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

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 799

[OPTS-42038; BH-FRL 2458-1]

Aryl Phosphates; Response to the

Interagency Testing Committee

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Advance Notice of Proposed

Rulemaking.

SUMMARY: In the Second Report of the

Interagency Testing Committee (ITC),

transmitted to the Administrator of the

EPA on April 10, 1978, the ITC

designated the aryl phosphate category

for testing consideration. The

manufacturers of aryl phosphates are

currently conducting a testing program

that EPA believes will provide adequate

data in some of the 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

this Notice.

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 of Pesticides 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 8:00 a.m. to 4:00 p.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) of the Toxic Substances

C',ntrol Act (TSCA) (Pub. L. 94-469, 90

Stat. 2003 et seq., 15 U.S.C. 2601 et seq.]

authorizes the EPA to promulgate

regulations requiring testing of chemical

substances and mixtures in order to

develop data relevant to determining the

risks that such chemicals may present to

health and the environment. Section 4(e)

of TSCA established an Interagency

Testing Committee (ITC) to recommend

to the EPA a list of chemicals to be

considered for the promulgation of

testing rules under section 4(a) of the

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

ITC defined "aryl phosphates" as

phosphate esters of phenol or of alkylsubstituted phenols. Tri-aryl and mixed

alkyl-aryl esters are included, but trialkyl esters are excluded. The ITC

recommended that the aryl phosphates

be considered for testing for the

following health effects: carcinogenicity,

mutagenicity, teratogenicity and chronic

effects (with special emphasis on

neurotoxicity). In addition, the ITC also

recommended that a epidemiology study

be considered because of the large-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 for aryl phosphates to persist

in the aquatic environment, to

bioaccumulate in aquatic species, and

the potential effects of aryl phosphates

on aquatic and terrestrial systems. This

Advance Notice of Proposed

Rulemaking provides EPA's response to

the ITC's designation of the aryl

phosphates as required by TSCA section

4(e).

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

Administrator shall by rule require

testing of a chemical substance to

develop appropriate test data if the

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

risk of injury to health or the environment,

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

effects of such manufacture, distribution in commerce, processing,

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

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

effects is necessary to develop 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 is or may be significant or substantial human exposure

to such substance or mixture,

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

effects of the manufacture, distribution in commerce, processing,

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

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

effects is necessary to develop such data.

EPA uses a weight of evidence

approach in making a section

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

exposure and toxicity information are

considered to make the finding that the

chemical may present an unreasonable

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

EPA considers only production,

exposure, and release information to

determine if there is substantial

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 is a suspicion of a hazard, under

section 4(a)(1)(B) EPA can require

testing whether or not there are data

suggesting adverse effects if the 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 if existing information is

adequate to reasonably determine or

predict the effects of human exposure to,

or environmental release of, the

chemical. In making the third finding,

that testing is necessary, EPA considers

whether ongoing testing will satisfy the

information needs for the chemical and

whether testing which the Agency might

require would be capable of developing

the necessary information.

EPA's process for determining when

these findings can be made is described
Federal Register / Vol. 48, No. 251 / Thursday, December 29, 1983 / Proposed Rules

in detail in EPA's first and second

proposed test rules as published in the

Federal Register of July 18, 1980 (45 FR

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

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

discussed in 45 FR 48528, and the

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

46 FR 30300.

In evaluating the ITC's testing

recommendations concerning 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 by manufacturers of aryl

phosphates under the TSCA section 8(a)

Preliminary Assessment Information

Rule (40 CFR Part 712); and published

and upublished data available to the

Agency, including information submitted

under the TSCA section 8(d) Health and

Safety Data Reporting Rule (40 CFR Part

716).

The nine aryl phosphates listed below

have been specifically identified by

industry as being 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

(also known 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 and Issues

A. Development of Rulemaking

The Agency has reviewed available

data which indicate that human

exposure to aryl phosphates as a category may be substantial; however,

the ambiguous nature of the information

available regarding changes in the

production, use and subsequent human

exposure to aryl phosphates, and the

lack of reliable environmental

monitoring data have prompted EPA to

issue an Advance Notice of Proposed

Rulemaking tANPR) for the aryl

phosphates, rather than issue a

proposed test rule.

Should data be submitted which

indicate that exposure levels are biologically insignificant or that the

number of people exposed to the aryl

phosphates is low, the Agency will

reconsider its decision to proceed with

this rulemaking action. EPA will, in the

intervening period between publication

of this ANPR and inssuance of a proposed section 4(a) rule, attempt to

refine the exposure data and reconsider

its decisions in light of any additional

data that become available.

EPA, in publishing this ANPR, 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 of the aryl

phosphates. The bases for the suggested

findings, and for the test3 under

consideration, are discussed below.

B. Preliminary Findings

1. Potential human exposure. The

Agency considers that publicly

available information indicates that the

nine aryl phosphates listed above may

meet the criteria for a finding under

section 4(a)[l(1)(i): that the chemicals

are produced in substantial quantities

and that there is or may be substantial

human exposure (see Table 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 and 50. Re. 46. Confidential industry estimates show a substantial drop in production since 1977. 'Reported jointly by industry. Subjecto regulation by FDA under 40 CFR Part 175,300; 380; 390; 176.170 and 177.1210

Most human exposure to aryl

phosphates occurs in the workplace. The

ITC cited the 1972-74 National

Occupational Hazard Survey (NOHS),

published in 1977 by the National

Institute for Occupational Safety and

Health (NIOSH) (Ref. 63), as one of their reasons for recommending testing of the

aryl phosphates.

Aryl phosphates are used primarily as fire retardant plasticizers (36.5 million

pounds in 1977), and as hydraulic 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 90 percent of the 36.5 million

pounds of aryl phosphates used as flame

retardant plasticizers are used in the

processing of polyvinyl chloride (Ref.

52). The remaining ten percent is used in

various other plastics. No major

difference in exposure profile would be

expected due to the particular type of

polymer in which the aryl phosphates are used. Certain procedures used to

manufacture PVC products, such as calendering, roll coating, film casting.

and dip molding, may afford

opportunities for exposure to plasticizer

mists containing aryl phosphates (Ref.

42).

Fire resistant hydraulic fluids

(excluding brake fluids) based on phosphate esters are used primarily in

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 fire hazard if the hydraulic

system developed leakage. The steel

and automotive industries account for

65-70 percent of aryl phosphate

hydraulic fluid uses (Ref. 42). Leakage of

fire resistant hydraulic fluids containing

phosphate esters may expose workers in

the basic metals industries, the

automotive industry, die casting

operations and steel foundries, and

military applications (Ref. 55). Evidence

that such leakage is not infrequent is

provided by estimates that as much as

80 percent of the annual use of

phosphate esters in hydraulic fluids may

be for replacement of losses (26.8 million

pounds in 1977) (Ref. 55).

NIOSH estimated in the 1972-74

National Occupational Hazard Survey

(NOHS) that up 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 of products in general use in the workplace which the surveyor

speculated might contain aryl

phosphates. EPA believes that, in this

instance, this "generic" NIOSH

methodology may have overestimated

actual aryl phosphate exposure by at

least a factor of ten (Ref. 60). EPA

believes that more recent NIOSIHI

estimates, based on actual observed use of aryl phosphates and the presence in

the workplace of tradename products

known to contain aryl phosphates, are

57453
57454 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 of the

survey indicate substantial human

exposure to some aryl phosphates.

However, it is not clear that the actual

and tradename survey results provide

an accurate picture of human exposure

due to changes in the market condition

for aryl phosphates over the last 5 years

(Table 1).

For instance, the production and use

of TCP reportedly has declined

dramatically since the 1972-74 NOHS

was performed (Ref. 54). This decline

has occurred as a result of the greater

availability and economy of synthetic

feedstocks and the intentional phase-out

of TCP from certain uses due to the

neurotoxicity of its ortho isomer (TOCP).

Manufacturers of TCP cite this decline as evidence that exposure to TCP has

also declined dramatically. If exposure

has decreased as much as production, it

would be more than an order of

magnitude lower than indicated by the

1972 NOHS and may not be considered

substantial by EPA. However,

manufacturers of TCP admit that their

knowledge of some of the downstream

uses of TCP is very limited and that it is

possible that small amounts (several

percent) of TCP could be added to

various specialty lubricants or other

similar products to which a substantial

number of persons might be exposed

(Ref. 54). The manufacturers believe that

the health significance of such

exposures would be minimal, but have

been unable to date to fully support this

contention. A new NIOSH survey is

currently being conducted; however,

results will not be available until at

least 1984. The replacement of TCP 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. If current

exposure estimates for these six aryl

phosphates indicate substantial TSCAcovered exposure, EPA would expect to

make substantial exposure findings

under section 4(a)(1)(B)(i) of TSCA for

each of these aryl phosphates.

(Exposure due to uses regulated under

the Federal Food, Drug and Cosmetic

Act are not covered by TSCA).

With the possible exception of TCP,

significant direct consumer exposure is

unlikely because other aryl phosphates

do not appear to be in consumer

products except as plasticizers. Because

of the tendency of the aryl phosphates

to remain bound within the polymer

matrix, they are not expected to leach or volatilize from plastics in which they are

contained in sufficient quantities to

cause concern due to this mode of

exposure (Ref. 42). The NOHS lists a

number of products which contained

TCP which might be expected to have

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

likely result in direct human 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. Adequacy of information and need

for health effects testing. EPA has

approached its analysis of human health

concerns for the aryl phosphates from

the standpoint of both potential

unreasonable risk (section 4(a)(1)(A))

and substantial production and

exposure (section 4(a)(1)(B)). (See Table

2). The specific justifications for each

approach are discussed below.

TABLE 2.-SUMMARY OF TENTATIVE HEALTH

EFFECTS TESTING REQUIREMENTS

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

Chronic/subchronic.. No ............. All.'

Mutagenicity .............. IPDP 4 ...................... AII.3''

Oncogenicity .............. No ............................. Triggered.'

Teratogenicity ............ TCP .......................... All except NPDP,

DBDP. TPP. Reproductive . TCP............ All.'

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

Epidemiology ............. No 7 .......................... No.7

I "May present an unreasonable risk" finding. 'Substantial production and substantial or significant human exposure finding. 3 All aryl phosphates meeting substantial production and exposure criteria. ' Ongoing industry testing meets testing needs of IPDP for gene mutations. If results are positive, EPA will propose higher tiered testing of IPDP to permit assessment of muta- genic risk. If substantial production and exposure criteria are met for IPDP, EPA will propose chromosomal abberations testing of IPDP. 'Testing requirement dependent upon results of mutagenicity and subchronic testing. t Ongoing industry testing meets testing needs of IPDP for neurotoxicity. EPA does not believe a suitable study population can be identified at this time.

a. Chronic toxicity. 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 of 28 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 of rats resulting from

inhalation for up to 90 days ranged from

450 ppm to 50,000 ppm with typical

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 of 90-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 of the aryl phosphates tested with

the exception of IPDP. These assays are

inadequate to completely characterize

the mutagenic potential of the aryl

phosphates, however, because the Ames

test is not generally recognized as a

stopping point in the tier testing of large

exposure chemicals. Therefore, EPA is

considering requiring that TCP, 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 the Agency

do not support testing under section

4(a)(1)(A) at this time.

Test results on IPDP were negative in

the Ames test and negative without

activation in the mouse mammalian cell

gene mutation test using lymphoma cells

(Ref. 49). However, IPDP results were

equivocal with activation in the mouse

lymphoma test. As a result, EPA

believes an additional confirmatory

gene mutation test is necessary for IPDP.

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 of IPDP 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. EPA believes 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, if any, 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 if the results of the

mutagenicity testing are positive or if

the toxicity shown in the organ-specific

subchronic testing indicates a likelihood

of oncogenicity. 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 of scientific investigation as

to the correlation between mutagenicity

and carcinogenicity (Ref. 71).

Prior to 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 in vivo system, the

host-mediated assay, to test for

potential mutagenicity (Ref. 72); and in

vitro testing of reactive forms of

carcinogenic chemicals (Refs. 73-76)

which resulted in a demonstration of the

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 of a chemical may reasonably

be predicted from the results of a

mutagenicity testing scheme for the

purposes of setting priorities for

conducting oncogenicity bioassays

under section 4 of TSCA. The Agency

requests public comment on this issue.

d. Terotogenicity. SOme data are

available relating to the teratogenic

potential of triorthocresyl 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 of TCP because 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 of prenatal

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 to inducing 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 of TCP is supported by

the suggestion that TOCP may interfere

with vitamin E metabolism (see Unit

II.B.2.e., Reproductive Effects, below);

vitamin E deficiency during gestation

produces severe and often lethal

syndromes of congenital malformations

in laboratory animals (Ref. 7). Thus, the

Agency intends to require teratogenicity

testing of TCP under section 4(a)(1)(A)

of TSCA. Because the Agency lacks data

on the teratogenicity of TXP, 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. Reproductive effects. 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 of tricresol, 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) of tricresyl 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 of degeneration of seminiferous

tubules was reported in three of four

testes examined from twelve dogs which

had been exposed to 20 subcutaneous

injections over a 4 to 5-week period of a

mixture of phosphate esters of cresols,

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 of early

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 of 0.72 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 of TCP appears to be

similar to features of tocols possessing

vitamin E activity, Carpenter suggested

the 'ossibility that interference with

vitamin E metabolism may be

responsible for toxic effects observed

following exposure to TCP (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 of animals on test were either

too few or not reported; (3) the duration

of exposure was either not reported or

too short; (4) the dosing of dogs which

showed evidence of testicular

degeneration wvas performed by

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subcutaneous injection, which is not

representative of potential 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.

If TCP or TOCP, indeed, are vitamin E

antagonists, their potential for inducing

adverse reproductive effects should be

of concern. Vitamin E is important in the

maintenance of normal testicular

function and is critical in the normal

development of offspring. 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 of reproductive toxicity on one category member raises some suspicion

of this hazard from the others, under

4(a)(1)(A) EPA would propose

reproductive effects testing only on TCP

at this time because of the weaknesses

of the reproductive effects studies of

TCP described above. If the results of

the study on TCP are 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 of certain

aryl phosphates (TCP, TXP, IPDP) is

well documented (Refs. 33-37). With the

exception of subchronic 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 of commercial IPDP as discussed in Unit III of this notice.

The results of this study will be

sufficient to reasonably predict or determine the neurotoxicity of IPDP.

The 2,3- and 2,4- isomers of TXP 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 TXP inadequate to assess the chronic neurotoxicity of TXP

because of the small numbers of animals

tested, the limited duration of exposure,

and the low levels of exposure to which

the test animals were subjected.

Because of the indications of neurotoxic

potential and lack of adequate data,

EPA expects to propose subchronic

neurotoxicity testing of a commercial

mixture of the isomers of TXP under

TSCA section 4(a)(1)(A).

The Agency has concluded that,

although data on the acute neurotoxicity

of TCP 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 of 28-day duration

(Refs. 17, 28), which are not sufficient to

adequately assess the effects of TCP

over time for a subchronic neurotoxic

effect. Industry's 90-day subchronic

neurotoxicity study in the hen on

isopropylphenyl diphenylphosphate

(IPDP) (see Unit 1II. 2.) will use

triorthocresyl phosphate (TOCP) as the

positive control. The neurotoxic activity of TCP has been conclusively'linked to

its ortho isomer, TOCP (Ref. 33).

Therefore, characterizing the subchronic

neurotoxicity of TOCP should allow

EPA to reasonably predict the

subchronic neurotoxicity of TCP whose

TOCP content is known. However, the

use of TOCP as a positive control in the

ongoing IPDP study will involve only

one dose level; this will not permit the

determination of a dose-response curve.

Therefore, EPA expects to propose

under TSCA section 4(a)(1)(A) a 90-day

subrhronic neurotoxicity study using three dose levels of TOCP. Analytical

data on each manufacturer's commercial

TCP product will allow the Agency to

assess the potential toxicity of the

commercial TCP product relative to the

content of TOCP within that product. In

addition, because the available data are

inadequate for assessing the

neurotoxicity of TXP and TCP, the

Agency is considering proposing such

testing under TSCA section 4(a)(1)(B) for

these two aryl phosphates if the

substantial production and exposure

findings are met.

g. Epidemiology. EPA believes that an

epidemiological study of workers

exposed to aryl phosphates could

potentially provide reliable data for

evaluating the potential risk of

neurologic harm from such exposure. EPA attempted to define a suitable

study population through extensive

contractor efforts. Excessive problems in terms of valid cohort identification

were presented, however. The number

of workers involved in manufacturing is

too small to permit a valid study for the

observation of neurotoxic effects, and

the number of processors is so large as

to present severe logistical problems. Further attempts to define a cohort were

not recommended by the contractor

(Ref. 53). Because of the 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 of aryl

phosphates in hydraulic fluids were

used to replace losses due to leakage

from pumps, primarily in the heavy

metal and automotive industries (Ref.

42). The fate of such leakage may be

aqueous discharge, landfill, and/or

reclamation. Typically, each hydraulic

machine has a catch basin or other

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 for reclamation.

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 aryl phosphates 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,

EPA believes that release to both

environments is possible. The

manufacturers of the aryl phosphates

question this conclusion. They state that

it is unrealistic to assume that

substantial amounts of hydraulic fluid

enter natural aquatic systems without

treatment. In support of their position,

the aryl phosphates manufacturers

submitted a monitoring study conducted

by Monsanto which reported that there

was a negligible or nonexistent release

of aryl 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 for the aryl phosphates. EPA

did not believe that the original data

submitted were adequate to support

industry's position of little or no

environmental release. In the Agency's

view, the study submitted contained too

few sampling sites, was conducted in a number of locations where the Agency

considered detection of aryl phosphates

unlikely, and did not provide a level of

detection sensitive enough to

adequately characterize the presence

and extent of aryl phosphate

contamination (Ref. 29).

To resolve the uncertainty regarding

the amount of aryl phosphates released

to the environment and the levels of aryl

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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 in which aryl phosphates

have never been monitored but might be

present (inner harbor 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 to procedures set

forth in Monsanto's Good Laboratory

Practices Manual (Ref. 43).

Monsanto proposed a detection limit

of 0.1 ppb for aryl phosphates in water.

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 of 100 ppb.

However, upon receipt of the results

of the 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 of statistical treatment (such as

unspecified degrees of freedom for each

entry in the data tables), that the results

of the 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 the Agency's interpretation and

analysis of the 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 of such disposal is

uncertain, but leaching of substantial

quantities of aryl 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 of aryl 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 to be

promarily disposed of as solid waste

and are primarily directed to landfills

(Ref. 42).

4. Environmental effects. Although a

great deal of environmental 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 is not 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 and qXP,

although acute data exist for these two

compounds (Ref. 45). Sufficient

bioconcentration data exist to

reasonably predict the bioconcentration

potential of the aryl phosphates in fish,

but not in benthic 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 of the 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 of the other

category members that have been

tested, the Agency believed that an

assessment based upon use of DBDP

data would provide an ample margin of

safety with respect to the potential

hazard of other aryl phosphates.

However, the Agency has concluded

that because the sediment detection

limits, the quality assurance methods,

the statistical treatment of the 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 of aryl phosphates.

The Agency believes that these data

can best be supplied by field monitoring

studies which can evaluate whether or

not trace concentrations of aryl

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 of the 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); of ecosystem

processes such as photosynthesis/

respiration rates; and of colonization

and decolonization of natural 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 of this testing

approach over conventional laboratory

testing is the ability of the tests to

indicate the extent to which the toxicity

of these nine aryl phosphates is additive

with each other and is multiplicative

(synergistic) with other environmental

contaminants such as malathion and

parathion. It is known that certain aryl

phosphate compounds, when used as

pesticides, exhibit this multiplicative

effect in the presence of contaminants

such as malathion and parathion,

primarily due to the reactivity of their

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 of each aryl phosphate

measured in the water column or

calculated in the sediment interstitial

water to gauge environmental risk

potential (the "ester by ester" approach

proposed by Monsanto (Refs. 65, 66, 67).

To address this uncertainty, the Agency

intends to propose supplemental testing

under section 4(a)(1)(B) of TSCA,

including tissue residue analysis of biota

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 of the 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 of fertilizer

and soil adjuvants on crop lands and

reclamation sites may provide a source

of significant 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 of these testing methods would

be most appropriate for assessing the

environmental effects of aryl

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. melanogaster after

the method of Brusick (Ref. 5).

Accumulated evidence has shown this

test to be the most sensitive among

different test systems in D melanogaster

(Ref. 56). The test measures the

frequency of lethal mutations in

approximately one-fifth of the total

genome of the 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 of both

negative and positive controls. A

commercial grade of IPDP is being

tested. This test is being performed

concurrently with the subchronic

neurotoxicity study described below. If

the result of this 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 of IPDP to

permit assessment of mutagenic risk.

2. Subchronic neurotoxicity. FMC

Corporation is currently conducting a go-day subchronic neurotoxicity study in

the hen to provide data on the

neurotoxicity of IPDP under the testing

guidelines set forth for testing 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 examined daily for signs of

ataxia. At the conclusion of the 90-day

period, the birds will be sacrificed and

examined histologically for neural

lesions.

3. Other pro visions of testing

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 of the 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 of a 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 or its authorized

representative.

Industry has agreed that TSCA

section 14(b)(1)(a)(ii) governs Agency

disclosure of all test data submitted

pursuant to these studies.

4. Timing of testing. Industry began

both the proposed 90-day subchronic

neurotoxicity and mutagenicity tests of

April 1, 1983. Final reports will be

submitted to EPA within 12 months of

study initiation for subchronic

neurotoxicity, and within 9 months for

mutagenicity.

IV. Issues for Comment

1. One of the reasons given for the

decline in production of TCP, the aryl

phosphate indicated by the 1972-74

NOlIS to be of greatest exposure

concern, is the substitution of aryl

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 the nature of the exposures? Are

any new uses expected for any of these

substances? What is the projected

market growth rate for these substances

over the next five years? Did any

notable changes occur in the production

volume of the individual substances

over the last five years?

2. EPA expects to propose a 90-day

subchronic neurotoxicity study for TCP,

using 3 dose levels. EPA favors testing

TOCP. Will the analytical data received

from the manufacturers of commercial

TCP relative to the TOCP content of

their commercial product, when

combined with the results of EPA's

proposed 90-day subchronic

neurotoxicity study using 3 dose levels

of TOCP, enable the Agency to

reasonably determine or predict the

neurotoxicity of a TCP commercial

product?

3. Should subchronic neurotoxicity

testing of TXP be required based upon

indications that certain TXP isomers are

acutely neurotoxic and the potential for

TXP exposure through use in consumer

products?

4. Do data implicate only TOCP as

responsible for the suggested

reproductive and teratogenic effects of

TCP? Should individual TCP isomers be

tested separately? Do the existing data

for TOCP provide sufficient evidence to

indicate that the other aryl phosphates

might cause teratogenic or reproductive

effects?

5. If there is substantial human

exposure to a number of aryl

phosphates, considerable testing would

be necessary to characterize the toxicity

of each individual aryl phosphate. Is

there a way to reduce this testing

burden by testing a subset of the aryl

phosphates, either by forming

subcategories of similar aryl phosphates

or by testing a subset which spans the

structural spectrum of the aryl

phosphates category?

6. EPA believes the monitoring studies

performed by Moftsanto were

inadequate to demonstrate that aryl

phosphates are not present in 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 of the monitoring study, such as

the detection limit sensitivity, quality

assurance evaluation, location and

selection of sampling sites, statistical

treatment of the data obtained,

analytical method, and the

interpretation of the results.

7. Because monitoring data alone will

not allow the calculation of a noobserved-effect level (NOEL), the

Agency is considering issuing a site57458
Federal Register / Vol. 48. No. 251 / Thursday, December 29, 1983 / Proposed Rules

specific test protocol for aquatic

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 order to

best quantify the levels of aryl

phosphates in water and sediment?

Should ecotoxicity testing for terrestrial

organisms be proposed, in addition to

aquatic toxicity testing, in order to more

accurately evaluate the effect of aryl

phosphates on the environment?

8. Should oncogenicity testing of the

substantial exposure aryl phosphates be

required only if the selected

mutagenicity tests produce non-negative

results, or should oncogenicity testing of

these compounds be required

immediately on the basis of TSCA

section 4(a)(1)(B) findings?

VI. References

(1) Aizenshtadt, vs. 1969. Toxicology of vat

residue of tricresylphosphate. Sb. Nauch. Tr.

Kulbyshev. Nauch-Issled. Inst. 68, 92-93.

(2) Aldridge WN. 1954. Tricresylphosphate

and cholinesterase. Biochem J. 56:185-9.

(3) Aldridge WN, Barnes JM. 1961.

Neurotoxic and biochemical properties of

some triaryl phosphates. Biochem.

Pharmacol. 6:177-188.

(4) Bondy HF et al. 1960. A study on the

acute toxicity of the triaryl phosphates used

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

200.

(5) Brusick, D. J. 1980. Principles of Genetic

Toxicity. Plenum Press, New York, NY.

(6) Carpenter, HM, et al. 1959. Toxicology

of a triaryl phosphate oil. 1. Experimental

toxicology. A.M.A. Arch. Ind. Health. 20:234-

252.

(7) Draper. HH, James, MF. and Johnson.

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 of MP-600.

(9) FMC. 1969b. January 8. Subacute oral

neurotoxicity study of Kronitex 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 of Kronitex 200 B. ICG/

T-77-110.

(12) FMC. 1977b. May 5. Oral and dermal

neurotoxicity study of Kronitex TXP. ICD/T77-062.

(13) FMC. 1977c. June 13. Oral neurotoxicity

study of Kronitex 50. ICG/T-77-079.

(14) FMC. 1977d. June 13. Oral

neurotoxicity study of Kronitex 100. ICG/T77-080.

(15) FMC. 1977e. September 15. Oral

neurotoxicity study of Kronitex 200. ICG/T77-109.

(16) FMC. 1977f. June 13. Oral neurotoxicity

study of Kronitex 300. ICG/T-77-081.

(17) FMC. 1977g. May 5. Oral and dermal

neurotoxicity of Kronitex TCP. ICG/T-77-

061.

(18) FMC. 1978a. November 17.

Mutagenicity screening test: Salmonella/

microsomal assay of Kronitex TCP (C--8824-

29). ICGIT-78--151. TRDB 0780-005.

(19) FMC. 1978b. November 15.

Mutagenicity screening test: Salmonellal

microsomal assay of Kronitex 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 of Kronitex TXP. #FCC7/79333.

(Unpublished Report)

(24) FMC. 1979a. April 24, 1979. Oral

toxicity of MP 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 of Kronitex 100. ;tFCC7/79329.

(Unpublished Report)

(27) FMC. 1979d. May 3, 1979. Oral

neurotoxicity of Kronitex 200. &FCC7/79330.

(Unpublished Report)

(28) FMC. 1979e. August 14, 1979. Oral

neurotoxicity of Kronitex TCP 5479-78a.

(Unpublished Report)

(29) USEPA. 1982. February 5. Memo from

Kevin McCormack to aryl phosphates docket

file. Minutes of December 8, 1981. meeting

with industry concerning monitoring protocol

design.

(30) lanna P], Dyer KF. 1975a.

Mutagenicity of organophosphorous

compounds in bacteria and Drosophila.

Mutat. Res. 28:405-420.

(31) Hegyvary C., Csalay L., 1963.

Endocrinological aspects of poisoning with

tri-o-cresyl phosphate. Endokrinologie 44, 62-

67.

(32) Henschler D. 1958. Die

TrikresylphosphatvergiftuAg: Experimentelle

Klarung von Problemen 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 of some

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 inhibitors of

hen brain neurotoxic esterase. Biochem.

Pharmacol. 24:747-805.

(39) Lombardo P. Egry 1. 1979. Identification

and gas liquid chromatographic

determination of aryl phosphate residues in

environmental samples. J. Assoc. Off. Anal.

Chem. 62:47-51.

(40) Lotti M, Johnson MK. 1978.

Neurotoxicity of organophosphorus

pesticides: predictions can be based on in

vitro studies 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

aquatic environmental assessment of Pydraul

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 of the 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 to Dr.

Carol Mapes from Monsanto with enclosuies.

TRDB 0780-010.

(45) Monsanto. 1981. August 7 letter from

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 of the

subacute toxicity of tricresylphosphate (TCPI

in rats. Oyo Yakuri 8:107-118.

(48) Sheaffer KK. 1977. November 14. Chief

Aquatic Field Services Unit, Pennsylvania

Department of Environmental Resources.

Toxicity of aryl phosphates found in

Kishacoquillas Creek, Pennsylvania. (Letter

to PH 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 of section 4

test rules.

57459
Federal Register / Vol. 48, No. 251 / Thursday, December 29, 1983 / Proposed Rules

(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

of Toxic Substances, U.S. Environmental

Protection Agency, Contract No. 068-01-5791.

(56) Wurgler FE, Sobels FH, Vogel E. 1977.

Drosophila as 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,

Mutchler MK, Fitzhugh OG, Garth, 0. 1963.

The injection of chemicals into the yolk sac

of fertile eggs prior to incubation as a toxicity

test. Toxicol. Appl. Pharmacol. 5:760-771.

(59) Mele JM, Jensh RP. 1977. Teratogenic

effects of orally 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 melonogaster and subchronic

neurotoxicity test in the hen. 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 of the 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

of aryl phosphates sampling and analysis

results.

(67) USEPA. 1983. June 13. Memo to Robert

Booth from Denis L. Foerst. Review of final

report of the 1982 industry-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 of effluents. (In

press). Society of Environmental Toxicology

and Chemistry. Pergamon Press.

(71) USEPA. 1982. Analysis of limited

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, .Gurney FG, 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 of polycyclic hydrocarbons are

frameshift mutagens. Science 176:47-49.

(75) Huberman E, Aspiras L, Heidelberger

C, Grover PL, Sims P. 1971. Mutagenicity to

mammalian cells of expoxides and other

derivatives of polycyclic hydrocarbons. Proc.

Nat'l. Acad. Sci. USA 68:3195-3199.

(76) Huberman E. Donovan PJ, DiPaolo JA.

1972. Mutation and transformation of cultured

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 of 0,0-

diethyl malathion and 0,0-diethyl maloxon.

Biochem. Pharmacol. 17:1431-1439.

(78) Dyte CE, Rowlands DG. 1967.

Specificity of insecticide 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 notice containing the

designation of the aryl phosphates to the

priority list and all comments on aryl

phosphates received in response to that

notice.

(2) Communications, consisting of letters,

contact reports of telephone conversations,

and meeting summaries of Agency-industry

and Agency-public meetings.

(3) Industry testing protocols 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 of sample

stability under conditions of preservation and

storage.

(d) Monsanto Stability Study of Natural

Sediment Samples Preserved by Frozen

Storage.

(e) Monsanto Standard Operating

Procedure for Homogenizing, Subdividing and

Preserving Sediment Samples.

(f) Monsanto Standard Practice for

Determination of Sorption Constants in Soil

and Sediments.

(g) FMC Protocols for Sex-Linked

Recessive Lethal Mutagenicity Test in

Drosophila melanogaster and Subchronic

Neurotoxicity Study in the Hen.

(h) Final Report of the 1982 Industry-EPA

Phosphate Ester Aquatic Surveillance

Program.

(4) Published and unpublished data.

The public 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; (15 U.S.C. 2601))

Dated: December 21, 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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