21940 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

24-hour exposures that may reasonably

be anticipated to occur. Accordingly, we

are denying AF&PA’s petition to remove

methanol from the list of HAP under

section 112(b) of the CAA. Moreover,

because we conclude that the

information submitted in connection

with this petition does not support a

determination that methanol emissions

will not cause adverse human health

effects, we are denying this petition

with prejudice, and any future petition

for the removal of methanol from the list

of HAP will be denied as a matter of law

unless such petition is accompanied by

substantial new information or analysis.

Dated: April 27, 2001.

Christine T. Whitman,

Administrator.

[FR Doc. 01–10990 Filed 5–1–01; 8:45 am]

BILLING CODE 6560–50–P

ENVIRONMENTAL PROTECTION

AGENCY

[OPPTS–00312; FRL–6776–3]

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 18 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 18 chemicals.

DATES: Comments, identified by the

docket control number OPPTS–00312,

must be received by EPA on or before

June 1, 2001.

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–00312 in the subject line on the

first page of your response.

FOR FURTHER INFORMATION CONTACT: For

general information contact: Barbara

Cunningham, Acting Director,

Environmental Assistance Division

(7401), Office of Pollution Prevention

and Toxics, 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 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 DFO

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,’’ ‘‘Proposed

Rules 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–00312. 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–00312 in the

subject line on the first page of your

response.

1. By mail. Submit your comments to:

Document Control Office (7407), Office

of Pollution Prevention and Toxics

(OPPT), Environmental Protection

Agency, 1200 Pennsylvania Ave., NW,

Washington, DC 20460. (Note: for

express delivery, please see ‘‘In person

or by courier’’ 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

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21941

use of special characters and any form

of encryption. Comments and data will

also be accepted on standard disks in

WordPerfect 6.1/8.1 or ASCII file

format. All comments in electronic form

must be identified by docket control

numbers OPPTS–00312. 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

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 DFO 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 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 on 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 Clean Air Act

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

minutes to 8 hours. AEGL–2 and AEGL–

3 levels, and AEGL–1 levels as

appropriate, will be developed for each

of five exposure periods (10 and 30

minutes, 1 hour, 4 hours, and 8 hours)

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

milligram/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 an

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 health

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

data bases, and individual experts in

both the public and private sectors. All

key data and information are

summarized for the Committee in draft

form by Oak Ridge National

Laboratories together with ‘‘draft’’ AEGL

values prepared in conjunction with

NAC/AEGL Committee members. Both

21942 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

the ‘‘draft’’ AEGLs and ‘‘draft’’ technical

support documents are reviewed and

revised as necessary by the NAC/AEGL

Committee members prior to formal

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

consensus. Once the NAC/AEGL

Committee reaches a consensus, 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 notice the NAC/AEGL

Committee publishes proposed AEGL

values and the accompanying scientific

rationale for their development for 18

hazardous substances. These values

represent the fourth set of exposure

levels proposed and published by the

NAC/AEGL 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); for

10 chemicals in the Federal Register of

March 15, 2000 (65 FR 14186–14196)

(FRL–6492–4); for 14 chemicals in the

Federal Register of June 23, 2000 (65 FR

39263–39277) (FRL–6591–2); and for 7

chemicals in the Federal Register of

December 13, 2000 (65 FR 77866–

77874) (FRL–6752–5) 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 (NAS) in 1993.

The term Community Emergency

Exposure Levels (CELLS) 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 consensus 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 arbiter 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. List of Chemicals

On behalf of the NAC/AEGL

Committee, EPA is providing an

opportunity for public comment on the

AEGLs for the 18 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 I.B.3.

A. Fax-On-Demand Table

TABLE 1.—FAX-ON-DEMAND NUMBERS

CAS No. Chemical name Fax-on-demand item no.

67–56–1 Methanol 4938

77–81–6,

107–44–8,

96–64–0,

329–99–7

Nerve Agents GA, GB, GD, GF 4940

79–10–7 Acrylic acid 4941

107–18–6 Allyl alcohol 4879

107–30–2 Chloromethyl methyl ether 4880

108–88–3 Toluene 4882

108–95–2 Phenol 4943

110–00–9 Furan 4885

127–18–4 Tetrachloroethylene 4889

509–14–8 Tetranitromethane 4894

594–42–3 Perchloromethyl mercaptan 4897

630–08–0 Carbon monoxide 4944

10294–34–5 Boron trichloride 4928

19287–45–7 Diborane 4931

50782–69–9 Nerve Agent VX 4945

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21943

B. Executive Summaries

The following are executive

summaries from the chemical specific

Technical Support Documents (which

may be obtained as described in Unit

I.B.) 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.

1. Methanol—i. Description. Methanol

is a clear, colorless, volatile flammable

liquid with a pungent odor. It is used in

industrial production as a solvent and

raw material for the production of many

important organic compounds.

The acute and short-term toxicity of

methanol varies greatly between

different species: Due to

pharmacokinetic differences, at higher

exposure concentrations rodents

develop higher blood methanol

concentrations than humans and

monkeys. Primate, but not rodent

species, show accumulation of the

metabolite formate. At lower

concentrations methanol causes

symptoms characteristic of effects on

the visual system, such as blurred

vision, and the central nervous system

(CNS), such as nausea, dizziness, and

headaches, as well as slight eye and

nose irritation. At high concentrations,

the accumulation of the toxic metabolite

formic acid may lead to blindness and

death by metabolic acidosis. In rodents

methanol causes developmental toxic

effects and fetal death.

The AEGL–1 was based on a

pharmacokinetic study in which human

volunteers were exposed to 800 ppm

methanol for 8 hours (Batterman et al.,

1998), because no other experimental

human study was available that used an

exposure concentration above a level of

200 ppm, which was used in other

studies and which was considered

below the AEGL–1 threshold. In this

pharmacokinetic study no statement

was made on the presence or absence of

any signs or symptoms of the methanol

exposure; in a personal communication,

the second author, Dr. Franzblau, stated

that none of the subjects reported

symptoms. A factor of 3 was applied for

intraspecies variation because the

exposure level in the Batterman et al.

(1998) study was considered below the

effect threshold and thus the effect level

was less severe than defined for the

AEGL–1 level. However, interindividual

variability with regard to slight

neurotoxic effects (e.g., headache) is

likely to exist (although it cannot be

quantified exactly from the existing

experimental and epidemiological

studies) and, thus, it cannot be ruled out

that a fraction of the general population

might experience slight effects under

the exposure conditions of the

experimental study of Batterman et al.

(1998), which used healthy individuals.

Because exposure repsonse data were

unavailable for all of the AGEL-specific

exposure durations, temporal

extrapolation was used in the

development of AEGL values for the

specific AEGL–time periods. The

concentration exposure-time

relationship for many systematically

acting vapors and gases may be

described by Cn × t = k, where C =

concentration, t = time, k is a constant,

and the exponent n ranges from 0.8 to

3.5. In this case, the value was scaled to

appropriate exposure periods according

to the dose-response regression equation

Cn × t = k, using the default of n = 3

for shorter exposure periods, due to the

lack of suitable experimental data for

deriving the concentration exponent.

The AEGL–2 values were based on

developmental toxic effects in mice.

After a single exposure to different

concentration-time combinations on

gestational day 7, the most sensitive

endpoint was cervical rib induction,

which occurred at concentration-time

products greater than or equal to 15,000

ppm × h, but not at concentration-time

products below 15,000 ppm × h (i.e., no

effects were observed after exposure to

2,000 ppm × 5 h, 2,000 ppm × 7 h and

5,000 ppm × 2 h; authors expressed data

only as C × t values) (Rogers et al. 1995,

abstract; Rogers, 1999, personal

communication). These results are

supported by a repeated exposure

teratogenicity study (Rogers et al.,

1993), in which a significant increase in

cervical vertebrae was observed at 2,000

ppm or higher, and by a single 7-hour

exposure study at 10,000 ppm (Rogers et

al., 1997). For the no-observed-effect

level (NOEL) of 2,000 ppm for 7 hours

(Rogers et al. 1995, abstract; Rogers,

1999, personal communication), the

corresponding end-of-exposure blood

concentration was measured as 487 mg/

Liter (l) (Rogers et al., 1993). A total

uncertainty factor (UF) of 10 was

applied. A factor of 1 was applied for

interspecies variability because a

sensitive species was used for

derivation of AEGL–2 values and

because toxicokinetic differences

between species were accounted for by

using a pharmacokinetic model for

calculating exposure concentrations. A

factor of 10 was used for intraspecies

variability because no information on

developmental toxic effects of methanol

on humans is available and because also

for other chemicals the variability in

susceptibility of humans for

developmental toxic effects is not well

characterized. The total UF was applied

to the blood methanol concentration

resulting in a concentration of 48.7 mg/

l. For this blood methanol

concentration, inhalation exposure

concentrations for appropriate time

periods were calculated so that a blood

methanol concentration of 48.7 mg/l

would be reached at the end of the time

period. For these calculations, a

pharmacokinetic model based on the

model from Perkins et al. (1995) was

used. The calculated exposure

concentrations were set as AEGL–2

values. For 10 minutes, a concentration

of 11,000 ppm was calculated using the

pharmacokinetic model. Since this

value was considered too close to the

10-minute AEGL–3 value of 15,000

ppm, the 10-minute AEGL–2 was set at

the 30-minute value.

The AEGL–3 values were based on

acute lethal effects on humans after oral

methanol uptake (Naraqi et al., 1979;

Erlanson et al., 1965; Bennett et al.,

1955; Gonda et al., 1978). For lethal

cases without relevant concommitant

ethanol exposure, the peak blood

methanol concentration was calculated

from the measured concentration and

the time between intoxication and

measurement using Michaelis-Menten

kinetics. The lowest calculated peak

blood concentration was 1,109 mg/l

from the study by Naraqi et al. (1979).

Due to the very steep dose-response

curve for lethality in monkeys (Gilger

and Potts, 1955), a factor of 2 was

applied to derive a peak blood

concentration of 555 mg/l as the NOEL

for lethality. An factor of 3 was applied

for intraspecies variability, because of

the very steep dose responserelationship for lethality after oral

exposure seen in rhesus monkeys

(Gilger and Potts, 1955) and because a

factor of 10 would have resulted in

blood methanol concentrations of about

70 mg/l which would be far below a

level of 130–200 mg/l, at which ethanol

therapy is recommended (ATSDR, 1993;

Becker, 1983; Meyer et al., 2000) (these

21944 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

values refer to concentrations measured

after hospital admission, which are

usually considerably lower than peak

concentrations). For the resulting blood

methanol concentration of 185 mg/l,

inhalation exposure concentrations for

appropriate time periods were

calculated so that a blood methanol

concentration of 185 mg/l would be

reached at the end of the time period.

For calculations, a pharmacokinetic

model based on the model from Perkins

et al. (1995) was used. These exposure

concentrations were set as AEGL–3

values. The 10-minute AEGL–3 was set

at the 30-minute value because at the

concentration of 44,000 ppm calculated

by the model additional immediate

toxic effects could not be excluded and

because the calculated value is close to

the lower explosive limit in air.

The calculated values are listed in

Table 2 below:

TABLE 2.—SUMMARY TABLE OF PROPOSED AEGL VALUES FOR METHANOLA

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

670 ppm

(880 mg/m3)

670 ppm

(880 mg/m3)

530 ppm

(690 mg/m3)

340 ppm

(450 mg/m3)

270 ppm

(350 mg/m3)

Pharmacokinetic study (Batterman

et al., 1998); according to a personal communication, none of

the subjects reported symptoms

(Franzblau, 1999; 2000)

AEGL–2

(Disabling)

4,000 ppm

(5,200 mg/m3)

4,000 ppm

(5,200 mg/m3)

2,100 ppm

(2,800 mg/m3)

720 ppm

(940 mg/m3)

510 ppm

(670 mg/m3)

No developmental toxic effects in

mice Rogers et al. (1993; 1995,

abstract; 1997); Rogers (1999,

personal communication)

AEGL–3

(Lethal)

15,000 ppm

(20,000 mg/m3)

15,000 ppm

(20,000 mg/m3)

7,900 ppm

(10,000 mg/m3)

2,500 ppm

(3,300 mg/m3)

1,600 ppm

(2,100 mg/m3)

Lethality in humans after oral exposure (Naraqi et al., 1979;

Erlanson et al., 1965; Bennett et

al., 1955; Gonda et al., 1978;

Meyer et al., 2000)

a Cutaneous absorption may occur; direct skin contact with the liquid should be avoided.

ii. References.

a. ATSDR (Agency for Toxic

Substances and Disease Registry). 1993.

Methanol toxicity. American Family

Physician. Vol. 47:163–171.

b. Batterman, S.A., Franzblau, A.,

D’Arcy, J.B., Sargent, NE., Gross, K.B.,

and Schreck, R.M. 1998. Breath, urine,

and blood measurements as biological

exposure indices of short-term

inhalation exposure to methanol.

International Archives of Occupational

and Environmental Health. Vol. 71:325–

335.

c. Becker, C.E. 1983. Methanol

poisoning. Journal of Emergency

Medicine. Vol. 1:51–58.

d. Bennett, I., Cary, F.H., Mitchell,

G.L., and Cooper, M.N. 1953. Acute

methyl alcohol poisoning: a review

based on experiences in an outbreak of

323 cases. Medicine. Vol. 32:431–463.

e. Erlanson, P., Fritz, H., Hagstam, K.

E., Liljenberg, B., Tryding, N., and Voigt,

G. 1965. Severe methanol intoxication.

Acta Medica Scandinavica. Vol.

177:393–408.

f. Franzblau, A. 1999. Dr. Alfred

Franzblau, University of Michigan

School of Public Health, Ann Arbor, MI.

Personal communication. E-mail dated

June 14, 1999.

g. Franzblau, A. 2000. Dr. Alfred

Franzblau, University of Michigan

School of Public Health, Ann Arbor, MI.

Personal communication. E-mail dated

October 3, 2000.

h. Gilger, A.P. and Potts, A.M. 1955.

Studies on the visual toxicity of

methanol. V. The role of acidosis in

experimental methanol poisonings.

American Journal of Ophthalmology.

Vol. 39:63–86.

i. Gonda, A., Gault, H., Churchill, D.,

and Hollomby, D. 1978. Hemodialysis

for methanol intoxication. The

American Journal of Medicine. Vol.

64:749–758.

j. Meyer, R.J., Beard, M.E.J., Ardagh,

M.W., and Henderson, S. 2000.

Methanol poisoning. New Zealand

Medical Journal. Vol. 113:11–13.

k. Naraqi, S., Dethlefs, R.F.,

Slobodniuk, R.A., and Sairere, J.S. 1979.

An outbreak of acute methyl alcohol

intoxication. Australia and New

Zealand Journal of Medicine. Vol. 9:65–

68.

l. Perkins, R.A., Ward, K.W., and

Pollack, G.M. 1995. A pharmacokinetic

model of inhaled methanol in humans

and comparison to methanol disposition

in mice and rats. Environmental Health

Perspectives. Vol. 103:726–733.

m. Rogers, J.M., Mole, M.L., Chernoff,

N., Barbee, B.D., Turner, C.I., Logsdon,

T.R., and Kavlock, R.J. 1993. The

developmental toxicity of inhaled

methanol in the CD-1 mouse, with

quantitative dose-response modeling for

estimation of benchmark doses.

Teratology. Vol. 47:175–188.

n. Rogers, J.M., Barbee, B.D., and M.L.

Mole. 1995. Exposure concentration and

time (C x T) relationships in the

developmental toxicity of methanol in

mice. Toxicologist. Vol. 15:164

(abstract).

o. Rogers. J.M. and Mole, M.L. 1997.

Critical periods of sensitivity to the

developmental toxicity of inhaled

methanol in the CD-1 mouse.

Teratology. Vol. 55:364–372.

p. Rogers, J.M. 1999. USEPA. National

Health and Environmental Effects

Research Laboratory, Research Triangle

Park, NC. Personal communication.

Letter dated May 27, 1999.

2–5. Nerve Agents GA, GB, GD, GF—

i. Description. The G-series agents [GA

(tabun), GB (sarin), GD (soman), and GF]

are all toxic ester derivatives of

phosphonic acid containing either a

cyanide or fluoride substituent group,

and are commonly termed ‘‘nerve’’

agents as a consequence of their

anticholinesterase properties. These

compounds were developed as chemical

warfare agents, and one was used by

chemical terrorists in the 1995 incident

of nerve agent exposure that took place

in the Tokyo subway system. The

chemical names of these 4 agents are as

follows: Agent GA,

dimethylamidocyanophosphate; Agent

GB, isopropyl methyl

phosphonofluoridate; Agent GD,

pinacolyl methylphosphonofluoridate;

and Agent GF, O-cyclohexylmethylfluorophosphonate.

The G-agents are all viscous liquids of

varying volatility (vapor density relative

to air between 4.86 and 6.33) with faint

odors (‘‘faintly fruity,’’ or ‘‘spicy,’’ ‘‘odor

of camphor’’). Toxic effects may occur at

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21945

concentrations below those of odor

detection.

The vapor pressures and acute

toxicity of the G-series agents are

sufficiently high for the vapors to be

rapidly lethal. Within the G-series, GB

is considered largely a vapor hazard,

while GD is considered mainly a vapor

hazard. GA represents a smaller vapor

hazard and is expected to present a

relevant contact hazard. The vapor

pressure of agent GF is intermediate

between that of agents GA and GD.

Exposure to acutely toxic

concentrations of G-agents can result in

excessive bronchial, salivary, ocular,

and intestinal secretion, sweating,

miosis, bronchospasm, intestinal

hypermotility, bradycardia, muscle

fasciculations, twitching, weakness,

paralysis, loss of consciousness,

convulsions, depression of the central

respiratory drive, and death. Minimal

effects observed at low vapor

concentrations include miosis

(pinpointing of the pupils of the eye,

with subsequent decrease in pupil area),

tightness of the chest, rhinorrhea, and

dyspnea.

The results of agent GB vapor

exposure studies conducted with

human volunteers indicate that the

threshold for miosis and other minimal

toxic effects falls in the range of 0.05 to

0.5 mg/m3 for 10–30 minute exposures.

These findings are based on the results

of low-concentration nerve agent

exposures to informed volunteers who

were under clinical supervision during

the periods of exposure as well as for

post-exposure periods of several

months. Inconsistencies between the

studies in identifying the toxicity

threshold may be due to differences in

individual sensitivities or breathing

rates of the test subjects, or to

differences in experimental protocols or

analytical methods.

There is at present no evidence to

indicate that asymptomatic exposures to

any of the G-agents result in chronic

neurological disorders. A major concern

associated with symptomatic exposures

to anticholinesterase compounds such

as the G agents is the possibility of

chronic neurological effects. In general,

the available epidemiological data

indicate that most clinical signs of

toxicity resolve within hours to days;

severe miosis may require several

months after exposure for resolution.

However, several studies have shown

that subclinical signs may persist for

longer periods. Following the chemical

terrorist attacks with nerve agent GB

that occurred in Japan in 1994 and 1995,

clinical signs of agent toxicity were no

longer apparent in the surviving victims

3 months after the exposures had

occurred. However, several studies

conducted on a small number of

asymptomatic individuals 6–8 months

after the attack revealed subclinical

signs of neurophysiological deficits as

measured by event-related and visual

evoked potentials, psychomotor

performance, and increases in postural

sway.

Small but measurable changes in

single fibre electromyography (SFEMG)

of the forearm were detectable between

4 and 15 months following exposure to

a concentration of agent GB that

produced minimal clinical signs and

symptoms in fully informed human

subjects who were under clinical

supervision in compliance with

Helsinki accords (Baker and Sedgwick,

1996). The SFEMG effects were not

clinically significant and were not

detectable after 15–30 months. In a

separate study of workers who had been

occupationally exposed to agent GB

(sarin), altered electroencephalograms

(EEGs) were recorded 1 year or more

after the last exposure had occurred.

Spectral analysis of the EEGs indicated

significant increases in brain beta

activity (12–30 Hz) in the exposed group

when compared to non-exposed

controls, and sleep EEGs revealed

significantly increased rapid eye

movement in the exposed workers;

these observations were not clinically

significant. Increases in beta activity

were also observed in rhesus monkeys

1 year after being dosed with 5 μg GB/

killogram (kg). Slight, but nonsignificant increases in beta activity,

without deleterious effects on cognitive

performance, were reported for

marmosets injected with 3.0 μg GB/kg

and tested 15 months later. The

significance of subclinical neurological

effects for the long-term health of

exposed individuals has not been

determined.

Animal data from vapor and oral

exposure studies for agent GB suggest

that agent GB does not induce

reproductive or developmental effects in

mammals. Oral exposure studies of

agents GB and GD in lab animals, as

well as injection exposure studies of

agent GA, likewise suggest the lack of

reproductive or development effects for

these agents. Agent GB was not found to

be genotoxic in a series of microbial and

mammalian assays, but agent GA was

reported to be weakly mutagenic. There

is no evidence that agents GB and GA

are carcinogenic.

The data base for toxicological effects

in humans is more complete for agent

GB than for any of the other G-agents.

Furthermore, agent GB is the only Gagent for which sufficient human data

are available to directly derive AEGL–1

and AEGL–2 values, and the only Gagent for which sufficient laboratory

animal data are available for deriving an

AEGL–3 value for all five AEGL time

periods. The AEGL–1 values for agent

GB were derived from a study on human

volunteers in which minimal and

reversible effects occurred as a

consequence of a 20-minute exposure to

a GB vapor concentration of 0.05 mg/m3

(Harvey, 1952; Johns, 1952).

The AEGL–2 values for agent GB were

derived from a study in which miosis,

dyspnea, photophobia, inhibition of red

blood cell cholinesterase (RBC-ChE),

and changes in SFEMG were observed

in human volunteers following a 30-

minute exposure to 0.5 mg/m3 (Baker

and Sedgwick, 1996). The SFEMG

changes noted in the study were not

clinically significant, and were not

detectable after 15–30 months. Baker

and Sedgwick considered SFEMG

changes to be a possible early indicator

or precursor of the nondepolarising

neuromuscular block found associated

with Intermediate Syndrome paralysis

in severe organophosphorous

insecticide poisoning cases. The study

concluded that these electromyographic

changes were persistent (>15 months),

but that they were reversible and

subclinical. While not considered

debilitating or permanent effects in

themselves, SFEMG changes are here

considered an early indicator of

exposures that could potentially result

in more significant effects. Selection of

this effect as a protective definition of

an AEGL–2 level is considered

appropriate given the steep doseresponse toxicity curve of nerve agents.

This concept of added precaution for

steep dose-response is consistent with

emergency planning guidance for nerve

agents previously developed by the

National Center for Environmental

Health of the Centers for Disease Control

and Protection.

Animals exposed to low

concentrations of the G agents exhibit

the same signs of toxicity as humans,

including miosis, salivation, rhinorrhea,

dyspnea, and muscle fasciculations.

Studies on dogs and rats indicate that

exposures to 0.001 mg GB/m3 for up to

6 hours per day are unlikely to produce

any signs of toxicity.

Because exposure-response data were

unavailable for all of the AEGL–specific

exposure durations, temporal

extrapolation was used in the

development of AEGL values for the

AEGL–specific time periods. The

concentration-exposure time

relationship for many systemically

acting vapors and gases may be

described by Cn × t = k, where the

exponent n ranges from 0.8 to 3.5.

21946 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

Ongoing but unpublished analyses of rat

exposure data as performed by

Mioduszewski and his colleagues is

indicating that the n value for agent GB

likely varies with exposure duration (t)

(Mioduszewski et al., 2000a, b). Future

analyses may provide separate n values

for different duration periods of

concern, and will be used when

available. Current analyses are based on

a log-log linear regression of the

lethality of GB to female SpragueDawley rats (Mioduszewski et al.,

2000a, b), which yields an n value of

1.93 with a r2 of 0.9948. This value

indicates a good agreement between the

data points. Given that all mammalian

toxicity endpoints observed in the data

set for all nerve agents represent

different points on the response

continuum for anticholinesterase

exposure, and that the mechanism of

mammalian toxicity (cholinesterase

inhibition) is the same for all nerve

agents, the experimentally derived n =

2 from the Mioduszewski et al. (2000a,

b) rat lethality data set is used as the

scaling function for the AEGL–1 and

AEGL–2 derivations rather than a

default value. An n of 1.16 was

calculated for comparison using other

data (human volunteer) and other

endpoints (e.g., GB-induced miosis in

humans; see Appendix B). However,

due to a poor r2 (0.6704) and other

uncertainties associated with some of

the exposure measurements in these

earlier studies, Mioduszewki et al., data

were determined to be the best source

of an estimate for n. An n value of 2 was

also used to derive the 8-hour AEGL–3

value for GB from the experimental rat

lethality data set in which animals were

exposed to GB vapor for a maximal

period of 6 hours (Mioduszewski et al.,

2000a, b).

The fact that AEGL–1 and AEGL–2

analyses for agent GB are based on data

from human volunteers (Harvey, 1952;

Johns 1952; Baker and Sedgwick, 1996)

precludes the use of an interspecies UF.

To accommodate known variation in

human cholinesterase activity that may

make some individuals susceptible to

the effects of cholinesterase inhibitors

such as nerve agents, a factor of 10 was

applied for intraspecies variability

(protection of susceptible populations).

A modifying factor is not applicable.

Thus, the total UF for estimating AEGL–

1 and AEGL–2 values for agent GB is 10.

In comparison to agent GB, the data

sets characterizing toxicity of agents GA,

GD, and GF are less complete.

Nevertheless, the literature clearly

indicates that inhibition of

cholinesterase activity is a common

mechanism of toxicity shared by all

these nerve agents. Thus, it was possible

to develop AEGL estimates for agents

GA, GD, and GF by a comparative

method of relative potency analysis

from the more complete data set for

agent GB. This approach has been

previously applied in the estimation of

nerve agent exposure limits, most

recently by Mioduszewski et al (1998).

The AEGL–1 and AEGL–2 values for

agents GA, GD, and GF were derived

from the AEGL–1 and AEGL–2 values

for GB using a relative potency

approach, based on the potency of the

agents to induce LOAEL effects of

miosis, rhinorrhea, and SFEMG; and

agent concentration in units of mg/m3.

Agents GA and GB were considered to

have an equivalent potency for causing

miosis. Agents GD and GF are each

considered approximately twice as

potent as agents GB or GA for these

endpoints, and equipotent to each other

for AEGL–1 and AEGL–2 effects. Thus,

the AEGL–1 and AEGL–2 concentration

values for agents GD and GF are equal

to 0.5 times those values derived for

agents GA and GB.

AEGL–3 values for agent GB were

derived from recent inhalation studies

in which the lethality of GB to female

Sprague-Dawley rats was evaluated for

the time periods of 10, 30, 60, 90, 240,

and 360 minutes (Mioduszewski et al.,

2000a, b). Both experimental LC01 and

LC50 values were evaluated. The use of

a rat data set resulted in selection of an

interspecies UF of 3; the full default

value of 10 was not considered

appropriate since the mechanism of

toxicity in mammals is cholinesterase

inhibition. The full default value of 10

for intraspecies uncertainty was

considered necessary to protect

susceptible populations. Since a

modifying factor is not applicable, the

total UF for AEGL–3 determination for

agent GB is equal to 30.

The AEGL–3 values for agent GA were

derived from the AEGL–3 values for GB

using a relative potency approach based

on lethality of the agents; the potency of

agent GA was considered to be only c

that of agent GB for this endpoint. Thus,

the AEGL–3 concentration values for

agent GA are equal to 2.0 times the

AEGL–3 values for agent GB.

The lethal potencies of agents GD and

GF are considered equivalent, and

equipotent to that of agent GB. Thus, the

AEGL–3 concentration values for agent

GB, GD, and GF are equivalent. A

secondary and short-term GD inhalation

study of rat lethality for exposure times

≤30 minutes (Aas et al., 1985) lends

support to the assumption of lethal

equipotency for agents GB and GD.

Since the principal mode of action

(cholinesterase inhibition) for the Gagents is identical, an n = 2 was used

for deriving AEGL–3 values from the

data of Aas and his colleagues. Due to

the sparse data set for this agent, the full

default values for interspecies (10) and

intraspecies (10) uncertainty were

applied. Since a modifying factor is not

applicable, a total UF of 100 was used

in deriving 10-minute AEGL–3 (0.27

mg/m3) and 30-minsute AEGL–3 (0.15

mg/m3) estimates for agent GD from Aas

et al. (1985).

The calculated values are listed in

Table 3 below:

TABLE 3.—SUMMARY OF PROPOSED AEGL VALUES FOR NERVE AGENTSA GA, GB, GD, AND GF [PPM (MG/M3)]

Agent Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

GA AEGL–1

(Non-disabling)

0.0010 ppm

(0.0069 mg/

m3)

0.00060 ppm

(0.0040 mg/

m3)

0.00042 ppm

(0.0028 mg/

m3)

0.00021 ppm

(0.0014 mg/

m3)

0.00015 ppm

(0.0010 mg/

m3)

Based on relative potency

from GBb

AEGL–2

(Disabling)

0.013 ppm

(0.087 mg/m3)

0.0075 ppm

(0.050 mg/m3)

0.0053 ppm

(0.035 mg/m3)

0.0026 ppm

(0.017 mg/m3)

0.0020 ppm

(0.013 mg/m3)

Based on relative potency

from GBb

AEGL–3

(Lethal)

0.11 ppm

(0.76 mg/m3)

0.057 ppm

(0.38 mg/m3)

0.039 ppm

(0.26 mg/m3)

0.021 ppm

(0.14 mg/m3)

0.015 ppm

(0.10 mg/m3)

Based on relative potency

from GBc

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21947

TABLE 3.—SUMMARY OF PROPOSED AEGL VALUES FOR NERVE AGENTSA GA, GB, GD, AND GF [PPM (MG/M3)]—

Continued

Agent Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

GB AEGL–1

(Non-disabling)

0.0012 ppm

(0.0069 mg/

m3)

0.00068 ppm

(0.0040 mg/

m3)

0.00048 ppm

(0.0028 mg/

m3)

0.00024 ppm

(0.0014 mg/

m3)

0.00017 ppm

(0.0010 mg/

m3)

Headache, eye pain,

rhinorrhea, tightness in

chest, cramps, nausea,

malaise, miosis in human

volunteers exposed to 0.05

mg/m3 for 20 minutes (Harvey, 1952; Johns, 1952)

AEGL–2

(Disabling)

0.015 ppm

(0.087 mg/m3)

0.0085 ppm

(0.050 mg/m3)

0.0060 ppm

(0.035 mg/m3)

0.0029 ppm

(0.017 mg/m3)

0.0022 ppm

(0.013 mg/m3)

Miosis, dyspnea, RBC-ChE inhibition, SFEMG changes in

human volunteers exposed

to 0.5 mg/m3 for 30 minutes

(Baker and Sedgwick,

1996)

AEGL–3

(Lethal)

0.064 ppm

(0.38 mg/m3)

0.032 ppm

(0.19 mg/m3)

0.022 ppm

(0.13 mg/m3)

0.012 ppm

(0.070 mg/m3)

0.0087 ppm

(0.051 mg/m3)

Based on experimental

Sprague-Dawley rat lethality

data (LC01 and LC50);

whole-body dynamic exposure to concentrations between 2–56 mg/m3 for 3,

10, 30, 60, 90, 240, and

360 minutes (Mioduszewski

et al., 2000a,b)

GD AEGL–1

(Non-disabling)

0.00046 ppm

(0.0035 mg/

m3)

0.00026 ppm

(0.0020 mg/

m3)

0.00018 ppm

(0.0014 mg/

m3)

0.000091 ppm

(0.00070 mg/

m3)

0.000065 ppm

(0.00050 mg/

m3)

Based on relative potency

from GBd

AEGL–2

(Disabling)

0.0057 ppm

(0.044 mg/m3)

0.0033 ppm

(0.025 mg/m3)

0.0022 ppm

(0.018 mg/m3)

0.0012 ppm

(0.0085 mg/

m3)

0.00085 ppm

(0.0065 mg/

m3)

Based on relative potency

from GBd

AEGL–3

(Lethal)

0.049 ppm

(0.38 mg/m3)

0.025 ppm

(0.19 mg/m3)

0.017 ppm

(0.13 mg/m3)

0.0091 ppm

(0.070 mg/m3)

0.0066 ppm

(0.051 mg/m3)

Based on relative potency

from GB. Supported by

Wistar rat LC50; dynamic

chamber exposures at 21

mg/m3 for 3 time periods of

<30 minutes duration (Aas

et al., 1985)e

GF AEGL–1

(Non-disabling)

0.00049 ppm

(0.0035 mg/

m3)

0.00028 ppm

(0.0020 mg/

m3)

0.00020 ppm

(0.0014 mg/

m3)

0.00010 ppm

(0.00070 mg/

m3)

0.000070 ppm

(0.00050 mg/

m3)

Based on relative potency

from GBd

AEGL–2

(Disabling)

0.0062 ppm

(0.044 mg/m3)

0.0035 ppm

(0.025 mg/m3)

0.0024 ppm

(0.018 mg/m3)

0.0013 ppm

(0.0085 mg/

m3)

0.00091 ppm

(0.0065 mg/

m3)

Based on relative potency

from GBd

AEGL–3

(Lethal)

0.053 ppm

(0.38 mg/m3)

0.027 ppm

(0.19 mg/m3)

0.018 ppm

(0.13 mg/m3)

0.0098 ppm

(0.070 mg/m3)

0.0071 ppm

(0.051 mg/m3)

Based on relative potency

from GBe

a Percutaneous absorption of G-agent vapor is known to be an effective route of exposure; nevertheless, percutaneous vapor concentrations

needed to produce similar adverse effects are greater than inhalation vapor concentrations by several orders of magnitude. Thus, the AEGL values presented are considered protective for both routes of exposure. b Based on relative potency equal to that of agent GB (see section 4.3 and Mioduszewski et al., 1998) c Agent GA is considered approximately c as potent as GB in causing lethality; thus, AEGL–3 values for GA are estimated by multiplying each

time-specific AEGL–3 value for agent GB by a factor of 2 (see section 4.3 and Mioduszewski et al., 1998) d Agents GD and GF are considered approximately twice as potent as agents GA and GB for causing miosis, and equipotent to each other.

Thus, AEGL–1 and AEGL–2 values are estimated by multiplying each time-specific AEGL–1 or AEGL–2 value for agent GB by a factor of 0.5

(see section 4.3 and Mioduszewski et al., 1998) e Based on a relative potency for lethality of GD = GF = GB and lethality data of Aas et al. (1985) (which provides a 10-minute AEGL–3 estimate of 0.27 mg/m3and a 30-minute AEGL–3 value of 0.15 mg/m3) (see section 4.3 and Appendix A)

ii. References.

a. Aas, P., Sterri, S.H., Hjermstad,

H.P., and Fonnum, F. 1985. A method

for generating toxic vapors of soman:

toxicity of soman by inhalation in rats.

Toxicology and Applied Pharmacology.

Vol. 80:437–445.

b. Baker, D.J. and Sedgwick, E.M.

1996. Single fibre electromyographic

changes in man after organophosphate

exposure. Human and Experimental

Toxicology. Vol. 15:369–375.

c. Harvey, J.C. 1952. Clinical

observations on volunteers exposed to

concentrations of GB. Medical

Laboratories Research Report No. 114,

21948 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

Publication Control No. 5030–114

(CMLRE–ML–52), MLCR 114. Army

Chemical Center, Aberdeen Proving

Ground, MD.

d. Johns, R.J. 1952. The effect of low

concentrations of GB on the human eye.

Research Report No. 100, Publication

Control No. 5030–100 (CMLRE–ML–52).

Chemical Corps Medical Laboratories,

Army Chemical Center, Aberdeen

Proving Ground, MD.

e. Mioduszewski, R.J., Reutter, S.H.,

Thomson, S.A., Miller, L.L., and Olajos,

E.J. 1998. Evaluation of airborne

exposure limits for G-agents:

occupational and general population

exposure criteria. ERDEC–TR–489. U.S.

Department of the Army, Edgewood

Research, Development and Engineering

Center, U.S. Army Chemical and

Biological Defense Command, Aberdeen

Proving Ground, MD.

f. Mioduszewski, R.J., Manthei, J.,

Way, R., Burnett, D., Gaviola, B., Muse,

W., Crosier, R., and Sommerville, D.

2000a. Estimating the probability of

sarin vapor toxicity in rats as a function

of exposure concentration and duration.

Presented at the 39th Annual Meeting of

the Society of Toxicology, March, 2000,

Philadelphia, PA. Toxicologist. Vol.

54(1):18 (#84).

g. Mioduszewski, R.J., Manthei, J.,

Way, R., Burnett, D., Gaviola, B. Muse,

W., Thomson, S., Sommerville, D., and

Crosier, R. 2000b. Estimating the

probability of sarin vapor toxicity in rats

as a function of exposure concentration

and duration. Proceedings of the

International Chemical Weapons

Demilitarization Conference (CWD–

2000), The Hague, NL. May 21–24, 2000.

6. Acrylic acid—i. Description.

Acrylic acid is a clear, colorless,

corrosive liquid with a pungent odor.

The primary use of acrylic acid,

accounting for about two third of its use,

is in the production of acrylic esters and

resins, which are used primarily in

coatings, paint, plastics, and adhesives.

Acrylic acid is also used in oil treatment

chemicals, detergent intermediates, and

water treatment chemicals.

Except for reports on odor threshold

and a personal communication about

irritative effects in humans no studies

reporting effects in humans are

available. Irritative effects of acrylic acid

in animals have been described in

studies using repeated 6-hour exposures

of rabbits, rats, and mice. Consistently,

histopathological alterations of the nasal

mucosa was a more sensitive

toxicological endpoint than the

appearance of clinical signs of irritation:

The lowest concentrations leading to

clinical signs of irritation

(concentrations without effect given in

brackets) were 129 (77) ppm in rabbits

(blepharospasm, perinasal and perioral

wetness), 218 (114) ppm in rats (eyelid

closure, discharge from eyes), and 223

(72) ppm in mice (scratching at the

nose). Repeated exposure for 1–2 weeks

led to histopatholgical changes of the

nasal mucosa at the lowest

concentrations tested, which were 34

ppm for rabbits, 74 ppm for rats and 25

ppm for mice. In mice, effects were

found after exposure to 5 ppm for 22

hours/day, but not 6 hours/day, for 2

weeks. A number of studies described

lethal effects in rats. In a study in which

rats were exposed to acrylic acid aerosol

(Hagan and Emmons, 1988), LC50 values

of 5,670; 3,804; and 2,553 ppm for 30

minutes, 1 hour, and 2 hours,

respectively, were reported. Studies

evaluating the acute toxicity of acrylic

acid vapors used very small numbers of

animals or were not reported in detail

and gave somewhat varying results. In

summary, the available studies do not

indicate a large difference in the toxicity

of acrylic acid vapor and aerosol. No

developmental toxic effects of acrylic

acid were found in several inhalation

studies. Acrylic acid may have a weak

clastogenic effect in vitro. No

carcinogenic effects were found after

application of acrylic acid in the

drinking water, while after

subcutaneous and topical application

tumors were found (probably

attributable to local irritative effects).

AEGL–1 values were based on the

odor recognition threshold of 1 ppm

determined by Hellman and Small

(1974). Since this odor threshold was

determined in a trained odor panel, it

was assumed that the olfaction of the

general population is less good. For this

reason, the reported recognition

threshold and not the detection

threshold was chosen for derivation of

AEGL–1 values. This concentration of

acrylic acid is supposed to have

warning properties since most people

should perceive the odor of acrylic acid

at this concentration. Since the odor

threshold is considered to depend

primarily on exposure concentration

and not much on exposure time, a flat

line was used for time scaling. An UF

of 1 was applied for intraspecies

variability because this factor was

considered adequate for an odor

threshold. The derived values are

supported by irritative effects in

humans: In a personal communication,

Renshaw (1991) reported that eye

irritation was noted after exposure to

concentrations of 5–23 ppm for 15–30

minutes and that slight eye irritation

was experienced after exposure to 0.3–

1.6 ppm for 30 minutes to 2.5 hours.

Since occurrence of slight eye irritation

can be tolerated at the AEGL–1 level

these data support AEGL–1 values in

the latter concentration range.

The AEGL–2 was based on

blepharospasm in rabbits observed

during the first and subsequent

exposures in a teratogenicity study

using repeated exposures (NeeperBradley et al., 1997). Blepharospasm

was considered a sign of impaired

ability to escape. The highest

concentration not leading to this effect

was 77 ppm (the LOEL was 129 ppm).

A total UF of 3 was used. An

interspecies factor of 1 was applied

because the rabbit was considered a

species especially sensitive for

blepharospasm/eyelid closure. An

intraspecies factor of 3 was used

because it was assumed that only

toxicodynamic, but not toxicokinetic

differences contribute to variability of

this local effect. No information was

available on the exposure concentration

dependence of the time to onset of

blepharospasm. Since the increase of

this effect with time was assumed to be

small and observations from 6-hour

exposure periods were available, use of

a flat line to derive values for

appropriate exposure periods was

considered an appropriate approach.The

AEGL–3 was based on a mortality study

in rats using single exposures against

acrylic acid aerosol for 30 minutes, 1

hour, or 2 hours (Hagan and Emmons,

1988). Using Probit analysis, maximum

likelihood estimates for LC01 values

were calculated for appropriate

exposure periods between 10 minutes

and 8 hours. These values were similar

to the lower 95% confidence limit of

LC05 values calculated by Probit

analysis. The same values were obtained

when time scaling was done according

to the dose-response regression equation

Cn × t = k, using an n of 1.7, that was

derived by Probit analysis from the data

of the AEGL–3 key study (Hagan and

Emmons, 1988) or by linear regression

of log (LC50)¥log (time) data. A total UF

of 10 was used. An interspecies factor

of 3 was applied because the

interspecies variability was assumed to

be small due to the facts that acrylic

acid is a contact-site, direct-acting

toxicant, the mechanism of action is

unlikely to differ between species and

the influence of metabolism,

detoxification, and elimination on lethal

effects after inhalation is estimated to be

small. An intraspecies factor of 3 was

applied because a small interindividual

variability can be assumed since acrylic

acid is a contact-site, direct-acting

toxicant not requiring metabolic

conversion.

The calculated values are listed in

Table 4 below:

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21949

TABLE 4.—SUMMARY TABLE OF PROPOSED AEGL VALUES FOR ACRYLIC ACID

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

1.0 ppm

(3.0 mg/m3)

1.0 ppm

(3.0 mg/m3)

1.0 ppm

(3.0 mg/m3)

1.0 ppm

(3.0 mg/m3)

1.0 ppm

(3.0 mg/m3)

Odor detection threshold in humans

(Hellman and Small, 1974)

AEGL–2

(Disabling)

26 ppm

(78 mg/m3)

26 ppm

(78 mg/m3)

26 ppm

(78 mg/m3)

26 ppm

(78 mg/m3)

26 ppm

(78 mg/m3)

Blepharospasm in rabbits (Neeper-Bradley et al., 1997)

AEGL–3

(Lethal)

470 ppm

(1,400 mg/m3)

250 ppm

(750 mg/m3)

170 ppm

(510 mg/m3)

77 ppm

(231 mg/m3)

51 ppm

(153 mg/m3)

Lethality in rats (Hagan and Emmons,

1988)

ii. References.

a. Hellman, T.M. and Small, F.H.

1974. Characterization of the odor

properties of 101 petrochemicals using

sensory methods. Journal of the Air

Pollution Control Association. Vol.

24:979–982.

b. Hagan, J.V. and Emmons, H.F.

1988. Acrylic acid—acute inhalation

toxicity study in rats. Unpublished

Report No. 87R–106. Rohm and Haas

Co., Spring House, PA.

c. Neeper-Bradley, T.L., Fowler, E.H.,

Pritts, I.M., and Tyler, T.R. 1997.

Developmental toxicity study of inhaled

acrylic acid in New Zealand White

rabbits. Food and Chemical Toxicology.

Vol. 35:869–880.

d. Renshaw, F.M. and Renshaw, F.M.

1988. Rohm and Haas Co. Personal

communication cited in Emergency

Response Planning Guidelines, Acrylic

acid. AIHA (American Industrial

Hygiene Association), Akron, OH.

7. Allyl alcohol—i. Description. Allyl

alcohol is a colorless liquid that is a

potent sensory irritant. Toxic effects

following inhalation exposures to allyl

alcohol vapor include lacrimation,

pulmonary edema and congestion, and

inflammation, hemorrhage, and

degeneration of the liver and kidney.

Human data were limited to voluntary

exposures for short durations and

general statements about the signs of

toxicity following accidental exposures

to unknown concentrations of allyl

alcohol for unspecified amounts of time

in the workplace. Animal data were

limited to studies in which lethality was

the only endpoint of interest,

subchronic exposures, or singleexposure experiments in which the

model was questionable.

The AEGL–1 value was based on the

mean odor detection threshold

concentration of 1.8 ppm (AIHA, 1989).

Odor is considered a threshold effect;

therefore the values were not scaled

across time, but rather the threshold

value is applied to all times.

The AEGL–2 values were based on a

subchronic exposure study in which

rats were repeatedly exposed to 40 ppm

for 7 hours/day (Dunlap et al., 1958).

Irritation was noted to occur during the

first few exposures. An UF of 3 was

applied for species to species

extrapolation because there did not

appear to be much variation between

species: A NOEL for lethality was the

same for 3 different species (mice, rats,

and rabbits). An UF of 3 was also

applied for intraspecies extrapolation.

Although the traditional approach for

UF in a case such as this would argue

for an uncertainty factor of 10 because

of the lack of data addressing

interindividual variability, this would

result in a composite uncertainty factor

of 30. An UF of 30 would drive the

AEGL–2 values (8 hour AEGL–2 of 1.2

ppm) to a level that would be

inconsistent with available data:

Dunlap, et al. (1958) reported that rats

exposed for 7 hours/day, 5 days/week

for 60 exposures to 1, 2, or 5 ppm had

no observable adverse effects, while rats

exposed to 20 ppm only exhibited

decreased body-weight gain, and

Torkelson et al. (1959) reported that no

adverse effects were noted when rats,

guinea pigs, rabbits, and dogs were

exposed to 2 ppm for 7 hours/day, 5

days/week for 28 exposures, while

exposure of rats, guinea pigs, and

rabbits exposed to 7 ppm for 7 hours/

day, 5 days/week for 134 exposures

exhibited only reversible liver and

kidney damage. Therefore, a total UF of

10 was applied to the AEGL–2 value.

The experimentally derived exposure

value was then scaled to AEGL time

frames using the concentration-time

relationship given by the equation Cn ×

t = k, where the exponent n generally

ranges from 1 to 3.5 (ten Berge, 1986).

The value of n was not empirically

derived due to the unreliability and

inconsistencies of the data; therefore,

the default value of n = 1 was used for

extrapolating from shorter to longer

exposure periods and a value of n = 3

was used to extrapolate from longer to

shorter exposure periods. The 10-

minute value was set equal to the 30-

minute value because it was considered

too precarious to extrapolate from the

exposure duration of 7 hours to 10

minutes.

The AEGL–3 values were based upon

a NOEL for lethality in mice, rats, and

rabbits of 200 ppm for 1 hour (Union

Carbide, 1951). An UF of 3 was applied

for species to species extrapolation

because there did not appear to be much

variation across species for lethality. A

NOEL for lethality was the same for 3

different species (mice, rats, and

rabbits), and this endpoint was used for

the AEGL–3 derivation. Additionally,

the use of a NOEL for lethality is

inherently conservative. An UF of 3 was

also applied for intraspecies

extrapolation. As discussed in the

AEGL–2 derivation unit, applying the

traditional UF of 10 to account for the

lack of data addressing interindividual

variability would result in a composite

UF of 30, which would drive the AEGL–

3 values to a level that would be

inconsistent with available data (1 hour

AEGL–3 of 6.7 ppm; see AEGL–2

derivation in this unit). Therefore, a

total UF of 10 was applied to the AEGL–

3 value.

The experimentally derived exposure

value was then scaled to AEGL time

frames using the concentration-time

relationship given by the equation

Cn × t = k, where the exponent n

generally ranges from 1 to 3.5 (ten

Berge, 1986). Again, the value of n was

not empirically derived due to the

unreliability and inconsistencies of the

data; therefore a default value of n

should be used in the temporal scaling

of AEGL values across time. If one

applies the default value of n = 1 for

extrapolating from shorter to longer

exposure periods and a value of n = 3

to extrapolate from longer to shorter

exposure periods, one obtains the

following values: 10 minutes: 36 ppm;

30 minute: 25 ppm; 1 hour: 20 ppm; 4

hours: 5.0 ppm; 8 hours: 2.5 ppm. Going

with a default value results in AEGL

values that are inconsistent with the

available data. The AEGL–2 data do not

support the hypothesis that n = 1 for

extrapolation to 4 or 8 hours: When

using an n = 1 (which assumes a ‘‘worse

case’’ scenario) to extrapolate from 1

hour to 4 or 8 hours, one obtains a 4-

hour AEGL–3 value of 5.0 ppm, which

21950 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

is almost identical to the 4-hour AEGL–

2 value of 4.8 ppm, and an 8-hour

AEGL–3 value of 2.5 ppm, which is

lower than the 8-hour AEGL–2 value of

3.5 ppm. The AEGL–2 values help to

serve as a baseline: They are based on

a multiple exposure scenario in which

rats exposed for 40 ppm for 7 hours/

days exhibited reversible signs of

irritation. It is unreasonable to have

AEGL–3 values below the AEGL–2

values. Therefore, in the absence of any

further data, an n of 2 was selected as

a reasonable compromise between the

possible values for n as reported by ten

Berge (1986): It is between the most

conservative n = 1 (which results in

unreasonable values) and an n = 3, a

least conservative value. AEGL–3 values

are therefore derived using an n = 3 for

extrapolation to 10 and 30 minutes and

an n = 2 for extrapolation to 4 or 8

hours.

The calculated values are listed in

Table 5 below:

TABLE 5.—SUMMARY OF PROPOSED AEGL VALUES FOR ALLYL ALCOHOL [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

1.8

(4.4)

1.8

(4.4)

1.8

(4.4)

1.8

(4.4)

1.8

(4.4)

Mean odor detection threshold (AIHA,

1989)

AEGL–2

(Disabling)

9.6

(23)

9.6

(23)

7.7

(19)

4.8

(12)

3.5

(8.5)

Irritation in rats at 40 ppm for 7 hours

(Dunlap et al., 1958)

AEGL–3

(Lethality)

36

(87)

25

(61)

20

(48)

10

(24)

7.1

(17)

NOEL for lethality in mice, rats, and rabbits exposed to 200 ppm for 1 hour

(Union Carbide, 1951)

ii. References.

a. AIHA. 1989. Odor thresholds for

chemicals with established occupational

health standards. AIHA, Fairfax, VA.

b. Dunlap, M.K., Kodama, J.K.,

Wellington, J.S., Anderson, H.H., and

Hine, C.H. 1958. The toxicity of allyl

alcohol. American Medical Association

Archives of Industrial Health. Vol.

18:303–311.

c. ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. Vol. 13:301–309.

d. Torkelson, T.R., Wolf, M.A., Oyen,

F., and Rowe, V.K. 1959a. Vapor toxicity

of allyl alcohol as determined on

laboratory animals. American Industrial

Hygiene Association Journal. Vol.

20:217–229.

e. Union Carbide and Carbon

Corporation. 1951. Initial submission:

letter from DuPont Chemical to USEPA

regarding a letter about toxicity studies

with allyl alcohol with cover letter

dated October 15, 1992. Doc. #88–

920009857. Union Carbide and Carbon

Corp., New York, NY.

8. Chloromethyl methyl ether—i.

Description. Chloromethyl methyl ether

(CMME) is a man-made chemical that is

highly flammable and a severe

respiratory, eye, nose, and skin irritant.

Technical grade CMME contains 1–8%

bis-chloromethyl ether (BCME) as a

contaminant. Since humans are only

exposed to technical grade CMME (a

great deal of effort is needed to remove

‘‘all’’ BCME from CMME), and the

human and animal inhalation exposure

data all involved technical grade

CMME, the AEGL values derived in this

document will address the toxicity and

carcinogenicity of technical grade

CMME.

Acute exposure to technical grade

CMME can lead to delayed fatal

pulmonary edema in humans and

animals, whereas chronic occupational

exposure is linked with small-cell lung

carcinoma. The carcinoma has a distinct

histology from that of cigarette smokingassociated lung cancer and has a shorter

latency period. BCME is a much more

potent carcinogen than CMME, and is

widely believed to account for most or

all of the carcinogenicity of technical

grade CMME. The EPA places technical

grade CMME (and BCME) in

classification A (‘‘human carcinogen’’)

based on sufficient human

carcinogenicity data. Technical grade

CMME acute inhalation toxicity has

been studied in rats, mice, and

hamsters. Numerous epidemiological

studies describe occupational exposure

to technical grade CMME, although

CMME concentrations were almost

never measured.

No data were available to determine

the concentration-time relationship for

CMME toxic effects. The concentrationtime relationship for many irritant and

systemically acting vapors and gases

may be described by Cn × t = k, where

the exponent n ranges from 0.8 to 3.5

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

protective AEGL–2 and AEGL–3 values

for 30–480 minutes, n = 3 and n = 1

were used to extrapolate to durations

shorter and longer, respectively, than

the exposure duration in the key study

(AEGL–1 values were not derived). The

10-minute values were not extrapolated

because the NAC determined that

extrapolating from ≥4 hours to 10

minutes is associated with unacceptably

large inherent uncertainty, and the 30-

minute values were adopted for 10

minutes to be protective of human

health.

AEGL–1 values were not

recommended because there were no

inhalation studies that had endpoints

consistent with the definition of AEGL–

1.

AEGL–2 values for technical grade

CMME were based on a study in which

rats were exposed 30 times (probably for

6 hours/day, 5 days/week) to 1 ppm

technical grade CMME vapor (Drew et

al., 1975). Two rats died (exposure days

16 and 22) but their cause of death was

not stated. Some of the rats were

allowed to live for their lifetime; they

had minimal mucosal effects and

several had lung hyperplasia or

squamous metaplasia, but no tumors

were reported. The AEGL–2 values were

based on a single 6-hour exposure,

which is expected to cause a similar or

lower incidence of hyperplasia and/or

metaplasia than 30 exposures. An UF of

10 was used: 3 to account for sensitive

humans (response to an irritant gas

hydrolyzed in situ is not likely to vary

greatly among humans) and 3 for

interspecies extrapolation (little

interspecies variability was seen; the

key study was repeat-exposure). A

modifying factor of 3 was applied to

account for potential differences in

BCME content of technical grade

CMME. The resulting AEGL values were

supported by a lifetime CMME rat and

hamster study (Laskin et al., 1975) and

a 6-month BCME rat and mouse study

(Leong et al., 1975, 1981).

CMME AEGL–2 values were also

calculated using a BCME inhalation

cancer slope factor with extrapolation to

c to 8 hours, and based on 10-4, 10-5, and

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21951

10-6 excess cancer risk levels (BCME

was assumed to represent 8% of CMME

and to account for all CMME

carcinogenicity). CMME AEGL–2 values

based on the noncarcinogenicity

endpoints were lower than those

calculated for 10-4 excess cancer risk but

were similar to or greater than those

calculated for 10-5 or 10-6 excess cancer

risk. AEGL–2 values based on the

noncarcinogenic endpoints were

considered to be more appropriate

because only multiple exposures to

CMME were shown to result in tumor

formation, and AEGL values are

applicable to rare events or single, oncein-a-lifetime exposures of small

populations in limited geographic areas.

AEGL–3 values were derived from a

rat inhalation LC50 study where

exposure was for 7 hours (Drew et al.,

1975). The threshold for lethality, as

represented by the LC01 (14.8 ppm)

calculated using probit analysis, was the

AEGL–3 toxicity endpoint. Animals that

died, and to a lesser degree, animals

surviving to 14 days, had increased

relative lung weights, congestion,

edema, hemorrhage, and acute

necrotizing bronchitis. An UF of 10 was

used: 3 for sensitive humans (response

to an irritant gas hydrolyzed in situ is

not likely to vary greatly among

humans) and 3 for interspecies

extrapolation (little interspecies

variability was seen, as expected for an

irritant gas hydrolyzed in situ). An

additional modifying factor of 3 was

applied to account for potential

differences in BCME content of

technical grade CMME. Comparable

AEGL–3 values were obtained with

CMME in a hamster LC50 study and in

a BCME single-exposure rat study (Drew

et al., 1975).

The calculated values are listed in

Table 6 below:

TABLE 6.—SUMMARY OF PROPOSED AEGL VALUES FOR CHLOROMETHYL METHYL ETHER (CMME) [PPM(MG/M3)]

Level 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

Not Recommended (No studies available consistent with AEGL–1 definition)

AEGL–2

(Disabling)

0.076

(0.25)

0.076

(0.25)

0.061

(0.20)

0.038

(0.13)

0.025

(0.082)

Tracheal or bronchial squamous

metaplasia; regenerative lung

hyperplasia (Drew et al., 1975).

AEGL–3

(Lethal)

1.2

(3.9)

1.2

(3.9)

0.94

(3.1)

0.59

(2.0)

0.43

(1.4)

Lethality threshold for rats (Drew et al.,

1975).

ii. References.

a. Drew, R.T., Laskin, S., Kuschner,

M., and Nelson, N. 1975. Inhalation

carcinogenicity of alpha halo ethers. I.

The acute inhalation toxicity of

chloromethyl methyl ether and

bis(chloromethyl)ether. Archives of

Environmental Health. Vol. 30:61–69.

b. Laskin, S., Drew, R.T., and

Cappiello, V., et al., 1975. Inhalation

carcinogenicity of alpha halo ethers. II.

Chronic inhalation studies with

chloromethyl methyl ether. Archives of

Environmental Health. Vol. 30:70–72.

c. Leong, B.K.J., Kociba, R.J., Jersey,

G.C., and Gehring, P.J. 1975. Effects

from repeated inhalation of parts per

billion of bis(chloromethyl)ether in rats.

Toxicology and Applied Pharmacology.

Vol. 33:175.

d. Leong, B.K.J., Kociba, R.J., and

Jersey, G.C. 1981. A lifetime study of

rats and mice exposed to vapors of

bis(chloromethyl)ether. Toxicology and

Applied Pharmacology. Vol. 58:269–

281.

e. 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. Vol. 13:302–309.

9. Toluene—i. Description. Toluene is

a ubiquitous substance that is widely

used as a raw material in the chemical

manufacturing industry, as an additive

in gasoline to increase the octane level,

and as a solvent in lacquers, paint

thinners, glue, and other compounds.

The odor threshold for toluene ranges

from 0.16 to 37 ppm for detection and

1.9 to 69 ppm for recognition; the odor

is not unpleasant. Toluene is readily

absorbed from the respiratory tract and

distributed throughout the body,

accumulating in tissues with high lipid

content. Toluene is a CNS depressant

and, at high concentrations, is irritating

to the eyes. Other toxic effects observed

in humans include renal toxicity,

cardiac arrhythmias, blood dyscrasias,

hepatomegaly, and developmental

abnormalities. A considerable amount of

human and animal data were available

for derivation of AEGLs.

Mouse lethality data were used for the

regression analyses of the concentrationexposure durations. Regression analysis

of the relationship between time and

concentration (Cn × t = k), based on four

studies with the mouse, the most

sensitive species, showed that n = 2.

This relationship was used for all AEGL

levels because the primary mechanism

of action of toluene is CNS depression,

which at high concentrations results in

death.

The AEGL–1 was based on

observations of mild sensory irritation

and headache in humans at a

concentration of 100 ppm for up to 6

hours in an atmosphere controlled

setting (Andersen et al., 1983; Rahill et

al., 1996; Dick et al., 1984; Baelum et

al., 1985; 1990). An UF of 3 was chosen

to protect sensitive individuals because

the mechanism of action for irritation is

not expected to vary greatly among

individuals and no effects on ventilatory

parameters were found at much higher

concentrations. Extrapolation was made

to the relevant AEGL time points using

the relationship Cn × t = k where n = 2,

based on the mouse lethality data. The

endpoint and values are supported by

the multiple studies with human

subjects, some of which reported no

effects at the 100 ppm concentration.

The AEGL–2 was based on more

serious effects in humans at

concentrations of ≥200 ppm for 8 hours

including incoordination, dizziness,

decreased reaction time, mental

confusion, muscular weakness, and

nausea (Wilson, 1943; von Oettingen et

al., 1942). These effects were considered

to represent the threshold for impaired

ability to escape. An UF of 3 was

applied to account for sensitive

individuals because the threshold for

CNS impairment does not vary greatly

among individuals. Extrapolation was

made to the 10-minute, 30-minute, 1-

hour and 4-hour time points using the

equation Cn × t = k where n = 2 (based

on mouse lethality data). The above

values are supported by the behavioral

effects observed in monkeys after a 50-

minute exposure to 2,000 ppm toluene

(Taylor and Evans, 1985). At this

concentration-duration, these animals

exhibited significantly decreased

21952 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

reaction time and decreased accuracy on

matching to sample tasks. Dividing the

2,000 ppm concentration by intra- and

interspecies UF of 3 each (for a total of

10) results in values similar to those

based on the human data.

The AEGL–3 values were derived

from the exposure concentrations equal

to one third of the mouse 1-hour LC50

reported by Moser and Balster (1985).

The 1-hour mouse LC50 of 19,018 ppm

was divided by 3 to estimate the

threshold for lethality. A total UF of 10

was applied which includes 3 to

account for sensitive individuals and 3

for interspecies extrapolation (the

mechanism of action for severe CNS

depression does not vary greatly among

individuals or among species). The

estimated 1-hour threshold for lethality

of 6,339 ppm was extrapolated to the

10-minute, 30-minute, 4-hour, and 8-

hour AEGL–3 time points using the

relationship Cn × t = k where n = 2

(calculated from the mouse lethality

data). These values are supported by the

accidental exposure of two men to an

estimated concentration of >1,842 ppm

toluene for an average duration of 2.5

hours which resulted in severe but

reversible CNS depression (Meulenbelt

et al., 1990). Scaling of this exposure to

the 10-minute, 30-minute, 1-, 4-, and 8-

hour time points yields slightly higher

values (2,400; 1,400; 970; 490; and 340

ppm, respectively) than those based on

the threshold for lethality in the mouse.

The proposed values are considered

adequately protective since the mouse is

more sensitive than humans to the CNS

effects of toluene.

The calculated values are listed in

Table 7 below:

TABLE 7.—SUMMARY OF PROPOSED AEGL VALUES FOR TOLUENE [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

260

(980)

120

(450)

82

(300)

41

(150)

29

(112)

Eye irritation, headache in humans (Andersen et al., 1983)

AEGL–2

(Disabling)

600

(2,260)

270

(1,020)

190

(710)

94

(340)

67

(260)

Incoordination, mental confusion, neurobehavioral deficits in humans (Wilson,

1943; von Oettingen et al., 1942)

AEGL–3

(Lethal)

1,600

(6,000)

900

(3,380)

630

(2,360)

320

(1,200)

220

(830)

Lethality, 1⁄3 of the mouse 1-hour LC50

(Moser and Balster, 1985)

ii. References.

a. Andersen, I., Lundqvist, G.R.,

Molhave, L., Pedersen, O.F., Proctor,

D.F., Vaeth, M., and Wyon, D.P. 1983.

Human response to controlled levels of

toluene in six-hour exposures.

Scandinavian Journal of Work and

Environmental Health. Vol. 9:405–418.

b. Wilson, R.H. 1943. Toluene

poisoning. Journal of American Medical

Association. Vol. 123:1106–1108.

c. von Oettingen, W.F., Neal, P.A.,

and Donahue, D.D., et al. 1942. The

toxicity and potential dangers of toluene

with special reference to its maximal

permissible concentration. U.S. Public

Health Service Publication Health

Bulletin No. 279:50.

d. Moser, V.C. and Balster, R.L. 1985.

Acute motor and lethal effects of

inhaled toluene, 1,1,1-trichloroethane,

halothane, and ethanol in mice: Effects

of exposure duration. Toxicology and

Applied Pharmacology. Vol. 77:285–

291.

10. Phenol—i. Description. Phenol is

a colorless to pink, hygroscopic solid

with a characteristic, sweet, tarry odor.

Pure phenol consists of white to clear

acicular crystals. In the molten state, it

is a clear, colorless liquid with a low

viscosity.

Cases of lethal poisoning of humans

by phenol have been reported in the

literature after oral uptake or skin

contact. Only few studies reporting

effects on humans after inhalation of

phenol are available: One study

reported slight effects on liver and blood

parameters (increased serum

transaminase activity, increased

hemoglobin concentration, increased

numbers of white blood cells) after

repeated occupational exposure to a

mean time-weighted average

concentration of 5.4 ppm phenol

(Shamy et al., 1994). Piotrowski (1971)

did not report on effects in a

toxicokinetic study, in which subjects

were exposed to 6.5 ppm for 8 hours.

Likewise, Ogata et al. (1974) in a

toxicokinetic field study did not

mention any effects on workers exposed

to mean workshift concentrations of

4.95 ppm. In persons exposed to >1 mg/

l phenol in contaminated drinking water

for several weeks following an

accidental spill of phenol,

gastrointestinal symptoms (diarrhea,

nausea, burning pain and sores in the

mouth) and skin rashes occurred (Baker

et al., 1978). A geometric mean odor

detection threshold of 0.060 ppm (range

of all critiqued odor thresholds 0.0045–

1 ppm) has been reported (AIHA, 1989).

No studies reporting LC50 values for

phenol in animals are available. Oral

LD50 values were reported as 420 mg/kg

for rabbits, 400–650 mg/kg for rats and

282–427 mg/kg for mice. In rats,

exposure to a phenol aerosol

concentration of 900 mg/m3 resulted in

ocular and nasal irritation and slight

incoordination after 4 hours and tremors

and prostration in 1 of 6 animals after

8 hours (Flickinger, 1976). After 4 hours

exposure to 211 and 156 ppm, a

decrease of the number of white blood

cells, but no signs of toxicity were

reported (Brondeau et al., 1990). After

exposure of rats to 0.5, 5, and 25 ppm

for 6 hours/day, 5 days/week for 2

weeks no clinical, hematological or

histopathological effects were found

(CMA, 1998; Hoffmann et al., 1999).

Continuous exposure to 5 ppm phenol

for 90 days caused no hematological or

histological effects in rhesus monkeys,

rats and mice. A concentration of 166

ppm (for 5 minutes) resulted in a 50%

decrease of respiration (RD50) in mice.

No teratogenic effects were found in rats

and mice. An oral carcinogenicity study

in rats and mice, using exposure

through drinking water, found an

increased tumor incidence in male rats

of the low exposure group, but not in

male rats of the high exposure group or

in female rats and mice. Phenol has

tumor promoting activity when applied

dermally and can cause clastogenic and

possibly very weak mutagenic effects.

The AEGL–1 was based on a repeated

inhalation exposure study in rats (CMA,

1998; Hoffmann et al., 1999), which

found no clinical, hematological or

histopathological effects after exposure

to 25 ppm phenol (highest

concentration used) for 6 hours/day, 5

days/week for 2 weeks. A total UF of 10

was used. An UF of 3 was applied for

interspecies variability because a

multiple exposure study was used for

the derivation of AEGL. A factor of 3

was applied for intraspecies variability

because the study reported no effects

and thus was below the AEGL–1 effect

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21953

level and because available human data

do not point at a large interindividual

variability. The other exposure

duration-specific values were derived

by time scaling according to the doseresponse regression equation Cn × t = k,

using the default of n = 3 for shorter

exposure periods and n = 1 for longer

exposure periods, due to the lack of

suitable experimental data for deriving

the concentration exponent.

Continuation of the time scaling to the

10-minute period is supported by the

reported RD50 value of 166 ppm for an

exposure period of 5 minutes in mice

(De Ceaurriz et al., 1981): The resulting

10-minute AEGL–1 is 20-fold below the

RD50 value in mice.

The AEGL–2 was based on a repeated

inhalation exposure study in rats (CMA,

1998; Hoffmann et al., 1999), which

found no clinical, hematological or

histopathological effects after exposure

to 25 ppm phenol (highest

concentration used) for 6 hours/day, 5

days/week for 2 weeks, and on a single

exposure study in rats, in which

exposure to 900 mg/m3 phenol aerosol

(equivalent to 234 ppm) led to ocular

and nasal irritation, muscle spasms and

slight loss of coordination within 4

hours of exposure and to tremors and

prostration in 1 of 6 animals at the end

of the 8-hour exposure period

(Flickinger, 1976). A total UF of 3 was

used for the study of CMA (1998),

because the exposure concentration

used was a no-observed-adverse-effect

level (NOAEL) in a repeated exposure

study and because use of a higher UF

would resulted in the same

concentrations set as AEGL–1. This

factor was formally split up into an

interspecies factor of 1 and an

intraspecies factor of 3. A total UF of 30

was used for the Flickinger (1976)

study. This factor was formally split up

into an interspecies factor of 3 and an

intraspecies factor of 10. The other

exposure duration-specific values were

derived by time scaling according to the

dose-response regression equation Cn ×

t = k, using the default of n = 3 for

shorter exposure periods, due to the

lack of suitable experimental data for

deriving the concentration exponent.

For the 10-minute AEGL–2 the 30-

minute value was applied because the

derivation of AEGL values was based on

a long experimental exposure period

and no supporting studies using short

exposure periods were available for

characterizing the concentration-timeresponse relationship. Calculations were

done on the basis of both studies and

resulted in very similar concentrations.

Since slightly lower values were

obtained on basis of the CMA (1998)

study, these values were set as AEGL–

2 values.

The AEGL–3 was based on an

inhalation study in rats, in which

exposure to a phenol aerosol

concentration of 900 mg/m3 phenol

(equivalent to 234 ppm phenol vapor)

for 8 hours resulted in tremors,

incoordination and prostration in 1 of 6

animals, but not in death (Flickinger,

1976). This study is supported by the

study of Brondeau et al. (1990), which

did report only slight effects after

exposure of rats to 211 ppm phenol

vapor for 4 hours. The comparison of

the dose equivalent to the derived

AEGL–3 values with human oral

lethality data supports use of a total UF

of 10. An additional argument for not

choosing a total UF higher than 10 is

that a factor of 30 would have resulted

in corresponding body doses in the dose

range described by Baker et al. (1978)

for an incident of drinking water

contamination. In this study mainly

mild gastrointestinal (local) effects, but

no systemic/severe effects, were

observed upon repeated oral exposure.

The total UF of 10 was formally split up

into an interspecies factor of 3 and an

intraspecies factor of 3. The other

exposure duration-specific values were

derived by time scaling according to the

dose-response regression equation Cn ×

t = k, using the default of n = 3 for

shorter exposure periods, due to the

lack of suitable experimental data for

deriving the concentration exponent.

For the 10-minute AEGL–3 the 30-

minute value was applied because the

derivation of AEGL values was based on

a long experimental exposure period

and no supporting studies using short

exposure periods were available for

characterizing the concentration-timeresponse relationship.

The calculated values are listed in

Table 8 below:

TABLE 8.—SUMMARY TABLE OF PROPOSED AEGL VALUES FOR PHENOL A

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

8.3 ppm

(32 mg/m3)

5.7 ppm

(22 mg/m3)

4.5 ppm

(17 mg/m3)

2.9 ppm

(11 mg/m3)

1.9 ppm

(7.3 mg/m3)

No effects in rats (CMA, 1998; Hoffmann

et al., 1999)

AEGL–2

(Disabling)

19 ppm

(73 mg/m3)

19 ppm

(73 mg/m3)

15 ppm

(58 mg/m3)

9.5 ppm

(36 mg/m3)

6.3 ppm

(24 mg/m3)

No effects in rats (CMA, 1998; Hoffmann

et al., 1999); irritation, loss of coordination, tremors, and prostration in rats

(Flickinger, 1976)

AEGL–3

(Lethal)

59 ppm

(230 mg/m3)

59 ppm

(230 mg/m3)

47 ppm

(180 mg/m3)

29 ppm

(110 mg/m3)

23 ppm

(88 mg/m3)

No lethality in rats (Flickinger, 1976)

a Rapid dermal penetration occurs from phenol vapor, molten phenol and phenol solutions; skin contact with molten phenol or concentrated

phenol solutions should be avoided; fatal intoxications have been observed when a small part of the body surface was involved.

ii. References.

a. Baker, E.L., Landrigan, P.J.,

Bertozzi, P.E., Field, P.H., Basteyns, B.J.,

and Skinner, H.G. 1978. Phenol

poisoning due to contaminated drinking

water. Archives of Environmental

Health. Vol. 33:89–94.

b. Brondeau, M.T., Bonnet, P.,

Guenier, J.P., Simon, P., and De

Ceaurriz, J. 1990. Adrenal-dependent

leucopenia after short-term exposure to

various airborne irritants in rats. Journal

of Applied Toxicology. Vol. 10:83–86.

c. CMA (Chemical Manufacturers

Association). 1998. Two-week (ten day)

inhalation toxicity and two-week

recovery study of phenol vapor in the

rat. Huntingdon Life Scienes Study No.

96–6107, CMA Reference No. PHL-4.0-

Inhal-HLS. CMA, Phenol Panel,

Arlington, VA 22209.

d. De Ceaurriz, J.C., Micillino, J.C.,

Bonnet, P., and Guinier, J.P. 1981.

Sensory irritation caused by various

industrial airborne chemicals.

Toxicology Letters. Vol. 9:137–143.

e. Flickinger, C.W. 1976. The

benzenediols: catechol, resorcinol and

hydroquinone—a review of the

industrial toxicology and current

industrial exposure limits. American

Industrial Hygiene Association Journal.

Vol. 37:596–606.

f. Hoffmann, G.M., Dunn, B.J., Morris,

C.R., Butala, J.H., Dimond, S.S., Gingell,

21954 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

R., and Waechter, Jr., J.M. 1999. Twoweek (ten-day) inhalation toxicity and

two-week recovery study of phenol

vapor in the rat. The Toxicologist. Vol.

48:115 (abstract).

g. Ogata, M., Yamasaki, Y., and

Kawai, T. 1986. Significance of urinary

phenyl sulfate and phenyl glucuronide

as indices of exposure to phenol.

International Archives of Occupational

and Environmental Health. Vol. 58:197–

202.

h. Piotrowski, J.K. 1971. Evaluation of

exposure to phenol: absorption of

phenol vapour in the lungs and through

the skin and excretion of phenol in

urine. British Journal of Industrial

Medicine. Vol. 28:172–178.

i. Shamy, M.Y., el Gazzar, R.M., el

Sa,yed, M.A., and Attia, A.M. 1994.

Study of some biochemical changes

among workers occupationally exposed

to phenol, alone or in combination with

other organic solvents. Industrial

Health. Vol. 32:207–214.

11. Furan—i. Description. Furan is a

colorless, highly flammable liquid with

a strong, ethereal odor. It is used

primarily as an industrial intermediate.

Because of its relatively high vapor

pressure, furan is predicted to exist

almost entirely in the vapor phase in the

atmosphere.

No toxicity data regarding human

exposures to furan were available.

Animal toxicity data were limited, with

much of the literature focused on

metabolism and disposition.

Metabolism studies indicate that furan

is bioactivated to a reactive metabolite,

cis-2-butene-1,4-dial, by cytochrome

P450 2E1. Quantitative toxicology data

for effects following inhalation exposure

to furan were limited to one study.

An AEGL–1 was not derived for furan.

No human or animal data relevant to the

derivation of an AEGL–1 for furan were

available in the searched literature.

The AEGL–2 derivation is based on

the threshold for adverse effects in male

and female rats at a concentration of

1,014 ppm for 1 hour (Terrill et al.,

1989). Although the severity of the

reported clinical signs (respiratory

distress, increased secretory response)

was not reported, this lowest-exposure

concentration group did not exhibit a

decrease in body weights like the rats

exposed to 2,851 ppm or 4,049 ppm.

The AEGL–3 derivation is based upon

the highest NOEL for mortality in male

and female rats of 2,851 ppm for 1 hour

(Terrill et al., 1989). Rats exposed to

1,014; 2,851; or 4,049 ppm exhibited

clinical signs including respiratory

distress and increased secretory

response: however, the degree of the

signs at each concentration was not

provided. Death occurred in the highest

exposure group.

An UF of 10 was applied for species

to species extrapolation because

quantitative toxicology data were

available in only one species, rats.

Despite the predicted lower absorbed

dose and liver dose of the reactive

metabolite in humans compared to

rodents (following a simulated exposure

to 10 ppm for 4 hours, the predicted

absorbed dose of furan (mg/kg) in

humans, and consequently the liver

dose of the reactive metabolite cis-2-

butene-1,4-dial, was 10-fold less than in

mice and 3.5-fold lower than in rats

(Kedderis and Held, 1996), the

differences between humans and

rodents in sensitivity to the reactive

metabolite are not known, and the liver

was the only organ investigated. An UF

of 3 was applied for sensitive

individuals (intraspecies) because

interindividual variations in the

activating enzyme are not predicted to

be a factor in bioactivation (Kedderis

and Held, 1996). A modifying factor of

3 was applied because only one data set

addressing furan toxicity following

inhalation exposure was available: This

study was not repeated, and there was

no information on furan toxicity in

other species or on reproductive/

developmental toxicity. Therefore, a

total uncertainty factor/modifying factor

of 100 was applied to the AEGL–2 and

-3 values.

The experimentally derived exposure

values were scaled to AEGL time frames

using the concentration-time

relationship given by the equation

Cn × t = k, where the exponent n

generally ranges from 1 to 3.5 (ten

Berge, 1986). The value of n was not

empirically derived because of

insufficient data; therefore, the default

value of n = 1 was used for extrapolating

from shorter to longer exposure periods

and a value of n = 3 was used to

extrapolate from longer to shorter

exposure periods.

The calculated values are listed in

Table 9 below:

TABLE 9.—SUMMARY OF PROPOSED AEGL VALUES FOR FURAN [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

Insufficient

Data (ID)a

ID ID ID ID ID were available to derive an AEGL–1

AEGL–2

(Disabling)

18 (50) 13 (39) 10 (28) 2.5 (7.0) 1.3 (3.6) 1,014 ppm for 1 hour: Threshold for adverse effects in rats (clinical signs: Severity of respiratory distress, increased

secretory response not reported; no

decrease in body weights) (Terrill et al.,

1989)

AEGL–3

(Lethality)

52 (140) 46 (100) 29 (81) 7.1 (20) 3.6 (10) 2,851 ppm for 1 hour: Threshold for

lethality in rats (Terrill et al., 1989)

a Absence of an AEGL–1 does not imply that exposure below the AEGL–2 is without adverse effects

ii. References.

a. ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. Vol. 13:301–309.

b. Terrill, J.B., Van Horn, W.E.,

Robinson, D., and Thomas, D.L. 1989.

Acute inhalation toxicity of furan, 2

methylfuran, furfuryl alcohol, and

furfural in the rat. American Industrial

Hygiene Association Journal. Vol.

50:A359–A361.

12. Tetrachloroethylene—i.

Description. Tetrachloroethylene (PCE),

also commonly known as

perchloroethylene or Perc, is a colorless,

nonflammable liquid. It has an ethereal

odor, with a reported odor threshold

ranging from 2–71 ppm. PCE is

commonly used as a dry-cleaning

solvent and as a degreaser, and is also

used as a chemical intermediate and as

a veterinary antithelmintic.

Following exposure to PCE, humans

primarily experience CNS effects and

irritation, with some cases of reversible

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21955

liver effects reported. CNS effects also

predominate in animals, although liver

effects are noted in mice, and

nephrotoxicity is observed in rats.

However, the hepatotoxicity and

nephrotoxicity is commonly associated

with repeated or chronic exposures.

The AEGL–1 derivation is based on

the exposure of six volunteers to 106

ppm for 1 hour (Rowe et al., 1952). At

this level, an apparent nonobjectionable odor and eye irritation

were noted, and one subject

experienced a light fullness in the head

An interspecies UF was not applicable.

An intraspecies UF of 3 is applied

because the Minimum Alveolar

Concentration (MAC; the concentration

that produces lack of movement in 50%

of persons exposed) for volatile

anesthetics does not vary by more than

a factor of 2–3-fold. The AEGL–1 values

are consistent with values that would be

obtained using a study addressing minor

central nervous effects (changes in

visual evoked potentials and visual

contrast sensitivity, significant

performance deficits for vigilance and

eye-hand coordination) following

exposure to 50 ppm for 4 hours

(Altmann et al., 1990; 1992). If one bases

on AEGL–1 on these exposure

parameters and uses the same UFs and

value of n, one obtains almost identical

values.

The AEGL–2 value is based upon the

no-effect level for ataxia in rats

following exposure to 1,150 ppm PCE

for 4 hours/day, 5 days/week for 2

weeks (4 hour time period was used for

the derivation) (Goldberg et al., 1964).

Exposure to the next higher

concentration of 2,450 ppm resulted in

reversible ataxia. An interspecies UF of

3 is applied based on the similarity of

effects manifested in rodents compared

to humans produced by agents that are

CNS depressants. Additionally, a noeffect level for lethality is identical for

rats and mice and the 4-hour and 6-hour

LC50 values in mice compared to rats

vary by less than 1.5-fold. An

intraspecies UF of 3 is applied because

the MAC for volatile anesthetics does

not vary by more than a factor of 2–3-

fold. The AEGL–2 values are supported

by the Carpenter (1937) inhalation study

in which volunteers exposed to 475

ppm for 2 hours, 10 minutes reported

salivation, slight eye irritation, tightness

in the frontal sinuses, increased hand

perspiration, and increased nasal

irritation. These effects are milder than

those defined by AEGL–2. An AEGL

derivation based on the exposure

parameters, a total UF of 3 (3 to account

for intraspecies variability; an

interspecies UF not needed because the

derivation is based on human data), and

an n of 2 results in identical AEGL–2

values.

The AEGL–3 derivation is based on a

no-effect-level for lethality in mice of

2,450 ppm for 4 hours and in rats of

2,445 ppm for 4 hours (Friberg et al.,

1953; NTP, 1986). An interspecies UF of

3 is applied because a no-effect level for

lethality is identical for rats and mice

and the 4-hour and 6-hour LC50 values

in mice compared to rats vary by less

than 1.5-fold. The interspecies UF of 3

is further supported by the similarity of

effects manifested in rodents compared

to humans produced by agents that are

CNS depressants. An intraspecies UF of

3 is applied because the MAC for

volatile anesthetics should not vary by

more than a factor of 2–3-fold. The

AEGL–3 values are supported by a

human study in which the effects noted

were milder than those defined by the

AEGL–3 definition (humans exposed to

934 ppm for 95 min experienced

tightness of the frontal sinuses,

increased hand perspiration, nostril

irritation, congestion of eustachian

tubes, lassitude, slight mental fogginess,

stinging eyes, exhilaration, and/or the

tip of nose and lips anesthetized;

Carpenter, 1937), and an animal study

in which rats exposed to 2,300 ppm for

4 hours/day, 5 days/week for 2 weeks

exhibited overt ataxia only following the

first 4 hour exposure (Goldberg et al.,

1964). Although the Carpenter study

(1937) was not used because the effects

were below that of the definition of

AEGL–3 type endpoints, the study does

support the use of a total UF of 10 for

the Friberg et al. (1953) and NTP (1986)

studies as being protective of human

health.

The experimentally derived exposure

values were then scaled to AEGL time

frames using the equation Cn × t = k,

where the exponent n generally ranges

from 1 to 3.5 (ten Berge, 1986). The

value of n used for PCE was the

calculated and published value of n = 2

based upon the Rowe et al. (1952) rat

mortality data for PCE (ten Berge, 1986).

The 10-minute AEGL–1, -2, and -3

values were set equal to the 30-minute

values. The 10-minute AEGL–1 value

was set equal to the 30-minute value of

50 ppm because human data indicated

that exposure to 75–80 ppm for 1–4

minutes resulted in slight eye irritation

(Stewart et al., 1961). The 10-minute

AEGL–2 value was set equal to the 30-

minute value of 330 ppm because it was

considered too precarious to extrapolate

from the exposure duration of 4 hours

to 10 minutes, and because a human

study demonstrated an exposure to 600

ppm for 10 minutes caused significant

effects (eye and nose irritation,

dizziness, tightness, and numbing about

the mouth, some loss of inhibitions, and

motor coordination required great effort;

Rowe et al., 1952). The 10-minute

AEGL–3 was set equal to the 30-minute

value of 690 ppm because it was

considered too precarious to extrapolate

from the exposure duration of 4 hours

to 10 minutes.

The calculated values are listed in

Table 10 below:

TABLE 10.—SUMMARY OF PROPOSED AEGL VALUES FOR TETRACHLOROETHYLENE [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

50

(340)

50

(340)

35

(240)

18

(120)

12

(81)

Mild eye irritation in six subjects exposed

to 106 ppm for 1 hour (Rowe et al.,

1952)

AEGL–2

(Disabling)

330

(2,200)

330

(2,200)

230

(1,600)

120

(810)

81

(550)

No-effect level for ataxia in rats following

exposure to 1,150 ppm PCE for 4

hours/day, 5 days/week for 2 weeks (4

hour time period used for the derivation) (Goldberg et al., 1964).

AEGL–3

(Lethal)

690

(4,700)

690

(4,700)

490

(3,300)

240

(1,600)

170

(1,200)

No-effect-level for lethality in mice of

2,450 ppm for 4 hours and in rats of

2,445 ppm for 4 hours (Friberg et al.,

1953; NTP, 1986)

21956 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

ii. References.

a. Altmann, L., Bottger, A., and

Wiegand, H. 1990. Neurophysiological

and psychophysical measurements

reveal effects of acute low-level organic

solvent exposure in humans. Archives

of Occupational and Environmental

Health. Vol. 62:493–499.

b. Altmann, L., Wiegand, H., Bottger,

A., Elstermeier, F., and Winneke, G.

1992. Neurobehavioral and

neurophysiological outcomes of acute

repeated perchloroethylene exposure.

Applied Psychology: International

Review. Vol. 41:269–279

c. Carpenter, C.P. 1937. The chronic

toxicity of tetrachloroethylene. Journal

of Industrial Hygiene and Toxicology.

Vol. 19:323–336.

d. Friberg, L., Kylin, B., and Nystrom,

A. 1953. Toxicities of trichloroethylene

and tetrachloroethylene and Fujiwara’s

pyrindine-alkali reaction. Acta

Pharmacologica et Toxicologica. Vol.

9:303–312.

e. Goldberg, M.E., Johnson, H.E.,

Pozzani, U.C., and Smyth, H.F. 1964.

Effect of repeated inhalation of vapors of

industrial solvents on animal behavior.

I. Evaluation of nine solvent vapors on

pole-climb performance in rats.

American Journal of Industrial Hygiene.

Vol. 25:369–375.

f. NTP (National Toxicology Program).

1986. Toxicology and Carcinogenesis

Studies of Tetrachloroethylene

(Perchloroethylene) (CAS No. 127–18–4)

in F344/N Rats and B6C3F1 Mice

(Inhalation Studies). NTP TR 311, NIH

Publication No. 86–2567, U.S.

Department of Health and Human

Services, Research Triangle Park, NC.

g. Rowe, V.K., McCollister, D.D.,

Spencer, H.C., Adams, E.M., and Irish,

D.D. 1952. Vapor toxicity of

tetrachloroethylene for laboratory

animals and human subjects. American

Medical Association Archives of

Industrial Hygiene and Occupational

Medicine. Vol. 5:566–579.

h. Stewart, R.D., Gay, H.H., Erley,

D.S., Hake, C.L., and Schaffer, A.W.

1961. Human exposure to

tetrachloroethylene vapor. Archives of

Environmental Health. Vol. 2:40–46.

i. ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. Vol. 13:301–309.

13. Tetranitromethane—i.

Description. Tetranitromethane (TNM)

is a highly explosive chemical that is

used as an oxidizer in rocket

propellants, to increase the cetane of

diesel fuels, and as a reagent to detect

double bonds in organic molecules

(Budavari et al., 1996; ACGIH, 1996).

TNM is also formed as an impurity

during the manufacture of

trinitrotoluene (TNT). In humans,

impure TNM has caused irritation of the

eyes, nose, throat, dizziness, chest pain,

dyspnea, methemoglobinemia, and

cyanosis (Budavari et al., 1996). TNM

causes a variety of lung lesions and

induced lung tumors in both rats and

mice (NTP, 1990).

No data were available to determine

the concentration-time relationship for

TNM concentration-time relationship

for many irritant and systemically acting

vapors and gases may be described by

Cn × t = k, where the exponent n ranges

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

To obtain protective AEGL values,

scaling across time was performed using

n = 3 to extrapolate to <6 hours

(exposure duration in key study) and n

= 1 to extrapolate to >6 hours. The 10-

minute values were not extrapolated

from 6 hours because the NAC

determined that extrapolating from ≥4

hours to 10 minutes is associated with

unacceptably large inherent uncertainty,

and the 30-minute values were adopted

for 10 minutes to be protective of

human health.

AEGL–1, AEGL–2, and AEGL–3

values were derived from an NTP (1990)

study in which rats and mice were

exposed to 2, 5, 10, 25, or 50 (mice only)

ppm TNM for 2 weeks (6 hours/day, 5

days/week). At 2 ppm, no effects were

specifically noted in either species. A

single 6-hour exposure to 2 ppm was

used for AEGL–1 derivation. An UF of

10 was applied: 3 to account for

sensitive humans (response to an

irritant gas is not likely to vary greatly

among humans) and 3 for interspecies

extrapolation (toxicity of TNM did not

vary greatly between two species; the

key study was repeat-exposure).

Exposure to 5 ppm TNM resulted in

lowered body weight gains and

reddened lungs in mice (rats may have

been lethargic), and one 6-hour

exposure is the basis for the derived

AEGL–2 values. An UF of 10 was used:

3 to account for sensitive humans

(response to an irritant gas is not likely

to vary greatly among humans) and 3 for

interspecies extrapolation (most

sensitive species was used; the key

study was repeat-exposure). The

resulting AEGL–2 values were similar to

those derived using a TNM inhalation

cancer slope factor (derived from a 103-

week NTP, 1990 carcinogenicity study)

and based on a 10-4 excess cancer risk

level. Use of the noncarcinogenicity

endpoints was considered to be more

appropriate because it appears that the

tumorigenic response to inhaled TNM is

a function of prolonged nasal and lung

tissue irritation resulting from repeated

exposures and not the result of a singlelow exposure.

Rats and mice exposed to 10 ppm in

the NTP (1990) 2-week study were

lethargic, lost weight, and the mice had

reddened lungs, polypnea, and ataxia,

whereas rats exposed to 25 ppm all died

on the first day, and most mice exposed

to 25 ppm died on day 3 or 4. Therefore,

10 ppm is considered to approximate

the lethality threshold for both species,

and is supported by an LC50 study in

which the NOEL for lethality for a 4-

hour exposure was 10 and 17 ppm for

rats and mice, respectively (Kinkead et

al., 1977a; 1977b). AEGL–3 values were

developed using one 6-hour exposure

and an UF of 10: 3 to account for

sensitive humans (response to an

irritant gas is not likely to vary greatly

among humans) and 3 for interspecies

extrapolation (toxicity of TNM did not

vary greatly between two species; the

key study was repeat-exposure).

The calculated values are listed in

Table 11 below:

TABLE 11.—SUMMARY OF PROPOSED AEGL VALUES FOR TETRANITROMETHANE (TNM) [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

0.46

(3.7)

0.46

(3.7)

0.36

(2.9)

0.23

(1.8)

0.15

(1.2)

No effects in rats or mice (NTP, 1990).

AEGL–2

(Disabling)

1.1

(9.1)

1.1

(9.1)

0.91

(7.3)

0.57

(4.6)

0.38

(3.5)

Lower weight gain and reddened lungs in

mice (NTP, 1990).

AEGL–3

(Lethal)

2.3

(28)

2.3

(28)

1.8

(15)

1.1

(9.2)

0.75

(6.0)

Lethality threshold for rats and mice

(NTP, 1990).

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21957

ii. References.

a. NTP. 1990. Toxicology and

carcinogenesis studies of

tetranitromethane in F344/N rats and

B6C3F1 mice. TR #386, U.S. Department

of Health and Human Services, Public

Health Service, National Institutes of

Health, Research Triangle Park, NC.

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. Vol. 13:302–309.

14. Perchloromethyl mercaptan—i.

Description. Perchloromethyl mercaptan

is an oily, yellow liquid with an

unbearable, acrid odor. Although it was

used as a chemical warfare gas by the

French in the battle of the Champagne

in 1915, its wartime use was abandoned

shortly thereafter because of its strong

warning odor, decomposition in the

presence of iron and steel, and because

the vapors could easily be removed by

charcoal (Prentiss, 1937). Today,

perchloromethyl mercaptan is used as

an intermediate in the synthesis of dyes

and fungicides (Captan, Folpet).

Data addressing human and animal

toxicity following exposure to

perchloromethyl mercaptan vapors were

very limited. Human data were

generally limited to case reports

describing exposures to an

unquantifiable amount of

perchloromethyl mercaptan, secondary

sources, and/or sources in which the

experimental details were not provided.

Animal data addressing the lethal and

nonlethal effects of perchloromethyl

mercaptan were primarily limited to

rats.

Exposure to perchloromethyl

mercaptan for 6 hours/day, 5 days/week

for 2 weeks at a concentration of 0.02

ppm did not result in any measurable

changes in rats, while exposure to 0.13

ppm resulted only in mild nasal

epithelial changes in rats (Knapp et al.,

1987). Likewise, no clear treatment

related changes were observed in rats

exposed to 0.014 or 0.079 ppm

perchloromethyl mercaptan for 6 hours/

day, 5 days/week, for a total of 70 to 72

exposure days (Knapp and Thomassen,

1987). Based on these data, a NOAEL of

0.079 ppm in rats exposed for 6 hours/

day, 5 days/week, for a total of 70 to 72

exposure days was used for the

derivation of an AEGL–1 (Knapp and

Thomassen, 1987). An interspecies

factor of 3 was applied because although

little is known about differences in

perchloromethyl mercaptan toxicity

between species, the AEGL–1 is based

on a NOAEL from a subchronic study

and is therefore inherently conservative.

An intraspecies UF of 3 was applied to

protect for sensitive individuals because

the mechanism of action of

perchloromethyl mercaptan is likely to

be that of an irritant.

A subchronic study in which rats

were exposed to 0.58 ppm for 6 hours/

day, 5 days/week for 70 days was

chosen for the AEGL–2 derivation

(Knapp and Thomassen, 1987). Rats

exposed to 0.58 ppm for 70 days

exhibited only minimal effects: Lung

weights were increased, and the only

treatment-related pulmonary lesion was

mild to minimal focal subacute

interstitial pneumonia in 28% of males

and 6% of females. An interspecies

factor of 10 was applied because little is

known about differences in

perchloromethyl mercaptan toxicity

between species. An intraspecies UF of

3 was applied to protect for sensitive

individuals because the mechanism of

action of perchloromethyl mercaptan is

likely to be that of an irritant.

The no-effect level for lethality of 9

ppm for 1 hour in male and female rats

was chosen for use in the AEGL–3

derivation (Stauffer Chemical Company,

1971). An interspecies factor of 10 was

applied because little is known about

differences in perchloromethyl

mercaptan toxicity between species. An

intraspecies UF of 3 was applied to

protect for sensitive individuals because

the mechanism of action of

perchloromethyl mercaptan is likely to

be that of an irritant.

The experimentally derived exposure

values were scaled to AEGL time frames

using the concentration-time

relationship given by the equation Cn ×

t = k, where the exponent n generally

ranges from 1 to 3.5 (ten Berge, 1986).

The value of n was not empirically

derived because of insufficient data;

therefore, the default value of n = 1 was

used for extrapolating from shorter to

longer exposure periods and a value of

n = 3 was used to extrapolate from

longer to shorter exposure periods. The

10-minute values for the AEGL–1 and

AEGL–2 levels were flat-lined from the

30-minute values because it was

considered too precarious to extrapolate

from an exposure duration of 6 hours to

an exposure duration of 10 minutes.

The calculated values are listed in

Table 12 below:

TABLE 12.—SUMMARY OF PROPOSED AEGL VALUES FOR PERCHLOROMETHYL MERCAPTAN [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

0.018

(0.14)

0.018

(0.14)

0.014

(0.11)

0.0090

(0.068)

0.0060

(0.046)

NOAEL of 0.079 ppm for 6 hours/day, 5

days/week for 70–72 exposure days

(Knapp and Thomassen, 1987)

AEGL–2

(Disabling)

0.044

(0.33)

0.044

(0.33)

0.035

(0.27)

0.022

(0.17)

0.015

(0.11)

Treatment-related mild to minimal focal

subacute interstitial pneumonia and

slightly increased lung weights in rats

exposed to 0.58 ppm for 6 hours/day, 5

days/week for 70 days (Knapp and

Thomassen, 1987)

AEGL–3

(Lethality)

0.54

(4.1)

0.38

(2.9)

0.30

(2.3)

0.075

(0.57)

0.038

(0.29)

No-effect level for lethality in rats (9 ppm

for 1 hour) (Stauffer Chemical Co.,

1971)

ii. References.

a. Knapp, H.F. and Thomassen, R.W.

1987. Subchronic inhalation study with

perchloromethyl mercaptan (PMM) in

rats. Stauffer Chemical Company.

Report No. T-11848. Submitted by

Zeneca, Inc., EPA/OTS; Doc. #86–

960000548. pp. 436.

b. Stauffer Chemical Co. 1971. Initial

submission: acute inhalation test with

perchloromethyl mercaptan in rats with

cover letter dated August 28, 1992.

Report No. T-1683. Submitted by ICI

Americas Inc., EPA/OTS, Doc #88–

920006928. pp. 7.

c. ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

21958 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

acting vapours and gases. Journal of

Hazardous Materials. Vol. 13:301–309.

15. Carbon monoxide—i. Description.

Carbon monoxide (CO) is a tasteless,

non-irritating, odorless and colorless

gaseous substance. The main source of

CO production is the combustion of

fuels. Environmental exposure to CO

can occur while traveling in motor

vehicles (9–25 and up to 35 ppm),

working, visiting urban locations with

heavily traveled roads (up to 50 ppm),

or cooking and heating with domestic

gas, kerosene, coal or wood (up to 30

ppm) as well as in fires and by

environmental tobacco smoke.

Endogenous CO formation during

normal metabolism leads to a

background carboxyhemoglobin

concentration ([COHb]) of about 0.5–

0.8%. Smokers are exposed to

considerable CO concentrations leading

to a [COHb] of about 3–8%.

CO binds to hemoglobin forming

[COHb] and thereby renders the

hemoglobin molecule less able to bind

oxygen. Due to this mechanism, the

oxygen transport by the blood and the

release of bound oxygen in the tissues

are decreased. Tissue damage results

from local hypoxia. Organs with a high

oxygen requirement, such as the heart

and the brain, are especially sensitive

for this effect.

CO is a tasteless, non-irritating,

odorless and colorless toxic gas which

can cause lethal poisonings with very

few and late occurring warning signs.

Until very severe symptoms occur none

or only nonspecific symptoms are

noted. For this reason, AEGL–1 values

were not recommended.

The AEGL–2 was based on

cardiovascular effects in patients with

coronary artery disease, which

constitute the most susceptible

subpopulation. For the derivation of

AEGL–2 values a level of 4% [COHb]

was chosen. At this exposure level,

patients with coronary artery disease

may experience a reduced time until

onset of angina (chest pain) during

physical exertion (Allred et al., 1989;

1991). In the available studies, the CO

exposure alone (i.e., with subjects at

rest) did not cause angina, while

exercise alone did so. However, it

should be noted that all studies used

patients with stable exertional angina,

who did not experience angina while at

rest. Thus, it cannot be ruled out that in

more susceptible individuals (a part of

the patients with unstable angina

pectoris might belong to this group) CO

exposure alone could increase angina

symptoms. The changes in the

electrocardiogram (ST-segment

depression of 1 mm or greater)

associated with angina symptoms were

fully reversible. An exposure level of

4% [COHb] is unlikely to cause a

significant increase in the frequency of

exercise-induced arrhythmias.

Ventricular arrhythmias have been

observed at [COHb] of 5.3%, but not at

3.7% (Sheps et al., 1990; 1991), while in

another study no effect of CO exposure

on ventricular arrhythmia was found at

3 and 5% [COHb] (Dahms et al., 1993).

An exposure level of 4% [COHb] was

considered protective of acute

neurotoxic effects in children, such as

syncopes, headache, nausea, dizziness,

and dyspnea (Crocker and Walker,

1985), and long-lasting neurotoxic

effects (defects in the cognitive

development and behavioral alterations)

in children (Klees et al., 1985). A

mathematical model (Coburn et al.,

1965; Peterson and Stewart, 1975) was

used to calculate exposure

concentrations in air resulting in a

[COHb] of 4% at the end of exposure

periods of 10 and 30 minutes and 1, 4,

and 8 hours. A total UF of 1 was used.

An intraspecies UF of 1 was considered

adequate because the values are based

on observations in the most susceptible

human subpopulation (patients with

coronary artery disease).

The AEGL–3 was based on

observations in humans. Several case

reports indicate that in patients with

coronary artery disease, CO exposure

can contribute to myocardial infarction

(which was considered an AEGL–3

endpoint). In the published cases of

myocardial infarction, the following

[COHb] were measured after transport to

the hospital: 52.2% (Marius-Nunez,

1990), 30%, 22.8% (Atkins and Baker,

1985), 21% (Ebisuno et al., 1986),

15.6% (Grace and Platt, 1981). Case

reports on stillbirths after CO poisoning

of pregnant women reported measured

maternal [COHb] of about 22–25% or

higher (Caravati et al., 1988; Koren et

al., 1991). Since in all case studies

COHb levels were determined after

admission to hospital, the [COHb] at the

end of the exposure were probably

higher than the measured

concentrations. These anecdotal case

reports were not considered an adequate

basis for the derivation of AEGL–3

values because of uncertainties in the

end-of-exposure [COHb] and the

insufficient characterization of the

exposure conditions (with repeated and/

or prolonged exposures in several

cases). Therefore, the experimental

studies of Chiodi et al. (1941) and

Haldane (1895), that reported no severe

or life-threatening symptoms in healthy

subjects exposed to a [COHb] of about

40–56%, were used as the basis for

derivation of AEGL–3 values. A

mathematical model (Coburn et al.,

1965; Peterson and Stewart, 1975) was

used to calculate exposure

concentrations in air resulting in a

[COHb] of 40% at the end of exposure

periods of 10 and 30 minutes and 1, 4,

and 8 hours. A total UF of 3 was used.

An intraspecies UF of 3 was applied to

the calculated CO concentrations in air

because a factor of 10 would have

resulted in exposure concentrations

sometimes found in homes and the

environment and because the derived

values (corresponding to a [COHb] of

about 15%) are supported by

information on effects, such as

myocardial infarction and stillbirths,

reported in more susceptible

subpopulations.

The calculated values are listed in

Table 13 below:

TABLE 13.—SUMMARY TABLE OF PROPOSED AEGL VALUES FOR CARBON MONOXIDE

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

NRa NR NR NR NR

AEGL–2

(Disabling)

420 ppm

(480 mg/m3)

150 ppm

(170 mg/m3)

83 ppm

(95 mg/m3)

33 ppm

(38 mg/m3)

27 ppm

(31 mg/m3)

Cardiac effects in humans with coronary

artery disease (Allred et al., 1989;

1991)

AEGL–3

(Lethal)

1700 ppm

(1,900 mg/m3)

600 ppm

(690 mg/m3)

330 ppm

(380 mg/m3)

150 ppm

(170 mg/m3)

130 ppm

(150 mg/m3)

No severe or life-threatening effects in

humans (Chiodi et al., 1941; Haldane,

1895)

a Not recommended since CO is a non-irritating orderless gas which can cause lethal poisonings with very few late occurring warning signs.

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21959

ii. References.

a. Allred, E.N., Bleecker, E.R.,

Chaitman, B.R., Dahms, T.E., Gottlieb,

S.O., Hackney, J.D., Pagano, M.,

Selvester, R.H., Walden, S.M., and

Warren, J. 1989. Short-term effects of

carbon monoxide exposure on the

exercise performance of subjects with

coronary artery disease. New England

Journal of Medicine. Vol. 321:1426–

1432.

b. Allred, E.N., Bleecker, E.R.,

Chaitman, B.R., Dahms, T.E., Gottlieb,

S.O., Hackney, J.D., Pagano, M.,

Selvester, R.H., Walden, S.M., and

Warren, J. 1991. Effects of carbon

monoxide on myocardial ischemia.

Environmental Health Perspectives. Vol.

91:89–132.

c. Atkins, E.H. and Baker, E.L. 1985.

Exacerbation of coronary artery disease

by occupational carbon monoxide

exposure: A report of two fatalities and

a review of the literature. American

Journal of Industrial Medicine. Vol.

7:73–79.

d. Caravati, E.M., Adams, C.J., Joyce,

S.M., and Schafer, N.C. 1988. Fetal

toxicity associated with maternal carbon

monoxide poisoning. Annals of

Emergency Medicine. Vol. 17:714–717.

e. Chiodi, H., Dill, D.B., Consolazio,

F., and Horvath, S.M. 1941. Respiratory

and circulatory responses to acute

carbon monoxide poisoning. American

Journal of Physiology. Vol. 134:683–693.

f. Coburn, R.F., Forster, R.E., and

Kane, P.B. 1965. Considerations of the

physiological variables that determine

the blood carboxyhemoglobin

concentration in man. Journal of

Clinical Investigation. Vol. 44:1899–

1910.

g. Crocker, P.J. and Walker, J.S. 1985.

Pediatric carbon monoxide toxicity. The

Journal of Emergency Medicine. Vol.

3:443–448.

h. Dahms, T.E., Younis, L.T., Wiens,

R.D., Zarnegar, S., Byers, S.L., and

Chaitman, B.R. 1993. Effects of carbon

monoxide exposure in patients with

documented cardiac arrhythmias.

Journal of the American College of

Cardiology. Vol. 21:442–450.

i. Ebisuno, S., Yasuno, M., Yamada,

Y., Nishino, Y., Hori, M., Inoue, M., and

Kamada, T. 1972. Myocardial infarction

after acute carbon monoxide poisoning:

case report. Angiology. Vol. 37:621–624.

j. Grace, T.W. and Platt, F.W. 1981.

Subacute carbon monoxide poisoning.

Journal of the American Medical

Association. Vol. 246:1698–1700.

k. Haldane, J. 1895. The action of

carbonic acid on man. Journal of

Physiology. Vol. 18:430–462.

l. Klees, M., Heremans, M., and

Dougan, S. 1985. Psychological sequelae

to carbon monoxide intoxication in the

child. The Science of the Total

Environment. Vol. 44:165–176.

m. Koren, G., Sharav, R., Pastuszak,

A., Garrettson, L.K., Hill, K., Samson, I.,

Rorem, M., King, A., and Dolgin, J.E.

1991. A multicenter, prospective study

of fetal outcome following accidental

carbon monoxide poisoning in

pregnancy. Reproductive Toxicology.

Vol. 5:397–403.

n. Marius-Nunez, A.L. 1990.

Myocardial infarction with normal

coronary arteries after acute exposure to

carbon monoxide. Chest. Vol. 97:491–

494.

o. Peterson, J.E. and Stewart, R.D.

1975. Predicting the carboxyhemoglobin

levels resulting from carbon monoxide

exposures. Journal of Applied

Physiology. Vol. 39:633–638.

p. Sheps, D.S., Herbst, M.C.,

Hinderliter, A.L., Adams, K.F., Ekelund,

L.G., O’Neill, J.J., Goldstein, G.M.,

Bromberg, P.A., Dalton, J.L., Ballenger,

M.N., Davis, S.M., and Koch, G.G. 1990.

Production of arrhythmias by elevated

carboxyhemoglobin in patients with

coronary artery disease. Annals of

Internal Medicine. Vol. 113:343–351.

q. Sheps, D.S., Herbst, M.C.,

Hinderliter, A.L., Adams, K.F., Ekelund,

L.G., O’Neill, J.J., Goldstein, G.M.,

Bromberg, P.A., Ballenger, M., Davis,

S.M., and Koch, G. 1991. Effects of 4

Percent and 6 Percent

Carboxyhemoglobin on Arrhythmia

Production in Patients with Coronary

Artery Disease. Research Report No. 41.

Health Effects Institute, Cambridge, MA.

16. Boron trichloride—i. Description.

Boron trichloride is a colorless gas at

room temperature that fumes in moist

air, or a colorless fuming liquid at low

temperatures. It hydrolyzes in water and

moist air to produce heat, hydrochloric

acid, and boric acid at ordinary

temperatures. No data were available

regarding human exposures to boron

trichloride, and animal inhalation

toxicity data were limited to two

studies. Vernot et al. (1977) reported 1-

hour LC50 values of 2,541 ppm for male

rats and 4,418 ppm for female rats. The

other available study by Stokinger and

Spiegl (1953) served only as a pilot

study, and provided preliminary data on

the toxicity of boron trichloride vapor

following inhalation exposure in rats,

mice, and guinea pigs.

No data relevant to the AEGL–1

defined endpoints were available. Based

on the knowledge that one mole of

boron trichloride theoretically

hydrolyzes to form 3 moles of hydrogen

chloride in moist air, the AEGL–1

values were derived by a 1⁄3 reduction

of the accepted hydrogen chloride (HCl)

values and are recommended as

guidance levelsa. The hydrogen chloride

AEGL–1 was based on a 45 minute

NOAEL in exercising adult asthmatics

(Stevens et al., 1992). No UFs 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-minute,

and 1-, 4-, and 8-hour exposure time

points since mild irritantcy is a

threshold effect and generally does not

vary greatly over time. Thus, prolonged

exposure will not result in an enhanced

effect.

No data relevant to the AEGL–2

defined endpoints were available. Based

on the knowledge that one mole of

boron trichloride theoretically

hydrolyzes to form 3 moles of hydrogen

chloride in moist air, the AEGL–2

values were derived by a 1⁄3 reduction

of the accepted HCl values and are

recommended as guidance levelsa. The

hydrogen chloride AEGL–2 for the 30-

minute, 1-, 4-, and 8-hour time points

was based on severe nasal or pulmonary

histopathology in rats exposed to 1,300

ppm hydrogen chloride for 30 minutes

(Stavert et al.,1991). An UF of 3 was

applied for interspecies variability

because the test species (rodents) is

more sensitive to the effects of hydrogen

chloride than primates and because

direct irritation is not expected to vary

greatly between species. An UF 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

modifying factor adjustment is 30-fold.

It was then time-scaled to the 1-, 4-, and

8-hour AEGL exposure periods using

the Cn × t = k relationship, where n =

1 based on regression analysis of

combined rat and mouse LC50 data (1

minute to 100 minutes) as reported by

ten Berge et al., 1986. The 10-minute

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 hydrogen

chloride 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 1⁄3 of the

1-hour boron trichloride LC50 of 2,541

ppm in male rats (Vernot et al., 1977).

An UF of 3 was applied for intraspecies

variability and an additional UF of 10

21960 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

was applied for interspecies

extrapolation to account for a poor data

base (total UF = 30). No boron

trichloride data were available from

which to derive an n value for the

scaling of the derived AEGL–3 value

across time. Because boron trichloride

hydrolyzes in moist air to form

hydrogen chloride, the value of n = 1 for

hydrogen chloride as calculated by ten

Berge (1986) was used for the scaling to

the 10- and 30-minute, 1-, 4-, and 8-hour

exposures using the relationship Cn × t

= k. The derived AEGL–3 values were

consistent with the application of the

Stokinger and Spiegl (1953) data where

exposure to 50 ppm for 2 x 7 hours in

rats, mice, and guinea pigs did not

result in mortality when clean cages

were substituted every 2 hours of the

exposure (to reduce contact with the

hydrolysis products formed in the cage).

It is recommended that in the event of

a boron trichloride release, the

concentrations of both boron trichloride

and HCl should be monitored. It is

conceivable that boron trichloride

concentrations could be within the

acceptable AEGL range, while the

hydrolysis product HCl could exceed

permissible AEGL levels. Another likely

situation is that the concentration of

each will fall below the AEGL criteria

but the combination of the two will

produce an overall HCl exposure

exceeding a given AEGL criteria and

thus produce more toxicity than

expected by the designated AEGL level.

The calculated values are listed in

Table 14 below:

TABLE 14.—SUMMARY OF PROPOSED AEGL VALUES FOR BORON TRICHLORIDE [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

0.6 (2.9) 0.6 (2.9) 0.6 (2.9) 0.6 (2.9) 0.6 (2.9) Recommended as guidance levels: 1⁄3 the

NAC-approved HCl values [NOAEL of

HCl in exercising human asthmatics

(Stevens et al., 1992)]

AEGL–2

(Disabling)

34 (160) 14 (67) 7.3 (35) 1.8 (8.6) 0.90 (4.3) Recommended as guidance levels: 1⁄3 the

NAC-approved HCl values [Mouse

RD50 (Barrow et al., 1977);

Histopathology in rats (Stavert et al.,

1991)]

AEGL–3

(Lethal)

170 (810) 57 (270) 28 (130) 7.1 (34) 3.5 (17) 1⁄3 the 1-hour boron trichloride LC50 value

of 2,541 ppm in male rats (Vernot et

al., 1977)

ii. References.

a. ASTM. (American Society for

Testing and Materials). 1991. Standard

Test Method for estimating sensory

irritancy of airborne chemicals. Method

E981, Vol. 11.04, pp. 610–619.

Philadelphia, PA.

b. 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. Vol.

32:68–76.

c. Tavert , 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 pseudo-mouthbreathing rats. Fundamental and

Applied Toxicology. Vol. 16:636–655.

d. 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. Vol. 34:923–929.

e. Stokinger, H.E. and Spiegl, C.J.

1953. Pharmacology and Toxicology of

Uranium Compounds. Vol. IV. McGrawHill, New York, NY.

f. ten Berge, W.F. 1986.

Concentration-time mortality response

relationship of irritant and systemically

acting vapours and gases. Journal of

Hazardous Materials. Vol. 13:301–309.

g. USEPA (Environmental Protection

Agency). 2000. Acute exposure

guideline levels (AEGLs) for hydrogen

chloride (NAC/Proposed Draft 1: 5/

2000).

h. 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. Vol. 42:417–

423.

17. Diborane—i. Description.

Diborane a highly unstable gas, and is

combustible upon exposure to moist air

or high heat. It rapidly hydrolyzes in

water to produce boric acid, hydrogen,

and heat. Because of its strong reducing

character, it has many industrial uses

such as a rubber vulcanizer, a catalyst

for olefin polymerization, an

intermediate in the production of other

boron hydrides, and as a doping gas in

the semiconductor industry. Diborane

was also investigated in the 1950’s as a

potential rocket fuel.

Data on acute exposures of humans to

diborane were limited to case reports of

accidental work-related exposures.

Signs and symptoms of exposure

included chest tightness, shortness of

breath and dyspnea, wheezing,

nonproductive cough, and precordial

pain. Workers exposed to diborane

generally experienced a complete

recovery of symptoms within a short

period following exposure. No

quantitative information was given

regarding the exposure terms of these

individuals, and the data were therefore

unsuitable for derivation of AEGLs. No

reports of death were found in the

literature.

Data on lethal and sublethal effects of

diborane were available for several

animal species, including dogs, rats,

mice, hamsters, rabbits, and guinea pigs.

Fifteen-minute LC50 values in rats

ranged from 159–182 ppm, and 4-hour

LC50 values ranged from 40–80 ppm in

rats and 29–31.5 ppm in mice. Animals

exposed to lethal and sublethal

concentrations developed pulmonary

hemorrhages, congestion, and edema,

and death was related to these severe

pulmonary changes. Recent studies in

rats and mice have also uncovered the

development of multi-focal and/or

diffuse inflammatory epithelial

degeneration in the bronchioles

following exposure to diborane. These

pulmonary changes produced by

exposure to sublethal concentrations

were completely reversible in rats by

two weeks after an acute exposure, and

were being repaired in the mouse by 2

weeks post-exposure. The signs of

toxicity and repair of pulmonary lesions

following acute exposure to sublethal

concentrations in animals were similar

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21961

to the human case reports. It is likely

that the mechanism of toxicity is due to

direct interaction of diborane with

cellular components, especially since

diborane is such a potent reducer. There

appears to be a similar mechanism of

toxicity between species because the

cause of death from diborane exposure

has always been from pulmonary

damage, including edema, hemorrhage,

and congestion. Mice appeared to be the

more sensitive species, and the mice

data were therefore used for the

derivations of AEGLs.

An AEGL–1 value was not derived

because it was not appropriate. The

AEGL–2 value is below the odor

threshold of diborane and no other data

pertaining to endpoints relevant to

AEGL–1 definition were available.

The AEGL–2 values were based on a

LOAEL (lowest-observed-adverse-effect

level) for pulmonary changes in male

ICR mice following acute inhalation

exposure to diborane. No effects were

observed in mice exposed to 5 ppm for

1 hour, while exposure to 5 ppm for 2

hours resulted in 4/10 mice developing

multi-focal and/or diffuse inflammatory

epithelial degeneration in the

bronchioles (Nomiyama et al., 1995).

There were no other treatment related

changes, such as changes in behavior or

appearance, body or organ weight, or in

hematological or clinical chemistry

indices.

The AEGL–3 values were based on the

estimate a 4-hour LC01 of 9.2 ppm

obtained by probit analysis of data from

a 4-hour LC50 study in male ICR mice

(Uemura et al., 1995).

A total UF of 10 was applied to the

AEGL–2 and AEGL–3 values. An

interspecies UF of 3 was applied

because the most sensitive species, the

mouse, was used, and the endpoint of

toxicity, histological changes in the

lungs, was the most sensitive endpoint.

Further support of a value of 3 is that

signs of toxicity and repair of

pulmonary lesions following acute

exposure to sublethal concentrations in

animals were similar to the human case

reports. It is likely that the mechanism

of toxicity is due to direct interaction of

diborane with cellular components,

especially since diborane is such a

potent reducer. There appears to be a

similar mechanism of toxicity between

species because the cause of death from

diborane exposure has always been from

pulmonary damage, including edema,

hemorrhage, and congestion. An

intraspecies factor of 3 was applied

because the mechanism of action is not

expected to differ greatly among

individuals. The lung remained the

target organ at all concentrations of

exposure, and the biological response

remained the same, becoming more

severe with increasing concentration

until death occurred from anoxia as a

consequence of severe pulmonary

changes.

The derived AEGL values were scaled

to 10-minute, 30-minute, 1-hour, 4-hour,

and 8-hour exposures using Cn × t = k.

To calculate n for diborane, a regression

plot of the effective concentration (EC50)

values was derived from the studies by

Nomiyama et al. (1995) and Uemura et

al. (1995) investigating 1-, 2-, and 4-

hour exposures to 1, 5, or 15 ppm

diborane, with multi-focal and/or

diffuse inflammatory epithelial

degeneration in the bronchioles as the

endpoint of toxicity. From the

regression analysis, the derived value of

n = 1 was used in the temporal scaling

of all the AEGL values (C1 × t = k;

Haber’s Law). For the AEGL–3, the 30-

minute value was flat-lined for the 10-

minute value because it was considered

too precarious to extrapolate from the

exposure duration of 4 hours to 10

minutes. Although it is considered

appropriate to extrapolate from a 2-hour

exposure to a 10-minute exposure

duration in the AEGL–2 derivation, the

10-minute value of 6.0 ppm would

approach that of the 10-minute AEGL–

3 value of 7.3 ppm. Therefore, the 30-

minute AEGL–2 value was flat-lined for

the 10-minute value.

The calculated values are listed in

Table 15 below:

TABLE 15.—SUMMARY OF PROPOSED AEGL VALUES FOR DIBORANE [PPM (MG/M3)]

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Nondisabling)

Not recommended

(NR)a

NR NR NR NR Not recommended because proposed

AEGL–2 value is below the odor

threshold, and no other data pertaining

to endpoints relevant to the AEGL–1

definition were available

AEGL–2

(Disabling)

6.0 (6.6) 2.0 (2.2) 1.0 (1.1) 0.25 (0.28) 0.13 (0.14) LOAEL for pulmonary changes in male

ICR mice; 5 ppm for 2 hour (Nomiyama

et al., 1995)

AEGL–3

(Lethality)

7.3 (8.0) 7.3 (8.0) 3.7 (4.1) 0.92 (1.0) 0.46 (0.51) 4-hour LC01 of 9.2 ppm estimated from a

4-hour LC50 in male ICR mice (Uemura

et al., 1995)

a Absence of an AEGL–1 does not imply that exposure below the AEGL–2 is without adverse effects.

ii. References.

a. Nomiyama, T., Omae, K., Uemura,

T., Nakashima, H., Takebayashi, T.,

Ishizuka, C., Yamazaki, K., and Sakurai,

H. 1995. No-observed-effect level of

diborane on the respiratory organs of

male mice in acute and subacute

inhalation experiments. Journal of

Occupational Health. Vol. 37:157–160.

b. Uemura, T., Omae, K., Nakashima,

H., Sakurai, H., Yamazaki, K., Shibata,

T., Mori, K., Kudo, M., Kanoh, H., and

Tati, M. 1995. Acute and subacute

inhalation toxicity of diborane in male

ICR mice. Archives of Toxicology. Vol.

69:397–404.

18. Nerve Agent VX—i. Description.

Nerve agent VX [O-ethyl-S-

(isopropylaminoethyl) methyl

phosphonothiolate] is a toxic ester

derivative of phosphonic acid

containing a sulfur substituent group,

and is commonly termed a ‘‘nerve’’

agent as a consequence of its

anticholinesterase properties. Agent VX

was developed as a chemical warfare

agent, and shares many of the same

properties as the G-series nerve agents

(GA, GB, GD, and GF).

Agent VX is a amber-colored liquid

with a molecular weight of 267.38; it

has a vapor density of 9.2 (air = 1) and

a liquid density of 1.006 gram/milliter

(g/ml) at 20° C; its water solubility is 3

g per 100 g at 25° C and 7.5 g per 100

g at 15° C. Agent VX was deliberately

formulated to possess a low volatility

(10.5 mg/m3 at 25° C), and is

approximately 2,000 times less volatile

21962 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

than nerve agent GB (DA, 1990). As a

consequence, agent VX is a persistent,

‘‘terrain denial’’ military compound

with the potential to off-gas toxic

concentrations for days following

surface application.

Toxic effects may occur at

concentrations below those of odor

detection.

Exposure to acutely toxic

concentrations of agent VX can result in

excessive bronchial, salivary, ocular,

and intestinal secretion, sweating,

miosis, bronchospasm, intestinal

hypermotility, bradycardia, muscle

fasciculations, twitching, weakness,

paralysis, loss of consciousness,

convulsions, depression of the central

respiratory drive, and death (Dunn and

Sidell, 1989). Minimal effects observed

at low vapor concentrations include

miosis (pinpointing of the pupils of the

eye, with subsequent decrease in pupil

area), tightness of the chest, rhinorrhea,

and dyspnea.

There is at present no evidence to

indicate that asymptomatic exposures to

agent VX result in chronic neurological

disorders. However, a major concern

associated with symptomatic exposures

to anticholinesterase compounds such

as agent VX is the possibility of chronic

neurological effects. No human data

exist for evaluating the potential of

agent VX for inducing chronic

neurological effects following acute

symptomatic exposures.

Animal studies have shown that

exposures to agent VX have not caused

reproductive or developmental effects.

Agent VX was not found to be genotoxic

in a series of microbial and mammalian

assays, and there is no evidence

indicating that VX is carcinogenic.

Animals exposed to acutely toxic

concentrations of agent VX exhibit the

same signs of toxicity as humans,

including miosis, salivation, and

tremors. In a short-term inhalation

toxicity study, no signs of toxicity,

except miosis, were observed in rats,

mice, guinea pigs, or rabbits exposed to

VX vapor concentrations of 0.0002 mg/

m3 or less (6 hours/day, 5 days/week,

for 2 weeks) (Crook et al., 1983).

Insufficient data are available from

which to derive AEGL values for VX

from human or animal inhalation

toxicity studies. The few studies

available are historical, and are

considered nonverifiable due to flawed

study design, poor sampling techniques,

or suspect contamination of sampling

and detection apparatus. Nevertheless,

available literature clearly indicates that

inhibition of cholinesterase activity is a

common mechanism of toxicity shared

by the G-series nerve agents and nerve

agent VX. Thus, it was possible to

develop AEGL estimates for agent VX by

a comparative method of relative

potency analysis from the more

complete data set for nerve agent GB.

This approach has been previously

applied in the estimation of nerve agent

exposure limits, most recently by

Reutter et al. (2000). Available literature

indicates that Agent VX is considered

approximately 12 times more potent

than agent GB (Callaway and Dirnhuber,

1971).

All mammalian toxicity endpoints

observed in the data set for nerve agent

VX as well as the G-series agents

represent different points on the

response continuum for

anticholinesterase effects. Further, the

mechanism of mammalian toxicity

(cholinesterase inhibition) is the same

for all nerve agents. As a consequence,

the experimentally derived n = 2 from

the Mioduszewski et al. (2000a, b) rat

lethality data set for agent GB is here

used as the scaling function for the

agent VX AEGL–1, AEGL–2, and AEGL–

3 derivations rather than a default value.

Under comparable conditions of

exposure, the current analysis finds that

agent VX has a potency to cause miosis

and other transient effects

approximately 12 times greater than that

of agent GB. The AEGL–1 values for

agent GB were derived from a study of

human subjects in which minimal

effects occurred following a 20-minute

exposure to a GB vapor concentration of

0.05 mg/m3 (Harvey, 1952; Johns, 1952).

These findings are based on the results

of low-concentration nerve agent

exposures to informed volunteers who

were under clinical supervision during

the periods of exposure as well as for

post-exposure periods of several

months.

The AEGL–2 values for agent GB were

derived from a study of human subjects

in which miosis, dyspnea, photophobia,

inhibition of red blood cell

cholinesterase (RBC-ChE) to

approximately 60% of individual

baseline, and small but measurable

changes in SFEMG of the forearm

occurred following a 30-minute

exposure to 0.5 mg GB/m3 (Baker and

Sedgwick, 1996). This recent study was

performed under Helsinki accords and

clinical supervision, and was conducted

with the cooperation of fully informed

human subjects.

The fact that AEGL–1 and AEGL–2

analyses for agent VX are based on data

from human volunteers (Harvey, 1952;

Johns 1952; Baker and Sedgwick, 1996;

GB vapor exposure to clinically

supervised human volunteers)

precludes the use of an interspecies UF.

To accommodate known variation in

human cholinesterase activity that may

make some individuals more

susceptible to the effects of

cholinesterase inhibitors such as nerve

agents, a factor of 10 was applied for

intraspecies variability (protection of

susceptible populations). With

application of a modifying factor of 3 for

the incomplete VX data set, the total UF

for estimating AEGL–1 and AEGL–2

values for agent VX is 30.

The SFEMG effects noted in the study

chosen for estimation of AEGL–2 values

were not clinically significant, and were

not detectable after 15–30 months.

Baker and Sedgwick (1996) considered

SFEMG changes to be a possible early

indicator or precursor of the

nondepolarising neuromuscular block

found associated with Intermediate

Syndrome paralysis in severe

organophosphorous insecticide

poisoning cases. The Baker and

Sedgwick (1996) study concluded that

these electromyographic changes were

persistent (>15 months), but that they

were reversible and subclinical. While

not considered debilitating or

permanent effects in themselves,

SFEMG changes are here considered an

early indicator of exposures that could

potentially result in more significant

effects. Selection of this effect as a

protective definition of an AEGL–2 level

is considered appropriate given the

steep dose-response toxicity curve of

nerve agents.

Insufficient data are available to

directly derive an AEGL–3 for agent VX.

The AEGL–3 values for agent VX were

indirectly derived from the AEGL–3

values for GB using a relative potency

approach in which agent VX is

considered 12 times more potent than

agent GB for lethality. As a result,

AEGL–3 values for agent VX were

derived from recent inhalation studies

in which the lethality of GB to female

Sprague-Dawley rats was evaluated for

the time periods of 10, 30, 60, 90, 240,

and 360 minutes (Mioduszewski et al.,

2000a, b). Both experimental LC01 and

LC50 values were evaluated. The use of

a rat data set resulted in selection of an

interspecies UF of 3; the full default

value of 10 was not considered

appropriate for the interspecies UF

since the mechanism of toxicity in both

laboratory rodents and humans is

cholinesterase inhibition. To

accommodate known variation in

human cholinesterase activity, the full

default value of 10 for intraspecies

uncertainty was considered necessary to

protect susceptible populations. With

the additional application of a

modifying factor of 3 for the incomplete

VX data set, the total UF for AEGL–3

determination for agent VX is equal to

100.

Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices 21963

The NAC noted that an earlier report

by the National Research Council (NRC)

(NRC, 1997) included an evaluation of

the same VX toxicity data base, and had

recommended at that time that

additional research was needed to more

fully characterize the toxicity of VX

vapor. The NAC further notes that such

studies could be limited and should

specifically focus on obtaining data that

would reduce uncertainties regarding

the relative potency between agents GB

and VX, or the potency of agent VX, for

critical effects such as miosis,

rhinorrhea, and lethality. To

acknowledge the significant gaps in the

data base for this nerve agent, the NAC

considers the proposed AEGL values to

be temporary in nature and subject to reevaluation in 3 years.

The calculated values are listed in

Table 16 below:

TABLE 16.—SUMMARY OF PROPOSED TEMPORARY AEGL VALUESA FOR AGENT VX [PPM (MG/M3)]B

Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)

AEGL–1

(Non-disabling)

0.000018 ppm

(0.00020 mg/

m3)

0.000010 ppm

(0.00011 mg/

m3)

0.0000073

ppm

(0.000080 mg/

m3)

0.0000037

ppm

(0.000040 mg/

m3)

0.0000026

ppm

(0.000028 mg/

m3)

Derived by relative potency from study of

multiple minimal effects in human volunteers exposed to 0.05 mg/m3 GB

vapor for 20 minutes; headache, eye

pain, rhinorrhea, tightness in chest,

cramps, nausea, malaise, miosis (Harvey, 1952; Johns, 1952)c

AEGL–2

(Disabling)

0.00022 ppm

(0.0024 mg/

m3)

0.00013 ppm

(0.0014 mg/

m3)

0.000090 ppm

(0.00098 mg/

m3)

0.000045 ppm

(0.00049 mg/

m3)

0.000032 ppm

(0.00035 mg/

m3)

Derived by relative potency from study of

GB vapor exposure to exercising

human volunteers exposed to 0.5 mg/

m3 for 30 minutes; miosis, dyspnea, inhibition of RBC-ChE changes in

SFEMG (Baker and Sedgwick, 1996)d

AEGL–3

(Lethal)

0.00088 ppm

(0.0096 mg/

m3)

0.00045 ppm

(0.0049 mg/

m3)

0.00030 ppm

(0.0033 mg/

m3)

0.00016 ppm

(0.0017 mg/

m3)

0.00012 ppm

(0.0013 mg/

m3)

Derived by relative potency from experimental Sprague-Dawley rat lethality

data (LC01 and LC50); whole-body dynamic exposure to GB vapor concentrations between 2–56 mg/m3 for 3,

10, 30, 60, 90, 240, and 360 minutes

(Mioduszewski et al., 2000a, b)e

a Percutaneous absorption of VX vapor is known to be an effective route of exposure; nevertheless, percutaneous vapor concentrations needed to produce similar adverse effects are greater than inhalation vapor concentrations by an approximate factor of 10. Thus, the AEGL values

presented in this table are considered protective for both routes of exposure. b Agent VX is considered approximately 12 times more potent than agent GB. (see section 4.3, and Callaway and Dirnhuber, 1971). c Derived from multiple minimal effects noted in human volunteers exposed to agent GB vapor at 0.05 mg-min/m3 for 20 minutes (Harvey,

1952; Johns, 1952). VX concentration to achieve same endpoint estimated by relative potency comparison presented in footnote ‘‘b’’ in this table. d Derived from transient effects noted in exercising human volunteers exposed to agent GB vapor at 0.5 mg-min/m3 for 30 minutes (Baker and

Sedgwick, 1996). VX concentration to achieve same endpoint estimated by relative potency comparison presented in footnote ‘‘b’’ in this table. e Derived from LC01 values for female Sprague-Dawley rats exposed to GB vapor in dynamic exposure chamber (Mioduszewski et al., 2000a,

b). VX concentrations to achieve same endpoint estimated by relative potency comparison presented in footnote ‘‘b’’ in this table.

ii. References.

a. Baker, D.J. and Sedgwick, E.M.

1996. Single fibre electromyographic

changes in man after organophosphate

exposure. Human and Experimental

Toxicology. Vol. 15:369–375.

b. Callaway, S. and Dirnhuber, P.

1971. Estimation of the concentration of

nerve agent vapour required to produce

measured degrees of miosis in rabbit

and human eyes. Technical Paper No.

64 Chemical Defence Establishment,

Porton Down, Salisbury, Wilts., UK

c. Crook, J.W., Hott, P., and Owens,

E.J., et al. 1983. The effects of subacute

exposures of the mouse, rat, guinea pig,

and rabbit, to low-level VX

concentrations. U.S. Army Armament

Research and Development Command,

Chemical Systems Laboratory,

Technical Report ARCSL-TR-82038,

Aberdeen Proving Ground, MD.

d. DA (U.S. Department of the Army).

1990. Potential military chemical/

biological agents and compounds. Field

Manual FM 3-9 (NAVFAC P-467, AFR

355-7), Headquarters, Department of the

Army, Department of the Navy,

Department of the Air Force,

Washington, DC (December 12, 1990).

e. Dunn, M.A. and Sidell, F.R. 1989.

Progress in the medical defense against

nerve agents. Journal of the American

Medical Association. Vol. 262:649–652.

f. Harvey, J.C. 1952. Clinical

observations on volunteers exposed to

concentrations of GB. Medical

Laboratories Research Report No. 114,

Publication Control No. 5030–114

(CMLRE-ML-52), MLCR 114. Army

Chemical Center, Aberdeen Proving

Ground, MD.

g. Johns, R.J. 1952. The effect of low

concentrations of GB on the human eye.

Research Report No. 100, Publication

Control No. 5030–100 (CMLRE-ML-52).

Chemical Corps Medical Laboratories,

Army Chemical Center, Aberdeen

Proving Ground, MD.

h. Mioduszewski, R.J., Manthei, J.,

Way, R., Burnett, D., Gaviola, B., Muse,

W., Crosier, R., and Sommerville, D.

2000a. Estimating the probability of

sarin vapor toxicity in rats as a function

of exposure concentration and duration.

Presented at the 39th Annual Meeting of

the Society of Toxicology, March, 2000.

Philadelphia, PA. Toxicologist. Vol.

54(1):18 (#84).

i. Mioduszewski, R.J., Manthei, J.,

Way, R., Burnett, D., Gaviola, B. Muse,

W., Thomson, S., Sommerville, D., and

Crosier, R. 2000b. Estimating the

probability of sarin vapor toxicity in rats

as a function of exposure concentration

and duration. Proceedings of the

International Chemical Weapons

Demilitarization Conference (CWD2000). The Hague, NL (May 21–24,

2000).

j. NRC. 1997. Review of the acute

human-toxicity estimates for selected

chemical warfare agents. Committee on

Toxicology, Subcommittee on Toxicity

Values for Selected Nerve Agents and

Vesicant Agents. National Academy

Press, Washington, DC.

21964 Federal Register / Vol. 66, No. 85 / Wednesday, May 2, 2001 / Notices

k. Reutter, S.A., Mioduszewski, R.J.,

and Thomson, S.A. 2000. Evaluation of

airborne exposure limits for VX: worker

and general population exposure

criteria. ECBC-TR-074. Edgewood

Chemical Biological Center, U.S. Army

Soldier and Biological Chemical

Command, Aberdeen Proving Ground,

MD.

IV. 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 2001.

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: April 23, 2001.

Stephen L. Johnson,

Acting Assistant Administrator for

Prevention, Pesticides and Toxic Substances.

[FR Doc. 01–11001 Filed 5–1–01; 8:45 am]

BILLING CODE 6560–50–S

ENVIRONMENTAL PROTECTION

AGENCY

[OPPTS–140289; FRL–6777–5]

Access to Confidential Business

Information by GEOMET Technologies

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: EPA has authorized Versar,

Incorporated’s (Versar) wholley owned

subsidiary GEOMET Technologies,

Incorporated (GEOMET) of

Germantown, MD access to information

which has been submitted to EPA under

sections 4, 5, 6, and 8 of the Toxic

Substances Control Act (TSCA). Some of

the information may be claimed or

determined to be confidential business

information (CBI).

DATES: Access to the confidential data

will occur no sooner than May 7, 2001.

FOR FURTHER INFORMATION CONTACT:

Barbara A. Cunningham, Acting

Director, Environmental Assistance

Division (7408), Office of Pollution

Prevention and Toxics, Environmental

Protection Agency, 1200 Pennsylvania

Ave., NW., Washington, DC 20460;

telephone number: (202) 554–1404; email address: TSCAHotline@epamail.epa.gov.

SUPPLEMENTARY INFORMATION:

I. Does this Notice Apply to Me?

This action is directed to the public

in general. This action may, however, be

of interest to ‘‘those persons who are or

may be required to conduct testing of

chemical substances under the Toxic

Substances Control Act (TSCA).’’ Since

other entities may also be interested, 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.

II. How Can I Get Additional

Information, Including Copies of this

Document or Other Related Documents?

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,’’

‘‘Regulations and Proposed Rules,’’ 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/.

III. What Action is the Agency Taking?

Under contract number 68–W–99–

041, Versar’s subsidiary, GEOMET of

20251 Century Boulevard, Germantown,

MD, will assist the Office of Pollution

Prevention and Toxics (OPPTS)

providing exposure assessments for new

and existing chemicals.

In accordance with 40 CFR 2.306(j),

EPA has determined that under EPA

contract number 68–W–99–041,

GEOMET will require access to CBI

submitted to EPA under sections 4, 5, 6,

and 8 of TSCA to perform successfully

the duties specified under the contract.

GEOMET personnel will be given

access to information submitted to EPA

under sections 4, 5, 6, and 8 of TSCA.

Some of the information may be claimed

or determined to be CBI.

EPA is issuing this notice to inform

all submitters of information under

sections 4, 5, 6, and 8 of TSCA that the

Agency may provide GEOMET access to

these CBI materials on a need-to-know

basis only. All access to TSCA CBI

under this contract will take place at

EPA Headquarters and at the Versar site

located at 6850 Versar Center,

Springfield, VA.

GEOMET will be required to adhere to

all provisions of EPA’s TSCA

Confidential Business Information

Security Manual.

Clearance for access to TSCA CBI

under this contract may continue until

April 30, 2004.

GEOMET personnel will be required

to sign nondisclosure agreements and

will be briefed on appropriate security

procedures before they are permitted

access to TSCA CBI.

List of Subjects

Environmental protection,

Confidential business information.

Dated: April 19, 2001.

Deborah A. Williams,

Acting Director, Information Management

Division, Office of Pollution Prevention and

Toxics.

[FR Doc. 01–10999 Filed 5–1–01; 8:45 am]

BILLING CODE 6560–50–S

ENVIRONMENTAL PROTECTION

AGENCY

[OPP–34171B; FRL–6770–9]

Ethyl Parathion; Receipt of Request

For Registration Cancellations and

Amendments

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: In accordance with section

6(f)(1) of the Federal Insecticide,

Fungicide, and Rodenticide Act

(FIFRA), as amended, EPA is issuing a

notice of receipt of request by a number

of registrants, including Cheminova,

Inc. and Cheminova A/S, for the

following actions: to immediately cancel

the registrations for their manufacturing

use products containing O, O-Diethyl-Op-nitrophenyl thiophosphate (ethyl

parathion), to immediately cancel the

use on corn grown for seed by amending

their ethyl parathion end-use product

registrations; and to cancel all of their

ethyl parathion end-use products

effective as of December 31, 2002. EPA

will decide whether to approve the

requests after consideration of public

comment.

DATE: Comments on the requested

cancellation of product and use

registrations must be submitted to the

address provided below by June 1, 2001.