39264 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

ENVIRONMENTAL PROTECTION

AGENCY

[OPPTS–00293; FRL–6591–2]

National Advisory Committee for Acute

Exposure Guideline Levels (AEGLs) for

Hazardous Substances; Proposed

AEGL Values

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: The National Advisory

Committee for Acute Exposure

Guideline Levels for Hazardous

Substances (NAC/AEGL Committee) is

developing AEGLs on an ongoing basis

to provide Federal, State, and local

agencies with information on short-term

exposures to hazardous chemicals. This

notice provides AEGL values and

Executive Summaries for 14 chemicals

for public review and comment.

Comments are welcome on both the

AEGL values in this notice and the

Technical Support Documents placed in

the public version of the official docket

for these 14 chemicals.

DATES: Comments, identified by the

docket control number OPPTS–00293,

must be received by EPA on or before

July 24, 2000.

ADDRESSES: Comments may be

submitted by mail, electronically, or in

person. Please follow the detailed

instructions for each method as

provided in Unit I. of the

‘‘SUPPLEMENTARY INFORMATION.’’

To ensure proper receipt by EPA, it is

imperative that you identify docket

control number OPPTS–00293 in the

subject line on the first page of your

response.

FOR FURTHER INFORMATION CONTACT: For

general information contact: Barbara

Cunningham, Director, Office of

Program Management and Evaluation,

Office of Pollution Prevention and

Toxics (7401), Environmental Protection

Agency, 1200 Pennsylvania Ave., NW.,

Washington, DC 20460; telephone

number: (202) 554–1404; e-mail address:

TSCA-Hotline@epa.gov.

For technical information contact:

Paul S. Tobin, Designated Federal

Officer (DFO), Office of Prevention,

Pesticides and Toxic Substances (7406),

1200 Pennsylvania Ave., NW.,

Washington, DC 20460; telephone

number: (202) 260–1736; e-mail address:

tobin.paul@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

This action is directed to the general

public to provide an opportunity for

review and comment on ‘‘Proposed’’

AEGL values and their supporting

scientific rationale. This action may be

of particular interest to anyone who may

be affected if the AEGL values are

adopted by government agencies for

emergency planning, prevention, or

response programs, such as EPA’s Risk

Management Program under the Clean

Air Act (CAA) and Amendments

Section 112r. It is possible that other

Federal agencies besides EPA, as well as

State and Local agencies and private

organizations, may adopt the AEGL

values for their programs. As such, the

Agency has not attempted to describe all

the specific entities that may be affected

by this action. If you have any questions

regarding the applicability of this action

to a particular entity, consult the

technical person listed under ‘‘FOR

FURTHER INFORMATION CONTACT.’’

B. How Can I Get Additional

Information, Including Copies of this

Document or Other Related Documents?

1. Electronically. You may obtain

electronic copies of this document, and

certain other related documents that

might be available electronically, from

the EPA Internet Home Page at http://

www.epa.gov/. To access this

document, on the Home Page select

‘‘Laws and Regulations’’ and then look

up the entry for this document under

the ‘‘Federal Register—Environmental

Documents.’’ You can also go directly to

the Federal Register listings at http://

www.epa.gov/fedrgstr/.

2. In person. The Agency has

established an official record for this

action under docket control number

OPPTS–00293. The official record

consists of the documents specifically

referenced in this action, any public

comments received during an applicable

comment period, and other information

related to this action, including any

information claimed as Confidential

Business Information (CBI). This official

record includes the documents that are

physically located in the docket, as well

as the documents that are referenced in

those documents. The public version of

the official record does not include any

information claimed as CBI. The public

version of the official record, which

includes printed, paper versions of any

electronic comments submitted during

an applicable comment period, is

available for inspection in the TSCA

Nonconfidential Information Center,

North East Mall Rm. B–607, Waterside

Mall, 401 M St., SW., Washington, DC.

The Center is open from noon to 4 p.m.,

Monday through Friday, excluding legal

holidays. The telephone number of the

Center is (202) 260–7099.

3. Fax-on-Demand. You may request

to receive a faxed copy of the

document(s) by using a faxphone to call

(202) 401–0527 and select the item

number 4800 for an index of the items

available by fax-on-demand in this

category, or select the item number for

the document related to the chemical(s)

identified in this document as listed in

the chemical table in Unit III. You may

also follow the automated menu.

C. How and to Whom Do I Submit

Comments?

You may submit comments through

the mail, in person, or electronically. To

ensure proper receipt by EPA, it is

imperative that you identify docket

control number OPPTS–00293 in the

subject line on the first page of your

response.

1. By mail. Submit your comments to:

OPPT Document Control Office (7407),

Office of Pollution Prevention and

Toxics (OPPT), Environmental

Protection Agency, 1200 Pennsylvania

Ave., NW., Washington, DC 20460. For

express delivery, use the address in Unit

I.C.2.

2. In person or by courier. Deliver

your comments to: OPPT Document

Control Office (DCO) in East Tower Rm.

G–099, Waterside Mall, 401 M St., SW.,

Washington, DC. The DCO is open from

8 a.m. to 4 p.m., Monday through

Friday, excluding legal holidays. The

telephone number for the DCO is (202)

260–7093.

3. Electronically. You may submit

your comments electronically by e-mail

to: ‘‘oppt.ncic@epa.gov,’’ or mail your

computer disk to the address identified

above. Do not submit any information

electronically that you consider to be

CBI. Electronic comments must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption. Comments and data will

also be accepted on standard disks in

WordPerfect 6.1/8.0 or ASCII file

format. All comments in electronic form

must be identified by docket control

numbers OPPTS–00293. Electronic

comments may also be filed online at

many Federal Depository Libraries.

D. How Should I Handle CBI that I Want

to Submit to the Agency?

Do not submit any information

electronically that you consider to be

CBI. You may claim information that

you submit to EPA in response to this

document as CBI by marking any part or

all of that information as CBI.

Information so marked will not be

disclosed except in accordance with

procedures set forth in 40 CFR part 2.

In addition to one complete version of

the comment that includes any

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39265

information claimed as CBI, a copy of

the comment that does not contain the

information claimed as CBI must be

submitted for inclusion in the public

version of the official record.

Information not marked confidential

will be included in the public version

of the official record without official

notice. If you have any questions about

CBI or the procedures for claiming CBI,

please consult the technical person

listed under ‘‘FOR FURTHER

INFORMATION CONTACT.’’

E. What Should I Consider as I Prepare

My Comments for EPA?

You may find the following

suggestions helpful for preparing your

comments:

1. Explain your views as clearly as

possible.

2. Describe any assumptions that you

used.

3. Provide copies of any technical

information and/or data that you used

that support your views.

4. If you estimate potential burden or

costs, explain how you arrived at the

estimate that you provide.

5. Provide specific examples to

illustrate your concerns.

6. Offer alternative ways to improve

the proposed notice.

7. Make sure to submit your

comments by the deadline in this

document.

8. To ensure proper receipt by EPA,

be sure to identify the docket control

number assigned to this action in the

subject line on the first page of your

response. You may also provide the

name, date, and Federal Register

citation.

II. Background

A. Introduction

EPA’s Office of Prevention, Pesticides

and Toxic Substances (OPPTS) provided

notice in the Federal Register of

October 31, 1995 (60 FR 55376) (FRL–

4987–3) of the establishment of the

NAC/AEGL Committee with the stated

charter objective as ‘‘the efficient and

effective development of Acute

Exposure Guideline Levels (AEGLs) and

the preparation of supplementary

qualitative information on the

hazardous substances for federal, state,

and local agencies and organizations in

the private sector concerned with

[chemical] emergency planning,

prevention, and response.’’ The NAC/

AEGL Committee is a discretionary

Federal advisory committee formed

with the intent to develop AEGLs for

chemicals through the combined efforts

of stakeholder members from both the

public and private sectors in a costeffective approach that avoids

duplication of efforts and provides

uniform values, while employing the

most scientifically sound methods

available. An initial priority list of 85

chemicals for AEGL development was

published in the Federal Register of

May 21, 1997 (62 FR 27734) (FRL–5718–

9). This list is intended for expansion

and modification as priorities of the

stakeholder member organizations are

further developed. While the

development of AEGLs for chemicals

are currently not statutorily based, at

lease one rulemaking references their

planned adoption. The CAA and

Amendments Section 112(r) Risk

Management Program states, ‘‘EPA

recognizes potential limitations

associated with the Emergency

Response Planning Guidelines and

Level of Concern and is working with

other agencies to develop AEGLs. When

these values have been developed and

peer-reviewed, EPA intends to adopt

them, through rulemaking, as the toxic

endpoint for substances under this rule

(see 61 FR 31685).’’ It is believed that

other Federal and State agencies and

private organizations will also adopt

AEGLs for chemical emergency

programs in the future.

B. Characterization of the AEGLs

The AEGLs represent threshold

exposure limits for the general public

and are applicable to emergency

exposure periods ranging from 10 mins.

to 8 hrs. AEGL–2 and AEGL–3 levels,

and AEGL–1 levels as appropriate, will

be developed for each of five exposure

periods (10 and 30 mins., 1 hr., 4 hrs.,

and 8 hrs.) and will be distinguished by

varying degrees of severity of toxic

effects. It is believed that the

recommended exposure levels are

applicable to the general population

including infants and children, and

other individuals who may be sensitive

and susceptible. The AEGLs have been

defined as follows:

AEGL–1 is the airborne concentration

(expressed as parts per million (ppm) or

milligrams/meter cubed (mg/m3) of a

substance above which it is predicted

that the general population, including

susceptible individuals, could

experience notable discomfort,

irritation, or certain asymptomatic, nonsensory effects. However, the effects are

not disabling and are transient and

reversible upon cessation of exposure.

AEGL–2 is the airborne concentration

(expressed as ppm or mg/m3) of a

substance above which it is predicted

that the general population, including

susceptible individuals, could

experience irreversible or other serious,

long-lasting adverse health effects or

impaired ability to escape.

AEGL–3 is the airborne concentration

(expressed as ppm or mg/m3) of a

substance above which it is predicted

that the general population, including

susceptible individuals, could

experience life-threatening effects or

death.

Airborne concentrations below the

AEGL–1 represent exposure levels that

could produce mild and progressively

increasing odor, taste, and sensory

irritation, or certain non-symptomatic,

non-sensory effects. With increasing

airborne concentrations above each

AEGL level, there is a progressive

increase in the likelihood of occurrence

and the severity of effects described for

each corresponding AEGL level.

Although the AEGL values represent

threshold levels for the general public,

including sensitive subpopulations, it is

recognized that certain individuals,

subject to unique or idiosyncratic

responses, could experience the effects

described at concentrations below the

corresponding AEGL level.

C. Development of the AEGLs

The NAC/AEGL Committee develops

the AEGL values on a chemical-bychemical basis. Relevant data and

information are gathered from all known

sources including published scientific

literature, State and Federal agency

publications, private industry, public

databases and individual experts in both

the public and private sectors. All key

data and information are summarized

for the NAC/AEGL Committee in draft

form by Oak Ridge National

Laboratories together with ‘‘draft’’ AEGL

values prepared in conjunction with

NAC/AEGL Committee members. Both

the ‘‘draft’’ AEGLs and ‘‘draft’’

Technical Support Documents are

reviewed and revised as necessary by

the NAC/AEGL Committee members

prior to formal NAC/AEGL Committee

meetings. Following deliberations on

the AEGL values and the relevant data

and information for each chemical, the

NAC/AEGL Committee attempts to

reach a concensus . Once the NAC/

AEGL Committee reaches a concensus,

the values are considered ‘‘Proposed’’

AEGLs. The Proposed AEGL values and

the accompanying scientific rationale

for their development are the subject of

this notice.

In this document the NAC/AEGL

Committee is publishing proposed

AEGL values and the accompanying

scientific rationale for their

development for 14 hazardous

substances. These values represent the

third set of exposure levels proposed

and published by the NAC/AEGL

39266 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

Committee. EPA published the first

‘‘Proposed’’ AEGLs for 12 chemicals

from the initial priority list in the

Federal Register of October 30, 1997 (62

FR 58840–58851) (FRL–5737–3) and for

10 chemicals in the Federal Register of

March 15, 2000 (65 FR 14186–14196)

(FRL–6492–4) in order to provide an

opportunity for public review and

comment. In developing the proposed

AEGL values, the NAC/AEGL

Committee has followed the

methodology guidance Guidelines for

Developing Community Emergency

Exposure Levels for Hazardous

Substances, published by the National

Research Council of the National

Academy of Sciences (NSC/NAS) in

1993. The term Community Emergency

Exposure Levels (CEELs) is synonymous

with AEGLs in every way. The NAC/

AEGL Committee has adopted the term

Acute Exposure Guideline Levels to

better connote the broad application of

the values to the population defined by

the NAS and addressed by the NAC/

AEGL Committee. The NAC/AEGL

Committee invites public comment on

the proposed AEGL values and the

scientific rationale used as the basis for

their development.

Following public review and

comment, the NAC/AEGL Committee

will reconvene to consider relevant

comments, data, and information that

may have an impact on the NAC/AEGL

Committee’s position and will again

seek concensus for the establishment of

interim AEGL values. Although the

interim AEGL values will be available to

Federal, State, and local agencies and to

organizations in the private sector as

biological reference values, it is

intended to have them reviewed by a

subcommittee of the NAS. The NAS

subcommittee will serve as a peer

review of the interim AEGLs and as the

final arbitor in the resolution of issues

regarding the AEGL values, and the data

and basic methodology used for setting

AEGLs. Following concurrence, ‘‘Final’’

AEGL values will be published under

the auspices of the NAS.

III. Fax-On-Demand Item Number for

Chemicals Listed in this Document

On behalf of the NAC/AEGL

Committee, EPA is providing an

opportunity for public comment on the

AEGLs for the 14 chemicals identified

in the following table. This table also

provides the fax-on-demand item

number for the chemical specific

documents, which may be obtained as

described in Unit ?????.

CAS No. Chemical name Fax-On-Demand Item No.

75–78–5 Dimethyldichlorosilane 4867

75–79–6 Methyltrichlorosilane 4868

91–08–7 and

584–84–9

2,4- and 2,6-Toluene diisocyanate 4873

107–11–9 Allylamine 4876

107–15–3 Ethylenediamine 4878

108–91–8 Cyclohexylamine 4883

123–73–9 (4170–

30–3)

trans-Crotonaldehyde (cis/trans Crotonaldehyde mixture) 4903

624–83–9 Methyl isocyanate 4898

7647–01–0 Hydrogen chloride 4907

7803–51–2 Phosphine 4923

13463–39–3 Nickel carbonyl 4929

13463–40–6 Iron pentacarbonyl 4930

IV. Executive Summaries

The following are executive

summaries from the chemical specific

Technical Support Documents (which

may be obtained as described in Unit

I.B.1 and III.) that support the NAC/

AEGL Committee’s development of

AEGL values for each chemical

substance. This information provides

the following information: A general

description of each chemical, including

its properties and principle uses; a

summary of the rationale supporting the

AEGL–1, 2, and 3 concentration levels;

a summary table of the AEGL values;

and a listing of key references that were

used to develop the AEGL values. More

extensive toxicological information and

additional references for each chemical

may be found in the complete Technical

Support Documents. Risk managers may

be interested to review the complete

Technical Support Document for a

chemical when deciding issues related

to use of the AEGL values within

various programs.

A. Dimethyldichlorosilane

1. Description.

Dimethyldichlorosilane is an alkylsubstituted silicon tetrahydride existing

as a clear liquid with a sharp acrid odor

that is similar to hydrogen chloride

(HCl) (HSDB, 1996).

Dimethyldichlorosilane is used as a

high-purity derivation reagent for gas

chromatography (HSDB, 1996) and as an

intermediate in the production of

silicones that are used as lubricating

fluids, resins, and plastic copolymers

(Bisesi, 1994). It reacts vigorously with

water and decomposes to form HCl and

other hydrolysis products (AIHA, 1996).

Complete hydrolysis of one mole of

dimethyldichlorosilane would yield a

maximum of two moles of HCl.

Hydrogen chloride is a known

respiratory irritant. Data on

dimethyldichlorosilane are limited to

LC50 studies in rats.

In the absence of appropriate

chemical-specific data for

dimethyldichlorosilane, a modification

of the AEGL–1 values for HCl was

utilized to derive AEGL–1 values for

dimethyldichlorosilane. The use of HCl

as a surrogate for

dimethyldichlorosilane was deemed

appropriate since it is believed that it is

the hydrolysis product, HCl, that is

responsible for the adverse effect. The

HCl AEGL–1 values were based on a noadverse-effect-level (NOAEL) in

exercising asthmatics (Stevens et al.,

1992). Since two moles of HCl are

produced for every mole of

dimethyldichlorosilane hydrolyzed, a

modifying factor of 2 was applied to the

HCl AEGL–1 values to approximate

AEGL–1 values for

dimethyldichlorosilane. The AEGL–1

values were held constant for all

specified exposure periods since mild

irritant effects represent threshold

effects and generally do not vary over

time.

The AEGL–2 was based on corneal

opacity, and grey spots on the lungs of

rats exposed to 1,309 ppm

dimethyldichlorosilane for 1 hr. (Dow

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39267

Corning, 1997a). This level was

considered to be the threshold for

impairment of escape and the onset of

serious long-term effects. An

uncertainty factor of 10 was applied to

account for interspecies variability since

data for dimethyldichlorosilane were

available for only one species and an

uncertainty factor of 3 was applied to

account for sensitive human

subpopulations since the irritant effects

observed are not likely to vary greatly

among individuals. A modifying factor

of 3 was applied to account for the

sparse database for effects as defined by

AEGL–2. Thus, the total uncertainty/

modifying factor is 100. The

concentration-exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5

(Ten Berge et al., 1986). Much of the

acute toxicity of dimethyldichlorosilane

appears to be due to HCl and the value

of n reported for HCl is 1 (Ten Berge et

al., 1986). Therefore, the exponent n =

1 was used for scaling of the AEGL

values for dimethyldichlorosilane across

time.

The AEGL–3 was based on the

calculated LC01 of 1,590 ppm in rats

exposed to dimethyldichlorosilane for 1

hr. (Dow Corning, 1997a). An

uncertainty factor of 10 was applied to

account for interspecies variability since

data for dimethyldichlorosilane were

available for only one species and an

uncertainty factor of 3 was applied to

account for sensitive human

subpopulations since the irritant effects

observed are not likely to vary greatly

among individuals. Thus, the total

uncertainty factor is 30. The

concentration-exposure time relationship for many irritant and systemically

acting vapors and gases may be

described by Cn x t = k, where the

exponent, n, ranges from 0.8 to 3.5 (Ten

Berge et al., 1986). Much of the acute

toxicity of dimethyldichlorosilane

appears to be due to HCl, the

dimethyldichlorosilane hydrolysis

product, and the value of n for HCl is

1 (Ten Berge et al., 1986). Therefore, the

exponent n = 1 was used for scaling of

the AEGL values for

dimethyldichlorosilane across time.

The calculated values are listed in the

table below.

SUMMARY OF PROPOSED AEGL VALUES FOR DIMETHYLDICHLOROSILANE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) Modification of HCl AEGL–1 values (USEPA,

1997)

AEGL–2 (Disabling) 78 (410) 26 (140) 13 (69) 3.3 (17) 1.6 (8.5) Corneal opacity, gray spots on lungs in rats

(Dow Corning, 1997a)

AEGL–3 (Lethality) 320 (1700) 110 (560) 53 (280) 13 (69) 6.6 (35) 1 hr. LC01 in rats (Dow Corning, 1997a)

2. References—i. AIHA (American

Industrial Hygiene Association). 1996.

Emergency Response Planning

Guidelines. Dimethyldichlorosilane.

AIHA, Fairfax, VA.

ii. Bisesi, M.S. 1994. Organic Silicon

Esters. Patty’s Industrial Hygiene and

Toxicology. Fourth Ed. Vol. II, Part D.

G.D. Clayton and F.E. Clayton, Eds. pp.

3096–3101.

iii. Dow Corning. 1997a. An acute

whole body inhalation toxicity study of

dimethyldichlorosilane in Fischer 344

rats. Report No. 1997–I0000–43381.

Study No. 8487. Dow Corning

Corporation. Health and Environmental

Sciences. Midland, MI.

iv. HSDB (Hazardous Substances Data

Bank). 1996. Dimethyldichlorosilane.

Retrieved online 7–22–96.

v. Stevens, B., Koenig, J.Q., Rebolledo,

V., Hanley, Q.S., and Covert, D.S. 1992.

Respiratory effects from the inhalation

of hydrogen chloride in young adult

asthmatics. Journal of Occupational

Medicine. 34:923–929.

vi. Ten Berge, W.F., Zwart, A., and

Appleman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapours

and gases. Journal of Hazardous

Materials. 13:301–309.

vii. USEPA (United States

Environmental Protection Agency).

1997. Acute exposure guideline levels

(AEGLs) for hydrogen chloride (NAC/

PRO Draft 3:7/97).

B. Methyltrichlorosilane

1. Description. Methyltrichlorosilane

is an alkyl-substituted silicon

tetrahydride existing as a clear liquid

with a sharp acrid odor that is similar

to HCl (HSDB, 1997).

Methyltrichlorosilane is used as an

intermediate in the production of

silicones that are used as lubricating

fluids, resins, and plastic copolymers

(Bisesi, 1994). It reacts vigorously with

water and may decompose to form three

moles of HCl for every mole of

methyltrichlorosilane (AIHA, 1996).

Hydrogen chloride is a known

respiratory irritant. Data on

methyltrichlorosilane are limited to 1-

hr. and 4-hr. LC50 studies in rats.

In the absence of relevant chemicalspecific data for methyltrichlorosilane,

AEGL a modification of the AEGL–1

values for HCl was utilized to derive

AEGL–1 values for

methyltrichlorosilane. The use of HCl as

a surrogate for methyltrichlorosilane

was deemed appropriate since it is

believed that it is the hydrolysis

product, HCl, that is responsible for the

adverse effect. The HCl AEGL–1 values

were based on a NOAEL in exercising

asthmatics (Stevens et al., 1992). Since

three moles of HCl are produced for

every mole of methyltrichlorosilane

hydrolyzed, a modifying factor of 3 was

applied to the HCl AEGL–1 values to

approximate AEGL–1 values for

methyltrichlorosilane. The AEGL–1

values were held constant for all

specified exposure periods since mild

irritant effects represent threshold

effects and generally do not vary over

time.

The AEGL–2 was based on ocular

opacity, clear fluid around the eyes,

nose, and mouth, nasal staining, and

hunched posture observed in rats

exposed to 622 ppm

methyltrichlorosilane for 1 hr. (Dow

Corning, 1997a). This level was

considered to be the threshold for

impairment of escape and the onset of

serious long-term effects. An

uncertainty factor of 10 was applied to

these data to account for interspecies

variability since data for

methyltrichlorosilane were available for

only one species and an uncertainty

factor of 3 was applied to account for

sensitive human subpopulations since

the irritant effects observed are not

likely to vary greatly among individuals.

A modifying factor of 3 was applied to

account for the sparse database for

effects as defined by AEGL–2. Thus, the

total uncertainty/modifying factor is

100. The concentration-exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5

(Ten Berge et al., 1986). Much of the

acute toxicity of methyltrichlorosilane

appears to be due to HCl and the value

39268 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

of n reported for HCl is 1 (Ten Berge et

al., 1986). Therefore, the exponent n =

1 was used for scaling of the AEGL

values for methyltrichlorosilane across

time.

The AEGL–3 was based on the

calculated LC01 of 844 ppm in rats

exposed to methyltrichlorosilane for 1

hr. (Dow Corning, 1997a). An

uncertainty factor of 10 was applied to

account for interspecies variability since

data were available for only one species

and an uncertainty factor of 3 was

applied to account for sensitive human

subpopulations since the irritant effects

observed are not likely to vary greatly

among individuals. Thus, the total

uncertainty/ modifying factor is 30. The

concentration-exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5

(Ten Berge et al., 1986). Much of the

acute toxicity of methyltrichlorosilane

appears to be due to HCl and the value

of n reported for HCl is 1 (Ten Berge et

al., 1986). Therefore, the exponent n =

1 was used for scaling of the AEGL

values for methyltrichlorosilane across

time.

The calculated values are listed in the

following table.

PROPOSED AEGL VALUES FOR METHYLTRICHLOROSILANE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) Modification of HCl AEGL–1 values (USEPA,

1997)

AEGL–2 (Disabling) 37 (230) 12 (73) 6.2 (38) 1.6 (9.8) 0.78 (4.8) Ocular opacity, irritation and hunched posture in rats (Dow Corning, 1997a)

AEGL–3 (Lethality) 170 (1000) 56 (340) 28 (170) 7.0 (43) 3.5 (21) 1 hr. LC01 in rats (Dow Corning, 1997a)

2. References—i. AIHA. 1996.

Emergency Response Planning

Guidelines. Methyltrichlorosilane.

AIHA, Fairfax, VA,

ii. Bisesi, M.S. 1994. Organic Silicon

Esters. Patty’s Industrial Hygiene and

Toxicology. Fourth Ed. Vol II, Part D.

G.D. Clayton and F.E. Clayton, Eds. pp.

3096–3101.

iii. Dow Corning. 1997a. An acute

whole body inhalation toxicity study of

methyltrichlorosilane in Fischer 344

rats. Report No. 1997–I0000–43537.

Study No. 8602. Dow Corning

Corporation. Health and Environmental

Sciences. Midland, MI.

iv. HSDB. 1997.

Methyltrichlorosilane. Retrieved online

10–10–97.

v. Stevens, B., Koenig, J.Q., Rebolledo,

V., Hanley, Q.S., Covert, D.S. 1992.

Respiratory effects from the inhalation

of hydrogen chloride in young adult

asthmatics. Journal of Occupational

Medicine. 34:923–929.

vi. Ten Berge, W.F. et al. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. 13:301–309.

vii. USEPA. 1997. Acute exposure

guideline levels (AEGLs) for hydrogen

chloride (NAC/PRO Draft 3:7/97).

C. and D. 2,4- and 2,6-Toluene

Diisocyanate (TDI)

1. Description. Toluene diisocyanate

(TDI) is among a group of chemicals, the

isocyanates, that are highly reactive

compounds containing an -NCO group.

Toluene diisocyanate exists as both the

2,4- and 2,6- isomers which are

available commercially usually in ratios

of 65:35 or 80:20 (Karol, 1986; WHO,

1987). Toluene diisocyanate is used

extensively in the manufacture of

polyurethane foam products as well as

paints, varnishes, elastomers, and

coatings (WHO, 1987).

Toxicological effects from inhaled TDI

consist of irritation and sensitization of

the respiratory tract. Sensitization may

occur from either repeated exposure

over a relatively long period of time

(i.e., years), or, it may consist of an

induction phase precipitated by a

relatively high concentration followed

by a challenge phase in which

sensitized individuals react to a low

concentration of TDI. Because repeated

exposures are required for sensitization,

only irritation effects were considered

in establishing AEGL values.

Human data were available for

derivation of AEGL–1 and -2.

Asthmatics were exposed to 0.01 ppm

(0.071 mg/m3) TDI for 1 hr., then after

a rest of 45 mins., to 0.02 ppm (0.142

mg/m3) TDI for 1 hr. Controls were

exposed to 0.02 ppm (0.142 mg/m3) TDI

for 2 hrs. (Baur, 1985). Although no

statistically significant differences in

lung function parameters were observed

among asthmatics during or after

exposure, non-pathological bronchial

obstruction was indicated in several

individuals. In the control group, there

was a significant increase in airway

resistance immediately and 30 mins.

after the beginning of exposure but none

of the subjects developed bronchial

obstruction. Both groups reported

symptoms of eye and throat irritation,

cough, chest tightness, rhinitis,

dyspnea, and/or headache but time to

onset of symptoms was not given. There

was also no indication whether the

effects were worse in asthmatics with

0.01 or 0.02 ppm. Therefore, the

concentration of 0.02 ppm (0.142 mg/

m3) was chosen as the basis for the 10-

mins., 30-mins., and 1-hr. AEGL–1

values and the concentration of 0.01

ppm (0.071 mg/m3) was chosen as the

4- and 8-hr. AEGL–1 values.

Extrapolations were not performed.

Derivation of AEGL–2 was based on

human data. Exposure of volunteers to

0.5 ppm (3.56 mg/m3) for 30 mins.

resulted in severe eye and throat

irritation and lacrimation (Henschler et

al., 1962). A higher-exposure

concentration was intolerable.

Extrapolations were made using the

equation Cn x t = k, where n ranges from

0.8 to 3.5 (Ten Berge et al., 1986). In the

absence of an empirically derived,

chemical-specific exponent, to obtain

conservative and protective AEGL–2

values, scaling was performed using n =

3 for extrapolating to the 10-min. time

point and n = 1 for the 1- and 4-hr. time

points. The 4-hr. value is also proposed

for the 8-hr. value since extrapolation to

8 hrs. resulted in a concentration similar

to that shown to be tolerated for >7 hrs.

with only mild effects. An uncertainty

factor of 3 was applied to account for

sensitive individuals because the

mechanism of action of an irritant gas is

not expected to differ among

individuals.

No human data were available for

derivation of AEGL–3 values. Reports of

human fatalities occurred under

unusual circumstances and exposure

concentrations were not measured.

Deaths were attributed to chemical

pneumonitis. Therefore, animal data

were used to derive AEGL–3 values.

Based on LC50 values, the mouse is the

most sensitive species to the effects of

TDI. The 4-hr. mouse LC50 of 9.7 ppm

(69.1 mg/m3) (Duncan et al., 1962) was

divided by 3 to estimate a threshold of

lethality. This estimated 4-hr. lethality

threshold was used to extrapolate to the

30-min. and 1- and 8-hr. AEGL–3 time

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39269

points. Values were scaled using the

equation Cn x t = k, where n ranges from

0.8 to 3.5 (Ten Berge et al., 1986). In the

absence of an empirically derived,

chemical-specific exponent, to obtain

conservative and protective AEGL–2

values, scaling was performed using n =

3 for extrapolating to the 30-min. and 1-

hr. time points and n = 1 for the 8-hr.

time point. A total uncertainty factor of

10 was applied which includes 3 to

account for sensitive individuals and 3

for interspecies extrapolation (the

mechanism of action of an irritant gas is

not expected to vary greatly between or

among species). The 10-min. values

were not extrapolated from 4 hrs.

because the NAC/AEGL Committee

determined that extrapolating from

greater than or equal to 4 hrs. to 10

mins. is associated with unacceptably

large inherent uncertainty, and the 30-

min. values were adopted for 10 min. to

be protective of human health.

Therefore, the 10-min. AEGL–3 value

was flatlined from the 30-min. value.

The NAC/AEGL Committee recognizes

that individuals pre-sensitized to TDI

may exist in the general population, but

that this rate of sensitization cannot be

predicted. If the rate of sensitization to

TDI in the general population were

quantifiable, the NAC/AEGL Committee

might have considered lower values for

AEGL–3. At the proposed AEGL–3

levels, there may be individuals who

have a strong reaction to TDI and these

individuals may not be protected.

SUMMARY OF PROPOSED AEGL VALUES FOR 2,4-/2,6-TOLUENE DIISOCYANATE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) 0.020

(0.14)

0.020

(0.14)

0.020

(0.14)

0.010

(0.07)

0.010

(0.07)

Chest tightness, eye and throat irritation

(Baur, 1985)

AEGL–2 (Disabling) 0.24 (1.71) 0.17 (1.21) 0.083

(0.59)

0.021

(0.15)

0.021

(0.15)

Severe eye and throat irritation, lacrimation

(Henschler et al., 1962)

AEGL–3 (Lethal) 0.65 (4.6) 0.65 (4.6) 0.51 (3.6) 0.32 (2.3) 0.16 (0.93) 4-hrs. LC50 in the mouse (Duncan et al.,

1962)

2. References—i. Baur, X. 1985.

Isocyanate hypersensitivity. Final

Report to the International Isocyanate

Institute. III File No. 10349; III Project:

E–AB–19.

ii. Duncan, B., Scheel, L.D., Fairchild,

E.J., Killens, R., and Graham, S. 1962.

Toluene diisocyanate inhalation

toxicity: Pathology and mortality.

American Industry Hygiene Association

Journal. 23:447–456.

iii. Henschler, D., Assman, W., and

Meyer, K. O. 1962. On the Toxicology of

Toluenediisocyanate [in German].

Archivs fur Toxikologie 19:364–387.

iv. Karol, M.H. 1986. Respiratory

effects of inhaled isocyanates. CRC

Critical Reviews in Toxicology. Vol. 16.

CRC Press.

v. Ten Berge, W.F., Zwart, A., and

Appelman, L. M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapours

and gases. Journal of Hazardous

Materials. 13:301–309.

vi. WHO (World Health Organization).

1987. Toluene diisocyanates.

Environmental Health Criteria 75.

WHO, Geneva. pp.72.

E. Allylamine

1. Description. Allylamine is a

colorless or yellowish volatile liquid

with a very sharp ammonia-like odor

that is irritating to mucous membranes.

It is highly flammable and moderately

reactive with oxidizing materials.

Industrially, it is used in the

vulcanization of rubber and in the

synthesis of pharmaceuticals. In

addition to being a severe respiratory,

eye, and skin irritant, allylamine is a

cardiovascular toxin when administered

at high doses orally, by injection or by

inhalation. Allylamine cardiotoxicity is

proposed to be related to its metabolism

to acrolein and hydrogen peroxide.

Allylamine acute inhalation toxicity has

been studied in rats and mice; the

response in human volunteers briefly

exposed to irritating levels has been

reported.

AEGL–1 values were based on an

occupational study in which exposure

to 0.2 ppm allylamine for 3–4 hrs. a day

was not associated with worker

detection or complaints, but exposure to

higher but undefined concentrations

caused mucous membrane irritation

(Shell Oil Co., 1992). The same AEGL–

1 value is proposed for 10 mins. to 8

hrs. (i.e., ‘‘flat-line’’) because 0.2 ppm is

expected to produce no or mild

irritation, which does not generally vary

greatly with time. No uncertainty factors

were applied because 0.2 ppm was a noeffect-level (NOEL) for mucous

membrane irritation in humans exposed

repeatedly.

The AEGL–2 was based on a rat study

in which exposure to 60 ppm for 14 hrs.

caused heart lesions including scattered

myofibril fragments with loss of

striation, perivascular edema, and

cellular infiltration (Guzman et al.,

1961). Extrapolation to 30, 60, 240, and

480 mins. was performed using the

equation Cn x t = k, where n = 1.71

(calculated from a linear regression of

rat cardiotoxicity data of Guzman et al.,

1961). The 10-min. value was not

extrapolated from 16 hrs. because the

NAC has determined that extrapolating

from 4 hrs. to 10 mins. is associated

with unacceptably large inherent

uncertainty, and the 30-min. value was

adopted for 10 mins. to be protective of

human health. An interspecies

uncertainty factor of 10 was applied to

account for the lack of acute toxicity

studies and toxicokinetic and

metabolism data from other species. An

intraspecies uncertainty factor of 10 was

applied because significant intraspecies

variation occurred in the rat cardiotoxic

responses in the key study, and there

were no data to determine the human

variability of allylamine-induced

cardiotoxicity.

The AEGL–3 values were derived

from a rat inhalation LC50 study where

exposure was for 1, 4, or 8 hrs. (Hine et

al., 1960). The threshold for lethality, as

represented by LC01 values calculated

using probit analysis, was the AEGL–3

toxicity endpoint. The 1, 4, and 8-hr.

AEGL–3 values were based on their

respective LC01 values, and the 10- and

30-min. AEGL–3 values were

extrapolated from the 1-hr. LC01 using

the equation Cn x t = k, where n = 0.8458

(calculated from a linear regression of

the Hine et al., 1960 data). An

uncertainty factor of 30 was applied: 10

to account for interspecies variability (to

account for the lack of acute toxicity

studies and toxicokinetic and

metabolism data from other species) and

3 for human variability (lethality, as an

endpoint associated with severe

pulmonary edema, is not likely to vary

greatly among humans). Similar AEGL–

3 values were obtained from other rat

studies that used fewer animals and

exposure concentrations.

39270 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

SUMMARY OF PROPOSED AEGL VALUES FOR ALLYLAMINE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) NOAEL for human mucous membrane irritation (Shell Oil Co., 1992)

AEGL–2 4.2 (9.8) 4.2 (9.8) 2.8 (6.5) 1.2 (2.8) 0.83 (1.9) Heart lesions in rats (Guzman et al., 1961)

AEGL–3 140 (330) 40 (94) 18 (42) 3.5 (8.1) 2.3 (5.4) Lethality threshold in rats (Hine et al., 1960)

2. References—i. Guzman, R.J.,

Loquvam, G.S., Kodama, J.K., and Hine,

C.H. 1961. Myocarditis produced by

allylamines. Archives of Environmental

Health. 2:62–73.

ii. Hine, C.H., Kodama, J.K., Guzman,

R.J., and Loquvam, G.S. 1960. The

toxicity of allylamines. Archives of

Environmental Health. 1:343–352.

iii. Shell Oil Co. 1992. Initial

submission: Letter submitting enclosed

information on exposure of workers to

mono-allylamine, di-allylamine, and triallylamine. EPA/OTS Doc. #88–

920002051.

iv. Ten Berge, W.F., Zwart, A., and

Appelman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapors

and gases. Journal of Hazardous

Materials. 13:302–309.

F. Ethylenediamine (EDA)

1. Description. Ethylenediamine

(EDA) is a basic, hygroscopic,

flammable liquid that is an eye, mucous

membrane, and respiratory irritant and

a known respiratory and skin sensitizer.

Occupational inhalation exposure has

resulted in an asthmatic response

including rhinitis, coughing, wheezing,

shortness of breath, and bronchospasm.

EDA is used to stabilize rubber latex, as

an inhibitor in antifreeze solutions, and

in the preparation of dyes, insecticides,

and fungicides.

The values developed for AEGL–2

and AEGL–3 level were based on

studies in which toxicity endpoints

occurred that were within the scope of

the definition for that level. However,

persons previously sensitized to EDA

may experience more severe effects, the

extent of which cannot be predicted

from the available information. No data

were available to determine the

concentration-time relationship for EDA

toxic effects. The concentration-time

relationship for many irritant and

systemically acting vapors and gases

may be described by Cn x t = k, where

the exponent n ranges from 0.8 to 3.5

(Ten Berge et al., 1986). To obtain

conservative and protective AEGL–2

and AEGL–3 values, scaling across time

was performed using n = 3 to

extrapolate to exposure times <8 hrs.,

except for the 10-min. values. The NAC

determined that extrapolating from 4

hrs. to 10 mins. is associated with

unacceptably large inherent uncertainty,

and the 30-min. values were adopted for

10 mins. to be protective of human

health. AEGL–1 values were not

recommended due to insufficient data.

AEGL–2 values were based on a study

in which rats and guinea pigs (6/group)

exposed for 8 hrs. to ≥484 ppm EDA

(1,000 ppm nominal) had bronchiolar

edema of unspecified severity and ‘‘light

cloudy swelling of the kidney’’ but none

died (Carpenter et al., 1948). An

uncertainty factor of 100 was used: 10

for intraspecies variability (mechanism

of toxicity and variability of the toxic

response among humans is uncertain)

and 10 for interspecies variability (key

study tested only one EDA

concentration and reported few

experimental details, not providing a

clear picture of species variability). The

derived AEGL–2 values are supported

by a study in which rats (15/sex)

exposed to 132 ppm 7 hours/day for 30

days had a slight increase in the

incidence (i.e., 1/26 vs. 0/27 for

controls) of unspecified ‘‘major’’

histopathological lesions (Pozzani and

Carpenter, 1954).

The AEGL–3 values were derived

from a range-finding test in which 0/6

rats died from exposure for 8 hrs. to

∼1,000 ppm (2,000 ppm nominal) but 6/

6 died from 8-hr. exposure to ∼2,000

ppm (4,000 ppm nominal) (Smyth et al.,

1951). Toxic effects (other than death)

were not described; 1,000 ppm was

considered to be the estimated lethality

threshold. An uncertainty factor of 100

was applied: 10 for intraspecies

variability (cause of death was not

defined in key study and variability of

the toxic response among humans

cannot be predicted) and 10 for

interspecies extrapolation (only one

EDA concentration was tested, the cause

of death was not defined in the key

study, and there were no data from

other species). The AEGL–3 values are

supported by a study in which rats (15/

sex) exposed to 225 ppm 7 hours/day

for 30 days had fractional mortality (first

two deaths were on exposure day 4),

and most rats had cloudy swelling of the

liver and kidney convoluted tubules

(Pozzani and Carpenter, 1954).

SUMMARY OF AEGL VALUES FOR ETHYLENEDIAMINE [PPM (MG/M3)]

Classification 10 mins. 30 min. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended

AEGL–2 12 (30) 12 (30) 9.7 (24) 6.1 (19) 4.8 (13) Bronchiolar edema, kidney

swelling (Carpenter et al.,

1948)

AEGL–3 25 (62) 25 (62) 20 (49) 13 (31) 10 (26) Lethality threshold; no stated toxic effects (Smyth et

al., 1951)

2. References—i. Carpenter, C.P.,

Smyth, Jr., H.F., and Shaffer, C.B. 1948.

The acute toxicity of ethylene imine to

small animals. Journal of Industrial

Hygiene and Toxicology. 30:2–6.

ii. Pozzani, U.C. and Carpenter, C.P.

1954. Response of rats to repeated

inhalation of ethylenediamine vapors.

AMA Archives of Industrial Hygiene

and Occupational Medicine. 9:223–226.

iii. Smyth, H.F., C.P. Carpenter, and

C.S. Weil. 1951. Range-finding toxicity

data: List IV. AMA Archives of

Industrial Hygiene and Occupational

Medicine. 4:119–122.

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39271

iv. Ten Berge, W.F., Zwart, A., and

Appelman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapors

and gases. Journal of Hazardous

Materials. 13:302–309.

G. Cylohexylamine

1. Description. Cyclohexylamine is a

respiratory, eye, and skin irritant, as

well as a strong base (pKa = 10.7) with

a fishy, amine odor that has only

recently been found naturally. It is used

primarily for boiler water treatment

(corrosion inhibition) as well as organic

synthesis of rubber and agricultural

chemicals. Occupational exposures to

cyclohexylamine caused headache,

nausea, dizziness, vomiting, eye, nose

and throat irritation, and rapid and

irregular heartbeats in some individuals.

Acute exposure in animals resulted in

extreme mucous membrane irritation,

gasping, CNS effects (tremors, clonic

muscular spasms), lung hemorrhage,

opaque corneas, vascular lesions, and

hemolysis.

No data were available to determine

the concentration-time relationship for

cyclohexylamine toxicity. The

concentration-time relationship for

many irritant and systemically acting

vapors and gases may be described by

Cn x t = k, where the exponent n ranges

from 0.8 to 3.5 (Ten Berge et al., 1986).

To obtain conservative and protective

AEGL–2 and AEGL–3 values, scaling

across time was performed using n = 3

to extrapolate to shorter exposure times

and n = 1 to extrapolate to longer

exposure times for 30 min. through 8-hr.

values (scaling was not performed for

AEGL–1 derivation). The 10-min. values

were not extrapolated from 4 hrs.

because the NAC determined that

extrapolating from 4 hrs. to 10 mins. is

associated with unacceptably large

inherent uncertainty, and the 30-min.

values were adopted for 10 mins. to be

protective of human health.

AEGL–1, AEGL–2, and AEGL–3

values were derived from a study in

which Sprague-Dawley rats (5/sex/dose)

were exposed for 4 hrs. to 54.2 ppm or

567 ppm cyclohexylamine vapor, or to

a vapor/aerosol combination containing

542 ppm vapor and 612 mg/m3 aerosol

(Bio/dynamics, Inc., 1990). At 54.2 ppm,

rats had labored breathing, partially

closed eyes, and red nasal discharge;

rats exposed to the two higher doses

additionally had rales, gasping, dried

red facial material, tremors, weight loss,

irreversible ocular lesions, and two rats

exposed to the aerosol-containing

atmosphere died. AEGL–1 values were

obtained by dividing the lowestobserved-adverse-effect-level (LOAEL)

of 54.2 ppm by 3 to estimate a NOAEL,

which may be associated with mild or

no respiratory and ocular irritation. An

uncertainty factor of 10 was applied: 3

to account for sensitive humans and 3

for interspecies variability, because mild

sensory irritation from a surface-contact,

basic irritant gas is not likely to vary

greatly among humans or animals. The

same AEGL value was adopted for 10

mins., 30 mins., 1, 4, and 8 hrs.; flatlining across time was considered

appropriate since mild irritant effects

generally do not vary greatly over time.

AEGL–2 values were based on

exposure for 4 hrs. to 54.2 ppm, at

which concentration the rats had

moderate respiratory effects and ocular

irritation, and which was a NOAEL for

irreversible ocular lesions. An

uncertainty factor of 10 was used: 3 for

interspecies variability and 3 for

intraspecies variability (moderate

respiratory and ocular irritation from a

surface-contact, basic irritant gas is not

likely to vary greatly among humans or

animals).

The AEGL–3 values were based on

exposure for 4 hrs. to 567 ppm, which

caused severe respiratory effects and

irreversible ocular lesions and was

regarded as an estimate of the lethality

threshold because 2/10 animals died at

the next higher concentration tested. An

uncertainty factor of 30 was applied: 3

to account for intraspecies variability

(lethality response resulting from a basic

irritant gas is not likely to vary greatly

among humans) and 10 for extrapolation

from animals to humans (significant

variation was seen among species for

the exposure causing lethality, and the

data were insufficient to determine that

rats were the most sensitive species).

SUMMARY OF PROPOSED AEGL VALUES FOR CYCLOHEXYLAMINE [PPM(MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) NOAEL for respiratory and ocular irritation; may

cause mild or no sensory irritation (Bio/dynamics,

Inc., 1990)

AEGL–2 11 (44) 11 (44) 8.6 (35) 5.4 (22) 2.7 (11) Moderate respiratory effects, ocular irritation;

NOAEL for irreversible ocular lesions (Bio/dynamics, Inc., 1990).

AEGL–3 38 (150) 38 (150) 30 (120) 19 (77) 9.4 (38) Lethality threshold, severe respiratory effects, and

irreversible ocular lesions (Bio/dynamics, Inc.,

1990).

2. References—i. Bio/dynamics, Inc.

1990. An acute inhalation toxicity study

of C-1388 in the rat. Final Report.

Project No. 89–8214. December 4, 1990.

ii. Ten Berge, W.F., Zwart, A., and

Appelman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapors

and gases. Journal of Hazardous

Materials. 13:302–309.

H. and I. Cis- and TransCrotonaldehyde

1. Description. Crotonaldehyde is a

colorless, flammable liquid and an

extreme eye, skin, and respiratory

irritant. It causes a burning sensation in

the nasal and upper respiratory tract,

lacrimation, coughing,

bronchoconstriction, pulmonary edema,

and deep lung damage. Crotonaldehyde

is used primarily for the manufacture of

sorbic acid and other organic chemicals.

It is found in tobacco smoke and is a

combustion product of diesel engines

and wood, but also occurs naturally in

meat, fish, and many fruits and

vegetables.

Crotonaldehyde can exist as either the

cis or the trans isomer; commercial

crotonaldehyde is a mixture of the two

isomers consisting of >95% trans

isomer. Because virtually no physical or

chemical data or in vivo exposure

studies were located for the cis or trans

isomers individually (information was

for the commercial mixture), and

because OSHA, NIOSH, and the ACGIH

have adopted the same occupational

exposure limits for both isomers, the

AEGL values prepared in this report

will apply to both trans-crotonaldehyde

(123–73–9) and to the cis/trans mixture

(4170–30–3), which contains

predominantly the trans isomer.

AEGL–1 values were derived from a

Health Hazard Evaluation conducted by

NIOSH where workers exposed to about

39272 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

0.56 ppm crotonaldehyde for >8 hrs.

reported occasional minor eye irritation

(Fannick, 1982). Exponential scaling

across time was not performed because

results from another study suggested

that the concentration-time relationship

determined from the rat LC50 study of

Rinehart (1967) was not appropriate for

predicting human sensory irritation (i.e.,

irritation was much greater for shorter

exposure durations than for longer

exposure durations yielding comparable

concentration x time (Ct) values. An

uncertainty factor of 3 was applied to

account for sensitive humans; a greater

uncertainty factor is not needed because

the endpoint of mild eye irritation is not

expected to vary greatly among humans.

AEGL–2 values were based on a study

in which rats exposed to 8,000 ppm-min

crotonaldehyde had about a 20–40%

reduction in pulmonary function

(manifested as a decrease in carbon

monoxide and ether uptake rates

compared to pre-exposure values). The

animals had proliferative lesions of the

respiratory bronchioles but there was

little or no evidence of alveolar edema

(Rinehart, 1967). The individual

experimental concentrations and

exposure times were not given, but

exposure was stated to be for 5–240

mins. AEGL–2 values were calculated

by dividing 8,000 ppm-min by 10, 30,

60, 240, or 480 mins. (concentration and

time appeared to be equally important

for toxicity). An uncertainty factor of 30

was used: 3 to account for sensitive

humans (crotonaldehyde acts primarily

as a surface-contact irritant and the

irritation response is not expected to

vary greatly among humans) and 10 for

extrapolation from animals to humans

(based on the lack of actual

concentration and time data, and the

stated variability in the animal

responses, and the absence of

supporting animal or human studies).

The AEGL–3 was based on a LC50

study in which Wistar rats were

exposed to crotonaldehyde vapor for 5

mins. to 4 hrs. (Rinehart, 1967). The 10-

min., 30-min., 1-hr., and 4-hr. AEGLs

were obtained using the respective LC01

values (268, 138, and 26 ppm,

respectively; calculated by probit

analysis from mortality data). The 8-hr.

AEGLs were derived from the 4-hr. LC01;

scaling across time was performed using

the exponential relationship Cn x t = k

, where n = 1.2 was derived by Ten

Berge et al. (1986) from this study LC50

data. During exposure, all animals

gasped and had a lowered breathing

rate; those exposed to >1,000 ppm had

an excitatory stage. Rats lost up to 25%

of their body weight by 1–3 days postexposure, after which time they began to

recover their weight. Most rats died by

4 days after exposure and had clear or

slightly blood-tinged nasal exudate; all

animals that died within 1 day also had

terminal convulsions. An uncertainty

factor of 10 was applied: 3 to account

for extrapolation of rats to humans, and

3 to account for sensitive humans.

Similar or higher AEGL–3 values were

obtained from LC50 studies in rats, mice,

and guinea pigs.

SUMMARY OF PROPOSED AEGL VALUES FOR CROTONALDEHYDE [PPM(MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) Human mild eye irritation (Fannick, 1982)

AEGL–2 (Disabling) 27 (76) 8.9 (25) 4.4 (13) 1.1 (3.2) 0.56 (1.6) Rat impaired pulmonary function, bronchiole

lesions (Rinehart, 1967)

AEGL–3 (Lethal) 44 (130) 27 (76) 14 (40) 2.6 (7.4) 1.5 (4.2) Rat lethality threshold using LC1 values

(Rinehart, 1967).

2. References—i. Fannick, N. 1982.

Sandoz Colors and Chemicals, East

Hanover, New Jersey (Health Hazard

Evaluation Report, No. HETA–81–102–

1244), Cincinnati, OH. United States

National Institute for Occupational

Safety and Health, Hazard Evaluations

and Technical Assistance Branch.

ii. Rinehart, W. 1967. The effect on

rats of single exposures to

crotonaldehyde vapor. American

Industrial Hygiene Association Journal.

28:561–566.

iii. Ten Berge, W.F., Zwart, A., and

Appelman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapors

and gases. Journal of Hazardous

Materials. 13:302–309.

J. Methyl Isocyanate (MIC)

1. Description. Methyl isocyanate

(MIC) is one of the most reactive of all

isocyanates and is rapidly degraded in

aqueous medium (Varma and Guest,

1993). Because of its reactivity, MIC is

used as an intermediate in the synthesis

of N-methylcarbamate and N

-methylurea insecticides and herbicides

(Hartung, 1994). During the night of

December 2/3, 1984, an estimated 30

tons of MIC was released from a

chemical plant in Bhopal, India,

resulting in one of the worst industrial

accidents in history (Karlsson et al.,

1985).

Signs of severe irritation to the

respiratory tract were reported for

victims of the Bhopal disaster and

autopsies revealed the cause of death to

be pulmonary edema (Weill, 1988).

Long-term pulmonary and ocular effects

have been documented in survivors.

The spontaneous abortion rate

(Arbuckle and Sever, 1998) and the

infant death rate (Varma, 1987) among

women who were pregnant at the time

of the release were significantly

increased in the months following the

disaster. Numerous animal studies

corroborate the epidemiological findings

in humans. A compilation of case

reports in industrial workers

consistently noted skin and respiratory

irritation in MIC exposed workers but

no definitive case of sensitization

(Ketcham, 1973). The mechanism of

action for the pulmonary, skin, and eye

effects is irritation, but the mechanism

of action for the systemic effects is

unknown.

AEGL–1 values were not derived.

Although human and animal data were

available for irritation levels, the

irritation threshold for MIC may be

above the level of concern for systemic

effects such as embryo and fetal

lethality.

Systemic and developmental toxicity

data from rats and mice were used for

derivation of AEGL–2. An increase in

cardiac arrhythmias occurred in rats 4

months after a 2-hr. exposure to 3 ppm

(Tepper et al., 1987). Pregnant SwissWebster mice were exposed to

analytically monitored concentrations of

0, 2, 6, 9, and 15 ppm MIC for 3 hrs.

on gestation day 8 (Varma, 1987).

Placental weights and fetal body

weights were significantly reduced at all

concentrations. Exposures to

concentrations of 9 and 15 ppm resulted

in deaths of two dams in each group, a

significant increase in complete litter

resorption among surviving dams, and

fetuses with significant reductions in

the lengths of the mandible and long

bones. The concentration of 2 ppm for

3 hrs. was an experimentally derived

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39273

lowest-observed effect level for

decreased fetal body weights. Values

scaled for the derivation of the 10- and

30-min., and 1-, 4-, and 8-hr. time points

were calculated from the equation Cn x

t = k, where n = 1. The value of n was

empirically derived from regression

analysis of lethality data for rats.

Identical AEGL–2 values are derived

based on the exposures of 3 ppm for 2

hrs. and 2 ppm for 3 hrs. The

experimental concentrations were

reduced by a factor of 3 to estimate a

threshold for effects on cardiac

arrhythmias or fetal body weights. A

total uncertainty factor of 30 was

applied including 3 for interspecies

variation because similar developmental

toxicity results have been obtained in

both rats and mice and 10 for

intraspecies variation since the

mechanism of action for systemic effects

is unknown.

The neonatal survival study with

mice by Schwetz et al. (1987) was used

for derivation of AEGL–3 values.

Pregnant mice were exposed to 0, 1, or

3 ppm for 6 hours/day on gestation days

14–17. Dams were allowed to litter for

evaluation of neonatal survival. A

concentration-related increase in the

number of dead fetuses at birth was

observed in both exposure groups and

an increase in pup mortality during

lactation was observed in the 3 ppm

group. No differences in pup body

weights occurred during lactation

between the treated and control groups.

The 6-hr. exposure to 1 ppm was used

to derive AEGL–3 values and is

considered a NOEL for pup survival

during lactation. Values scaled for the

derivation of the 10- and 30-min., and

1-, 4-, and 8-hr. time points were

calculated from the equation Cn x t = k,

where n = 1. The value of n was

empirically derived from regression

analysis of lethality data for rats. A total

uncertainty factor of 30 was applied

including 3 for interspecies variation

because similar developmental toxicity

results have been obtained in both rats

and mice and 10 for intraspecies

variation since the mechanism of action

for systemic effects is unknown.

However, because n was derived from

exposures ranging from 7.5 to 240 mins.,

it is felt that extrapolation from 6 hrs.

to the 10-min. AEGL–3 value is valid.

The proposed values for the three

AEGL classifications for the five time

periods are listed in the table below.

SUMMARY OF PROPOSED AEGL VALUES FOR METHYL ISOCYANATE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) NA NA NA NA NA NA

AEGL–2 (Disabling) 0.40

(0.94)

0.13

(0.32)

0.067

(0.16)

0.017 (0.034) 0.0083 (0.019) Decreased fetal body weights

(Varma, 1987); cardiac arrhythmias (Tepper et al., 1987)

AEGL–3 (Lethal) 1.2 (2.8) 0.40

(0.95)

0.20

(0.47)

0.050 (0.12) 0.025 (0.059) Decreased pup survival during lactation (Schwetz et al., 1987)

NA: Not assigned, since AEGL–1 effects would occur at concentration levels higher than AEGL–2 levels.

2. References—i. Arbuckle, T.E. and

Sever, L.E. . 1998. Pesticide exposures

and fetal death: a review of the

epidemiologic literature. Critical

Reviews in Toxicology . 28:229–270.

ii. Hartung, R. 1994. Cyanides and

Nitriles. Patty’s Industrial Hygiene and

Toxicology . 4th Ed. G.D. Clayton and

F.E. Clayton, Eds. New York: John Wiley

& Sons, Inc. pp. 3161–3172.

iii. Karlsson, E., Karlsson, N.,

Lindberg, G., Lindgren, B., and Winter

S. 1985. The Bhopal catastrophe—

consequences of a liquefied gas

discharge. National Defense Research

Institute, Sweden. NTIS ISSN 0347–

2124.

iv. Ketcham, N.H. 1973. Methyl

isocyanate (MIC) survey of experience

concerning human sensitization. Union

Carbide Corporation. EPA/OTS; Doc

#86– 910000666D.

v. Schwetz, B.A., Adkins, Jr., B.,

Harris, M., Moorman, M., and Sloane, R.

1987. Methyl isocyanate: reproductive

and developmental toxicology studies in

Swiss mice. Environmental Health

Perspectives. 72:149–152.

vi. Tepper, J.S., Wiester, M.J., Costa,

D.L., Watkinson, W.P., and Weber, M.F.

1987. Cardiopulmonary effects in awake

rats four and six months after exposure

to methyl isocyanate. Environmental

Health Perspectives 72:95–103.

vii. Varma, D.R. 1987.

Epidemiological and experimental

studies on the effects of methyl

isocyanate on the course of pregnancy.

Environmental Health Perspectives.

72:153–157.

viii. Varma, D.R. and Guest, I.. 1993.

The Bhopal accident and methyl

isocyanate toxicity. Journal of

Toxicology and Environmental Health.

40:513–529.

ix. Weill, H. 1988. Disaster at Bhopal:

the accident, early findings and

respiratory health outlook in those

injured. Physiology. 23:587–590.

K. Hydrogen Chloride (HCl)

1. Description. Hydrogen chloride

(HCl) is a colorless gas with a pungent

suffocating odor. It is used in the

manufacture of organic and inorganic

chemicals, oil well acidizing, steel

pickling, food processing, and

processing of minerals and metals. A

large amount of HCl is released from

solid rocket fuel exhaust. It is an upper

respiratory irritant at relatively low

concentrations and may cause damage

to the lower respiratory tract at higher

concentrations. Hydrogen chloride is

very soluble in water, and the aqueous

solution is highly corrosive.

The AEGL–1 values are based on a 45

min. NOAEL in exercising adult

asthmatics (Stevens et al., 1992). No

uncertainty factors were applied for

inter- or intraspecies variability since

the study population consisted of

sensitive humans. Additionally, the

same value was applied across the 10-

and 30-min., and 1-, 4-, and 8-hr.

exposure time points since mild

irritancy is a threshold effect and

generally does not vary greatly over

time. Thus, prolonged exposure will not

result in an enhanced effect.

The AEGL–2 for the 30-min., 1-, 4-,

and 8-hr. time points was based on

severe nasal or pulmonary

histopathology in rats exposed to 1,300

ppm HCl for 30 mins. (Stavert et

al.,1991). An uncertainty factor of 3 was

applied for interspecies variability

because the test species (rodents) is 2–

3 times more sensitive to the effects of

HCl than primates. An uncertainty

factor of 3 was applied for intraspecies

extrapolation since the mechanism of

action is direct irritation and the

subsequent effect or response is not

expected to vary greatly among

individuals. An additional modifying

factor of 3 was applied to account for

the sparse database of effects defined by

AEGL–2 and since the effects observed

at the concentration used to derive

AEGL–2 values were somewhat severe.

Thus, the total uncertainty and

39274 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

modifying factor adjustment is 30-fold.

It was then time-scaled to the, and 1-,

4-, and 8-hr. AEGL exposure periods

using the Cn x t = k relationship, where

n = 1 based on regression analysis of

combined rat and mouse LC50 data (1

min. to 100 min1.) as reported by Ten

Berge et al., 1986. The 10-min. AEGL–

2 value was derived by dividing the

mouse RD50 of 309 ppm by a factor of

3 to obtain a concentration causing

irritation (Barrow et al., 1977). Onethird of the mouse RD50 for HCl

corresponds to an approximate decrease

in respiratory rate of 30%, and

decreases in the range of 20 to 50%

correspond to moderate irritation

(ASTM, 1991).

The AEGL–3 was based on an

estimated NOEL for death of one-third

of a 1-hr. LC50 reported for rats (Vernot

et al., 1977; Wohlslagel et al., 1976). An

uncertainty factor of 3 was applied for

interspecies variability because the test

species (rodents) is 2-3 times more

sensitive to the effects of HCl than

primates. An uncertainty factor of 3 was

applied for intraspecies extrapolation

since the mechanism of action is direct

irritation and the subsequent effect or

response is not expected to vary greatly

among individuals. Thus, the total

uncertainty factor is 10. It was then

time-scaled to the specified 10- and 30-

min., and 1-, 4-, and 8-hr. AEGL

exposure periods using the Cn x t = k

relationship, where n = 1 based on

regression analysis of combined rat and

mouse LC50 data (1 min. to 100 mins.)

as reported by Ten Berge et al., 1986.

The calculated values are listed in the

table below.

SUMMARY OF PROPOSED AEGL VALUES FOR HYDROGEN CHLORIDE [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) NOAEL in exercising human asthmatics

(Stevens et al., 1992)

AEGL–2 (Disabling) 100 (160) 43 (65) 22 (33) 5.4 (8.1) 2.7 (4.1) Mouse RD50 (Barrowet al, 1977);

Histopathology in rats (Stavert et al.,

1991)

AEGL–3 (Lethality) 620 (940) 210 (310) 100 (160) 26 (39) 13 (19) Estimated NOEL for death from 1-hr. rat

LC50 (Wohlslagel et al., 1976; Vernot et

al., 1977)

2. References—i. ASTM. (American

Society for Testing and Materials). 1991.

Standard Test Method for estimating

sensory irritancy of airborne chemicals.

Method E981, Volume 11.04, p. 610–

619. ASTM Philadelphia, PA.

ii. Barrow, C.S., Alarie, Y., Warrick,

M., and Stock, M.F. 1977. Comparison

of the sensory irritation response in

mice to chlorine and hydrogen chloride.

Archives of Environmental Health.

32:68–76.

iii. Stavert , D.M., Archuleta, D.C.,

Behr, M.J., and Lehnert, B.E. 1991.

Relative acute toxicities of hydrogen

fluoride, hydrogen chloride, and

hydrogen bromide in nose- and pseudomouth-breathing rats. Fundamental and

Applied Toxicology. 16:636–655.

iv. Stevens, B., Koenig, J.Q.,

Rebolledo, V., Hanley, Q.S., and Covert,

D.S. 1992. Respiratory effects from the

inhalation of hydrogen chloride in

young adult asthmatics. Journal of

Occupational Medicine. 34: 923–929.

v. Ten Berge, W.F., Zwart, A., and

Appleman, L.M. 1986. Concentrationtime mortality response relationship of

irritant and systemically acting vapours

and gases. Journal of Hazardous

Materials. 13:301–309.

vi. Vernot, E.H., MacEwen, J.D., Haun,

C.C., and Kinkead, E.R. 1977. Acute

toxicity and skin corrosion data for

some organic and inorganic compounds

and aqueous solutions. Toxicology and

Applied Pharmacology. 42:417–423.

vii. Wohlslagel, J., DiPasquale, L..C.,

and Vernot, E.H. 1976. Toxicity of solid

rocket motor exhaust: effects of HCl, HF,

and alumina on rodents. Journal of

Combustion Toxicology. 3:61–70.

L. Phosphine

1. Description. Phosphine is a

colorless gas used as a fumigant against

insects and rodents in stored grain. The

pesticide is usually applied as a metal

phosphide and reacts with moisture to

liberate phosphine gas. Phosphine is

also used in the semiconductor

industry. Information concerning

human exposure to phosphine is of

limited use in derivation of AEGL

values since exposure durations and

concentrations are not precisely

reported. Appropriate animal data are

more abundant; however, data

consistent with the definition of AEGL–

1 values are not available. Therefore,

due to insufficient data, AEGL–1 values

were not derived.

The AEGL–2 was based on a NOEL for

renal, cardiac, and liver histopathology

in mice exposed to 5 ppm phosphine 6

hours/day for 4 days (Morgan et al,

1995). Values were derived assuming a

single 6 hr. exposure. An uncertainty

factor of 3 was applied to account for

interspecies variability since lethality

data from rats, mice, rabbits, and guinea

pigs suggest little species variability. An

uncertainty factor of 10 was applied to

account for intraspecies variability since

the human data suggest that children

may be more sensitive than adults when

exposed to presumably similar

phosphine concentrations (total UF =

30). The concentration-exposure time

relationship for many irritant and

systemically-acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5

(Ten Berge , 1986). To obtain

conservative and protective AEGL

values for the 30-min., 1-, 4-, and 8-hr.

time points in the absence of an

empirically derived chemical-specific

scaling exponent, temporal scaling was

performed using n = 3 when

extrapolating to shorter time points and

n = 1 when extrapolating to longer time

points using the Cn x t = k equation. The

30-min AEGL–2 value was also adopted

as the 10-min. value due to the fact that

reliable data are limited to durations 4

hrs., and it is considered inappropriate

to extrapolate back to 10-mins.

The AEGL–3 was based on a NOEL for

lethality (18 ppm phosphine) in Sprague

Dawley rats exposed to phosphine for 6

hrs. (Newton, 1991). An uncertainty

factor of 3 was applied to account for

interspecies variability since lethality

data from rats, mice, rabbits, and guinea

pigs suggest little species variability. An

uncertainty factor of 10 was applied to

account for intraspecies variability since

the human data suggest that children

may be more sensitive than adults when

exposed to presumably similar

phosphine concentrations (total UF =

30). The concentration-exposure time

relationship for many irritant and

systemically-acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5

(Ten Berge , 1986). To obtain

conservative and protective AEGL

values for the 30-min., 1-, 4-, and 8-hr.

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39275

time points in the absence of an

empirically derived chemical-specific

scaling exponent, temporal scaling was

performed using n = 3 when

extrapolating to shorter time points and

n = 1 when extrapolating to longer time

points using the Cn x t = k equation. The

30-min AEGL–3 value was also adopted

as the 10-min. value due to the fact that

reliable data are limited to durations 4

hrs., and it is considered inappropriate

to extrapolate back to 10-mins.

The calculated values are listed in the

table below.

SUMMARY OF PROPOSED AEGL VALUES FOR PHOSPHINE [PPM(MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) Appropriate data not available

AEGL–2 (Disabling) 0.38 (0.54) 0.38 (0.54) 0.30 (0.42) 0.19 (0.27) 0.13 (0.18) NOEL for histopathology in mice exposed to

5 ppm phosphine 6 hours/day for 4 days.

Values were calculated assuming a single

6 hr exposure (Morgan et al., 1995)

AEGL–3 (Lethality) 1.4 (1.9) 1.4 (1.9) 1.1 (1.6) 0.69 (0.97) 0.45 (0.63) NOEL for lethality in rats exposed to 18 ppm

phosphine for 6 hrs. (Newton, 1991)

2. References—i. Newton, P.E. 1991.

Acute Inhalation exposures of rats to

phosphine. Bio/Dynamics, Inc. East

Millstone, NJ. Project No. 90–8271.

ii. Morgan, D.L., Moorman, M.P.,

Elwell, M.R., Wilson, R.E., Ward, S.M.,

Thompson, M.B., O’Connor, R.W., and

Price, H.C. 1995. Inhalation toxicity of

phosphine for Fischer 344 rats and

B6C3F1 mice. Inhalation Toxicology. 7:

225–238.

iii. Ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. 13:301–309.

M. Nickel Carbonyl

1. Description. Nickel carbonyl,

formed by the reaction of carbon

monoxide with metallic nickel, is used

in nickel refining, in the synthesis of

acrylic and methacrylic esters, and for

other organic synthesis. In air, nickel

carbonyl rapidly decomposes to nickel

and carbon monoxide with a 50%

decomposition at room temperature and

total decomposition at 150–200°C.

Human data are limited to case

reports, primarily of nickel workers, that

affirm the extreme toxicity of the

compound. However, definitive

exposure terms are lacking in these

reports. Significant signs and symptoms

of toxicity are known to occur in the

absence of recognizable odor. Human

case studies have shown that a latency

period of 10 occurs between initial signs

of toxicity and subsequent serious

effects that may progress to death. The

primary target of nickel carbonylinduced acute toxicity appears to be the

lungs, although extrapulmonary

involvement has also been reported. The

specific mechanism of toxicity is

unclear but appears to involve damage

to pulmonary tissue.

Animal data are limited to lethality

and developmental toxicity. Lethality

values (LC50) are available for rats, mice,

cats, and rabbits. Thirty-minute LC50

values for these species range from 33.6

to 266 ppm. These lethality data

indicate notable species variability in

the lethal response to inhaled nickel

carbonyl; smaller species are generally

more sensitive. Developmental toxicity

has been demonstrated in rats and

hamsters following single 30-min.

(11.2–42 ppm, rats) or 15-min. (8.4 ppm,

hamsters) exposures of dams during

gestation.

Limited data in rats have provided

equivocal evidence of pulmonary

carcinogenicity following acute or longterm exposure to nickel carbonyl.

Studies of respiratory tract cancer in

nickel workers suggest that nickel dusts

and nickel sulfides may be more

relevant than nickel carbonyl. Data are

unavailable for a quantitative

assessment of the carcinogenic potential

of nickel carbonyl in humans or

animals.

Exposure-response data over multiple

time periods are unavailable for nickel

carbonyl and, empirical derivation of a

scaling factor (n) was not possible. The

concentration exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by Cn x t = k, where

the exponent, n, ranges from 0.8 to 3.5.

In the absence of an empirically derived

exponent (n), and to obtain conservative

and protective AEGL values, temporal

scaling was performed using n = 3 when

extrapolating to shorter time points and

n = 1 when extrapolating to longer time

points using the Cn x t = k equation.

Neither human nor animal data are

available for deriving AEGL–1 values.

Both human and animal data affirm the

extreme toxicity of nickel carbonyl, and

human exposures indicate that signs

and symptoms of toxicity may occur in

the absence of detection. Therefore,

AEGL–1 values are not recommended.

With the exception of teratogenicity

and fetotoxicity data in rats and

hamsters, neither human nor animal

data are available that identify effects

consistent with AEGL–2. The

developmental effects are notable

(ocular malformations, fetotoxicity, and

neonate lethality) and the exposures

producing these effects approach those

known to cause lethality in animal

species. The AEGL–2 values were based

upon significantly increased incidences

of malformations in the offspring of

Syrian hamsters which had been

exposed to 8.4 ppm nickel carbonyl for

15 mins. per day on gestation days 4 or

5 (Sunderman et al., 1980). As

previously noted, time scaling was

accomplished by the use of linear C1 x

t = k) extrapolation for 30-min., 1-hr.

and 4-hr. AEGL–2 time points and

exponential extrapolation C 3 x t = k) for

the 10-min. AEGL–2 values. A total

uncertainty factor adjustment of 100 (10

for interspecies variability and 10 for

intraspecies variability) was applied.

The interspecies uncertainty factor

adjustment is justified by the absence of

human data and only limited data in

animal species with which to assess

species variability in the toxic responses

to nickel carbonyl. The uncertainty

factor for individual variability

accounted for lack of data with which

to identify sensitive subpopulations or

to determine individual variability in

the toxic responses to nickel carbonyl.

AEGL–3 values were derived based

upon an estimated lethality threshold in

mice (3.17 ppm) exposed to nickel

carbonyl for 30 mins. (Kincaid et al.,

1953). Lethality data were available for

several species (rats, mice, rabbits, and

cats). A total uncertainty adjustment of

10 was applied (each uncertainty factor

of 3 is the approximate logarithmic

mean of 10 which is 3.16; hence, 3.16

x 3.16 = 10). Analysis of the available

data indicated that the mouse was the

most sensitive species and larger species

tended to be somewhat less sensitive.

Therefore the uncertainty factor

adjustment for interspecies variability

39276 Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices

was limited to 3. An additional factor of

3 was applied to account for

uncertainties regarding individual

variability in the lethal response due to

direct contact pulmonary damage by

nickel carbonyl.

There are limited, equivocal data

showing the development of pulmonary

tumors in rats exposed chronically to

nickel carbonyl and equivocal data

suggestive of a tumorigenic response

following a single massive exposure of

rats to nickel carbonyl. However, a

quantitative cancer assessment was not

feasible.

SUMMARY OF PROPOSED AEGL VALUES FOR NICKEL CARBONYL [PPM MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) NR NR NR NR NR Not recommended

AEGL–2 (Disabling) 0.096

(0.66)

.042 (0.29) 0.021

(0.14)

0.0053

(0.037)

NA Developmental toxicity in hamsters; gestational exposure (15 mins., 8.4 ppm)

AEGL–3 (Lethal) 0.46 (3.2) 0.32 (2.2) 0.16 (1.1) 0.040

(0.27)

NA Estimated lethality threshold (LC01 of 3.17

ppm); mouse lethality data (Kincaid et al.,

1953)

NR: Not recommended. Numeric values for AEGL–1 are not recommended because:

1. The lack of available data,

2. An inadequate margin of safety exists between the derived AEGL–1 and the AEGL–2, or

3. The derived AEGL–1 is greater than the AEGL–2. Absence of an AEGL–1 does not imply that exposure below the AEGL–2 is without adverse effects.

NA: Not appropriate. AEGL values for 8 hrs. were not developed due to the rapid decomposition of nickel carbonyl under ambient atmospheric

conditions.

2. References—i. Kincaid, J.F., Strong,

J.S., and Sunderman, F.W. 1953. Nickel

poisoning. Experimental study of the

effects of acute and subacute exposure

to nickel carbonyl. Archives of

Industrial Hygiene and Occupational

Medicine. 8:48–60.

ii. Sunderman, F.W., Jr., Shen, S.K.,

Reid, M.C., and Alpist, P.R. 1980.

Teratogenicity and embryotoxicity of

nickel carbonyl in Syrian hamsters.

Teratogenicity Carcinogenicity

Mutagenicity. 1:223–233.

N. Iron Pentacarbonyl

1. Description. Iron pentacarbonyl is

one of several iron carbonyls. It is

formed by the interaction of carbon

monoxide with finely divided iron. Iron

pentacarbonyl is used in the

manufacture of powdered iron cores for

electronic components, as a catalyst and

reagent in organic reactions, and as an

anti-knock agent in gasoline. Iron

pentacarbonyl is pyrophoric in air

(¥15°C flashpoint), burning to ferric

oxide.

Quantitative toxicity data and odor

detection data for humans are

unavailable. Qualitative descriptions of

the signs and symptoms of iron

pentacarbonyl exposure include

giddiness and headache, and

occasionally dyspnea and vomiting.

With the exception of dyspnea, these

signs and symptoms are alleviated upon

removal from exposure but fever,

cyanosis, and coughing may occur at 12

to 36 hrs. after exposure. This

information could not be validated and

additional details were unavailable.

Animal data are limited to lethality

findings in rats, mice, and rabbits. Based

upon the limited data available, the rat

appears to be the most sensitive species

as determined by the 30-min. LC50 of

118 ppm and a 4-hr LC50 of 10 ppm

relative to the 30- min. LC50 of 285 ppm

for the mouse. A steep exposureresponse relationship is suggested by

data showing 50% lethality in rats

following only two 6-hr exposures to 3

ppm. For mice, a 1.35-fold increase in

the LC50 results in near 100% mortality

for the same exposure duration,

suggesting a steep exposure-response

relationship for this species as well.

Similarly, a 2.8-fold increase in

exposure concentration (86–244 ppm)

results in a mortality rate in rats of 4/

12 to 11/12. No reproductive/

developmental toxicity, genotoxicity, or

carcinogenicity data are available for

iron pentacarbonyl.

Although exposure-response data for

the same toxicity endpoint over

multiple time periods were limited to

several LC50 values, these data suggested

a near-linear relationship. Therefore, the

value of n was set at unity for the

exponential temporal scaling equation,

Cn×t=k AEGL values were developed for

10 mins., 30 mins., 1 hr., and 4 hrs.

only. AEGL values were not developed

for the 8-hr. time point due to the rapid

decomposition of iron pentacarbonyl

under ambient atmospheric conditions.

Data consistent with AEGL–1 effects

were limited to labored breathing and

signs of irritation in rats exposed to 5.2

ppm for 4 hrs. and no observable effects

in rats exposed for 6 hours/day to 1 ppm

for 28 days. However, analysis of the

overall data set for iron pentacarbonyl

indicated a very steep exposureresponse curve with little margin

between exposures producing no

observable effects and those resulting in

lethality. Therefore, it was the

consensus of the NAC/AEGL Committee

on AEGLs to recommend no AEGL–1

values.

Limited data in rats revealed that

there is only a small margin between

exposures causing little or no toxicity

and those causing more severe effects

and death. No effect was observed

following exposure of rats to 1 ppm, 6

hours/day for up to 28 days while a

single exposure to 2.91 ppm for 6 hours/

day caused notable signs of toxicity

with a 10% mortality. The occurrence of

deaths in laboratory species several days

following cessation of exposure is also

a factor to consider in the derivation of

AEGL–2 values showed. In the absence

of exposure-response data for serious

and/or possibly irreversible effects,

AEGL–2 value were developed by a

three-fold reduction in the AEGL–3

values. This 3-fold reduction was

justified by the apparently steep

exposure-response relationship in rats

where there appears to be about a threefold difference between exposures that

produce no lethality and those resulting

in 50–100% lethality. The AEGL–2

values also reflect the application of

uncertainty factors of 10 for interspecies

variability and 3 for intraspecies

variability as described for the

development of AEGL–3 values.

Animal data consistent with AEGL–3

were limited to 30-min. LC50 values for

rats (118 ppm) and mice (285 ppm), a

45.5-min. LClo value for rabbits (250

ppm), and 4-hr. LC50 in rats (10 ppm).

In addition to a 4-hr. LC50 value for rats,

Biodynamics (1988) also provided 4-hr.

LC16 estimate of 6.99 ppm and an

estimated lethality threshold (4 hrs) of

5.2 ppm for male and female rats. Data

from a study by BASF (1995), however,

Federal Register / Vol. 65, No. 122 / Friday, June 23, 2000 / Notices 39277

showed that a single 6-hr exposure to

2.91 ppm resulted in 10% (1 of 10 rats)

mortality and that a second exposure

resulted in 50% mortality. Remaining

rats, however, survived an additional 26

6-hr. exposures. A total uncertainty

factor of 30 was applied. An uncertainty

factor of 10 was applied to account for

interspecies variability and justified due

to the absence of definitive quantitative

lethality data in humans and the

uncertainties regarding the mechanism

of iron pentacarbonyl-induced lethality.

An additional factor of 3 was applied to

account for uncertainties regarding

individual variability in the toxic

response to iron pentacarbonyl. The

adjustment for this area of uncertainty

was limited to 3 because the available

data did not indicate a high level of

variability among test species and

because the mechanism of action for the

observed toxic responses appears to be

a port-of-entry effect mediated by

contact irritation and destruction of

pulmonary epithelium. The AEGL

values for iron pentacarbonyl are

presented in the table below.

Neither quantitative nor qualitative

data are available regarding the

potential carcinogenicity of iron

pentacarbonyl by any route of exposure.

Therefore, a quantitative assessment of

potential risk is not possible.

Genotoxicity tests in several strains of

Salmonella typhimurium were negative.

SUMMARY OF PROPOSED AEGL VALUES FOR IRON PENTACARBONYL [PPM (MG/M3)]

Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. Endpoint (Reference)

AEGL–1 (Nondisabling) NR NR NR NR NR Not recommended; insufficient data

AEGL–2 (Disabling) 1.2 (9.6) 0.40 (3.2) 0.19 (1.5) 0.050

(0.40)

NA Based upon a three-fold reduction in the

AEGL–3 values

AEGL–3 (Lethal) 3.5 (28) 1.2 (9.6) 0.58 (4.6) 0.15 (1.2) NA Estimated lethality threshold in rats (6-hr. exposure to 2.91 ppm) (BASF, 1995). n = 1;

UF = 30 (10 for interspecies variability, 3

for individual variability)

NR: Not recommended. Numeric values for AEGL–1 are not recommended because:

1. The lack of available data,

2. An inadequate margin of safety exists between the derived AEGL–1 and the AEGL–2, or

3. The derived AEGL–1 is greater than the AEGL–2. Absence of an AEGL–1 does not imply that exposure below the AEGL–2 is without adverse effects.

NA: Not appropriate; AEGL values for 8 hr. were not developed due to the rapid decomposition of iron pentacarbonyl under ambient atmospheric conditions.

2. References —i. BASF (Badische

Anilin & Soda Fabrik). 1995. Study on

the inhalation toxicity of

eisenpentacarbonyl as a vapor in rats—

28 day test. BASF Department of

Toxicology. Environmental Protection

Agency/Office of Toxic Substances,

Document #89–950000244.

ii. Biodynamics. 1988. An acute

inhalation toxicity study of iron

pentacarbonyl in the rat. Final Report.

Environmental Protection Agency/

Office of Toxic Substances, Document

#88–920001300.

V. Next Steps

The NAC/AEGL Committee plans to

publish ‘‘Proposed’’ AEGL values for

five-exposure periods for other

chemicals on the priority list of 85 in

groups of approximately 10 to 20

chemicals in future Federal Register

notices during the calendar year 2000.

The NAC/AEGL Committee will

review and consider all public

comments received on this notice, with

revisions to the ‘‘Proposed’’ AEGL

values as appropriate. The resulting

AEGL values will be established as

‘‘Interim’’ AEGLs and will be forwarded

to the NRC/NAS, for review and

comment. The ‘‘Final’’ AEGLs will be

published under the auspices of the

NRC/NAS following concurrence on the

values and the scientific rationale used

in their development.

List of Subjects

Environmental protection, Hazardous

substances.

Dated: June 16, 2000.

Susan H. Wayland,

Acting Assistant Administrator for

Prevention, Pesticides and Toxic Substances.

[FR Doc. 00–15916 Filed 6–22–00; 8:45 am]

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