86-90.

(70)Kimerle, RA., et al. A tiered approach
to aquatic safety assessment ofeffluents. (In press). Society ofEnvironmental Toxicology and Chemistry. Pergamon Press.

(71) USEPA. 1982. Analysis oflimited bioassays as potential carcinogenicity screening tests. EPA 68-01-6196.

(72) Gambridge, MG, Legator, MS. 1969. A host-mediated bioassay for the detection of mutagenic compounds. Proc. Soc. Exptl.Biol. Med. 130:831-834.

(73) Ames BN, .GurneyFG,Miller JA, Bartoch H. 1972a. Carcinogens as frameshift mutagens: Metabolities and derivatives of acetyl aminofluorene and other aromatic amine carcinogens. Proc. Nat'l.Acad. Sci. USA, 69:3128-3132.

(74) Ames BN, Sims P, Grover Pl. 1972b. Epoxides ofpolycyclic hydrocarbons are frameshift mutagens. Science 176:47-49.

(75) Huberman E, Aspiras L, Heidelberger C, GroverPL, Sims P.1971. Mutagenicity to mammalian cells ofexpoxides and other derivatives ofpolycyclic hydrocarbons. Proc. Nat'l. Acad. Sci. USA 68:3195-3199.

(76) Huberman E. Donovan PJ, DiPaolo JA. 1972. Mutation and transformation ofcultured mammalian cells by N-acetoxy-N-2-fluorenylacetamide. J.National Cancer Institute. 48:837-840.

(77) Hassan A, Dauterman WC. 1968. Studies on optically active isomers of0,0- diethyl malathion and 0,0-diethyl maloxon. Biochem. Pharmacol. 17:1431-1439.

(78) Dyte CE, Rowlands DG. 1967. Specificity ofinsecticide synergists. Proc. Brit. Insectic. Furigi. Conf. pp. 344-354.

V1. Public Record

The EPA has established a public record for this testing decision (docket number OPTS-42038) which is available for inspection in the OPTS Reading Room from 8:00 a.m. to 4:00 p.m. Monday through Friday (except legal holidays) in Rm. E-107, 401 M St., SW., Washington, DC 20460.The record includes the following information:

(1)Federal Register noticecontaining the designation of thearyl phosphates to the priority list and all comments on aryl phosphates received inresponse to that notice.

(2)Communications, consisting ofletters,
contact reports of telephone conversations, and meeting summaries ofAgency-industry and Agency-public meetings.

(3)Industry testingprotocols and methods: (a) Monsanto Good Laboratory Practices Manual (Environmental Analysis Laboratory).

(b) Monsanto Good Laboratory Practices Manual (Environmental Assessment Laboratory).

(c) Monsanto Standard Operating Procedure for determination ofsample stability under conditions ofpreservation and storage.

(d)Monsanto Stability StudyofNatural Sediment Samples Preserved by Frozen Storage.

(e) Monsanto Standard Operating Procedure forHomogenizing, Subdividing and Preserving Sediment Samples.

(f)Monsanto Standard Practice for Determination ofSorption Constants in Soil and Sediments.

(g)FMC Protocols for Sex-Linked Recessive Lethal Mutagenicity Testin Drosophilamelanogaster and Subchronic Neurotoxicity Studyin the Hen.

(h) Final Report ofthe 1982Industry-EPA Phosphate EsterAquatic Surveillance Program.

(4)Published andunpublished data.

Thepublic record enumerated above includes basic information considered by the Agency in developing this decision. The Agency will supplement the record periodically with additional relevant information received. (Sec. 4,90 Stat. 2003; (15U.S.C. 2601))

Dated: December21, 1983. William D.Ruckelshaus, Administrator.

[FR Doc. 83-34450 Filed 12-28-3; 8:45 am]

BILLING CODE 6560-50-1 

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