33178 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 799

[OPPTS–42187; FRL–4869–1]

RIN 2070–AC76

Proposed Test Rule for Hazardous Air

Pollutants

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA is proposing a test rule

under section 4(a) of the Toxic

Substances Control Act (TSCA) to

require manufacturers and processors of

21 hazardous air pollutants (HAPs)

(biphenyl, carbonyl sulfide, chlorine,

chlorobenzene, chloroprene, cresols [3

isomers], diethanolamine, ethylbenzene,

ethylene dichloride, ethylene glycol,

hydrochloric acid, hydrogen fluoride,

maleic anhydride, methyl isobutyl

ketone, methyl methacrylate,

naphthalene, phenol, phthalic

anhydride, 1,2,4-trichlorobenzene,

1,1,2-trichloroethane, and vinylidene

chloride) to test these substances for

certain health effects. EPA is also

soliciting proposals for enforceable

consent agreements (ECAs) regarding

the performance of pharmacokinetics

studies which would permit

extrapolation from oral data to predict

risk from inhalation exposure. EPA is

also withdrawing the oncogenicity

testing proposed for vinylidene chloride

on August 12, 1986 (51 FR 28840).

DATES: Written comments on this

proposed HAPs test rule must be

received by EPA on or before December

23, 1996. Proposals for

pharmacokinetics studies must be

received by EPA on or before October

24, 1996. EPA will hold a public

meeting in Washington, DC prior to the

close of the comment period. If any

person requests an additional public

meeting by November 25, 1996, EPA

will hold a second public meeting in

Washington, DC.

ADDRESSES: Submit three copies of

written comments on this proposed

HAPs test rule, identified by document

control number (OPPTS–42187A; FRL–

4869–1) and three copies of proposals

for pharmacokinetics studies, identified

by document control number (OPPTS–

42187B; FRL–4869–1) to: U.S.

Environmental Protection Agency,

Office of Pollution Prevention and

Toxics (OPPT), Document Control

Office (7407), Rm. G–099, 401 M St.,

SW., Washington, DC, 20460.

A public version of the rulemaking

record supporting this action, excluding

confidential business information (CBI),

is available for inspection at the TSCA

Nonconfidential Information Center,

Rm. NE–B607, 401 M St., SW.,

Washington, DC 20460, from 12 noon to

4 p.m., Monday through Friday, except

on legal holidays.

All comments which contain

information claimed as CBI must be

clearly marked as such. Three

additional sanitized copies of any

comments containing information

claimed as CBI must also be submitted.

Nonconfidential versions of comments

on this proposed rule will be placed in

the rulemaking record and will be

available for public inspection at the

TSCA Nonconfidential Information

Center. Unit IX of this preamble

contains additional information on

submitting comments containing

information claimed as CBI.

Comments and data may also be

submitted in electronic form by sending

electronic mail (e-mail) to:

ncic@epamail.epa.gov. Such comments

and data must be submitted in an ASCII

file avoiding the use of special

characters and any form of encryption.

Comments and data will also be

accepted on disks in WordPerfect in 5.1

file format or ASCII file format. All

comments and data in electronic form

must be identified by (OPPTS–42187A)

(FRL–4869–1). No information claimed

as CBI should be submitted through email. Comments in electronic form may

be filed online at many federal

depository libraries. Additional

information on electronic submissions

can be found under Unit X of this

preamble.

FOR FURTHER INFORMATION CONTACT:

Susan B. Hazen, Director,

Environmental Assistance Division

(7408), Office of Pollution Prevention

and Toxics, U.S. Environmental

Protection Agency, Room E–543B, 401

M St., SW., Washington, DC 20460;

telephone: (202) 554–1404; TDD: (202)

554–0551; e-mail: TSCAHotline@epamail.epa.gov. For specific

information regarding this action or

related activities, contact Gary E. Timm,

Chemical Control Division, OPPT;

telephone: (202) 260–1859; e-mail:

timm.gary@epamail.epa.gov.

SUPPLEMENTARY INFORMATION:

Regulated persons. Potentially

regulated persons are manufacturers

(including importers) and processors of

the chemical substances included in

this proposed test rule. Processors,

small-quantity manufacturers, and

manufacturers of small quantities of

these substances solely for research and

development purposes, while legally

subject to the rule, would be required to

comply with the rule only if directed to

do so in a subsequent notice.

Category Examples of regulated persons

Manufacturers Persons who manufacture or

import 500 kg (1,100 lbs)

or more of a subject chemical per year.

Persons who produce a subject chemical as a byproduct.

Processors Persons who process one or

more subject chemicals.

Small-quantity

manufacturers

Persons who manufacture or

import less than 500

kg(1,100 lbs) per year of a

subject chemical.

Manufacturers

of small

quantities of

these substances

solely for research and

development purposes

Persons who manufacture

quantities of these substances no greater than

those necessary for purposes of scientific experimentation or analysis for

research and development

purposes.

This table is not intended to be

exhaustive, but, rather, provides a guide

for readers regarding entities likely to be

regulated by this action. This table lists

the types of persons of which EPA is

now aware that potentially could be

regulated by this action. To determine

whether you would be subject to this

rule, you should examine Unit IV.F. of

the preamble entitled ‘‘Persons Required

to Test’’ and consult 40 CFR 790.42.

I. Statutory Authority

This notice proposes a test rule under

section 4 of the Toxic Substances

Control Act (TSCA), 15 U.S.C. 2603 et

seq., that would require certain health

effects testing for 21 chemical

substances listed as hazardous air

pollutants (HAPs) in section 112 of the

Clean Air Act (CAA), 42 U.S.C. 7412.

Section 2(b)(1) of TSCA, 15 U.S.C.

2601(b)(1), states that it is the policy of

the United States that ‘‘adequate data

should be developed with respect to the

effect of chemical substances and

mixtures on health and the environment

and that the development of such data

should be the responsibility of those

who manufacture and those who

process such chemical substances and

mixtures[.]’’ To implement this policy,

section 4(a) of TSCA authorizes EPA to

require by rule that manufacturers and

processors of chemical substances

conduct testing if the Administrator

finds that:
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33179

(1)(A)(i) the manufacture, distribution in

commerce, processing, 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, [or]

(1)(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, [and]

(1)(A)(ii) and (1)(B)(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

(1)(A)(iii) and (1)(B)(iii) testing of such

substance or mixture with respect to such

effects is necessary to develop such data[.]

Thus once the Administrator has

made a finding under TSCA section

4(a)(1)(A)(i) that a chemical substance

may present an unreasonable risk of

injury to health or the environment or

a finding under section 4(a)(1)(B)(i) that

a chemical substance is or will be

produced in substantial quantities and

either it may enter the environment in

substantial quantities or there may be

significant substantial human exposure

to the chemical substance, EPA may

require any type of health effects or

environmental testing necessary to

address unanswered questions about the

effects of the chemical substance. EPA

need not limit the scope of testing

required to the factual basis for the

section 4(a)(1)(A)(i) or (B)(i) findings as

long as EPA finds that data relevant to

a determination of whether a substance

does or does not present an

unreasonable risk of injury to health or

the environment are insufficient and

that testing is necessary to develop such

data. This concept is explained in more

detail in EPA’s statement of policy for

making findings under TSCA section

4(a)(1)(B) (frequently described as the

‘‘B policy’’) in the Federal Register of

May 14, 1993 (58 FR 28736). Unit V of

this preamble also describes the B

policy. Moreover, EPA need not limit

the scope of the requirement only to

testing needed to support regulatory

action under TSCA. For further

discussion of findings under TSCA

section 4, see Unit V of this preamble

and the document entitled ‘‘TSCA

Section 4 Findings for 21 Hazardous Air

Pollutants’’ in the record for this

rulemaking.

In this proposed rule, EPA intends to

use its TSCA section 4 authority to

obtain data necessary to implement

section 112 of the CAA, which provides

a detailed strategy for the assessment

and management of HAPs. EPA has

used this broad TSCA section 4

authority in the past to support

regulatory programs requiring health

and environmental effects testing data.

See, e.g., final test rule for the Office of

Solid Waste chemicals (53 FR 22300,

June 15, 1988); final test rule for the

Office of Water Chemicals (58 FR 59667,

November 10, 1993). Additional users of

information collected under this test

rule would include other federal

agencies (e.g. the Agency for Toxic

Substances and Disease Registry

(ATSDR), the National Institute for

Occupational Safety and Health

(NIOSH), the Occupational Safety and

Health Administration (OSHA), the

Consumer Product Safety Commission

(CPSC), other program areas within EPA

(such as the hazardous waste program

under the Resource Conservation and

Recovery Act (RCRA), the Toxics

Release Inventory (TRI), the Integrated

Risk Information System database

(IRIS), and the Office of Pesticide

Programs (OPP)), and state and local

environmental authorities.

Supporting statutory authority for this

proposed rule is provided by section

112(b)(4) of the CAA, 42 U.S.C.

7412(b)(4), which specifically

authorizes EPA to use any authority

available to EPA to obtain the

information needed to make

determinations regarding the addition or

deletion of substances to the statutory

list of HAPs in CAA section 112(b)(1),

42 U.S.C. 7412(b)(1). If the data

collected under this proposed test rule

show that a chemical substance is not a

concern to human health, this

information would be helpful in making

decisions concerning delisting the

substance from the Clean Air Act HAPs

list.

This toxicity testing program is also

intended to fulfill in part EPA’s

statutory obligation under section

103(d) of the CAA, 42 U.S.C. 7403(d), to

conduct a research program on the

health effects of HAPs. This preamble,

along with the supporting material in

the record, provides information that

would be used in the research program

under CAA section 103(d) for the HAPs

proposed for testing in this rule.

II. Uses for Data

EPA will primarily use the data

proposed to be collected under this rule

to implement several provisions of

section 112 of the CAA, including the

determination of residual risk (see

below), the estimation of the risks

associated with accidental releases of

chemicals, and determinations whether

or not substances should be removed

from the CAA section 112(b)(1) list of

hazardous air pollutants (delisting). The

acute toxicity test data and

developmental toxicity test data will be

useful in judging risks from accidental

release. The term ‘‘accidential release’’

is used broadly in this proposal to

include any short-term, relatively highlevel chemical exposure lasting from

several minutes to several hours. Such

a release may result from various

causes, including spills, transportation

accidents, process-upset conditions, or

short bursts during charging of reaction

vessels. All data are relevant to delisting

decisions and all non-acute data will be

used by EPA in meeting its statutory

obligation under CAA section 112(f), 42

U.S.C. 7412(f), to assess the risk

remaining (i.e. residual risk) after the

imposition of technology-based

emission standards (maximum

achievable control technology or MACT

standards) required by CAA section

112(d), 42 U.S.C. 7412(d). Section 112(e)

of the CAA, 42 U.S.C. 7412(e), directs

EPA to promulgate these standards

between 1992 and 2000.

Section 112(f)(1) of the CAA requires

EPA to submit, by November 1996, a

report to Congress that will describe the

methods for assessing the risk remaining

after the application of technologybased standards under section 112(d) of

the CAA. These methods will be used to

assess any residual risk for persons

exposed to MACT-regulated emissions.

The assessment will include an analysis

of both cancer and noncancer

endpoints. Data generated by the

proposed test rule would be used in the

analysis to determine the nature and

magnitude of any residual risk.

Within eight years after the

promulgation of technology-based

standards, EPA may need to set

additional standards (‘‘post-MACT

standards’’) to protect public health

with an ample margin of safety. Section

112(f)(2) of the CAA specifies that if

MACT standards have not reduced

lifetime cancer risk to the individual

most exposed to known or suspected

carcinogenic emissions from a source to

a level of less than 1 in a million (1 x

10-6), health-based emission standards

must be promulgated in order to protect

public health with an ample margin of

safety. EPA, therefore, would use data

obtained under this proposed rule to

determine whether health-based postMACT standards are needed and, if they

are needed, to assist in establishing the

appropriate level of these standards.

For noncancer health effects, EPA

applies an appropriate mathematical

model to toxicity data in order to

determine the benchmark dose level.

The benchmark dose or concentration

(BMD/C) is defined as the statistical
33180 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

lower confidence limit on the dose

estimated to produce a predetermined

level of change in response (the

benchmark response—BMR) relative to

controls. If the data are not amenable to

modeling, a no-observed-adverse-effect

level (NOAEL) or a lowest-observedadverse-effect level (LOAEL) may be

obtained from an evaluation of the

toxicity database. ‘‘Uncertainty factors’’

are then applied to these levels to

account for uncertainties in deriving a

dose-response estimate for human

exposure (reference concentration (RfC))

from experimental data. An RfC is

defined as ‘‘an estimate (with

uncertainty perhaps spanning an order

of magnitude) of a continuous

inhalation exposure to the human

population (including sensitive

subgroups) that is likely to be without

appreciable risk of deleterious

noncancer health effects during the

lifetime’’ (Ref. 1).

Uncertainties due to the extrapolation

of effects data between species and for

individual susceptibility within a

species are accounted for by uncertainty

factors. Because RfCs are intended to

characterize risk for lifetime exposures,

an uncertainty factor may be applied if

the effects data are extrapolated from a

subchronic study. An additional

uncertainty factor is applied if a LOAEL

is used to derive the RfC rather than a

NOAEL. To provide an accurate

characterization of lifetime risk, the

database for a chemical should be

comprehensive and, in principle,

should address all potential endpoints

at critical life stages. Therefore, an

uncertainty factor also may be applied

if data for appropriate endpoints are not

available. Thus while each uncertainty

factor may range up to 10, the composite

factor used to derive an RfC for a

chemical with a limited database may

be on the order of up to 3,000 for

inhalation studies and up to 10,000 for

oral studies. Five uncertainty factors are

never applied at the same time (i.e. no

composite uncertainty factor can be

greater than 10,000) because such

derivations are considered too

inaccurate to be used.

Large composite uncertainty factors

result in lower RfCs (higher risk

estimates) than do smaller composite

uncertainty factors. If the RfC is low,

EPA may be required to promulgate

more stringent emission standards.

Industrial plants subject to these

standards would, in turn, be required to

meet such standards, perhaps

necessitating the installation of more

costly emission controls. Better and

more complete health effects data, on

the other hand, may permit EPA to use

smaller composite uncertainty factors,

resulting in higher RfCs and, as a

consequence, less stringent emission

standards. Thus the economic cost of

using poor-quality health effects data to

make residual risk determinations under

CAA section 112(f) could be

considerable.

In addition, secondary—though as

important—uses of the data to be

collected under this proposed rule

would be:

(1) Helping to better inform

communities and citizens of toxic

chemical hazards in their own localities.

Understanding health effects associated

with these chemicals is integral to

furthering the public’s involvement in

environmental decisionmaking,

especially at the state and local level. To

be an effective participant in this

process, the public needs information

on both the inherent toxicity (i.e.,

hazard) of a chemical and the potential

sources of exposure to the chemical.

This rule will provide valuable

information on health effects related to

the affected chemicals, and under

TSCA, such health and safety data are

available to the public. Taken together

with such publicly available

information sources such as the Toxics

Release Inventory (TRI), which provides

site-specific information on chemical

releases into the environment, the

health effects data generated under this

rule will allow all segments of the

public to better assess the risks

associated with the releases of these

chemicals. Taken as part of a

comprehensive right-to-know program,

these data will provide the basis for

individuals, communities, governments,

producers, and users to assess the

nature and relative severity of toxicity

among different chemicals, as well as to

assess site-specific, individual chemical

risk.

(2) Assisting other agencies (e.g.,

ATSDR, NIOSH, OSHA, CPSC) in

assessing chemical risks and in taking

appropriate action within their

programs. For example, OSHA has

expressed a need for the data that will

be acquired under the proposed rule.

Fifteen of the 21 HAPS are candidates

for OSHA’s Permissible Exposure Limit

(PEL) update and an additional 3 have

no corresponding PEL. OSHA does not

have authority to require testing, and

must rely on toxicology data collected

by other agencies for their risk

assessments (Ref. 2). Establishing an

ongoing mechanism for updating its

PELs continues to be a high priority for

OSHA. Five of the HAPs are on

ATSDR’s list of hazardous substances

found at National Priorities List sites

and are the subject of toxicological

profiles. CPSC noted that 11 of the 21

substances are found in or are emitted

by consumer products (Ref. 3).

(3) Assisting EPA in evaluating

delisting petitions received under the

CAA and the Emergency Planning and

Community Right-to-Know Act

(EPCRA), 42 U.S.C. 1101 et seq., in

making better clean-up decisions under

the Comprehensive Environmental

Response, Compensation, and Liability

Act (CERCLA), 42 U.S.C. 9601 et seq., in

assessing inert ingredients in pesticide

products, in setting more appropriate

standards for hazardous wastes under

RCRA, and by providing support for

chemical risk assessment activities

under TSCA.

(4) Assisting state and local

permitting authorities in setting

standards within their programs.

(5) Supporting assessments of ‘‘burst’’

exposures (high-level releases of short

duration), such as in the accidental

release prevention program under

section 112(r) of the CAA, 42 U.S.C.

7412(r), due to the inclusion of an acute

testing protocol.

Many HAPs are of broad

programmatic interest, and are included

in the Agency’s Integrated Risk

Assessment System (IRIS) database.

Thus, a secondary benefit of this rule is

that the health effects data generated by

the rule may result in improvement to

the data and increased confidence in the

RfCs contained in IRIS. Improvements

to the IRIS data can result in

considerable benefits to the public since

IRIS is publicly available and is used by

a wide variety of governmental and nongovernmental entities to assess the

safety of chemicals.

In some cases where EPA has had

access to better data, the Agency has

been able to revise standards to make

them less stringent, thus mandating less

economically costly levels of control.

For example, EPA has revised the

maximum contaminant levels (MCL) of

barium (from 1 mg/L to 2 mg/L) and

selenium (from 0.01 mg/L to 0.05 mg/L)

in drinking water and withdrew the

MCL for silver (0.05 mg/L) based on

new data (Ref. 4).

Data have also been used to remove

chemical substances from lists of

regulatory significance. Acrylic acid was

removed from a list of ‘‘high-risk’’

pollutants developed under section

112(i)(5) of the CAA, 42 U.S.C.

7412(i)(5), for the early reductions

program. The high-risk listing for this

chemical was based on its predicted

environmental exposure being at least

10 times larger than its RfC. Designation

of acrylic acid as ‘‘high risk’’ had the

effect of limiting the use of offsetting

reduction of other pollutants in meeting

early reduction goals. Recent data,
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33181

including those related to reproductive

effects, developmental toxicity, and

bioavailability, resulted in a decrease in

the uncertainty factor for database

deficiency by a factor of three and an

increase in the RfC by the same amount

(i.e. from 0.0003 mg/m3 to 0.001 mg/

m3). Consequently, acrylic acid no

longer met the criteria for the high-risk

list.

Serious deficiencies exist in the

current toxicity database for the 189

HAPs listed in the CAA, in that no

toxicity data exist for many HAPs

regarding various endpoints of concern.

This problem is expected to be

especially serious because post-MACT

residual risks will arise primarily from

exposures to emissions that contain

different combinations of HAPs in

varying concentrations. In view of the

large number of HAPs of concern and

the much larger number of

combinations of those HAPs found in

the mixtures of emissions subject to

residual risk evaluation, the toxicity

database should provide consistent

characterization of individual HAPs.

Therefore, EPA is proposing to obtain an

even, across-the-board database for the

HAPs listed in this proposed rule.

In its report regarding the risk

assessment of HAPs, the National

Academy of Sciences (NAS) states that

‘‘[a]vailability of requisite data varies

widely among the 189 [HAPs]

chemicals’’ (Ref. 5). According to this

report, ‘‘the toxicity data are incomplete

on almost all 189 chemicals’’ (Ref. 5).

For example, the level of carcinogenic

risk for approximately 40% of the 189

HAPs cannot be classified under EPA’s

current cancer risk classification system

(Ref. 6). Moreover, while quantitative

estimates exist for 70% of the HAPs that

have been classified for cancer risk,

about 70% of these estimates are based

only on oral data and thus may not

reliably characterize the potential risk

encountered through inhalation

exposure.

In evaluating 124 of the 189 HAPs for

noncancer risk, EPA found that the

databases for about 62% of the 124

HAPs were not adequate for deriving an

RfC (Ref. 7). Even for those HAPs that

have an RfC, the level of uncertainty

associated with such figures is often

high. EPA would use data from the

testing proposed in this rule to identify

the critical health risks posed by many

individual HAPs and to characterize the

adverse impact posed by exposure to

mixtures of HAPs. EPA anticipates that

the test data produced in response to

this rule would provide the consistent

database that the National Academy

says is lacking at this time.

III. Testing Approach and Selection of

Chemical Substances for This Proposed

Rule

A. Testing Approach Chosen by EPA

With respect to EPA’s responsibilities

for meeting the requirements under

section 112 of the CAA, the central

question is: How broad and deep a data

set should EPA require on each HAP?

Regarding specific endpoints and

routes of exposure, CAA section

112(b)(2), 42 U.S.C. 7412(b)(2), indicates

that Congress intended that adverse

effects from any endpoint by any route

of exposure be taken into account in

listing substances as HAPs. According

to this subsection, substances added to

the Clean Air Act HAPs list shall

include:

* * * pollutants which present, or may

present, through inhalation or other routes of

exposure, a threat of adverse human health

effects (including, but not limited to,

substances which are known to be, or may

reasonably be anticipated to be, carcinogenic,

mutagenic, teratogenic, neurotoxic, which

cause reproductive dysfunction, or which are

acutely or chronically toxic) * * * .

Thus the CAA indicates that Congress

was very concerned about the wide

variety of health risks attributable to

HAPs and intended that data necessary

for characterizing both cancer and

noncancer health risks from exposure to

HAPs be developed.

Faced with a broad range of options

and little specific guidance from

Congress, EPA decided that some

provision should be made for evaluating

the health effects endpoints listed in the

CAA, including respiratory tract

toxicity, systemic effects, reproductive

toxicity, developmental toxicity,

genotoxicity, neurotoxicity, and

carcinogenicity. EPA’s objective was to

select endpoints representing serious

health effects that could occur as a

result of exposure to HAPs. Each

endpoint represents a health effect of

concern arising from one or more of the

following exposures—local

concentrations (e.g., hotspots and

plumes), area-wide sources, or

accidental releases of HAPs.

EPA believes that it is critical to

evaluate the respiratory tract thoroughly

in addition to examining extrarespiratory effects (i.e., systemic

toxicity) because inhalation is an

important exposure route of concern.

Carcinogenicity testing is significant

because cancer is a serious health effect

that may be caused by long-term, lowlevel exposure to toxic substances.

Developmental toxicity addresses the

potential of chemical substances to

interfere adversely with human

development (i.e., to cause death,

structural abnormalities, growth

alterations, and/or functional deficits in

the immature organism that may be

more sensitive than the adult to many

chemical substances). Reproductive

testing is designed to assess the effects

of an environmental agent on male and

female fertility and general reproductive

function to humans exposed prenatally

as well as postnatally. There is general

consensus among toxicologists

regarding the assessment of cancer and

reproductive and developmental effects,

and further explanation can be found in

EPA’s risk assessment guidelines

(Guidelines for Carcinogen Risk

Assessment (51 FR 33992, September

24, 1986); Guidelines for Developmental

Toxicity Risk Assessment (56 FR 63798,

December 5, 1991); Guidelines for

Reproductive Toxicity Risk Assessment

(Pub. No. EPA/600/AP–94/001,

February 1994). Finally, certain aspects

of the neurotoxicity and

immunotoxicity testing required in this

proposed rule warrant more

explanation, which is provided below.

EPA recently published a proposed

revision of the 1986 Guidelines for

Carcinogen Risk Assessment (see

‘‘Proposed Guidelines for Carcinogen

Risk Assessment’’ at 61 FR 17960, April

23, 1996 (FRL–5460–3)).

Neurotoxicity resulting from chemical

exposure can affect an organism in

many ways, causing, for example,

functional and structural deficits as well

as behavioral effects. To assess

neurotoxicity, EPA is proposing a

screening-level battery, consisting of the

functional observational battery and

motoractivity and neuropathology tests.

At this time, EPA is not proposing to

require additional, more specialized

testing for cognitive functions such as

learning, memory, and performance.

The interest in the potential toxic

effects of chemicals on the immune

system arises from the critical role that

the immune system plays in

maintaining health. EPA considers the

field of immunotoxicity a promising,

scientifically sound, and important area

in public health protection. From time

to time, the Agency has considered

information on the effects of chemicals

on the immune system in risk

assessments. For example, in its draft

report reassessing the effects of dioxin

compounds on human health (Ref. 8),

EPA considered the effects of dioxin on

the immune system to serve as an

important health endpoint that provides

useful information in developing a

hypothesis about toxicity. In the draft

reassessment report, however, EPA

arrived at the preliminary conclusion

that ‘‘the impact of dioxin and related

compounds on the immune system and
33182 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

implications for characterizing risks are

largely unknown at this time.’’

This rule calls for an immunotoxicity

screening test which can be performed

as a satellite test to either a 90-day

subchronic test or a reproductive effects

test. This immunotoxicity screen will

help identify chemicals as potential

immunotoxicants. EPA is not proposing

more comprehensive immunotoxicity

testing at present because the

application of immunotoxicity data in

risk assessment has not yet sufficiently

matured. As EPA’s science policy

develops and the Agency’s use of

immunotoxicity data in risk assessment

increases, EPA will reconsider this

position. Meanwhile, EPA seeks

comments on its proposed approach of

using a minimal screen and its

preliminary conclusion that it is

premature at this time to include more

comprehensive immunotoxicity testing

in this proposed HAPs test rule.

In developing this proposed rule, EPA

considered the following range of

options to select the information needed

to characterize health effects of concern

to implement section 112 of the CAA.

Option 1. One-species 90-day

inhalation subchronic plus follow-up for

known or suspect toxicities. Under this

option, a 90-day inhalation subchronic

test would be required, as well as testing

for endpoints that have already been

identified as existing or potential

concerns, including cancer, by previous

test results of the HAP at issue or

structurally similar agents. A onespecies 90-day inhalation test is

considered the minimum information

for the development of an RfC. The

inhalation RfC takes into account toxic

effects both for the respiratory tract

(portal-of-entry effects) and peripheral

to the respiratory system (extrarespiratory effects). Well-defined and

well-conducted inhalation subchronic

toxicity studies—that provide for

histopathologic evaluation of organ

toxicities, including the respiratory

tract—are considered to be reliable

predictors of certain kinds of chronic

toxicity. But such studies do not, or do

not adequately, account for

neurological, developmental and

reproductive toxicities. An RfC based

solely on a 90-day subchronic test is,

thus, usually given a low confidence

rating because some potentially

important toxic endpoints are not

characterized.

In addition, EPA believes that for 90-

day inhalation subchronic testing to

constitute a minimally credible option,

such a test should at least be augmented

by testing for adverse health effects that

are suggested or indicated, but not

adequately characterized, by existing

information such as short-term test data,

mechanistic information or structureactivity relationships (SAR). Even with

this modification, however, Option 1

still provides no test data on those

health endpoints of concern for which

no current information exists. If such

testing were included, these effects

might become critical in evaluating

dose-response relationships or in

demonstrating that a standard

uncertainty factor is inadequate or

inappropriate.

EPA thus believes that Option 1 is

insufficient to meet EPA’s mandate

under section 112 of the CAA because

the endpoints listed in section 112(b)(2)

of the CAA, in particular, reproductive,

developmental, and neurological

toxicities, would be considered for

testing only if data already exist that

indicate or suggest the potential for

these adverse effects. Moreover, this

option also does not adequately address

health risks associated with acute or

accidental releases.

EPA did not select Option 1 for the

reasons stated above. EPA believes that

the TSCA section 4 program adopted for

testing HAPs must go further toward

ensuring that no serious health threat

exists from both long- and short-term

exposure for endpoints of potential

concern for which there are no existing

data.

Option 2. Option 1 plus inhalation

screening for untested toxicity

endpoints. The second option

considered by EPA would require the

incorporation of screening level testing

for certain untested toxicities into

Option 1. Like Option 1, Option 2

would include testing for endpoints

(including cancer) that have already

been identified as existing or potential

concerns. At a minimum Option 2

would consist of—a 90-day subchronic

inhalation study, a screening test for

reproductive effects (i.e., a onegeneration reproductive effects study), a

subchronic inhalation neurotoxicity

screening battery (consisting of the

functional observation battery and

motor activity and neuropathology

tests), an E. coli reverse mutation assay,

gene mutation in somatic cells in

culture detection, an in vivo

cytogenetics test (chromosomal analysis

or micronucleus assay), and an

immunotoxicity screening test. Any

toxicity suggested but not characterized

by existing studies in the toxicological

literature would still be followed up on

through more rigorous protocols.

Although Option 2 would conserve

resources while allowing for the testing

of a broader range of endpoints,

including cancer, it has serious

shortcomings. First, a one-generation

reproductive test does not adequately

address reproductive and

developmental risk. Two-generation

tests (in which animals have been

exposed prenatally as well as

postnatally, including the prepubertal

period) are generally needed to evaluate

the effects on reproduction from most

exposures to chemical substances (Ref.

9). Two-generation tests permit the

evaluation of delayed or latent

manifestations of some toxicities,

detection of effects absent in the first

generation, and the expression and

detection of some effects that may have

a heritable basis. Because the standard

two-generation reproductive test would

not detect internal malformations,

however, developmental toxicity testing

is also needed for an adequate

assessment of developmental risk. The

Agency’s policy is to require

developmental testing in two species to

adequately characterize the risk because

of species-specific differences.

EPA did not select Option 2 because

this level of testing would not provide

an adequate evaluation of

developmental or reproductive toxicity.

Additional follow-up testing would be

required to confirm suggestive results

obtained in screening studies and

provide data adequate for risk

assessment under this option. Such

testing would require an additional

rulemaking cycle, costing further

resources and incurring so much delay

that data would not be available to meet

the deadlines for setting risk-based

standards. Moreover, this option does

not adequately address health risks,

such as respiratory tract effects and

neurotoxicity, associated with acute or

accidental releases.

Option 3. Option 1 plus less than

chronic testing for noncancer endpoints

of concern. In addition to the 90-day

inhalation subchronic testing specified

in Option 1, this option would add

inhalation testing to assess reproductive

effects (i.e., two-generation reproductive

test) and developmental effects

(developmental toxicity tests in two

mammalian species). Option 3 includes

an acute toxicity testing guideline for

histopathology of the respiratory tract,

kidney, and liver and a bronchoalveolar

lavage after four hours of exposure. EPA

believes that it is necessary to

characterize the acute effects associated

with accidental releases of HAPs. In

addition, a respiratory sensory irritation

assay is included. Acute and subchronic

inhalation neurotoxicity screening

batteries consisting of the functional

observation battery, and motor activity

and neuropathology tests would also be

conducted. As in Option 2, first-tier

tests would be required for mutagenicity
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33183

(i.e., an E. coli reverse mutation assay,

gene mutation in somatic cells in

culture detection, an in vivo

cytogenetics test (chromosomal analysis

or micronucleus assay)), as well as

immunotoxicity.

Option 3 would follow Options 1 and

2 in requiring a cancer bioassay where

concern for cancer is indicated by shortterm data, general toxicity data,

mechanistic information or structureactivity relationships (SAR). Where no

cancer bioassay data exist, testing two

species in both sexes would be required.

If cancer bioassay data exist but are

found to be too uncertain for inhalation

dose-response assessment, a modified

test, such as testing of the opposite sex

in two species, may be required (Ref.

10).

The Option 3 level of testing would

enable EPA to better characterize risk

associated with both acute and longerterm exposures by providing data to

identify and evaluate all the health

effects listed under section 112 of the

CAA and by providing data for doseresponse evaluation within the general

time frame for risk-based standards

under CAA section 112(f). Accordingly,

EPA has selected the Option 3 level as

its preferred option for testing under

this proposed rule.

Option 4. Option 3 plus chronic

testing. Under this option, in the

absence of existing adequate data, EPA

would require chronic inhalation

bioassays (for both cancer and

noncancer effects) in two different

mammalian species for each chemical

substance. The balance of the test

program would be the same as under

Option 3 (developmental studies in two

mammalian species, a two-generation

reproductive study, acute and

subchronic neurotoxicity screening

batteries, first-tier mutagenicity tests, an

immunotoxicity screening test, and

acute testing). In general, cancer

bioassay data in two species, a twogeneration reproductive test, and a

developmental study in two species are

required to establish a high-confidence

RfC. Because the RfC is intended to

serve as a lifetime estimate, lifetime

exposure studies to evaluate potential

health endpoints at various critical life

stages should be considered.

To a greater degree than under other

options, the broad and deep database

that would be produced by this

comprehensive testing scheme could

help defuse complaints that EPA

frequently regulates industrial activities

without sufficient data regarding either

the need for an appropriate level of

regulation or what such a level should

be. EPA has decided, however, that the

disadvantages of choosing this option

outweigh its considerable benefits. The

extensive chronic testing required under

Option 4 would impose a significant

cost on industry. In addition, as

compared to Option 3, the strain that

choosing this option would place on

certain resources—such as inhalation

testing facilities and supplies of

laboratory animals—would significantly

diminish the cost-effectiveness of

compiling the data. For these reasons,

EPA did not select this option. EPA is

soliciting comments on the testing

approach to the HAPs that it has

selected in this proposal.

It should be noted that, regardless of

the test option chosen, if adequate

toxicity data on a HAP is produced by

testing using a route of exposure other

than inhalation, route-to-route

extrapolation may be possible (see Unit

IV.D. of this preamble).

B. National Academy of Sciences

Approach

In section 112(o) of the CAA, 42

U.S.C. 7412(o), Congress directed EPA

to arrange for the NAS to review EPA’s

risk assessment methodology relevant to

HAPs subject to section 112. EPA has

considered the recommendations of the

NAS regarding the assessment of risks

associated with HAPs. The NAS

recommended that EPA ‘‘* * * compile

for each of the 189 chemicals an

inventory of the existing and relevant

chemical, toxicologic, clinical, and

epidemiologic literature’’ (Ref. 5). It also

recommended that EPA ‘‘screen the 189

chemicals for priorities for the

assessment of health risks, identify the

data gaps, and develop incentives to

expedite generation of the needed data

by other public agencies (such as the

National Toxicology Program, the

Agency for Toxic Substances and

Disease Registry, and state agencies) and

by other organizations (industry,

academia, etc.)’’ (Ref. 5). As discussed

in Unit III.C. of this preamble, EPA

agrees and has taken this approach. To

identify testing needs and help

prioritize HAPs testing, Syracuse

Research Corporation, an EPA

contractor, has identified and

summarized the existing health and

exposure literature on the HAPs, and

has identified testing programs

currently in progress (Refs. 11, 12).

The NAS report also discussed how a

gradual, highly iterative testing

approach to the generation of health

effects data on HAPs might work. The

report recommended that HAPs could

be prioritized on the basis of their acute

toxicity and chemical structure, and

testing might proceed stepwise, on a

case-by-case basis, from acute toxicity to

studies of the uptake, distribution,

retention, and excretion of the

substance, to subchronic toxicity, and

ultimately, if needed, to endpoint

testing in animals. Depending on the

animal toxicity data produced by this

iterative testing scheme, according to

the NAS, EPA might decide that further

studies of human toxicity or

mechanisms of toxicity are warranted.

Although EPA agrees with the need to

prioritize testing, it has taken a different

approach to prioritization that is based

on consideration of exposure potential

and the rulemaking schedule of section

112 of the CAA. The amount and type

of existing data vary greatly among the

chemical substances that Congress

designated as HAPs. In practice,

therefore, no single uniform iterative

approach based on toxicity factors alone

would apply to all chemical substances.

For example, one HAP might have only

acute and short-term test data, while

longer-term studies might exist for

another HAP. Nevertheless, both the

NAS and EPA approaches recognize that

existing data must be considered if EPA

is to avoid requiring duplicative testing

that previously produced adequate data.

An iterative testing approach based on

toxicity factors alone would be time

consuming and require multiple

rulemakings. This process would take

too long to collect useful data for

making decisions needed to meet

upcoming statutory deadlines

established in the CAA. Furthermore,

multiple iterative rulemakings to

develop needed test data would be

prohibitively costly to EPA and would

not recognize limitations on EPA

resources. For Option 3, EPA’s preferred

testing level, follow-up testing would

rarely be required beyond that level

proposed in this rule. Such testing, if

necessary, would be required in a

separate rulemaking.

To make the multichemical decisions

required under section 112 of the CAA

regarding, for example, residual risk and

delisting HAPs, EPA believes that it

needs a consistent, even database

covering HAPs across the same broad

set of endpoints. EPA believes that

Option 3 will permit timely gathering of

a consistent database on HAPs more

efficiently and at less cost to industry

and EPA than is possible with other

approaches.

C. Review of Data and Selection of

HAPs

In choosing candidates for this

proposed test rule, EPA considered,

consistent with TSCA section 4

requirements, the potential for a

chemical substance to present an

unreasonable risk of injury to health or

the environment, the production
33184 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

volume of the substance, the amount of

emissions produced by the chemical

substance entering or reasonably

anticipated to enter the environment or

become a source of exposure for

humans, the sufficiency of the existing

database, and the need for further

testing to develop needed data.

Consequently, as indicated in Unit IV of

this preamble, and explained in a

separate document in the record entitled

‘‘TSCA Section 4 Findings for 21

Hazardous Air Pollutants’’, each

candidate listed for testing in this

proposed rule is:

(1) Considered to have the potential of

presenting an unreasonable risk of

injury to health or the environment

(except in the case of ethylene glycol,

for which no A finding was made—see

the table in Unit V of this preamble);

(2) Produced in quantities exceeding

1,000,000 pounds per year;

(3) Emitted (i.e., released into the

atmosphere) in the amount of 50 tons

(100,000 pounds) per year or more

according to the 1993 Toxics Release

Inventory (TRI);

(4) Considered to have health effects

data needs not addressed in other

testing and research programs;

(5) Considered to have health effects

data that are insufficient under TSCA

section 4 for determining effects of the

HAP on health; and

(6) Considered to need further testing

to develop the needed data.

The determination that data are

insufficient to ascertain the effects of the

HAPs on human health is based on

several factors. First, EPA determined

the effects of concern (toxicological

endpoints) and the depth and quality of

data which the Agency needs in order

to make residual risk determinations.

This decision and the range of options

EPA considered are discussed in Unit

III.A. of this preamble. Having made the

decision that standard endpoint tests are

appropriate, EPA reviewed existing

studies and, for the purposes of this

rule, compared such studies against the

testing methodology used in the 1985

version of the EPA test guidelines for

these endpoints. The 1985 test

guidelines were the first test guidelines

issued by EPA for its TSCA chemical

testing program and represent widely

accepted, peer-reviewed methods for

characterizing chemical toxicity.

The reasons why existing studies

were judged to be inadequate are

explained in a separate document in the

record entitled ‘‘TSCA Section 4

Findings for 21 Hazardous Air

Pollutants’’, and summarized in the

table in Unit V of this preamble. The

reasons are varied but include the

following examples—not studying the

appropriate endpoint; too few dose

levels; inappropriately high- or lowdose levels; and too few animals to have

statistical confidence in the results.

Nevertheless, in some cases, EPA

toxicologists determined that data were

adequate when the weight of evidence

from several flawed studies, which,

when considered individually were

determined to be inadequate, gave an

adequate characterization of the toxicity

of the substance. Thus expert judgment

must always play a role in

determinations of data adequacy.

Indeed, the determination of adequacy

is so intimately connected to the unique

characteristics of study design for each

toxicological endpoint that EPA is

unable to articulate a universal test of

data adequacy that might be applied

consistently in all situations. EPA is

soliciting comments on its approach to

determining data adequacy for the

HAPs.

To select HAPs for testing, EPA

initially reviewed the production data

and TRI data for all 189 HAPs. EPA

realizes that TRI data represent

estimates of environmental emissions of

the TRI-listed chemicals and do not

account for all chemical substances in

the United States. Nevertheless, TRI

figures offer the most complete, readily

available emissions data, and EPA has

determined that this database is

sufficient for the purpose of helping

EPA select high-emission HAPs for

consideration as potential test

candidates. While publicly available

sources of production data are cited in

the analysis supporting this rule, data

from these sources were checked against

the TSCA chemical inventory update

production data, most of which are

claimed as CBI.

After reviewing TRI data for all HAPs,

EPA decided to select a number of HAPs

for initial consideration by focusing its

attention on HAPs with TRI emissions

of 50 tons or more per year. The 66

HAPs in this group constituted a

reasonably sized group for further

review. The selection of 50 tons per year

or more as a cutoff is appropriate

because this number captures highemission HAPs and because section 112

(a)(1) of the CAA, 42 U.S.C. 7412(a)(1),

defines ‘‘major source’’ as emitting ‘‘* *

* 10 tons per year or more of any

hazardous air pollutant or 25 tons per

year or more of any combination of

hazardous air pollutants * * *.’’

A survey of testing conducted by EPA

under TSCA section 4, the Federal

Insecticide, Fungicide, and Rodenticide

Act (FIFRA), and other testing programs

supplemented a preliminary review of

health findings from secondary source

documents and the IRIS database. This

initial survey revealed that certain HAPs

having high emissions (50 tons or more)

already have a large inhalation

toxicology database or are subject to

testing or research in existing programs.

Therefore, EPA decided not to pursue

additional testing under this rule for

benzene, butadiene, carbon disulfide,

chromium, cyanide, ethylene oxide,

formaldehyde, lead, methanol, methyl

tertiary butyl ether, methylene chloride,

tetrachloroethylene, toluene,

trichloroethylene, vinyl chloride, and

vinyl acetate. Additional testing under

TSCA for these chemicals may be

considered at some time in the future.

EPA decided that the remaining group

of 50 HAPs could be handled most

efficiently by promulgating more than

one rule. Consequently, 21 highemission HAPs were scrutinized further

and were selected as candidates for this

proposed rule, and the remaining 29

HAPs were deferred for consideration in

subsequent HAPs test rulemaking

efforts. In the second HAPs test rule,

EPA plans to focus on persistent HAPs

that may bioaccumulate. EPA may,

therefore, require ecological and

environmental testing for these HAPs.

EPA also may require testing in the

second rule to collect data needed to

implement the ‘‘Great Waters’’ program

of section 112(m) of the CAA, 42 U.S.C.

7412(m).

During the selection process for this

proposed rule, EPA’s contractor

undertook a comprehensive search of

the toxicological, health, and exposure

literature for the 21 HAPs proposed for

testing in the current rule (Refs. 11, 12).

EPA’s contractor performed the

literature search in a stepwise manner to

save both time and expense. The first

step was to review secondary source

health effects documents. EPA’s

contractor identified documents

published by EPA, the International

Agency for Research on Cancer (IARC),

and ATSDR and extracted relevant data.

EPA performed online Environmental

Mutagen Information Center (EMIC)

searches for genetic toxicity information

(Ref. 13). In addition, an article entitled

‘‘Genetic Activity Profiles of 110

Hazardous Air Pollutants Listed Under

Title III of the Clean Air Act’’ (Ref. 14)

and the International Commission for

Protection against Environmental

Mutagens and Carcinogens (ICPEMC)

have provided useful summary

information.

EPA realizes that using secondary

sources of information is not ideal. For

example, it is possible that a secondary

source document could miss an

important study or that the document

could fail to properly interpret a study.

Consequently, whenever essential
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information appeared to be missing

from the review documents or was not

explained clearly, EPA’s contractor

consulted original articles.

Through its contractor, EPA next

checked several sources for relevant

published and unpublished studies. It

obtained unpublished but publicly

available studies submitted to EPA

under TSCA, searched the Toxic

Substances Control Act Test

Submissions (TSCATS) database by

CAS Registry number, and reviewed the

National Toxicology Program (NTP)

Results Report (generated from NTP’s

CHEMTRACK database) to locate

completed but unpublished NTP

studies. With the contractor’s assistance,

EPA next undertook an update search of

the open literature to locate any as yet

unidentified studies published either

shortly before or after the review

documents appeared. For this purpose,

EPA’s contractor searched the National

Library of Medicine (NLM) TOXLINE

database for studies published during a

period of time beginning three years

prior to the date of the review document

initially used to obtain toxicity

information and ending on the date of

the search.

In addition, EPA’s contractor

consulted with representatives of

NIOSH, OSHA, the Food and Drug

Administration (FDA), the National

Institute of Environmental Health

Sciences (NIEHS), and various chemical

companies. The purpose of these

inquiries was to determine if these

organizations had any information on

completed or ongoing studies that might

not be found in any readily available

database. Through its contractor, EPA

also contacted the Chemical Industry

Institute of Toxicology (CIIT), as well as

trade associations and allied

organizations to determine whether

these organizations were sponsoring or

knew of any relevant studies currently

in progress. Finally, EPA’s contractor

closely reviewed data sheets compiled

by EPA’s IRIS RfD/RfC Working Group

to ascertain if the group had identified

any additional, otherwise unlocated

information.

Varied levels of scrutiny were applied

to different types of toxicity testing

information throughout the literature

search. Because the primary focus of the

review of acute, subchronic, and

chronic systemic toxicity literature was

inhalation exposure, only inhalation

studies were reviewed for these

endpoints. Although oral studies can

provide important information on target

organ toxicity and should be considered

in the design of any testing protocol,

these studies usually provide limited

information on the effects of a

compound on the respiratory tract. In

addition, the systemic dose remote to

the respiratory tract for many

compounds is affected by modulation of

uptake at the portal of entry into the

body. This modulation is not only from

first-pass effects but from other

influences of anatomy and physiology

(Ref. 15). Because EPA’s literature

search did not encompass oral acute and

subchronic toxicity studies, the

preliminary findings of risk that EPA is

making below, under TSCA section

4(a)(1)(A), are not based on such

studies. Thus, oral acute and subchronic

studies may provide additional

evidence of potential toxicity.

The contractor reviewed studies of

carcinogenicity, neurotoxicity, and

reproductive and developmental

toxicity, regardless of the route of

administration.

EPA took a different approach to

identify HAP candidates for

immunotoxicity testing. EPA relied on

an EPA document ‘‘Hazardous Air

Pollutants: Profiles of Non-Cancer

Toxicity from Inhalation Exposures’’

(Ref. 16), containing a database that was

developed from EPA and ATSDR

documents and data files, and from the

Hazardous Substances Data Bank

(HSDB) of NLM. The contractor

searched recent literature (i.e., 1989 to

present) for immunotoxicity data on the

21 HAPs in both MEDLINE and

TOXLINE. For chemicals with ATSDR

Toxicological Profiles, the profile was

used to identify immunotoxicity data.

Much of the identified immunotoxicity

literature used rather insensitive

indicators of impact (e.g., organ weight

changes, histopathology, leukocyte

counts, and total serum protein

determinations), that were judged to

constitute an inadequate evaluation of

suppression of immune system

responsiveness (Ref. 17). Thus, an

immunotoxicity screening test is being

proposed in this rule for many of these

HAPs.

Although EPA has made intense and

thorough attempts to identify all

relevant studies, EPA recognizes the

limitations inherent in relying on

secondary sources and realizes that its

literature search may have failed to

locate studies recently undertaken or

completed. Therefore, EPA solicits

comments bringing to its attention any

valid studies not identified in its search

efforts.

D. Previous TSCA Testing Actions

Affecting These Chemical Substances

Eight of the substances included in

this proposed rule have been the subject

of previous testing under TSCA section

4. Testing by the inhalation route was

not generally required, however, and

acute effects—including respiratory

tract effects—were not generally a target

endpoint. This subunit will briefly

summarize previous testing decisions

and explain the relationship between

those activities and this proposed rule.

1,1’-Biphenyl was recommended by

the Interagency Testing Committee (ITC)

in its 10th report for environmental

effects and chemical fate testing (47 FR

22585, May 25, 1982). Focusing only on

environmental testing, EPA found that

1,1’-biphenyl may present an

unreasonable risk to the environment

and issued a test rule requiring

environmental effects and chemical fate

testing of the chemical on September 12,

1985 (50 FR 37182). This proposed rule

complements the earlier action by

requiring health effects testing of 1,1’-

biphenyl, namely, acute toxicity,

respiratory sensory irritation,

subchronic toxicity, developmental

toxicity, reproductive toxicity,

neurotoxicity and immunotoxicity.

Chlorobenzene was recommended to

EPA for health and environmental

effects testing in the first report of the

ITC (42 FR 55026, October 12, 1977).

Subsequently, EPA found that the

chemical may present an unreasonable

risk to human health (an A finding) and

issued a rule requiring reproductive

effects testing (51 FR 24657, July 8,

1986). Although the preamble of the

proposed rule described specific

neurotoxicity concerns, EPA stated that

neurotoxicity testing requirements were

not being proposed because it had not

issued neurotoxicity test guidelines at

that time. Instead EPA explained its

then-current views on neurotoxicity

testing in the preamble and solicited

public comment on those views (45 FR

48524, July 18, 1980). Because a

neurotoxicity screening battery

guideline (OPPTS 870.6200) has since

been proposed, this rule proposes the

testing of chlorobenzene for

neurotoxicity, acute toxicity, respiratory

sensory irritation, subchronic toxicity,

and immunotoxicity.

Cresols are members of a chemical

category consisting of three isomers:

ortho-, para-, and meta-cresol. Based on

both A and B findings, a test rule

proposed on July 11, 1983 (48 FR 31812)

would have required testing of cresols

for subchronic toxicity, mutagenicity,

carcinogenicity, developmental toxicity,

reproductive effects, neurotoxicity, and

skin sensitization. The final rule,

published on April 28, 1986 (51 FR

15771), which specified testing for all

three isomers and provided a rationale

for this decision, required testing for

mutagenicity, developmental toxicity,

and reproductive effects. Data received
33186 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

under this test rule satisfy the HAPs

data needs for these endpoints. Based

on the results from this first tier of tests,

a conditionally required cancer bioassay

was not triggered. In addition, oral

subchronic toxicity studies and

subchronic neurotoxicity studies were

conducted by EPA’s Office of Solid

Waste. In accordance with the need for

data on respiratory tract effects, today’s

rule proposes acute and subchronic

inhalation toxicity, respiratory sensory

irritation, acute neurotoxicity, and

immunotoxicity tests for all three cresol

isomers (see Unit IV.B. of this

preamble). For the purposes of this

proposal, the three cresol isomers are

counted as a single chemical.

Methyl isobutyl ketone was the

subject of a negotiated testing agreement

between EPA and industry for

mutagenicity, developmental toxicity,

and subchronic testing (47 FR 58025,

December 29, 1982, and 48 FR 44905,

September 30, 1983). Data received

under the negotiated testing agreement

satisfy the HAPs data needs for these

endpoints. Methyl isobutyl ketone is

also being tested for neurotoxicity under

a TSCA enforceable consent agreement

(ECA) with industry (announced at 60

FR 4514, January 23, 1995 (FRL–4924–

8)). This rule proposes testing for

reproductive toxicity, acute toxicity,

respiratory sensory irritation, and

immunotoxicity to complement ongoing

testing and existing data.

Phenol is the subject of a test rule

proposed on the basis of A and B

findings on November 22, 1993 (58 FR

61654). That rule proposed subchronic

toxicity, neurotoxicity, and reproductive

and developmental toxicity testing and

a study of phenol’s pharmacokinetics.

EPA has received a proposal for an ECA

for this chemical substance that would

cover the testing proposed in the 1993

rule. The rule proposed herein would

add acute inhalation toxicity,

respiratory sensory irritation, and

immunotoxicity to the testing program

for phenol. Under the procedures set

forth at 40 CFR 790.22, members of the

CMA Phenol Panel and EPA have

negotiated an ECA which provides for

the testing proposed in November 1993

as well as additional testing, including

immunotoxicity. Such testing would

meet the HAPs-related data needs for

phenol. If the ECA is successfully

concluded, EPA will drop the testing

requirement for phenol from the final

HAPs rule.

1,2,4-Trichlorobenzene has been

tested for carcinogenicity under a test

rule (51 FR 24657, July 8, 1986) based

on an A finding. Data received under

this test rule satisfy the HAPs data

needs for this endpoint. Although the

preamble of the proposed rule described

specific neurotoxicity concerns, EPA

stated that neurotoxicity testing

requirements were not being proposed

because it had not issued neurotoxicity

test guidelines at that time (45 FR

48545, July 18, 1980). Because a

neurotoxity screening battery guideline

(OPPTS 870.6200) has since been

proposed, this rule proposes the testing

of 1,2,4-trichlorobenzene for acute

toxicity, respiratory sensory irritation,

neurotoxicity, immunotoxicity, and

developmental toxicity.

Oncogenicity testing for vinylidene

chloride was called for in a proposed

test rule based on an A finding on

August 12, 1986 (51 FR 28840). The rule

proposed that distribution, metabolism,

and excretion studies and an inhalation

oncogenicity study be conducted in

mice on behalf of EPA’s Office of Air

Quality Planning and Standards

(OAQPS). EPA has not finalized the

vinylidene chloride proposal and is

hereby withdrawing it. EPA is not

pursuing these studies because the

Agency has concluded that, at this time,

an oncogenicity bioassay would do little

to add to EPA’s understanding of the

oncogenic potential of the substance.

Today’s rule proposes testing for acute

toxicity, respiratory sensory irritation,

and neurotoxicity.

IV. Proposed Testing

A. Testing and Reporting Requirements

EPA is proposing specific testing and

reporting requirements for each of the

21 HAPs as specified in table 1 in

§ 799.5053(a)(5) of this proposed rule.

EPA is proposing for the first time in a

TSCA section 4 rule to require an

immunotoxicity screen and an acute

inhalation toxicity test that focuses on

respiratory damage and sublethal

systemic toxicity. These and other test

guidelines are discussed below in Unit

IV.C. of this preamble.

EPA is proposing to require a

modified inhalation carcinogenicity

bioassay using only the male rat and

female mouse when existing oral

carcinogenicity data and supporting

information for a chemical substance are

deemed too uncertain to determine its

carcinogenicity via inhalation (Ref. 10).

The reduced protocol is less expensive

than a traditional bioassay. However,

test sponsors would also have the

alternative of performing

pharmacokinetics studies and using

route-to-route extrapolation from

existing adequate oral toxicity data

under enforceable consent agreements

(EDAs) in lieu of this and other test

requirements if the Agency decides to

use this approach (see Units IV.D. and

IV.E. of this preamble).

A total of 21 months would be given

for the submission of final reports for

acute toxicity testing because the acute

inhalation toxicity with histopathology

guideline proposes to make certain

histopathology studies contingent upon

the results of the 90-day subchronic

studies. The time for the submission of

immunotoxicity studies would vary as a

function of the test with which they can

be combined (e.g., subchronic and

reproductive effects).

B. Test Substance

EPA is proposing that a substance of

at least 97% purity be used as the test

substance. EPA recognizes that exposure

to HAPs will occur as exposure to

complex mixtures and that ideally one

would like data on the mixtures

themselves. However, it is not practical

to test mixtures due to the huge number

of possible combinations. EPA will thus

evaluate the toxicity of HAP mixtures

using data on the relatively pure

components in order to avoid the

possible confounding effects of

impurities that might be found in

technical grade substances. These

impurities, if substantial contributors to

air pollution, should also be captured as

separate entries on the CAA list of

HAPs. EPA believes that a purity of 97%

is available or readily achievable for all

substances covered by this rule.

For cresols, the subject of the test rule

is a mixture (CAS No. 1319–77–3) of

three isomers: ortho- (CAS No. 95–48–

7), para- (CAS No. 106–44–5) and meta-

(CAS No. 108–39–4). The mixture and

individual isomers are contained in the

CAA section 112(b)(1) list of hazardous

air pollutants. Most human exposure is

to the mixture. However, because the

mixture is of variable composition, EPA

believes that it would be very

burdensome to test every possible

variation of the mixture, which would

have different proportions of isomers.

Therefore EPA is proposing to follow

the approach taken in the final test rule

for cresols (51 FR 15771, 15776, April

28, 1986) and test each isomer (see Unit

III.D. of this preamble).

Another critical factor in study design

for HAP testing is the low vapor

pressure of several of these substances

(diethanolamine, 1,1’-biphenyl, phthalic

anhydride). This raises two questions.

To which forms of the chemical are

humans exposed—vapor, aerosol or

particle? How does one design a valid

toxicity study that can be used to assess

human risk to such exposures? Given

the reported TRI releases to the

atmosphere for these substances, EPA

has assumed that exposures are to
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33187

aerosols or particulates from the

condensation of high temperature stack

gases. EPA is proposing that

diethanolamine, 1,1’-biphenyl and

phthalic anhydride be tested via aerosol

exposure. EPA invites manufacturers

and processors to submit information

about the forms of these substances that

are encountered in ambient exposures

and the forms that should be tested, and

encourages the development of

pharmacokinetics data that would

permit testing by the less expensive oral

route for HAPs with low vapor pressure.

C. Test Guidelines

The 11 guidelines being proposed for

use in testing HAPs under this rule are

included in the recently harmonized

health effects test guidelines proposed

by EPA’s Office of Prevention,

Pesticides, and Toxic Substances

(OPPTS). When final, these harmonized

guidelines will incorporate an updated

version of the test guidelines previously

developed for use under TSCA and

FIFRA into a single set. A notice of

availability and request for comments

on the proposed guidelines was

published in the Federal Register of

June 20, 1996 (61 FR 31522).

The 11 guidelines proposed for use in

testing HAPs are included in the public

version of the record for this rulemaking

at the address specified in the

‘‘ADDRESSES’’ section of this

document. The complete set of

proposed guidelines is available

electronically from the EPA Public

Access Gopher (gopher.epa.gov) under

the heading: ‘‘Environmental Test

Methods and Guidelines’’; by internet email: guidelines@epamail.epa.gov; by

mail: Public Docket and Freedom of

Information Section, Field Operations

Division (7506C), Office of Pesticide

Programs, U.S. Environmental

Protection Agency, Washington, DC

20460; or in person or for courier pickup: Room 1132, CM #2, 1921 Jefferson

Davis Highway, Arlington, VA;

telephone: (703) 305–5805.

The 11 guidelines proposed to be

used for testing HAPs are as follows:

(1) Acute Inhalation Toxicity with

Histopathology, OPPTS 870.1350, EPA

Pub. No. 712–C–96–291, June 1996;

(2) Subchronic Inhalation Toxicity,

OPPTS 870.3465, EPA Pub. No. 712–C–

96–204, June 1996;

(3) Inhalation Developmental Toxicity

Study, OPPTS 870–3600, EPA Pub. No.

712–C–96–206, June 1996;

(4) Reproduction and Fertility Effects,

OPPTS 870.3800, EPA Pub. No. 712–C–

96–208, February 1996;

(5) Carcinogenicity, OPPTS 870.4200,

EPA Pub. No. 712–C–96–211, June 1996;

(6) Escherichia coli WP2 and WP2

uvrA Reverse Mutation Assays, OPPTS

870.5100, EPA Pub. No. 712–C–96–247,

June 1996;

(7) Detection of Gene Mutations in

Somatic Cells in Culture, OPPTS

870.5300, EPA Pub. No. 712–C–96–221,

June 1996;

(8) In Vivo Mammalian Cytogenetics

Tests: Bone Marrow Chromosomal

Analysis, OPPTS 870.5385, EPA Pub.

No. 712–C–96–225, June 1996;

(9) In Vivo Mammalian Cytogenetics

Tests: Erythrocyte Micronucleus Assay,

OPPTS 870.5395, EPA Pub. No. 712–C–

96–226, June 1996;

(10) Neurotoxicity Screening Battery,

OPPTS 870.6200, EPA Pub. No. 712–C–

96–238, June 1996; and

(11) Immunotoxicity, OPPTS

870.7800, EPA Pub. No. 712–C–96–351,

June 1996.

To be considered in this rulemaking,

comments on the 11 proposed test

guidelines that are specific to HAPs

testing must be submitted to the OPPT

Document Control Office. The

comments must be submitted in the

manner specified in the ‘‘DATES’’ and

‘‘ADDRESSES’’ sections at the

beginning of this document. Comments

on the 11 proposed guidelines, which

are not specific to the HAPs test rule

must be submitted to the Office of

Pesticide Programs by August 19, 1996,

at the address identified in the Federal

Register of June 20, 1996 (61 FR 31522).

The process of developing OPPTS

harmonized guidelines described above

is proceeding at the same time as the

development of the HAPs test rule. The

OPPTS harmonization process may

result in the revision of the guidelines

prior to the end of the ocmment period

for this proposed rule. If so, EPA will

announce the availability of those of the

11 guidelines used in the HAPs rule that

have been revised in order to allow for

public comment on the applicability of

the revised guidelines to the HAPs rule.

If any of these 11 guidelines has not

been revised by the end of the comment

period for this proposed rule, EPA may

issue the corresponding HAPs-specific

guideline independent of the OPPTS

harmonization process.

EPA is proposing to modify the

subchronic inhalation toxicity test

guideline (OPPTS 870.3465) for the

purposes of this rulemaking to include

enhanced histopathology of the

respiratory tract and an assay for cell

damage via lung lavage. EPA is

requesting comment on adding these

parameters to the subchronic test

guideline for testing HAPs.

As part of this rulemaking, EPA

proposes to use the acute inhalation

toxicity with histopathology test

guideline (OPPTS 870.1350). As

indicated in Unit III.A. of this preamble,

the study of sublethal effects, especially

effects on the respiratory system,

associated with accidental release and

acute exposures is necessary for the

HAPs. The standard acute inhalation

toxicity test guideline (OPPTS 870.1300)

focuses on gross lesions, body weight

changes, and effects on mortality. The

acute inhalation toxicity with

histopathology test guideline assesses

two endpoints: (1) histopathology of the

respiratory tract, kidney, liver, and other

target organs; and (2) cell damage via

lung lavage. The guideline takes a

stepwise approach to the evaluation of

acute toxicity and initially requires a 4-

hour exposure at three concentration

levels. If the 4-hour study shows

positive results in histopathology or the

bronchoalveolar lavage, a 1-hour study

and an 8-hour study would be required

to define better the time and

concentration dependence of acute

exposures. Histopathology is being

proposed for the respiratory tract, liver,

and kidney. Other target organs

identified by either gross pathology in

the 4-hour acute study or by

histopathology in the 90-day study

would also have to be examined by

histopathology in the 4-hour acute

study. If these results are positive in the

4-hour study, histopathology in the 1-

hour and 8-hour studies would be

required. The 4-hour acute testing may

be combined with acute neurotoxicity

testing.

A respiratory sensory irritation test

using American Standard Test Method

(ASTM) E 981–84 is also being proposed

to provide a quantitative estimate of the

sensory irritant potential of an inhaled

chemical. Irritation is detected by a

characteristic change in the breathing

pattern of mice, which results in a

reduction in the breathing rate during

exposure to a test atmosphere.

For all testing proposed in this rule,

test sponsors would have to conduct

testing and generate data in accordance

with the specified test guideline. Data

developed under the final rule must be

reported in accordance with TSCA Good

Laboratory Practice (GLP) Standards, 40

CFR part 792.

EPA is considering three alternative

procedures for handling these test

guidelines in the context of the final

HAPs test rule. The first alternative is

for the final HAPs rule to incorporate

the guidelines by reference. Under this

alternative, the text of the guideline

would not appear in the Code of Federal

Regulations. Instead the rule would

include a reference to the guideline

which would be available on the

internet and elsewhere, as noted above.
33188 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

A copy of the applicable guideline

would also be maintained in the public

version of the rulemaking record.

The second alternative would be for

the final HAPs rule to refer to the

guideline, the text of which would be

available on the internet and elsewhere,

as the pre-approved protocol. However,

test sponsors may use other protocols

after such protocols have been approved

by EPA (‘‘previously approved

equivalents’’). If EPA decides on this

course of action, the Agency may issue

a supplemental notice proposing

specific implementation procedures if

they are significantly different from the

following procedures. A test sponsor

would be required to submit to EPA for

review and approval each test protocol

that such sponsor believes is equivalent

to the corresponding OPPTS test

guideline. A submission would have to

demonstrate equivalency, include a

description of the differences between

the sponsor’s protocol and the

corresponding OPPTS guideline, and

indicate the rationale for changing the

guideline. The deadline for these

submissions would be 90 days after the

effective date of the final HAPs rule. In

the case of a study where the design

depends upon the results of an earlier

test (such as carcinogenicity where the

dose level is contingent upon the results

of a subchronic study), the deadline is

90 days following the date of

submission of the final report for that

study.

The third alternative is for the final

HAPs rule to reference the guidelines

currently in part 798 of title 40 of the

Code of Federal Regulations and modify

these guidelines to make them as nearly

identical as possible to the harmonized

OPPTS guidelines. The modifications

that the Agency currently believes

would be appropriate are set forth in a

separate document in the record entitled

‘‘Modifications to Health Effects Test

Guidelines Currently in 40 CFR Part 798

for Use in the HAPs Test Rule’’. EPA is

soliciting comment on these three

alternative procedures.

D. Route-to-Route Extrapolation

EPA would consider route-to-route

extrapolation of toxicity data from

routes other than inhalation when it is

scientifically defensible to empirically

derive the inhalation risk. Derivation of

the inhalation risk is generally only

reasonable when portal-of-entry effects

(toxic effects on the respiratory tract

from inhalation exposure) and/or firstpass effects can be ruled out or

adequately characterized.

‘‘First-pass’’ effects refer to the

metabolism that can take place in

portal-of-entry tissue, prior to a

chemical’s entry into the systemic

circulation. For example, after oral

administration, many chemicals are

delivered to the liver via the portal vein

from the gastrointestinal (GI) tract before

they enter into the systemic circulation.

The respiratory tract can also exhibit a

first-pass effect after inhalation due to

its various cell types and metabolic

enzyme systems. The first-pass action

can alter the disposition of the parent

and metabolites, thereby modulating the

dose to remote or systemic target tissues

in a route-dependent fashion. Therefore,

unless this first-pass effect and

dosimetry are adequately understood

and taken into account, substantial error

can be introduced in route-to-route

extrapolation.

In the absence of data to determine

dosimetry via inhalation, quantitative

route-to-route extrapolation is subject to

substantial error when a chemical is

thought to be susceptible to first-pass

effects (e.g., metabolized) or when a

potential for portal-of-entry effects is

indicated (e.g., skin irritation after

dermal administration). There are

situations where oral data should not be

used for route extrapolation to

inhalation. For example, chemicals with

a short active half-life that were

administered by gavage may result in

high short-term blood concentrations

and consequently much greater effects

than the much lower constant blood

levels that occur with inhalation

exposure. Conversely, if a chemical

requires metabolic activation via a ratelimited reaction, bolus dosing via

gavage may underestimate the dose.

Consideration of factors such as these is

important in judging whether the oral

study of interest qualifies for route

extrapolation.

Regardless of the toxic endpoint

considered, EPA’s ability to perform

quantitative route-to-route extrapolation

is critically dependent on the amount

and type of data available. The

minimum information generally needed

includes both the nature of the toxic

effect and a description of the

relationship between exposure and the

toxic effect. The actual impact of

exposure by different routes can best be

estimated by taking account of factors

that influence absorption at the portal of

entry, such as:

(1) Physicochemical characteristics of

the chemical (e.g., disassociation state,

molecular weight, partition coefficient,

reactivity, solubility);

(2) Exposure factors (e.g.,

concentration, duration, regimen); and

(3) Physiologic parameters (e.g.,

barrier capacity as related to variability

in species, blood flow, cell types and

morphology, metabolism, pH,

specialized absorption sites, storage in

cells) and those parameters that

influence dose that are remote to the

portal of entry including metabolism,

clearance, tissue binding, tissue blood

flows, tissue:blood partition

coefficients, and tissue volumes.

Oral toxicity data are the most

commonly available data as alternatives

to inhalation data. Oral data are

problematic for route-to-route

extrapolation in the following instances:

(1) When groups of chemicals are

expected to have different toxicities by

the two routes, for example, metals,

irritants, and sensitizers.

(2) When a first-pass effect by the

liver is expected.

(3) When a respiratory tract effect is

established but nodosimetry comparison

can be clearly established between the

two routes.

(4) When the respiratory tract was not

adequately studied in the oral studies.

(5) When short-term inhalation

studies, dermal irritation, or in vitro

studies indicate potential portal-of-entry

effects at the respiratory tract, but the

studies themselves are not adequate for

risk assessment.

Dose-response data from other routes

of exposure, such as intravenous,

intraperitoneal, subcutaneous, dermal,

and intramuscular routes also may be

available. Intravenous data can provide

reliable information on blood levels, but

such information should be

supplemented by knowledge of the

quantitative relationship between

exposure concentration and blood levels

in order to be useful. The other routes

usually are less useful in route-to-route

extrapolation because the

pharmacokinetics are, in general, poorly

characterized.

Methods for route-to-route

extrapolation vary in accuracy and,

therefore, in inherent uncertainty. The

simplest approach is to use default

absorption values for each exposure

route dependent on the chemical class

in question. Such values have only been

developed for a few classes of organic

chemicals. Because this approach

entails increased uncertainty compared

with those that use pharmacokinetics

(PK) data and physiologically based

pharmacokinetics (PBPK) modeling, use

of default absorption values is generally

considered highly uncertain for

quantitative dose-response assessment.

EPA’s optimal but most complex and

data intensive method for performing

route-to-route extrapolation involves the

development of a PBPK model that

describes the disposition (deposition,

absorption, distribution, metabolism,

and elimination) of the chemical for the

routes of interest (Ref. 15). Such models
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33189

account for fundamental physiological

and biochemical parameters and

processes such as blood flows,

ventilatory parameters, metabolic

capacities, and renal clearance tailored

by the physicochemical (e.g., blood:air

and tissue:blood partitions) and

biochemical properties (e.g., binding,

depletion of cofactors) of the chemical

in question. PBPK models should be

used in conjunction with toxicity and

mechanistic studies in order to relate

the effective dose associated with an

adverse effect for the test species and

conditions to other scenarios. Although

the development of a full PBPK model

can involve greater effort than other

methods using pharmacokinetics data,

the application of pharmacokinetics

modeling to determine health risk

provides a considerable improvement in

the reliability of an extrapolation across

routes. The use of an existing model

structure, essentially a template, can

greatly reduce the effort required for

model development of analogous

chemicals.

More limited pharmacokinetics data

such as measurement of bioavailability

and disposition of an internal dose

marker (e.g., blood cholinesterase

activity, enzyme elevation, and amount

of chemical bound to protein) may be

used for route-to-route extrapolation in

conjunction with a consideration of the

uncertainties involved in each case. As

above, if the portal of entry is affected

by the agent, then more elaborate data

may be required.

EPA realizes that the use of

pharmacokinetics data for route-to-route

extrapolation, as well as for the broader

purpose of generally identifying the

mechanisms by which exposure to a

specific agent causes particular health

effects, is a fast-developing and often

controversial area of science at this

time. However, under certain

circumstances, as explained above,

route-to-route extrapolation based on

valid pharmacokinetics data can offer a

useful and less expensive alternative to

testing or retesting by another route of

exposure.

E. Opportunity To Submit Proposals for

Enforceable Consent Agreements for

Pharmacokinetics Studies

Basic pharmacokinetics parameters

provide information on a substance’s

absorption, distribution,

biotransformation, and excretion which

can aid in understanding the potential

for accumulation of the substance in

various tissues or organs and the

mechanism of toxicity. Basic PK

parameters can be determined through

use of the OPPTS harmonized test

guideline for pharmacokinetics studies

(870.7485). EPA considered but rejected

the option of requiring the use of this

guideline in this proposed rule because

the Agency is interested in a more

sophisticated level of study that could

potentially support PBPK modeling.

EPA believes that enforceable consent

agreements (ECAs) and testing consent

orders offer an opportunity to obtain

this more in-depth understanding of the

pharmacokinetics of HAPs. The Agency,

therefore, is inviting manufacturers to

submit proposals for pharmokinetics

studies for HAPs to be used in the ECA

process. Each study proposal should

include the name of the chemical(s), a

detailed description of the proposed

pharmacokinetics study, and discussion

of the application of the

pharmacokinetics data in performing

route-to-route extrapolations. Study

proposals should reflect an

understanding of the scientific

reasoning presented in Unit IV.D. of this

preamble, the existing database on the

chemical and testing required under this

proposed test rule. EPA expects to use

a previously published decision tree

(Ref. 15) as an element in the evaluation

of these proposals. As noted in Unit

IV.D., these data may be used for routeto-route extrapolation with a level of

uncertainty in inverse proportion to

their level of complexity and

sophistication.

Each study proposal should be

labeled: ‘‘Proposal for Pharmacokinetics

Study of (name of chemical),’’ identified

by document control number (OPPTS–

42187B, FRL–4869–1), and sent to: U.S.

Environmental Protection Agency,

Office of Pollution Prevention and

Toxics, Document Control Office (7407),

Room G–099, 401 M St., SW.,

Washington, DC 20460. Proposals for

pharmacokinetics studies must be

received by EPA no later than October

24, 1996. Enforceable consent

agreements must be negotiated and

signed no later than 12 months after the

date of proposal of this rule in order to

permit timely development of the final

HAPs rule.

EPA will review the submissions and

will select promising candidates for

negotiation under the procedures in 40

CFR 790.22. If the Agency decides to

proceed with the ECA process, it will

publish a notice in the Federal Register

soliciting persons interested in

participating in or monitoring

negotiations for the development of

ECAs for PK studies to notify the

Agency in writing.

EPA noted in Unit IV.D. that the

development and use of a PBPK model

represents the optimal approach to

route-to-route extrapolation. The

development of such models is often a

complex and uncertain task that in most

cases lies beyond the expectations of

performance that could be embodied in

an ECA. However, EPA would like to

encourage extension of the data

generated under the ECAs described

above to the development of PBPK

models. EPA envisions that PBPK

models could be developed through

voluntary cooperative arrangements and

is interested in a dialogue with industry

and others on ways to encourage and

support PBPK model development.

F. Persons Required To Test

Based on the findings in Unit V of this

preamble, EPA is proposing that persons

who manufacture (including import) or

process, or who intend to manufacture

or process 1,1’-biphenyl, carbonyl

sulfide, chlorine, chlorobenzene,

chloroprene, cresols (all three isomers),

diethanolamine, ethylbenzene, ethylene

dichloride, ethylene glycol,

hydrochloric acid, hydrogen fluoride,

maleic anhydride, methyl isobutyl

ketone, methyl methacrylate,

naphthalene, phenol, phthalic

anhydride, 1,2,4-trichlorobenzene,

1,1,2-trichloroethane, and vinylidene

chloride, other than as an impurity, at

any time from the effective date of the

final test rule to the end of the

reimbursement period, be subject to the

testing requirements in this rule.

Manufacturers would be required to

submit letters of intent to conduct

testing or exemption applications (40

CFR 790.45). However, under 40 CFR

790.42, processors, small-quantity

manufacturers, and manufacturers of

small quantities of these substances

solely for research and development

purposes would not be required to

submit letters of intent or exemption

applications unless directed to do so in

a subsequent notice as described in 40

CFR 790.48(b).

EPA is proposing to exempt those

manufacturers and processors that

produce the chemical substances listed

above only as an impurity, as defined in

40 CFR 790.3, because it would be

difficult and prohibitively expensive for

EPA, manufacturers, and processors to

identify with complete assurance all

chemical substances that contain the 21

substances solely as an impurity. In

addition, EPA would find it difficult to

apply both the exemption and

reimbursement processes to those who

manufacture and/or process these

chemical substances solely as an

impurity. EPA’s reimbursement

regulations, issued pursuant to TSCA

section 4(c), 15 U.S.C. 2603(c), state that

those persons who manufacture or

process chemical substances as

impurities are not subject to test
33190 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

requirements unless a particular test

rule specifically states otherwise (40

CFR 791.48(b)). EPA finds no basis to

propose such a requirement in this rule.

Persons who manufacture these

substances as byproducts, as defined in

40 CFR 791.3(c), would be subject to the

testing requirements set forth in this

proposed rule. The total amount of

imports and domestic production of

these chemical substances, including

the amount produced as a byproduct,

would be used in determining

reimbursement shares under the TSCA

section 4 data reimbursement

regulations in 40 CFR part 791. In a

previous multichemical test rule

(undertaken for EPA’s Office of Solid

Waste) for which EPA had likewise

proposed that byproducts be subject to

the rule, an industry commenter

objected to this inclusion based on

historical grounds. The commenter said,

‘‘The historical roots of section 4 in the

Eckart Subcommittee work on TSCA

were the sharing of the costs of test

generation in direct proportion to the

economic benefits which producers

derived from the chemicals.’’ In

response to this comment, EPA

explained that,

EPA does not agree that the intention of

Congress to have producers share the cost of

testing should be interpreted to exclude

producers of byproducts from TSCA section

4 testing requirements. While economic

benefit is not derived directly from the

production of the subject chemical, the

production and disposal of the byproduct are

a result of a production process by which the

company does derive economic benefit (an

indirect benefit). (53 FR 22300, 22305, June

15, 1988)

Carbonyl sulfide would be the first

chemical substance subject to a TSCA

section 4 test rule that is produced

almost exclusively as a byproduct.

Although some carbonyl sulfide is

reported to be used in chemical

synthesis, its large production and

release, as reported in the TRI, is due to

its creation as a byproduct which is

unwanted. Consistent with EPA’s

position on byproducts testing, as

explained above, all persons reporting

the release of carbonyl sulfide in the TRI

would be considered to be

manufacturers of carbonyl sulfide and

would be subject to the provisions of

this proposed rule.

V. Findings

As explained in Unit I of this

preamble, EPA is proposing findings

under TSCA sections 4(a)(1)(A) and

4(a)(1)(B) for the 21 HAPs subject to this

rule. The findings are summarized in

the table below. The detailed discussion

of the findings for each chemical

substance included in this rule is

contained in a separate document

entitled ‘‘TSCA Section 4 Findings for

21 Hazardous Air Pollutants’’ that is

available in the rulemaking record.

Requirements for sections 4(a)(1)(A) and

4(a)(1)(B) findings appear in Unit I of

this preamble.

In articulating its policy for making

findings under TSCA section 4(a)(1)(B)

(frequently described as the ‘‘B policy’’,

see Unit I of this preamble), EPA has

defined ‘‘substantial production’’ as

aggregate annual production of 1

million pounds or more and

‘‘substantial release’’ as an annual

release, from all sources, into the

environment of 1 million pounds or

10% of production, whichever is lower

(58 FR 28736, 28746, May 14, 1993).

These definitions apply to the terms

‘‘substantial production’’ and

‘‘substantial release’’ as used in this

preamble. (As explained in Unit III.C. of

this preamble, all the chemical

substances proposed for testing in this

proposed rule are emitted into the

atmosphere in the amount of 50 tons per

year or more according to the TRI.) EPA

also defined ‘‘substantial human

exposure’’ as an annual exposure of

100,000 members of the general

population, 10,000 consumers, or 1,000

workers. Id.

TSCA Section 4(a) Statutory Findings

Chemical substance 4(a)(1)(A)(i) Finding is

based on: 4(a)(1)(B)(i) Findinga is based on:

4(a)(1)(A)(ii)/(iii) and

4(a)(1)(B)(ii)/(iii) Finding

are for:

1,1’-Biphenyl

(CAS No. 92-52-4)

Reproductive toxicity

Respiratory toxicity

Substantial production: 53.5 million lbs

Substantial human exposure: 20,351 workers

Consumer exposure

Acute toxicity6,9

Subchronic toxicity5,9

Developmental toxicity2

Reproductive toxicity1

Neurotoxicity7

Immunotoxicity7

Respiratory sensory irritation7

Carbonyl Sulfide

(CAS No. 463-58-1)

Oncogenicity

Neurotoxicity

Substantial production: production is at least as

much as environmental release (produced as a

byproduct)

Substantial environmental release: 16.7 million lbs

Acute toxicity6

Subchronic toxicity7

Developmental toxicity7

Reproductive toxicity5,6

Neurotoxicity6,7

Oncogenicity7

Immunotoxicity7

Genetic toxicity7

Respiratory sensory irritation7

Chlorine

(CAS No. 7782-50-5)

Respiratory toxicity Substantial production: 22.3 billion lbs

Substantial human exposure: 170,000 workers

Consumer exposure

Substantial environmental release: 78,498 million

lbs

Acute toxicity5,8
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33191

TSCA Section 4(a) Statutory Findings—Continued

Chemical substance 4(a)(1)(A)(i) Finding is

based on: 4(a)(1)(B)(i) Findinga is based on:

4(a)(1)(A)(ii)/(iii) and

4(a)(1)(B)(ii)/(iii) Finding

are for:

Chlorobenzene

(CAS No. 108-90-7)

Respiratory toxicity

Developmental toxicity

Reproductive toxicity

Liver toxicity

Kidney toxicity

Neurotoxicity

Substantial production: 210 million lbs

Substantial human exposure: 17,056 workers

General population

Substantial environmental release: 2.58 million lbs

Acute toxicity6

Subchronic toxicity3,4,6,8

Neurotoxicity7

Immunotoxicity6,7

Chloroprene

(CAS No. 126-99-8)

Respiratory toxicity

Reproductive toxicity

Liver toxicity

Neurotoxicity

Hematotoxicity

Developmental toxicity

Substantial production: 321 million lbs

Substantial human exposure: 17,749 workers

General population

Substantial environmental release: 1.7 million lbs

Acute toxicity3,6

Reproductive toxicity7,8

Neurotoxicity6,8

Immunotoxicity7

Respiratory sensory irritation7

Cresols

(CAS No. 1319-77-3)

mixture of 3 isomers:

ortho-isomer

(CAS No. 95–48–7)

para-isomer

(CAS No. 106–445)

meta-isomer

(CAS No. 108–39–4)

Respiratory toxicity

Developmental toxicity

Neurotoxicity

Substantial production: 84.3 million lbs

Substantial human exposure: 132,742 workers

Consumer exposure

General population

Substantial environmental release: 1.5 million lbs

Acute toxicity8

Subchronic toxicity5,8

Acute neurotoxicity5,6

Immunotoxicity6,7

Respiratory sensory irritation7

Diethanolamine

(CAS No. 111-42-2)

Reproductive toxicity

Neurotoxicity

Substantial production: 198 million lbs

Substantial human exposure: 573,025 workers

Consumer exposure

Acute toxicity8

Subchronic toxicity5

Developmental toxicity6

Reproductive toxicity7

Neurotoxicity5,6,7

Immunotoxicity7

Respiratory sensory irritation7

Ethylbenzene

(CAS No. 100-41-4)

Developmental toxicity

Kidney toxicity

Neurotoxicity

Substantial production: 11.4 billion lbs

Substantial human exposure: 80,726 workers

Consumer exposure

General population

Substantial environmental release: 8.8 million lbs

Acute toxicity6

Developmental toxicity2

Reproductive toxicity7

Neurotoxicity6,7

Immunotoxicity6,7

Respiratory sensory irritation7

Ethylene dichloride

(CAS No. 107-06-2)

Oncogenicity

General systemic toxicity

Substantial production: 14.3 billion lbs

General population

Substantial human exposure: 77,111 workers

Consumer exposure

Substantial environmental release: 4 million lbs

Acute toxicity1,4,5,6

Subchronic toxicity4,5,8

Developmental toxicity2

Reproductive toxicity9

Neurotoxicity6,7

Respiratory sensory irritation7

Ethylene glycol

(CAS No. 107-21-1)

Substantial production: 7.2 billion lbs

Substantial human exposure: 1,133,792 workers

Consumer exposure

Substantial environmental release: 17.5 million lbs

Acute toxicity7

Subchronic toxicity4,6

Neurotoxicity7

Immunotoxicity5

Respiratory sensory irritation7

Hydrochloric acid

(CAS No. 7647-01-0)

Respiratory toxicity Substantial production: 5.75 billion lbs

Substantial human exposure: 1,131,879 workers

Consumer exposure

Substantial environmental release: 287.7 million lbs

Acute toxicity5,6
33192 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

TSCA Section 4(a) Statutory Findings—Continued

Chemical substance 4(a)(1)(A)(i) Finding is

based on: 4(a)(1)(B)(i) Findinga is based on:

4(a)(1)(A)(ii)/(iii) and

4(a)(1)(B)(ii)/(iii) Finding

are for:

Hydrogen fluoride

(CAS No. 7664-39-3)

Respiratory toxicity

Liver toxicity

Eye irritation

Substantial production: 322 million lbs

Substantial human exposure: 182,589 workers

Substantial environmental release: 9.2 million lbs

Acute toxicity3,5,6,8

Subchronic toxicity8,10

Developmental toxicity7

Reproductive toxicity7

Neurotoxicity7

Immunotoxicity7

Respiratory sensory irritation7

Maleic anhydride

(CAS No. 108-31-6)

Respiratory toxicity

Eye irritation

Substantial production: 382 million lbs

Substantial human exposure: 37,897 workers

Acute toxicity7

Developmental toxicity2

Neurotoxicity7

Oncogenicity5,6

Immunotoxicity7

Respiratory sensory irritation7

Methyl isobutyl ketone

(CAS No. 108-10-1)

Developmental toxicity

Neurotoxicity

Substantial production: 175 million lbs

Substantial human exposure: 467,763 workers

Consumer exposure

General population

Substantial environmental release: 27.7 million lbs

Acute toxicity5,6

Reproductive toxicity7

Immunotoxicity7

Respiratory sensory irritation

Methyl methacrylate

(CAS No. 80-62-6)

Respiratory toxicity

Liver toxicity

Kidney toxicity

Neurotoxicity

Substantial production: 1,200 million lbs

Substantial human exposure: 120,788 workers

Consumer exposure

Substantial environmental release: 2.8 million lbs

Acute toxicity1,3,4,6

Developmental toxicity2

Reproductive toxicity7

Neurotoxicity3,4,6,8

Immunotoxicity6,7

Respiratory sensory irritation7

Naphthalene

(CAS No. 91-20-3)

Respiratory toxicity

Neurotoxicity

Substantial production: 235 million lbs

Substantial human exposure: 23,092 workers

Consumer exposure

General population

Substantial environmental release: 2.8 million lbs

Acute toxicity5,6

Reproductive toxicity5,6,7

Immunotoxicity6,7

Respiratory sensory irritation7

Phenolb

(CAS No. 108-95-2)

Respiratory toxicity Substantial production: 3.9 billion lbs

Substantial human exposure: 192,739 workers

Consumer exposure

General population

Substantial environmental release: 10 million lbs

Acute toxicity4,5,8

Immunotoxicity4,5,6

Respiratory sensory irritation

Phthalic anhydride

(CAS No. 85-44-9)

Respiratory sensitizationSubstantial production: 874 million lbs

Substantial human exposure: 62,644 workers

Acute toxicity6,7

Subchronic toxicity7

Developmental toxicity5,8

Reproductive toxicity7

Neurotoxicity7

Oncogenicity5

Immunotoxicity7

Respiratory sensory irritation7

1,2,4-Trichlorobenzene

(CAS No. 120-82-1)

Oncogenicity

Developmental toxicity

Substantial production: CBI

Substantial human exposure: 4,032 workers

General population

Acute toxicity1,3,6

Developmental toxicity1,5,6

Neurotoxicity6

Immunotoxicity7

Respiratory sensory irritation7
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33193

TSCA Section 4(a) Statutory Findings—Continued

Chemical substance 4(a)(1)(A)(i) Finding is

based on: 4(a)(1)(B)(i) Findinga is based on:

4(a)(1)(A)(ii)/(iii) and

4(a)(1)(B)(ii)/(iii) Finding

are for:

1,1,2-Trichloroethane

(CAS No. 79-00-5)

Oncogenicity

Liver toxicity

Kidney toxicity

Neurotoxicity

Substantial production: estimated - 210 million lbs

Substantial human exposure: 1,036 workers

General population

Acute toxicity7

Subchronic toxicity7

Developmental toxicity5,6

Reproductive toxicity7

Neurotoxicity6,7

Oncogenicity5

In vivo cytogenicity7

Immunotoxicity6

Respiratory sensory irritation7

Vinylidene chloride

(CAS No. 75-35-4)

Oncogenicity

Respiratory toxicity

Developmental toxicity

Liver toxicity

Kidney toxicity

Substantial production: 230 million lbs

Substantial human exposure: 2,675 workers

Consumer exposure

Acute toxicity5,6

Neurotoxicity7

Respiratory sensory irritation7

1 Too few animals were tested. 2 Only one species was adequately tested. 3 Only one sex was tested. 4 Too few exposure levels were tested. 5 Inadequate exposure duration, schedule, or route. 6 Only limited endpoints were assessed. 7 No study addressing the specific endpoint was found. 8 Insufficient reporting of data to make the study useful. 9 No no-observed-adverse-effect level (NOAEL) was identified. 10 No lowest-observed-adverse-effect level (LOAEL) was identified.

Notes to table:

a ‘‘B’’ findings are based on Ref. (10). It

should be noted that all HAPs meet the 50

tons of emissions per year selection criteria

discussed in Unit III.C. of this preamble.

b Findings made in 58 FR 61654, 61659-

60, November 22, 1993.

VI. Economic Analysis of the Proposed

Rule

EPA has prepared and placed in the

record for this proposed rule an

economic analysis that evaluates the

potential for significant economic

impacts as a result of the testing

proposed in this notice. The total cost

of this proposed rule is estimated to

range up to $41.4 million. The total cost

of testing for each chemical substance

has been annualized and compared with

annual revenues (defined as the product

of sales price and total supply) as an

indication of potential economic

impact. Annualized test costs,

calculated over 15 years using a 7%

discount rate, represent the equivalent

constant costs that would have to be

recouped each year of the payback

period to finance the testing

expenditure in the first year.

Annualized test costs are then divided

by the total supply of the chemical

substance to derive the annualized unit

test costs. The percent price impact is

calculated by dividing the annualized

unit test costs by the sales price and

multiplying by 100.

The upper-bound estimated total costs

of testing (including both laboratory

costs and administrative costs),

annualized tests costs, and price impact

for the chemicals in this proposed rule

are as follows:

Chemical Substances Total test cost ($) Annualized test cost ($) Price impact (%)

1,1’-Biphenyl 2,213,900 243,074 0.64

Carbonyl sulfide 5,509,163 609,876 NA

Chlorine 85,400 9,376 0.0003

Chlorobenzene 972,900 106,819 0.098

Chloroprene 1,603,488 176,054 0.076

Cresols (all 3 isomers) 2,139,600 234,917 0.39

Diethanolamine 2,327,838 255,584 0.23

Ethylbenzene 1,732,050 190,170 0.013

Ethylene dichloride 2,007,325 220,393 0.0071

Ethylene glycol 986,638 108,327 0.0097

Hydrochloric acid 85,400 9,376 0.0040

Hydrogen fluoride 2,135,888 234,509 0.094

Maleic anhydride 4,148,588 454,834 0.25

Methyl isobutyl ketone 1,228,913 134,928 0.16

Methyl methacrylate 1,732,050 190,170 0.023

Naphthalene 1,242,650 136,436 0.16

Phenol 85,400 9,376 0.0010
33194 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

Chemical Substances Total test cost ($) Annualized test cost ($) Price impact (%)

Phthalic anhydride 5,650,338 620,377 0.21

1,2,4-Trichlorobenzene 963,163 105,750 CBI

1,1,2-Trichloroethane 3,837,900 421,381 0.41

Vinylidene chloride 708,700 77,811 0.12

Note: The table shows the maximum

costs and impacts estimated by EPA.

The full range of estimates is given in

the economic analysis document placed

in the record for this proposed rule.

EPA believes, on the basis of these

calculations, that the proposed testing of

the HAPs presents a low potential for

adverse economic impact. Because these

chemical substances have relatively

large production volumes, with the

exception of carbonyl sulfide (to which

this methodology does not apply) the

annualized costs of testing, expressed as

a percentage of annual revenue, are very

small—ranging from 0.0003% to 0.64%.

Costs of testing are therefore found to be

insignificant relative to revenues for

these chemical substances.

VII. Availability of Test Facilities and

Personnel

Although earlier studies indicated

that test facilities and personnel were

available to perform the testing

specified in this proposed rule (Ref. 18),

the impact of this rule combined with

other testing requirements may exceed

capacity for inhalation testing facilities

in the short term. While EPA believes

that over the longer term, additional

inhalation facilities will become

available, any short-term effects can be

dealt with by adjusting study due dates

in response to comments on this rule or

in response to a request for modification

of reporting deadlines.

VIII. Public Meeting

EPA will hold a public meeting in

Washington, DC prior to the close of the

comment period. Announcemment of

this meeting will be published in the

Federal Register. If requested, EPA will

hold an additional public meeting in

Washington, DC.

IX. Comments Containing Confidential

Business Information

All comments will be placed in the

public version of the rulemaking record

unless they are clearly labeled as

containing information claimed as CBI

when they are submitted. CBI claims

will be deemed to have been waived if

they are not made at the time of

submission of the document containing

the information claimed as CBI, and

such document may be made public

with no further notice to the submitter.

While a part of the rulemaking record,

comments claimed as CBI will be

treated in accordance with 40 CFR part

2. A sanitized version of all comments

containing information claimed as CBI

must be submitted to EPA for inclusion

in the public version of the rulemaking

record.

It is the responsibility of the submitter

to comply with 40 CFR part 2 so that all

materials claimed as CBI may be

properly protected. This includes, but is

not limited to, clearly indicating on the

face of the revelant section of the

comment (as well as on any revelant

associated correspondence) that

information claimed as CBI is included

and marking ‘‘CONFIDENTIAL,’’ ‘‘TSCA

CBI,’’ or similar designation on the face

of each section of any document or

attachment in the comment that

contains information claimed as CBI.

Should putatively private information

be put into the public file because of the

submitter’s failure to clearly claim and

designate its confidential claim on the

face of the comment, EPA will presume

any such information that has been in

the public file for more than 30 days to

be in the public domain.

X. Rulemaking Record

EPA has established a record for this

rulemaking (docket number OPPTS–

42187) (including comments and data

submitted electronically). This record

contains the basic information

considered by EPA in developing this

proposal and appropriate Federal

Register notices. EPA will supplement

this record as necessary.

A public version of this record,

including printed, paper versions of

electronic comments, which does not

include any information claimed as CBI

is available for inspection from 12 noon

to 4 p.m., Monday through Friday,

except legal holidays. The public record

is located in the TSCA Nonconfidential

Information Center, Rm. NE–B607, 401

M St., SW., Washington, DC 20460.

Comments in electronic form may be

submitted directly to EPA at:

ncic@epamail.epa.gov

Comments in electronic form must be

submitted in an ASCII file avoiding the

use of special characters and any form

of encryption.

The official record for this

rulemaking, as well as the public

version, will be kept in paper form.

Accordingly, EPA will transfer all

comments received electronically into

printed, paper form as they are received

and will place the paper copies in the

official rulemaking record which will

also include all comments submitted

directly in writing.

The record includes the following

information.

A. Supporting Documentation

(1) Federal Register notices/EPA

documents pertaining to this proposed

rule consisting of:

(a) ‘‘TSCA Interagency Testing

Committee; Initial Report to the

Administrator, Environmental

Protection Agency’’ (42 FR 55026,

October 12, 1977).

(b) ‘‘Chloromethane and Chlorinated

Benzenes Proposed Test Rule;

Amendment to Proposed Health Effects

Standards’’ (45 FR 48524, July 18, 1980).

(c) ‘‘Dichloromethane, Nitrobenzene

and 1,1,1-Trichloroethane; Proposed

Test Rule’’ (46 FR 30300, June 5, 1981).

(d) ‘‘Tenth Report of the Interagency

Testing Committee to the Administrator;

Receipt of Report and Request for

Comments Regarding Priority List of

Chemicals’’ (47 FR 22585, May 12,

1982).

(e) ‘‘Methyl Isobutyl Ketone and

Methyl Ethyl Ketone; Response to the

Interagency Testing Committee’’ (47 FR

58025, December 29, 1982).

(f) ‘‘Toxic Substances Control Act;

Data Reimbursement’’ (48 FR 31786,

July 11, 1983).

(g) ‘‘Cresols; Proposed Test Rule’’ (48

FR 31813, July 11, 1983).

(h) ‘‘Methyl Isobutyl Ketone and

Methyl Ethyl Ketone Decision to Adopt

Negotiated Testing Program’’ (48 FR

44905, September 30, 1983).

(i) ‘‘Toxic Substances; Biphenyl; Test

Rule’’ (50 FR 37182, September 12,

1985).

(j) ‘‘Cresols; Testing Requirements’’

(51 FR 15771, April 28, 1986).

(k) ‘‘Chlorinated Benzenes; Final Test

Rule’’ (51 FR 24657, July 8, 1986).

(l) ‘‘Toxic Substances, 1,1,-

Dichloroethylene; Proposed Test Rule’’

(51 FR 28840, August 12, 1986).

(m) ‘‘Guidelines for Carcinogen Risk

Assessment’’ (51 FR 33992 (September

24, 1986).
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33195

(n) ‘‘Office of Solid Waste Chemicals;

Final Test Rule’’ (53 FR 22300, June 15,

1988).

(o) ‘‘Toxic Substances Control Act

(TSCA); Good Laboratory Practice

Standards’’ (54 FR 34034, August 17,

1989).

(p) ‘‘Metabolism and

Pharmacokinetics Test Guideline’’ (56

FR 32537, July 17, 1991).

(q) ‘‘Guidelines for Developmental

Toxicity Risk Assessment’’ (56 FR

63798, December 5, 1991).

(r) ‘‘TSCA section 4(a)(1)(B) Final

Statement of Policy; Criteria for

Evaluating Substantial Production,

Substantial Release, and Substantial or

Significant Human Exposure’’ (58 FR

28736, May 14, 1993).

(s) ‘‘Office of Water Chemicals; Final

Test Rule’’ (58 FR 59667, November 10,

1993).

(t) ‘‘Acetophenone, Phenol, N,NDimethylaniline, Ethyl Acetate, and 2,6-

Dimethylphenol; Proposes Test Rule,

Notice of Opportunity to Initiate

Negotiations for TSCA Section 4 Testing

Consent Agreements’’ (58 FR 61654,

November 22, 1993).

(u) ‘‘Testing Consent Orders for

Acetone, n-Amyl Acetate, n-Butyl

Acetate, Ethyl Acetate, Isobutyl Alcohol,

Methyl Isobutyl Ketone, and

Tetrahyrofuran’’ (60 FR 4514, January

23, 1995).

(v) ‘‘Executive Order 12866 of

September 30, 1993; Regulatory

Planning and Review’’ (58 FR 51735,

October 4, 1993).

(w) ‘‘Executive Order 12898 of

February 11, 1994; Federal Actions to

Address Environmental Justice in

Minority Populations and Low-Income

Populations’’ (59 FR 7629, February 16,

1994).

(x) ‘‘Guidelines for Reproductive

Toxicity Risk Assessment’’ (Pub. No.

EPA/600/AP-94/001, February 1994).

(2) OPPTS test guidelines used in this

proposed rule:

(a) Acute Inhalation Toxicity with

Histopathology, OPPTS 870.1350, EPA

Pub. No. 712–C–96–291, June 1996;

(b) Subchronic Inhalation Toxicity,

OPPTS 870.3465, EPA Pub. No. 712–C–

96–204, June 1996;

(c) Inhalation Developmental Toxicity

Study, OPPTS 870–3600, EPA Pub. No.

712–C–96–206, June 1996;

(d) Reproduction and Fertility Effects,

OPPTS 870.3800, EPA Pub. No. 712–C–

96–208, February 1996;

(e) Carcinogenicity, OPPTS 870.4200,

EPA Pub. No. 712–C–96–211, June 1996;

(f) Escherichia coli WP2 and WP2

uvrA Reverse Mutation Assays, OPPTS

870.5100, EPA Pub. No. 712–C–96–247,

June 1996;

(g) Detection of Gene Mutations in

Somatic Cells in Culture, OPPTS

870.5300, EPA Pub. No. 712–C–96–221,

June 1996;

(h) In Vivo Mammalian Cytogenetics

Tests: Bone Marrow Chromosomal

Analysis, OPPTS 870.5385, EPA Pub.

No. 712–C–96–225, June 1996;

(i) In Vivo Mammalian Cytogenetics

Tests: Erythrocyte Micronucleus Assay,

OPPTS 870.5395, EPA Pub. No. 712–C–

96–226, June 1996;

(j) Neurotoxicity Screening Battery,

OPPTS 870.6200, EPA Pub. No. 712–C–

96–238, June 1996; and

(k) Immunotoxicity, OPPTS 870.7800,

EPA Pub. No. 712–C–96–351, June 1996.

(3) Technical Support Documents

consisting of:

(a) TSCA Section 4 Findings for 21

Hazardous Air Pollutants.

(b) Exposure Profiles for HAPs—

Group 1.

(c) Summary Tables on the Health

Effects Data for Hazardous Air

Pollutants (HAPs)—Group 1.

(d) Economic Analysis of the Impact

of the Test Rule.

(4) Communications consisting of:

(a) Written letters and memoranda.

(b) Contact reports of telephone

conversations.

(c) Meeting summaries.

B. References

(1) U.S. Environmental Protection

Agency. ‘‘Methods for derivation of

inhalation reference concentrations and

application of inhalation dosimetry.’’ p.

xxviii. Prepared by the Office of Health

and Environmental Assessment,

Washington, DC. EPA/600/8–90/066F

(1994).

(2) Letter from John F. Martonik,

OSHA, to Susan B. Hazen, EPA, May 31,

1995.

(3) Letter from Val Schaeffer, CPSC, to

Joe Carra, EPA, June 2, 1995.

(4) Orme-Zavaleta, J. ‘‘OMB QuestionReply.’’ Memorandum to Vicki Dellarco.

May 9, 1996.

(5) NAS. National Academy of

Sciences, Washington DC, ‘‘Science and

Judgment in Risk Assessment’’ pp. 154,

157, 265 (1994).

(6) Siegel-Scott, C. ‘‘Slope factors for

hazardous air pollutants.’’

Memorandum to Vicki Dellarco.

September 7, 1994.

(7) Shoaf, C.R. ‘‘Clean Air Act

chemicals with adequate databases for

development of RfC’s.’’ Memorandum to

Vicki Dellarco. September 20, 1994.

(8) U.S. Environmental Protection

Agency. Health assessment document

for 2,3,7,8-tetrachlorodibenzo-p-dioxin

(TCDD) and related compounds, Vol. III

of III, pp. 9–48 to 9–50. Prepared by the

Office of Health and Environmental

Assessment, Washington, DC. EPA/600/

PB–92/001C (1994).

(9) Francis, E.Z., and Kimmel, G.A.

‘‘Proceedings of the workshop on one

versus two-generation reproductive

effects studies.’’ Journal of the American

College of Toxicology. 7:911–925 (1988).

(10) Lai, D.Y., Baetcke, K.P., Vu, V.T.,

Cotruvo, J.A., and Eustis, S.L.

‘‘Evaluation of reduced protocols for

carcinogenicity testing of chemicals:

Report of a joint EPA/NIEHS

workshop.’’ Regulatory Toxicology and

Pharmacology. 19:183–201 (1994).

(11) Syracuse Research Corporation.

‘‘Summary tables on the health effects

data for hazardous air pollutants

(HARs)–Group 1.’’ Syracuse, New York.

(1995a).

(12) Syracuse Research Corporation.

‘‘Exposure profiles for HAPs–Group 1.’’

Syracuse, New York. (1995b).

(13) Valcovic, L.R. Memorandum:

‘‘Genetic toxicity evaluation of HAPs’’

to Vicki Dellarco, July 14, 1994.

(14) Waters, M.D., Stack, H.F., and

Jackson, M.A. 1990. ‘‘Genetic Activity

Profiles of 110 Hazardous Air Pollutants

Listed Under Title III of the Clean Air

Act, as amended.’’ U. S. Environmental

Protection Agency. Internal Report.

October 30, (1990).

(15) Gerrity, T.R., and Henry, C.J. ed.

Principles of Route-to-Route

Extrapolation for Risk Assessment. pp

1–12. Elsevier Science Publishing Co.,

Inc. New York, N.Y. (1990).

(16) U.S. Environmental Protection

Agency. ‘‘Hazardous Air Pollutants:

Profiles of Non-Cancer Toxicity from

Inhalation Exposures.’’ Washington, DC.

EPA/600/R-93/142. September 1993.

(17) Luster, M.I., Portier, C., Pait, D.G.,

White, K.L., Genings, C., Munson, A.E.,

and Rosenthal, G.J. ‘‘Risk assessment in

immunotoxicology. I. Sensitivity and

predictability of immune tests.’’

Fundamental and Applied Toxicology.

18:200–210 (1992).

(18) U.S. Environmental Protection

Agency. ‘‘EPA census of the

toxicological testing industry final

report.’’ (1990).

XI. Regulatory Assessment

Requirements

A. Executive Order 12866

Pursuant to Executive Order 12866

(58 FR 51735, October 4, 1993), it has

been determined by OMB that this is a

‘‘significant regulatory action.’’ OMB

was concerned that the amount of

inhalation testing required by this rule

may exceed the capacity of the testing

industry, at least in the short run. This

action was submitted to OMB for

review, and any comments or changes

made during that review have been

documented in the public record.

In addition, EPA has prepared an

economic analysis of the impact of this
33196 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

action, which is contained in a

document entitled ‘‘Test Rule Support

for 21 Hazardous Air Pollutants.’’ This

document is available as a part of the

public record at the address listed in

Unit X of this preamble and is briefly

summarized in Unit VI of this preamble.

B. Regulatory Flexibility Act

Under the Regulatory Flexibility Act

(5 U.S.C. 601 et seq.), EPA has

determined that this test rule, if

promulgated, would not have a

significant impact on small businesses.

EPA has identified the entities that

currently manufacture or import the

chemical substances required to be

tested under this proposed rule and

examined the practices that industry

uses in carrying out chemical testing in

response to EPA test rules. EPA believes

that: (1) small businesses would not be

expected to perform testing themselves,

or to participate in the organization of

the testing effort, because health effects

testing of chemical substances is

generally carried out by consortia of the

large manufacturers or importers of the

chemical substances; (2) small

businesses would experience only very

minor costs, if any, in securing

exemption from testing requirements

because exemption request

requirements, described at 40 CFR

790.82, are minimal—particularly when,

as in this proposed rule, EPA is not

requiring exemption applicants to

submit equivalence data (see Unit IV.F

of this preamble)—and EPA does not

charge a fee for filing such requests; and

(3) small businesses are unlikely to be

affected by reimbursement requirements

because under the reimbursement rules

(at 40 CFR 791.40 through 791.52),

manufacturers or importers with a

significant share of production or

importation are the entities that must

share testing costs under the

reimbursement rules, and small

businesses generally do not manufacture

or import a significant portion of highvolume chemical substances.

C. Paperwork Reduction Act

OMB has approved the information

collection requirements contained in

this proposed rule under the provisions

of the Paperwork Reduction Act, 44

U.S.C. 3501 et seq., and has assigned

OMB control number 2070–0033.

The public reporting burden for this

collection of information is estimated to

average approximately the following

number of hours per response for the

chemicals listed below, including time

for reviewing instructions, searching

existing data sources, gathering and

maintaining the data needed, and

completing and reviewing the collection

of information.

Chemical substance Total burden

1,1’-Biphenyl 20,620

Carbonyl sulfide 47,644

Chlorine 693

Chlorobenzene 7,707

Chloroprene 13,039

Cresols (all 3 isomers) 6,048

Diethanolamine 21,826

Ethylbenzene 14,400

Ethylene dichloride 16,707

Ethylene glycol 7,816

Hydrochloric acid 693

Hydrogen fluoride 18,068

Maleic anhydride 35,849

Methyl isobutyl ketone 10,471

Methyl methacrylate 14,400

Naphthalene 10,580

Phenol 693

Phthalic anhydride 51,032

1,2,4-Trichlorobenzene 8,091

1,1,2-Trichloroethane 33,133

Vinylidene chloride 5,439

The total public reporting burden is

estimated to be 357,045 hours for all

responses. The overall average per

chemical is 15,524 hours.

Burden means the total time, effort, or

financial resources expended by persons

to generate, maintain, retain, or disclose

or provide information to or for a

Federal agency. This includes the time

needed to review instructions; develop,

acquire, install, and utilize technology

and systems for the purposes of

collecting, validating, and verifying

information, processing and

maintaining information, and disclosing

and providing information; adjust the

existing ways to comply with any

previously applicable instructions and

requirements; train personnel to be able

to respond to a collection of

information; search data sources;

complete and review the collection of

information; and transmit or otherwise

disclose the information.

An Agency may not conduct or

sponsor, and a person is not required to

respond to a collection of information

unless it displays a currently valid OMB

control number. The OMB control

numbers for EPA’s regulations are listed

in 40 CFR part 9 and 48 CFR chapter 15.

Comments are requested on the

Agency’s need for this information, the

accuracy of the provided burden

estimates, and any suggested methods

for minimizing respondent burden,

including through the use of automated

collection techniques. Send comments

on the ICR to Sandy Farmer, OPPE

Regulatory Information Division; U.S.

Environmental Protection Agency

(2136), 401 M St., SW., Washington, DC

20460, (202) 260–2740, or electronically

by sending an e-mail message to:

farmer.sandy@epamail.epa.gov. Send a

copy of these comments to the Office of

Information and Regulatory Affairs,

Office of Management and Budget, 725

17th St., NW., Washington, DC 20503,

marked ‘‘Attention: Desk Officer for

EPA.’’ Please remember to include the

ICR number in any correspondence. The

final rule will respond to any comments

on the information collection

requirements contained in this proposal.

D. Unfunded Mandates Reform Act and

Executive Order 12875

Pursuant to Title II of the Unfunded

Mandates Reform Act of 1995 (UMRA)

(Pub. L. 104–4), EPA has determined

that this action does not contain a

Federal mandate that may result in

expenditures of $100 million or more

for State, local, and tribal governments,

in the aggregate, or the private sector in

any one year. (The analysis of the costs

associated with this action is referenced

in Unit XI.A. of this preamble.)

Therefore, this action is not subject to

the requirements of sections 202 and

205 of the UMRA.

E. Executive Order 12898

Pursuant to Executive Order 12898

(59 FR 7629, February 16, 1994),

entitled ‘‘Federal Actions to Address

Environmental Justice in Minority

Populations and Low-Income

Populations,’’ the Agency has

considered environmental justicerelated issues with regard to the

potential impacts of this action on the

environmental and health conditions in

low-income and minority communities.

Because many sources of HAP

emissions are located near populations

of lower socioeconomic status and with

a higher proportion of minorities, the

improved health database that will be

generated by this action will help to

protect these individuals and

communities.

List of Subjects in 40 CFR Part 799

Environmental protection, Chemicals,

Hazardous substances, and Reporting

and recordkeeping requirements.

Dated: June 20, 1996.

Lynn R. Goldman,

Assistant Administrator for Prevention,

Pesticides and Toxic Substances.

Therefore, it is proposed that 40 CFR,

chapter I, subchapter R, be amended as

follows:
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33197

PART 799—[AMENDED]

3. The authority citation for part 799

would continue to read as follows:

Authority: 15 U.S.C. 2603, 2611, 2625.

4. By adding § 799.5053 to Subpart D

of part 799 to read as follows:

§ 799.5053 Chemical testing requirements

for hazardous air pollutants.

(a) General testing provisions—(1)

Identification of test substances. Table 1

in paragraph (a)(5) of this section

identifies those chemical substances

that shall be tested in accordance with

this section. The purity of each test

substance shall be 97 percent or greater

unless otherwise specified.

(2) Persons required to submit study

plans, conduct tests, and submit data.

All persons who manufacture (including

those who import the substance or

manufacture it as a byproduct) or intend

to manufacture one or more of the

substances listed in table 1 after the

effective date listed in table 1 until the

end of the reimbursement period shall

submit letters of intent to conduct

testing, submit study plans, conduct

tests and submit data, or submit

exemption applications, as specified in

this section, subpart A of this part and

parts 790 and 792 of this chapter.

Persons who manufacture or process

these substances only as an impurity are

not subject to these requirements. As

explained in part 790 of this chapter,

processors, small-quantity

manufacturers, and manufacturers of

small quantities of these substances

solely for research and development

purposes would become subject to these

requirements only after notification in

the Federal Register that no

manufacturer had notified EPA of its

intent to conduct testing.

(3) Applicability of test guidelines.

The guidelines and other test methods

cited in table 1 in paragraph (a)(5) of

this section are referenced here as they

exist on the effective date listed in table

1 for that specific test. Testing shall be

conducted in accordance with the

designated Series 870—Health Effects

Test Guidelines and other test methods.

This incorporation by reference was

approved by the Director of the Federal

Register in accordance with 5 U.S.C.

552(a) and 1 CFR part 51. Copies may

be obtained from the Public Docket and

Freedom of Information Section, Field

Operations Division (7506C), Office of

Pesticide Programs, Environmental

Protection Agency, 401 M St., SW.,

Washington, DC 20360. Copies may be

inspected at the above address or at the

Office of the Federal Register, 800 North

Capitol Street, NW., suite 700,

Washington, DC.

(4) Interim reporting requirements. All

testing requirements in this section are

subject to the submission of interim

progress reports every 6 months

beginning 6 months after the effective

date for any specific test listed in table

1 in paragraph (a)(5) of this section. The

date for the submission of final reports

is specified as the number of months

after the effective date for the specific

test listed in table 1.

(5) Testing and reporting

requirements. The substances identified

by CAS Registry number and chemical

name in the following table 1 shall be

tested in accordance with the

designated OPPTS Harmonized

Guideline testing requirements and any

additional requirements and limitations

specified in the ‘‘Specific requirements

under this section’’ column of table 1.

The numbers and letters in this column

refer to the specific requirements set

forth in paragraph (b) of this section.

Final reports shall be submitted by the

deadlines indicated as the number of

months after the effective date shown in

table 1.

TABLE 1

CAS No. Chemical substance/required testing

OPPTS harmonized

guidelines

Specific requirements

under this section Final report Effectivedate

75-35-4 Vinylidene chloride:

Acute 870.1350 (b)(2) 21 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

79-00-5 1,1,2-Trichloroethane:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Developmental 870.3600 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Carcinogenicity 870.4200 (b)(1)(i)(D), (b)(1)(ii)(A) 60 mo

In vivo cytogenetics 870.5385 or 870.5395 (b)(1)(ii)(A) 14 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo

80-62-6 Methyl methacrylate:

Acute 870.1350 (b)(2) 21 mo

Developmental 870.3600 (b)(1)(i)(A) 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

85-44-9 Phthalic anhydride:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(1)(ii)(B), (b)(3) 18 mo

Developmental 870.3600 (b)(1)(ii)(B) 12 mo

Reproductive 870.3800 (b)(1)(ii)(B), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(B), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Carcinogenicity 870.4200 (b)(1)(ii)(B) 60 mo
33198 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

TABLE 1—Continued

CAS No. Chemical substance/required testing

OPPTS harmonized

guidelines

Specific requirements

under this section Final report Effectivedate

Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo

91-20-3 Naphthalene:

Acute 870.1350 (b)(2) 21 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

92-52-4 1,1’-Biphenyl:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(1)(ii)(B), (b)(3) 18 mo

Developmental 870.3600 (b)(1)(i)(A), (b)(1)(ii)(B) 12 mo

Reproductive 870.3800 (b)(1)(ii)(B), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(B), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo

95-48-7,

106-44-5, and

108-39-4

Cresols:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A) 21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo

100-41-4 Ethylbenzene:

Acute 870.1350 (b)(2) 21 mo

Developmental 870.3600 (b)(1)(i)(A) 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

107-06-2 Ethylene dichloride:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Developmental 870.3600 (b)(1)(i)(C) 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

107-21-1 Ethylene glycol:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo

108-10-1 Methyl isobutyl ketone:

Acute 870.1350 (b)(2) 21 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 29 mo

108-31-6 Maleic anhydride:

Acute 870.1350 (b)(2) 21 mo

Developmental 870.3600 (b)(1)(i)(A) 12 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Carcinogenicity 870.4200 (b)(1)(ii)(A) 60 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

108-90-7 Chlorobenzene:

Acute 870.1350 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules 33199

TABLE 1—Continued

CAS No. Chemical substance/required testing

OPPTS harmonized

guidelines

Specific requirements

under this section Final report Effectivedate

108-95-2 Phenol:

Acute 870.1350 (b)(2) 21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 12 mo

111-42-2 Diethanolamine:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(1)(ii)(B), (b)(3) 18 mo

Developmental 870.3600 (b)(1)(ii)(B) 12 mo

Reproductive 870.3800 (b)(1)(ii)(B), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(B), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo

120-82-1 1,2,4-Trichlorobenzene:

Acute 870.1350 (b)(2) 21 mo

Developmental 870.3600 12 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

126-99-8 Chloroprene:

Acute 870.1350 (b)(2) 21 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo

463-58-1 Carbonyl sulfide:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Developmental 870.3600 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Carcinogenicity 870.4200 (b)(1)(ii)(A) 60 mo

E.coli reverse mutation 870.5100 6 mo

Gene mutation 870.5300 6 mo

In vivo cytogenetics 870.5385 or 870.5395 (b)(1)(ii)(A) 14 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo

7647-01-0 Hydrochloric acid:

Acute 870.1350 (b)(2) 21 mo

7664-39-3 Hydrogen fluoride:

Acute 870.1350 (b)(2) 21 mo

Subchronic 870.3465 (b)(3) 18 mo

Developmental 870.3600 12 mo

Reproductive 870.3800 (b)(1)(ii)(A), (b)(5) 29 mo

Neurotoxicity 870.6200 (b)(1)(ii)(A), (b)(1)(iii)(A),

(b)(1)(iii)(B)

21 mo

Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo

7782-50-5 Chlorine:

Acute 870.1350 (b)(2) 21 mo

(b) Test-specific requirements—(1)

General. In addition to the testing

requirements specified in table 1 in

paragraph (a)(5) of this section and

applicable test guideline-specific

modifications listed therein, the

following additional requirements and

limitations also apply when specified

for a particular chemical substance in

table 1 under ‘‘Specific requirements

under this section’’.

(i) Test species. The test animal shall

be:

(A) A mammalian species other than

the rat.

(B) A mammalian species other than

the mouse.

(C) A mammalian species other than

the rabbit.

(D) The male rat and the female

mouse.

(ii) Route of exposure. Animals shall

be exposed:

(A) Via vapor-phase inhalation.

(B) Via inhalation of aerosol.

(C) Orally in the diet.

(iii) Duration and frequency of

exposure. (A) Animals shall be exposed

for a 4-hour period in an acute study.
33200 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Proposed Rules

(B) Animals shall be exposed for 6

hours per day, 5 days per week for a 90-

day period in a subchronic study.

(2) Acute test modifications. In

addition to the acute testing

requirements specified in table 1 in

paragraph (a)(5) of this section, the

following additional requirements and

limitations also apply when specified

for a particular chemical substance in

table 1 under ‘‘Specific requirements

under this section’’.

(i) The appraisal of pulmonary

irritation shall be evaluated during

exposure to the substance by the use of

the mouse respiratory sensory irritation

assay method as outlined in ASTM E

981–84 (see paragraph (b)(2)(iii)(C) of

this section). This method assesses the

breathing patterns of test animals. This

incorporation by reference was

approved by the Director of the Federal

Register in accordance with 5 U.S.C.

552(a) and 1 CFR part 51. This material

is incorporated as it exists on the date

of approval and notice of any change in

this material will be published in the

Federal Register. Copies of the

incorporated materials may be obtained

from the TSCA Nonconfidential

Information Center, Rm. NE–B607, 401

M St., SW., Washington, DC, 20460 or

from the American Society for Testing

and Materials (ASTM), 1916 Race Street,

Philadelphia, PA 10103. Copies may be

inspected at the above address or at the

Office of the Federal Register, 800 North

Capitol Street, NW., suite 700,

Washington, DC. For information on

this test guideline, the references in

paragraph (b)(2)(iii) should be

consulted.

(ii) Results of respiratory sensory

irritation assay. (A) Data shall be

included in the final report and

tabulated to show:

(1) The magnitude of change in

respiratory rate with exposure

concentration and with time for each

animal.

(2) A response concentration, which

indicates the concentration at which the

respiration rate is decreased by 50%

(RD50), will be calculated, along with

the 95% confidence limits.

(B) Time-effect curves shall be

included in the final report to evaluate

the onset and shape of the response.

(iii) References.

(A) Alarie, Y., and Luo, J.E. ‘‘Sensory

Irritation by Airborne Chemicals: A

basis to establish acceptable levels of

exposure.’’ Toxicology of the Nasal

Passages. Hemisphere Publishing

Corporation: New York pp. 91–100

(1986).

(B) Alarie, Y., and Stokinger, H.E.

‘‘Sensory Irritation by Airborne

Chemicals.’’ CRC Critical Reviews in

Toxicology. pp. 299–363 (1973).

(C) ASTM. ‘‘Standard Test Method for

Estimating Sensory Irritancy of Airborne

Chemicals.’’ In: 1984 Annual Book of

ASTM Standards. Water and

Environmental Technology. Section 11.

Volume 11.04 Designation E 981–84 pp.

572–584 (1984).

(3) Subchronic test modifications. In

addition to the subchronic testing

requirements specified in table 1 in

paragraph (a)(5) of this section, the

following additional requirements and

limitations also apply when specified

for a particular chemical substance in

table 1 under ‘‘Specific requirements

under this section’’.

(i) Respiratory tract pathology. (A)

Care shall be taken that the method used

to kill the animal does not result in

damage to the tissues of the upper or

lower respiratory tract. The heart-lung,

including the trachea, shall be removed

in bloc.

(B) Representative sections of the

lungs shall be examined histologically.

This shall include trachea, major

conducting airways, alveolar region,

terminal and respiratory bronchioles,

alveolar ducts and sacs, and interstitial

tissues.

(C) The nasopharyngeal tissue shall be

examined for histopathologic lesions.

This shall include sections through the

nasal cavity, and examination of the

squamous, transitional, respiratory, and

olfactory epithelia.

(D) The larynx mucosa shall be

examined for histopathologic changes.

Sections of the larynx to be examined

include the epithelium covering the

base of the epiglottis, the ventral pouch,

and the medial surfaces of the vocal

processes of the arytenoid cartilages.

(ii) Bronchoalveolar lavage. (A) The

lungs shall be lavaged in situ or after

sacrifice. If the study will not be

compromised, one lobe of the lungs may

be used for lung lavage while the other

is fixed for histologic evaluation. The

lungs shall be lavaged using

physiological saline after cannulation of

the trachea. The lavages shall consist of

two washes each of which consists of

approximately 80 percent (e.g., 5 ml in

rats and 1 ml in mice) of total lung

volume. Additional washes merely tend

to reduce the concentrations of the

material collected. The lung lavage fluid

shall be stored on ice at approximately

5 °C until assayed.

(B) The following parameters shall be

determined in the lavage fluid as

indicators of cellular damage in the

lungs: total protein, cell count and

percent leukocytes. In addition, a

phagocytosis assay using the procedure

of Burleson (Burleson et al., 1987;

Gilmour and Selgrade, 1993) shall be

performed to determine macrophage

activity. The following references may

be consulted:

(1) Burleson, G.R. et al. ‘‘Poly (I): poly

(C)-enhanced alveolar peritoneal

macrophage phagocytosis:

Quantification by a new method

utilizing fluorescent beads.’’

Proceedings of the Society for

Experimental Biology and Medicine.

184:468–476 (1987).

(2) Gilmour, G.I., and Selgrade, M.K.

‘‘A Comparison of the Pulmonary

Defenses against Streptococcal Infection

in Rats and Mice Following O3

Exposure: Differences in Disease

Susceptibility and Neutrophil

Recruitment.’’ Toxicology and Applied

Pharmacology. 123:211–218 (1993).

(4) [Reserved]

(5) Reproductive toxicity and fertility

study test modifications. In addition to

the reproductive toxicity and fertility

testing requirements specified in table 1

in paragraph (a)(5) of this section, the

following additional requirements and

limitations also apply when specified

for a particular chemical substance in

table 1 under ‘‘Specific requirements

under this section’’.

(i) Administration of the test

substance. The test substance shall be

administered by inhalation. The

requirements of OPPTS

870.3800(e)(2)(iii) do not apply.

(ii) [Reserved]

[FR Doc. 96–16203 Filed 6–25–96; 8:45 am]

BILLING CODE 6560–50–F