58840 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

ENVIRONMENTAL PROTECTION

AGENCY

[OPPTS–00218; FRL–5737–3]

National Advisory Committee for Acute

Exposure Guideline Levels for

Hazardous Substances

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 Acute Exposure Guideline

Levels (AEGLs) on an on going basis to

assist Federal and State agencies and

private sector organizations with their

needs for short-term hazardous

chemical exposure information (one

time only exposures during chemical

emergency situations). The NAC/AEGL

Committee has completed work on

‘‘Proposed AEGLs’’ for 12 chemicals.

The purpose of today’s notice is to

solicit comments on proposed values

and the accompanying scientific

rationale for their development. More

specifically, this notice solicits

comments on the proposed AEGL

values, the methodologies used to

determine no-observed-adverse-effectlevels (NOAELs) or lowest-observedadverse-effect-levels (LOAELs) for

specific effects, the uncertainty factors

selected for intraspecies and

interspecies extrapolation, the

uncertainity factors used to

accommodate for sensitive or

susceptible individuals in the human

population, the use of modifying factors

and the values applied, and other

aspects related to the development of

the AEGL values.

DATES: Submit written comments on or

before December 1, 1997.

ADDRESSES: Submit three copies of

written comments on the Proposed

AEGLs, identified by docket control

number (OPPTS–00218; FRL– 5737–3)

to: Environmental Protection Agency,

Office of Pollution Prevention and

Toxics (OPPT), Document Control

Office (7407), Rm. G–009, 401 M St.,

SW., Washington, DC 20460.

Comments and data may also be

submitted electronically to:

oppt.ncic@epamail.epa.gov. Follow the

instructions under Unit V. of this

document. No Confidential Business

Information (CBI) should be submitted

through e-mail.

All comments which contain

information claimed as CBI must be

clearly marked as such. Three sanitized

copies of any comments containing

information claimed as CBI must also be

submitted and will be placed in the

public record for this notice. Persons

submitting information on any portion

of which they believe is entitled to

treatment as CBI by EPA must assert a

business confidentiality claim in

accordance with 40 CFR 2.203(b) for

each such portion. This claim must be

made at the time that the information is

submitted to EPA. If a submitter does

not assert a confidentiality claim at the

time of submission, EPA will consider

this as a waiver of any confidentiality

claim and the information may be made

available to the public by EPA without

further notice to the submitter.

FOR FURTHER INFORMATION CONTACT:

Susan B. Hazen, Director,

Environmental Assistance Division

(7408), Rm. ET–543B, Office of

Pollution Prevention and Toxics,

Environmental Protection Agency, 401

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

telephone: (202) 554–1404; TDD: (202)

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

SUPPLEMENTARY INFORMATION:

Electronic Availability

Internet

Electronic copies of this notice and

various support documents are available

from the EPA Home Page at the Federal

Register—Environmental Documents

entry for this document under ‘‘Laws

and Regulations’’ (http://www.epa.gov/

fedrgstr/).

Fax-On-Demand

Using a faxphone call (202) 401–0527

and select item 3800 for an index of

items in this category. For a more

specific item number, see the table in

Unit IV. of this document.

I. 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

objective stated in the charter 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 using a cost-effective

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 May 21,

1997 (62 FR 27734 (FRL–5718–9)). This

list is intended to be expanded and also

may be modified as priorities of the

stakeholder member organizations are

further developed.

While the development of AEGLs for

chemicals is not statutorily based; at

least one EPA rulemaking references

their planned adoption. In the final

Clean Air Act and Amendment section

112 Risk Management rulemaking (June

20, 1996, 61 FR 31685, (FRL–5516–5)),

‘‘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

toxicity reference for substances under

this rule.’’ Federal and State agencies

and private organizations may also

adopt AEGLs for chemical emergency

programs in the future.

The NAC/AEGL Committee meets

four times per year and plans to develop

AEGL values for 30–40 chemicals per

year during the next 8 to 10 years. Since

its first meeting on June 19–21, 1996,

the NAC/AEGL Committee has

completed work on ‘‘Proposed AEGLs’’

for 12 chemicals. The basic approach

and guidance used to derive AEGLs has

been the National Academy of Sciences

(NAS) publication, ‘‘Guidelines for

Developing Community Emergency

Exposure Levels for Hazardous

Substances’’ (National Academy Press,

Washington, DC, 1993; copies are

available in the Docket). The NAC/

AEGL Committee meetings have been

public and numerous public comments

and presentations have been made. At

this time, the NAC/AEGL Committee is

providing further opportunity for public

input through this notice. Comments are

welcome on both the AEGL values and

their related Technical Support

Documents (filed in the public Docket).

The NAC/AEGL Committee will

review comments received and revise

the Proposed AEGLs as deemed

appropriate. The resulting values will be

established as ‘‘Interim AEGLs’’ and

will be available for use in various

public and private sector programs on

human health effects related to shortterm exposures to hazardous chemicals.

It is planned that Interim AEGLs will be

forwarded to the National Research

Council, National Academy of Sciences

(NRC/NAS) for further review,

collaboration with the NAC/AEGL

Committee, and possible revision of the
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58841

AEGL values and the methodologies

used to derive them. It is anticipated

that ‘‘Final AEGLs’’ will be published

under the auspices of the NAS following

concurrence on the values and the

scientific rationale used for their

development. Until Final AEGLs are

published by the NAS, the Interim

AEGLs are intended for use as needed

by individuals or organizations in both

the public and private sectors.

II. Characterization of the AEGLs

The AEGLs represent short-term

threshold or ceiling exposure values

intended for the protection of the

general public, including susceptible or

sensitive individuals, but not

hypersusceptible or hypersensitive

individuals. The AEGLs represent

biological reference values for this

defined human population and consist

of three biological endpoints for each of

four different exposure periods of 30

minutes (mins), l hour (hr), 4 hours

(hrs), and 8 hrs. In certain instances,

AEGL values have been and will be

developed for additional exposure

periods of 5 or 10 mins. The biological

endpoints include AEGL–1, AEGL–2,

and AEGL–3 and are defined as follows:

AEGL–1 is the airborne concentration

(expressed as parts per millions (ppm)

or milligrams (mg)/meters (m)3) of a

substance at or above which it is

predicted that the general population,

including ‘‘susceptible’’ but excluding

‘‘hypersusceptible’’ individuals, could

experience notable discomfort. Airborne

concentrations below AEGL–1 represent

exposure levels that could produce mild

odor, taste, or other sensory irritations.

AEGL–2 is the airborne concentration

(expressed as ppm or mg/m3) of a

substance at or above which it is

predicted that the general population,

including ‘‘susceptible’’ but excluding

‘‘hypersusceptible’’ individuals, could

experience irreversible or other serious,

long-lasting effects or impaired ability to

escape. Airborne concentrations below

the AEGL–2 but at or above AEGL–1

represent exposure levels that may

cause notable discomfort.

AEGL–3 is the airborne concentration

(expressed as ppm or mg/m3) of a

substance at or above which it is

predicted that the general population,

including ‘‘susceptible’’ but excluding

‘‘hypersusceptible’’ individuals, could

experience life-threatening effects or

death. Airborne concentrations below

AEGL–3 but at or above AEGL–2

represent exposure levels that may

cause irreversible or other serious, longlasting effects or impaired ability to

escape.

III. 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 NAC/AEGL

Committee in draft form by Oak Ridge

National Laboratories and ‘‘Draft AEGL’’

values are prepared in conjunction with

designated NAC/AEGL Committee

members. Both the Draft AEGLs and

draft technical support documents are

reviewed and revised as necessary by

the NAC/AEGL Committee members

prior to formal NAC/AEGL Committee

meetings. Following deliberations on

the Draft AEGL values and the relevant

data and information for each chemical

presented at the meeting, the NAC/

AEGL Committee attempts to reach a

consensus on acceptable values. 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 12

hazardous substances. These values

represent the first exposure levels

proposed and published by the NAC/

AEGL Committee. 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

(copies of this guidance document are

available for review in the Docket). The

term Community Emergency Exposure

Levels (CEELs) used by the NAS is

synonymous with AEGLs in every way.

The NAC/AEGL Committee has adopted

the term Acute Exposure Guideline

Levels or AEGLs to better connote the

broad application of the values to the

population defined by the NAS in its

guidance document and addressed by

the NAC/AEGL Committee in its

development of the AEGLs. 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 proposed values 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. It has been

planned to have the NAS subcommittee

participate in the peer review of the

Interim AEGLs and in the resolution of

issues regarding the AEGL values and

the data and basic methodology used for

setting AEGLs. It is anticipated that

‘‘Final AEGL’’ values will be published

under the auspices of the NAS.

IV. List of Twelve Chemicals With

Proposed AEGL Values

CAS No. Chemical name

Fax-OnDemand

item no.

57–14–7 ... 1,1–

Dimethylhydrazine

3852

60–34–4 ... Methylhydrazine 3853

62–53–3 ... Aniline 3854

75–21–8 ... Ethylene oxide 3861

302–01–2 Hydrazine 3891

540–59–0 1,2–Dichloroethene 3895

540–73–8 1,2–

Dimethylhydrazine

3852

7697–37–2 Nitric acid 3912

7782–41–4 Fluorine 3915

7782–50–5 Chlorine 3916

7784–42–1 Arsine 3921

7803–51–2 Phosphine 3923

Chemicals With Proposed AEGLs

(Alphabetical Order)

Aniline

Aniline is an aromatic amine used

chiefly in the chemical industry in the

manufacture of dyes, dye intermediates,

rubber accelerators, antioxidants, drugs,

photographic chemicals, isocyanates,

herbicides, and fungicides. The primary

effect of an acute exposure to aniline is

on the hemoglobin of the red blood cell,

resulting in the formation of

methemoglobin. The effect may occur

following inhalation, ingestion, or

cutaneous absorption. In addition to

methemoglobinemia, chronic exposures

or exposures to high concentrations may

produce signs and symptoms of

headache, paresthesia, tremor, pain,
58842 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

narcosis/coma, cardiac arrhythmia, and

possibly death.

All AEGL values are based on a study

in which rats were exposed to

concentrations of 0, 10, 30, 50, 100, or

150 ppm for 8 hrs (Kim and Carlson,

1986). The only reported effect was

formation of methemoglobin. At a

constant concentration (100 ppm), the

formation of methemoglobin over time

was basically linear, reaching an

asymptote at 8 hrs.

The AEGL–1 was based on a

concentration of 100 ppm for 8 hrs

which resulted in elevation of

methemoglobin from a control value of

1.1% (range, 0.4–2.1%) to 22%. This

level of methemoglobin results in

clinical cyanosis but no hypoxic

symptoms. Additional studies on oral

ingestion showed that humans are much

more sensitive than rats to aniline

exposure as indicated by formation of

methemoglobin. Thus, an uncertainty

factor of 10 was used for interspecies

extrapolation. Several sources also

indicate that newborns are more

sensitive to methemoglobin-forming

chemicals than adults; thus, an

intraspecies uncertainty factor of 10 was

applied. The data were scaled across

time using C1 x t = k (the relationship

between concentration of aniline and

methemoglobin formation at a fixed

time [8 hrs] is linear as is the

relationship between time and severity

of effect when concentration is held

constant; in addition, data from several

lethality [LC50] studies show that the

relationship between C and t is linear).

The AEGL–2 was based on the same

study with rats in which a concentration

of 150 ppm for 8 hrs resulted in

elevation of methemoglobin from a

control value of 1.1% to 41%. This level

of methemoglobin is associated with

fatigue, lethargy, exertional dyspnea,

and headache in humans and was

considered the threshold for disabling

effects. The 150 ppm concentration was

divided by a combined uncertainty

factor of 100 and scaled across time

using the same reasons and

relationships as for the AEGL–1 above.

Because of the small data base and the

lack of recent, reliable human inhalation

studies, uncertainty factors of 10 were

applied for each of the interspecies and

intraspecies variabilities.

Data on concentrations of aniline

inducing methemoglobin levels at the

threshold for lethality were not

available. Based on the fact that the

relationship between concentration of

aniline and methemoglobin formation is

linear, the dose-response curve from the

study on which the AEGL–1 and AEGL–

2 were based was extrapolated to a

concentration resulting in >70%

formation of methemoglobin, the

threshold for lethality. The

concentration of 250 ppm for 8 hrs was

chosen as the threshold for lethality.

The AEGL–3 was based on dividing the

250 ppm value by a combined

uncertainty factor of 100 and scaled

across time using the same reasons and

relationships as for the AEGL–1 above.

The uncertainty factors of 10 for each of

the interspecies and intraspecies

variabilities are supported by the small

data base of information and the lack of

recent, reliable human inhalation

studies.

Studies with repeated exposures at

approximately the same concentrations

in the rat resulted in additional effects

on the blood and spleen, but

concentrations up to 87 ppm, 6 hrs/day,

5 days/week, for 2 weeks were not

disabling or life-threatening. The

calculated values are listed in the table

below. Because aniline is absorbed

through the skin, a skin notation was

added to the summary table.

SUMMARY TABLE OF PROPOSED AEGL VALUES FOR ANILINE a

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 16 ppm (61 mg/m3) 8.0 ppm (30 mg/

m3)

2.0 ppm (7.6 mg/

m3)

1.0 ppm (3.8 mg/

m3)

22% methemoglobin—cyanosis (Kim and

Carlson, 1986)

AEGL–2 24 ppm (91 mg/m3) 12 ppm (46 mg/

m3)

3.0 ppm (11 mg/

m3)

1.5 ppm (5.7 mg/

m3)

41% methemoglobin—lethargy (Kim and

Carlson, 1986)

AEGL–3 40 ppm (152 mg/

m3)

20 ppm (76 mg/

m3)

5.0 ppm (19 mg/

m3)

2.5 ppm (9.5 mg/

m3)

>70% methemoglobin—lethality (extrapolated

from data of Kim and Carlson, 1986)

aCutaneous absorption may occur; direct skin contact with the vapor or liquid should be avoided.

References

1. Kim, Y.C. and G.P. Carlson. 1986. The

effect of an unusual workshift on chemical

toxicity. Part II. Studies on the exposure of

rats to aniline. Fundamental and Applied

Toxicology 7:144–152.

Arsine

Arsine is an extremely toxic, colorless

gas used in the semiconductor industry.

Exposure to arsine may also result from

mining and manufacturing processes

involving arsenicals, and from paints

and herbicides containing arsenicals.

Arsine is a potent hemolytic agent,

ultimately causing death via renal

failure. Numerous human case reports

are available documenting the extreme

toxicity of arsine exposure but these

reports lack definitive quantitative

exposure data.

Exposure-response data from animal

studies were used to derive AEGL

values for arsine. AEGL values derived

with animal data were more

conservative than AEGLs estimated

from limited anecdotal human data. The

greater conservatism afforded by the

animal data may be justified by the

incomplete and often equivocal data for

human exposures, the documented

extreme toxicity of arsine, and the

known latency involved in arsineinduced lethality. The AEGL values for

the various exposure periods of concern

(0.5, 1, 4, and 8 hrs) were scaled from

the experimental exposure duration

using exponential scaling (C2 x t = k),

where n = 2 represented an estimate of

the concentration-time relationship. The

concentration exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by cn x t = k, where

the exponent, n, ranges from 1 to 3.5

(ten Berge et al 1986). The mid-point

value of 2 was used as the exponent n

for scaling the AEGL values for arsine

across time, because no exposure versus

time data were available.

Based upon the available data,

derivation of AEGL–1 values was

considered to be inappropriate. The

available human and animal data affirm

that there is little margin between

exposures that result in little or no signs

of toxicity and those that result in

lethality. The mechanism of arsine

toxicity (induction of hemolysis that

may rapidly result in renal failure and

death), and the fact that toxicity in

animals and humans has been

demonstrated at concentrations at or

below the odor threshold also support
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58843

such a conclusion by the NAC/AEGL

Committee.

The AEGL–2 values were based upon

exposure levels that did not result in

significant alterations in hematologic

parameters in mice exposed to arsine for

1 hr (Peterson and Bhattacharyya, 1985).

AEGL–2 derivations based upon several

data sets were similar, thereby

providing validation to the proposed

AEGLs. Derivation of AEGLs based

upon limited data for humans resulted

in values indicative of potentially

hazardous exposures. Uncertainty factor

application included a factor of 10 for

interspecies variability because of

uncertainties regarding species-specific

sensitivity to arsine-induced hemolysis.

Uncertainty regarding intraspecies

variability was limited to 3 because the

hemolytic response to arsine is not

expected to vary greatly among

individuals.

The AEGL–3 values were based upon

data assessing the lethality in mice

exposed to arsine for 1 hr (Peterson and

Bhattacharyya, 1985). A total

uncertainty factor application of 30 was

applied as for AEGL–2 values and for

the same reasons. Derivation of AEGL–

3 values using limited data in monkeys

affirmed the values derived based upon

the mouse data. AEGL–3 values derived

from limited human exposure data

resulted in levels considered potentially

hazardous.

The three AEGL exposure levels

reflect the narrow range between

exposures resulting in minor effects and

those producing lethality. A

conservative approach in the

development of AEGLs for arsine was

justified by the known steep doseresponse curve, the induction of

hemolysis by arsine at extremely low

concentrations, and the potential of

hemolysis to progress to life-threatening

renal failure.

SUMMARY OF PROPOSED AEGL VALUES FOR ARSINE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 NAa ....................... NAa ....................... NAa ....................... NAa ....................... Inappropriate based upon steep dose-response

relationship, mechanism of toxicity, and because toxicity occurs at or below the odor

threshold

AEGL–2 0.24 ppm (0.8 mg/

m3).

0.17 ppm (0.5 mg/

m3).

0.08 ppm (0.3 mg/

m3).

0.06 ppm (0.3 mg/

m3).

Absence of significant hematological alterations

in mice consistent with the known continum

of arsine toxicity (Peterson and

Bhattacharyya, 1985)

AEGL–3 0.7 ppm (2.2 mg/

m3).

0.5 ppm (1.6 mg/

m3).

0.25 ppm (0.8 mg/

m3).

0.18 ppm (0.6 mg/

m3).

Estimated threshold for nonlethality in mice (Peterson and Bhattacharyya, 1985)

a NA Not appropriate

References

1. Peterson, D.P. and Bhattacharyya, M.H.

1985. Hematological responses to arsine

exposure: quantitation of exposure response

in mice. Fundamental and Applied

Toxicology 5:499–505.

Chlorine

Chlorine is a greenish-yellow, highly

reactive halogen gas with a pungent,

suffocating odor. Like other halogens,

chlorine does not occur in the elemental

state in nature; it rapidly combines with

both inorganic and organic substances.

Chlorine is used in the manufacture of

a wide variety of chemicals, as a

bleaching agent in industry and

household products, and as a biocide in

water and waste treatment plants.

Chlorine is an irritant to the eyes and

respiratory tract; reaction with moist

surfaces produces hydrochloric and

hypochlorous acids. Its irritant

properties have been studied in human

volunteers and its acute inhalation

toxicity has been studied in several

laboratory animal species. The data

from the human and laboratory animal

studies were sufficient for development

of three AEGLs for four time periods

(i.e., 30 mins and 1, 4, and 8 hrs). Probit

and regression analyses of the animal

exposure time-concentration-mortality

data determined that the relationship

between concentration and time is

approximately C2 x t = k.

The AEGL–1 was based on the

observation that exposure to human

volunteers, including a sensitive

individual, of 0.5 ppm for 4 hrs

produced no sensory irritation but did

result in transient changes in some

pulmonary function parameters for the

sensitive individual (Rotman et al.,

1983). Because both sexes were tested

and all subjects were undergoing light

exercise, making them more vulnerable

to sensory irritation, and because a

sensitive individual was included in the

test, no uncertainty factor to account for

differences in human sensitivity was

applied. The 0.5 ppm exposure for 4 hrs

was scaled to the other time periods

using the relationship C2 x t = k. The

scaling factor n = 2 was based on probit

and regression analyses of animal

lethality data.

The AEGL–2 values were derived

based on the same study (Rotman et al.,

1983) in which healthy human subjects

experienced transient changes in

pulmonary function measurements and

a sensitive individual experienced an

asthmatic attack (shortness of breath

and wheezing) at a concentration of 1

ppm for 4 hrs. The sensitive individual

remained in the exposure chamber for

the full 4 hrs. Because both sexes were

tested and all subjects were undergoing

light exercise, making them more

vulnerable to sensory irritation, and

because a sensitive individual was

included in the test, no uncertainty

factor to account for differences in

human sensitivity was applied. The 4-

hr 1 ppm concentration was scaled to

the other time periods using the C2 x t

= k relationship. The scaling factor or

exponent of n = 2 is based on probit and

regression analyses of animal lethality

data.

In the absence of human data, the

AEGL–3 values were based on animal

lethality data. Because the mouse was

shown to be more sensitive than other

mammals to irritant gases including

chlorine and does not provide an

appropriate basis for quantitatively

predicting mortality in humans, a value

below that resulting in no deaths in the

rat, 213 and 322 ppm in two studies

(MacEwen and Vernot, 1972; Zwart and

Woutersen, 1988) and above that

resulting in no deaths in the mouse (150

ppm) for exposure periods of 1 hr was

chosen. Mice exposed to chlorine

experienced delayed deaths attributable

to bronchopneumonia. The AEGL–3

values were derived from a 1-hr

concentration of 200 ppm. This value

was divided by a combined uncertainty

factor of 10. An uncertainty factor of 3
58844 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

was used to extrapolate from rats to

humans, since interspecies values for

the same endpoint differed by a factor

of approximately 2 within each of

several studies. An uncertainty factor of

3 was used to account for differences in

human sensitivity, since the toxic effect

is due to a chemical reaction with

biological tissue of the respiratory tract

which is unlikely to be different among

individuals. The AEGL–3 values were

scaled to the other exposure periods

based on the C2 x t = k relationship. The

scaling factor or exponent of n = 2 is

based on probit and regression analyses

of animal lethality data.

Based on the large data base and the

extensive, well-conducted studies,

confidence in the AEGL values is high.

The calculated values are listed in the

table below.

SUMMARY OF PROPOSED AEGL VALUES FOR CHLORINE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 1.4 ppm (4.1 mg/

m3).

1.0 ppm (2.9 mg/

m3).

0.5 ppm (1.5 mg/

m3).

0.5 ppm (1.5 mg/

m3).

Pulmonary function—human (Rotman et al., 1983)

AEGL–2 2.8 ppm (8.1 mg/

m3).

2.0 ppm (5.8 mg/

m3).

1.0 ppm (2.9 mg/

m3).

0.7 ppm (2.0 mg/

m3).

Asthmatic attack—human (Rotman et al., 1983)

AEGL–3 28 ppm (81 mg/

m3).

20 ppm (58 mg/

m3).

10 ppm (29 mg/

m3).

7.1 ppm (21 mg/

m3).

Lethality—rat (MacEwen and Vernot, 1972; Zwart

and Woutersen, 1988)

References

1. MacEwen, J.D. and E.H. Vernot. 1972.

Toxic Hazards Research Unit Annual

Technical Report: 1972. AMRL-TR-72–62,

Aerospace Medical Research Laboratory,

Wright-Patterson Air Force Base, OH;

National Technical Information Service,

Springfield, VA.

2. Rotman, H.H., M.J. Fliegelman, T.

Moore, R.G. Smith, D.M. Anglen, C.J.

Kowalski, and J.G. Weg. 1983. Effects of low

concentration of chlorine on pulmonary

function in humans. Journal of Applied

Physiology 54:1120–1124.

3. Zwart, A. and R.A. Woutersen. 1988.

Acute inhalation toxicity of chlorine in rats

and mice: time-concentration-mortality

relationships and effects on respiration.

Journal of Hazardous Material 19:195–208.

1,2-Dichloroethene

1,2-dichloroethene is a flammable,

colorless liquid existing in both cis- and

trans- forms and as a mixture of these

two isomers. It has been used as an

intermediate in the production of

chlorinated solvents and as a lowtemperature extraction solvent for

decaffeinated coffee, dyes, perfumes,

lacquers, and thermoplastics. The

compound is a narcotic. Data on

narcosis in humans, cats, rats, and mice,

and systemic effects in cats, rats, and

mice were available for development of

AEGLs. The data were considered

adequate for derivation of the three

AEGL classifications for four time

periods.

The AEGL–1 was based on a human

exposure concentration of 1,100 ppm

trans-1,2-dichloroethene for 5 mins

(Lehmann and Schmidt-Kehl 1936).

Although this is a no-effect-level for

narcotic effects it represents a

concentration that is above the odor

threshold. Because of the mode of action

and similarity in response to this

chemical as an irritant, this value was

divided by an uncertainty factor of 3 to

protect sensitive individuals and by a

modifying factor of 2 to account for the

probable difference in toxicity between

the cis- and trans- isomers. It was then

scaled to the 30-min, 1-, 4-, and 8-hr

exposures using the cn x t = k

relationship, where n = 2. The

concentration: exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by cn x t = k, where

the exponent, n, ranges from 1 to 3.5

(ten Berge et al 1986). Because no

exposure versus time data were

available, the mid-point value of 2 was

used as the exponent n for scaling the

AEGL values for dichloroethene across

time.

The AEGL–2 was based on slight

dizziness in humans exposed to 3300

ppm trans-1,2-dichloroethene for 5 mins

(Lehmann and Schmidt-Kehl 1936).

Because of the mode of action and

similarity in response to this chemical,

this value was divided by an

uncertainty factor of 3 to protect

sensitive individuals and by a

modifying factor of 2 to account for the

probable difference in toxicity between

the cis- and trans- isomers. It was then

scaled up to the 30-minute (min), 1-, 4-

, and 8-hr exposure periods using the cn

x t = k relationship, where the midpoint of the exponential range n = 2 was

used.

The AEGL–3 was based on fibrous

swelling and hyperemia of cardiac

muscle with little striation in rats

exposed to 3000 ppm trans-1,2-

dichloroethene for 8 hrs. Because the

lethality data are limited and quite

variable across species for the data that

do exist this value was divided by an

uncertainty factor of 10 to account for

interspecies variation. An additional

uncertainty factor of 3 was applied to

protect sensitive individuals and a

modifying factor of 2 was also applied

to account for the probable difference in

toxicity between the cis- and transisomers. The 8-hr AEGL value was then

scaled to the 30-min, 1-, and 4-hr

exposures using the cn x t = k

relationship, where the midpoint of the

experimental range n = 2 was used. The

calculated values are listed in the table

below.

SUMMARY OF PROPOSED AEGL VALUES FOR 1,2-DICHLOROETHENE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 (Nondisabling) 19 ppm (75 mg/m3) 13 ppm (53 mg/m3) 6.6 ppm (26 mg/

m3)

4.7 ppm (19 mg/

m3)

No effect in humans (Lehmann

and Schmidt-Kehl, 1936)

AEGL–2 (Disabling) 56 ppm (224 mg/

m3)

40 ppm (160 mg/

m3)

20 ppm (80 mg/m3) 14 ppm (56 mg/m3) Slight dizziness in humans

(Lehmann and Schmidt-Kehl,

1936)
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58845

SUMMARY OF PROPOSED AEGL VALUES FOR 1,2-DICHLOROETHENE—Continued

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–3 (Lethality) 200 ppm (800 mg/

m3)

141 ppm (564 mg/

m3)

71 ppm (284 mg/

m3)

50 ppm (200 mg/

m3)

Fibrous swelling and hyperemia of cardiac muscle with

poorly maintained striation in

rats (Freundt et al., 1977)

References

1. Freundt, K.J., Liebalt, G.P., and

Lieberwirth, E. 1977. Toxicity studies on

trans-1,2-dichloroethylene. Toxicology

7:141–153.

2. Lehmann, K.B. and Schmidt-Kehl, L.

1936. The thirteen most important

chlorinated aliphatic hydrocarbons from the

standpoint of industrial hygiene. Archive Fur

Hygiene 116:9–268.

3. ten Berge, W.F., Zwart. A, and

Appelman, L.M. 1986. Concentration-time

mortality response relationship of irritant

and systemically acting vapours and gases.

Journal of Hazardous Materials 13:301–309.

1,1- and 1,2-Dimethylhydrazine

Dimethylhydrazine occurs as a

symmetrical (1,2-dimethylhydrazine)

and asymmetrical (1,1-

dimethylhydrazine) isomer. Both

compounds are clear, colorless liquids.

Asymmetrical dimethylhydrazine (1,1-

dimethylhydrazine) is a component of

jet and rocket fuels and is also used as

an absorbent for acid gas, as a plant

growth control agent, and in chemical

synthesis. Although it has been

evaluated as a high-energy rocket fuel,

commercial use of the symmetrical

isomer (1,2-dimethylhydrazine) is

limited to small quantities and it is

usually considered to be a research

chemical. Because data are limited for

1,2-dimethylhydrazine (symmetrical

dimethylhydrazine), the AEGL values

are based upon 1,1-dimethylhydrazine

(asymmetrical). Limited data suggest

that1,1-dimethylhydrazine may be

somewhat more toxic than 1,2-

dimethylhydrazine.

Data on acute exposures of humans to

both isomers of dimethylhydrazine are

limited to case reports of accidental

exposures. Signs and symptoms of

exposure include respiratory irritation,

pulmonary edema, nausea, vomiting,

and neurological effects. However,

definitive exposure data (concentration

and duration) were unavailable for these

exposures.

Toxicity data of varying degrees of

completeness are available for several

laboratory species, including, rhesus

monkeys, dogs, rats, mice, and hamsters

(Weeks et al., 1963). Most of the animal

studies were conducted using 1,1-

dimethylhydrazine, although limited

data suggest that 1,2-dimethylhydrazine

exerts similar toxic effects. Minor

nonlethal effects such as respiratory

tract irritation appear to occur at

cumulative exposures of <100

(ppm)(hrs). At cumulative exposures at

or only slightly greater than 100

(ppm)(hrs), more notable effects have

been reported, including, muscle

fasciculation, behavioral changes,

tremors, and convulsions. At only

slightly higher exposure levels, lethality

has been demonstrated. The available

data suggest that there is very little

margin between exposure levels

resulting in no significant toxicity and

those causing substantial lethality (LC50

≈900–2,000 ppm hrs).

Developmental toxicity of

dimethylhydrazines has been

demonstrated in rats following

parenteral administration of maternally

toxic doses. Both isomers of

dimethylhydrazine have been shown to

be carcinogenic in rodents following

oral exposure and 6-month inhalation to

1,1-dimethylhydrazine resulted in an

increased tumor response in mice,

although these findings are

compromised by the contaminant

dimethylnitrosamine. Inhalation slope

factors are currently unavailable. It was

the consensus of the NAC/AEGL

Committee that AEGL–1 values for

dimethylhydrazine are inappropriate.

This conclusion was based upon the

onset of toxic effects at or below the

odor threshold, and a concentrationresponse relationship for

dimethylhydrazine that indicated little

margin between exposures producing no

toxic response and those resulting in

significant toxicity.

Behavioral changes and muscle

fasciculations in dogs exposed for 15

mins to 360 ppm 1,1-dimethylhydrazine

(Weeks et al., 1963) served as the basis

for deriving AEGL–2 values. Following

temporal scaling (C1 x t = k) to AEGLspecific exposure durations, the values

were adjusted by an uncertainty factor

of 30. An uncertainty factor of 3 for

interspecies variability was applied

because the toxic response to

dimethylhydrazine was similar across

the species tested. An uncertainty factor

of 10 for intraspecies variability was

applied because of the uncertainties

regarding the mechanism of action of

dimethylhydrazine toxicity and its

impact on susceptible individuals.

The AEGL–3 was derived from the 1-

hr LC50 (981 ppm) for 1,1-

dimethylhydrazine in dogs (Weeks et

al., 1963). Because of the steep slope of

the dose-response curve of 1,1-dimethyl

hydrazine, a modifying factor of 3 was

applied to the 1-hr LC50 of 981 ppm.

Hence, the modified lethality threshold

used to determine the AEGL–3 was 327

ppm. The downward adjustment of the

LC50 using a modification factor of 3

was considered a conservative approach

and, in part, justified the total

uncertainty factor of 30 (3 for

interspecies variability and 10 for

intraspecies variability). An uncertainty

factor of 3 for interspecies variability

was applied because the toxic response

to dimethylhydrazine was similar across

the species tested. An uncertainty factor

of 10 for intraspecies variability was

applied because of the uncertainties

regarding the mechanism of action of

dimethylhydrazine toxicity and its

potential impact on susceptible

individuals. Temporal scaling as

previously described was applied to

obtain exposure values for AEGLspecific exposure periods.

An estimation of AEGLs based upon

carcinogenic potential resulting from a

one time, short term exposure was

conducted and the assessment revealed

that AEGLs derived from carcinogenic

toxicity for a 10-4 carcinogenic risk

exceeded AEGL–3 values based on non

cancer endpoints. The relationship of

the various AEGL values reflects the

exposure-response relationship shown

by available animal data.
58846 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

SUMMARY OF PROPOSED AEGL VALUES FOR 1,1- AND 1,2-DIMETHYLHYDRAZINES

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 NAb ....................... NAb ...................... NAb ...................... NAb ...................... Inappropriate because notable toxicity may occur

at concentrations below the odor threshold;

concentration-response relationships suggest

little margin between exposures causing minor

effects and those resulting in serious toxicity.a

AEGL–2 6 ppm (14.7 mg/

m3)

3 ppm (7.4 mg/m3) 0.8 ppm (2 mg/m3) 0.4 ppm (1 mg/m3) Behavioral changes and muscle fasciculations in

dogs exposed to 360 ppm for 15 mins (Weeks

et al., 1963)

AEGL–3 22 ppm (54 mg/

m3)

11 ppm (27 mg/

m3)

3 ppm (7.4 mg/m3) 1.5 ppm (3.7 mg/

m3).

Lethality threshold of 327 ppm for 1-hr estimated

from 1-hr LC50 in dogs (Weeks et al., 1963)

aRefer to AEGL–1 for hydrazine if hydrazine is also present.

bNA Not appropriate

References

1. Weeks, M.H., Maxey, G.C., Sicks, and

Greene, E.A. 1963. Vapor toxicity of UDMH

in rats and dogs from short exposures.

American Industrial Hygiene Association

Journal 24:137–143.

Ethylene Oxide

Ethylene oxide is a highly flammable

gas produced in very large quantities in

the United States (5.3–6.3 billion

pounds). It is very reactive with

nucleophiles, such as water, alcohols,

halides, amines, and sulfhydryl

compounds. Ethylene oxide is used as

an intermediate in the production of

ethylene glycol and nonionic

surfactants; a small amount is used as a

fumigant for sterilizing foods and heatsensitive medical equipment. The odor

detection level for ethylene oxide is 260

ppm (468 mg/m3) to 700 ppm (1,260

mg/m3).

The database of toxicity to ethylene

oxide vapor in humans and

experimental animals is very extensive

including data on all aspects of toxicity

except lethality in humans.

Pharmacokinetics data show that

ethylene oxide is readily absorbed from

the respiratory tract of both humans and

animals. It alkylates proteins and DNA,

and it is metabolized by hydrolysis and

glutathione conjugation.

In humans, inhaled ethylene oxide

vapor affects the eyes, respiratory tract,

central and peripheral nervous systems,

gastrointestinal tract (probably

secondary effects to nervous system

toxicity), hematopoietic system, and

possibly the reproductive system, and

fetus. Acute exposure to ethylene oxide

at the odor detection level (≥260 ppm)

causes eye and upper respiratory tract

irritation and signs and symptoms of

effects on the central and peripheral

nervous system. Acute exposure to a

calculated concentration of 500 ppm for

2 to 3 minutes caused hematologic

effects and more severe effects on the

central nervous system than those noted

at the odor detection level. Effects

observed after acute exposure are

reversible, including severe nervous

system effects. Peripheral nervous

damage is exacerbated by repeated

exposures. Human studies have

provided suggestive evidence of

reproductive toxicity, some evidence of

an association between exposure to

ethylene oxide and genetic damage to

somatic cells and limited evidence of

carcinogenicity.

Acute lethality studies in

experimental animals showed that mice

are the most sensitive species (4-hrs

LC50 = 660–835 ppm) (Jacobson et al.,

1956), followed by the dog (4-hrs LC50

= 960 ppm) (Jacobson et al., 1956) and

rat (4-hrs LC50 = 1537–1972 ppm; 1-hr

LC50 = 4439–5748 ppm) (Jacobson et al.,

1956). Immediate deaths were due to

respiratory failure and delayed deaths

were due to secondary respiratory

infections. Experimental animals

exposed to lethal and nonlethal

concentrations of ethylene oxide

showed evidence of eye and respiratory

irritation and effects on the central and

peripheral nervous system (Embree et

al., 1977). Additional studies in animals

exposed to ethylene oxide for various

durations up to 6 hrs/day provided

evidence of reproductive toxicity at ≥50

ppm, developmental toxicity at ≥50

ppm, genetic toxicity in germ cells at

≥75 ppm, and carcinogenicity at 100

ppm.

Data were available for deriving

AEGL–2 and –3 values. Values for

AEGL–1 were not derived because the

odor threshold and concentrations

causing mild sensory irritation would be

above the AEGL–2 levels.

The AEGL–2 values were based on a

rat study showing central nervous

system depression, diarrhea, and eye

and respiratory tract irritation after

exposure to 1,000 ppm of ethylene

oxide for 4 hrs (Embree et al., 1977);

genetic toxicity (dominant lethality) was

also seen at this concentration in this

same study. An uncertainty factor of 10

was applied for intraspecies variability,

because of the steep slope of the dose

response relationship from severe

irritation and central nervous system

depression to the lethality threshold. An

uncertainty factor of 3 was applied for

interspecies sensitivity, because modes

of action are likely to be similar between

rodents and humans and systemic

uptake of ethylene oxide is similar

across species. The time-scaling

approach used ten Berge’s equation in

which Cn t = k, and n = 1.2 based on

analysis of rat lethality data.

AEGL–3 values were derived from

lethality data in the rat. An LC01 value

(628 ppm), which is considered an

approximation of the lethality

threshold, was estimated from data in a

4-hr acute inhalation study with rats

reported by Jacobson et al. (1956). An

uncertainty factor of 10 for intraspecies

sensitivity was applied to the LC01

estimated value and this was followed

by scaling to the different AEGL

exposure periods based on ten Berge’s

equation (Cn t = k, where n = 1.2 was

used based on reported lethality data for

1- and 4-hr exposures). An interspecies

uncertainty factor of 3 was applied

because systemic uptake, distribution,

and modes of action are likely to be

similar between rodents and humans.

There are differences in metabolism

kinetics, but they are unlikely to affect

responses to high acute exposures.

Assessment of carcinogenicity data

(lung adenomas/carcinomas in female

mouse) (NTP, 1987) showed that

extrapolating the total cumulative

exposure over a 2-year period to single

exposures and estimating a 10-4 risk

resulted in AEGL–3 values of 2,764,

1,382, 346, and 173 ppm for 0.5-, 1-, 4-

, and 8-hr exposures. These values

exceed those derived from lethality

data.
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58847

AEGL values derived for ethylene

oxide are summarized below:

SUMMARY OF PROPOSED AEGL VALUES FOR ETHYLENE OXIDE

Classification

Exposure Periods

Endpoint (Reference)

30-minute 1-hour 4-hour 8-hour

AEGL–1 No values derived No values derived No values derived No values derived

AEGL–2 190 ppm (342 mg/

m3)

110 ppm (198 mg/

m3)

33 ppm (59 mg/

m3)

19 ppm (34 mg/

m3)

Central nervous system effects Embree et al.,

1977

AEGL–3 360 ppm (648 mg/

m3)

200 ppm (360 mg/

m3)

63 ppm (113 mg/

m3)

35 ppm (63 mg/

m3)

Lethality threshold Jacobson et al., 1956

References

1. Embree, J.W., Lyon, J.P., and Hine, C.H.

1977. The mutagenic potential of ethylene

oxide using the dominant-lethal assay in rats.

Toxicology and Applied Pharmacology

40:261–267.

2. Jacobson, K.H., Hackley, E.B., and

Feinsliver, L. 1956. The toxicity of inhaled

ethylene oxide and propylene oxide vapors.

Archive for Industrial Health 13:237–244.

Fluorine

Fluorine is a reactive, highly irritant

gas used in the nuclear energy industry,

as an oxidizer of liquid rocket fuels, and

in the manufacture of various fluorides

and fluorocarbons. Fluorine is a severe

irritant to the eyes, mucous membranes,

lungs, and skin; the eyes and the

respiratory tract are the target organ/

tissues of an acute exposure. Data on

irritant effects in humans and lethal and

sublethal effects in five species of

mammals (dog, rat, mouse, guinea pig,

and rabbit) were available for

development of AEGLs (Keplinger and

Suissa, 1968). Regression analyses of the

concentration-exposure durations (for

the fixed endpoint of mortality) for all

of the animal species reported

determined that the relationship

between concentration and time is Cn x

t = k, where n = approximately 2 (actual

value for n for the most sensitive

species, the mouse = 1.77). The data

were considered adequate for derivation

of the three AEGL classifications for

four time periods.

The AEGL–1 was based on the

observation that human volunteers

could tolerate exposure to 10 ppm for 15

mins without irritant effects (Keplinger

and Suissa, 1968). An uncertainty factor

of 3 was applied to this NOAEL value

to protect sensitive individuals, since

fluorine reacts corrosively with the

tissues of the respiratory tract and

effects are not likely to differ greatly

among individuals, including sensitive

individuals. The value was then scaled

to the 30-min and 1-, 4-, and 8-hr

exposure durations using the C1.77 x t =

k concentration-exposure duration

relationship. It was the consensus of the

NAC/AEGL Committee that at mildly

irritating concentrations there is a

tolerance to irritating gases. Therefore,

the calculated 30-min and 1-hr values of

2.3 and 1.5 ppm, respectively, were

rounded to 2 ppm and the calculated 4-

and 8-hr values of 0.7 and 0.5 ppm,

respectively, were rounded to 1 ppm. The AEGL–2 was based on an animal

study in which mild lung congestion

was observed in mice at 67 ppm for 30

mins and 30 ppm for 60 mins (Keplinger

and Suissa, 1968). Although

concentrations causing irritant effects

for each species for the same time

periods suggested similar species

sensitivity, the mouse data, because of

slightly lower values, were chosen as

the basis for developing the AEGL–2

and AEGL–3. Because the action of

irritant and corrosive gases is directly

on the tissues, with no pharmacokinetic

component involved in the toxicity,

there is likely to be little difference

among species in response to fluorine

exposure. Because similar sensitivity

was observed among all species in the

key study, no uncertainty factor for

interspecies variability was applied. The

values were divided by an intraspecies

uncertainty factor of 3 to protect

sensitive individuals, since effects are

not likely to differ greatly among

individuals. The values also were

adjusted by a modifying factor of 2,

based on a limited data base. AEGL–2

values for the other exposure periods

were scaled based on the C1.77 x t = k

relationship.

The AEGL–3 values were derived

from exposure concentrations equal to

one half of the LC50 values reported

(Keplinger and Suissa, 1968). The

experimental 1⁄2 LC50 concentrations

tested resulted in no deaths in any

species for up to 45 days post exposure,

but did produce severe lung congestion

in the mouse (Keplinger and Suissa,

1968). For the mouse, the 60-min value

was 75 ppm. Because of the similar

species sensitivity in the key study, no

uncertainty factor for interspecies

variability was applied. The values were

divided by an uncertainty factor of 3 to

protect sensitive individuals and by a

modifying factor of 2, based on a limited

data base. AEGL–3 values for the other

exposure times were calculated based

on the C1.77 x t = k relationship.

The calculated values are listed in the

table below.

SUMMARY OF PROPOSED AEGL VALUES FOR FLUORINEa

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 2ppm (3.1 mg/m3) 2 ppm (3.1 mg/

m3)

1 ppm (1.6 mg/

m3)

1 ppm (1.6 mg/

m3)

No irritant effect-humans (Keplinger and Suissa,

1968)

AEGL–2b 11 ppm (17 mg/

m3).

5.0 ppm (7.8 mg/

m3).

2.3 ppm (3.6 mg/

m3).

1.5 ppm (2.3 mg/

m3).

Mild lung congestion—mice (Keplinger and

Suissa, 1968)

AEGL–3 19 ppm (29 mg/

m3).

13 ppm (20 mg/

m3).

5.7 ppm (8.8 mg/

m3).

3.9 ppm (6.0 mg/

m3).

Severe lung congestion—mice (Keplinger and

Suissa, 1968)

a AEGL–1 values were rounded off because of tolerance to low concentrations of irritant gases. AEGL–2 and AEGL–3 values were rounded to

two significant figures. b30-min and 1-hr AEGL–2 values are based on separate data points.
58848 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

1 Each uncertainty factor of 3 is actually the

geometric mean of 10 which is 3.16, hence 3.16 x

3.16 = 10.

References

1. Keplinger, M.L. and L.W. Suissa. 1968.

Toxicity of fluorine short-term inhalation.

American Industrial Hygiene Association

Journal 29:10–18.

Hydrazine

Hydrazine is a highly reactive

reducing agent used in various chemical

manufacturing processes. Hydrazine is

used by the military as a missile and

rocket propellant, and in power sources.

Human data on the toxicity of

hydrazine following acute inhalation

exposure are limited to anecdotal

accounts that lack definitive exposure

data. The utility of this information is

compromised by concurrent exposure to

other chemicals and involvement of

simultaneous multiple exposure routes.

Studies have shown that the toxicity

of methylated derivatives of hydrazine

is qualitatively similar to that of

hydrazine except in dogs wherein

methylhydrazine has been observed to

cause intravascular hemolysis. Based

upon limited acute toxicity data,

methylhydrazine and symmetrical

dimethylhydrazine appear to be

somewhat more toxic in rats and mice

than is hydrazine while asymmetrical

hydrazine appears to be slightly less

toxic.

Data from animal studies indicate that

hydrazine may be metabolized to

acetylhydrazine, diacetylhydrazine,

ammonia, and urea, and may form

hydrazones with pyruvate and 2-

oxoglutarate. The biotransformation of

hydrazine is mediated, at least in part,

by hepatic monooxygenases. The role of

metabolism and absorption/excretion

kinetics is uncertain regarding

immediate port-of-entry toxic effects

from acute inhalation exposures. The

highly reactive nature of hydrazine per

se is a plausible determinant of acute

port-of-entry toxic effects.

AEGLs were based upon data sets

defining toxicity endpoints that were

specific for the AEGL level. Values for

the specific exposure durations were

derived based upon exponential scaling

(Cn x t = k, where n = 2) from the

experimental exposure period. This

method was more appropriate for

concentration-dependent effects than

linear (Haber’s Law) scaling. The

concentration exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by cn x t = k, where

the exponent, n, ranges from 1 to 3.5

(ten Berge et al 1986). Because no

exposure versus time data were

available, the mid-point value of 2 was

used as the exponent n for scaling the

AEGL values for hydrazine across time.

AEGL–1 values were based upon a

study by House (1964) in which male

monkeys exhibited skin flushing and

eye irritation after a 24-hr continuous

exposure to 0.4 ppm hydrazine. A total

uncertainty factor of 10 was applied to

derive the AEGL–1 values.1 An

uncertainty factor of 3 was applied for

interspecies variability because the

contact irritation response to the highly

reactive hydrazine is not likely to vary

greatly among species, and because a

nonhuman primate was the test species.

An uncertainty factor of 3 was applied

for intraspecies variability because the

contact irritation from the highly

reactive hydrazine is not expected to

vary greatly among individuals. The 24-

hr experimental value was scaled to 8

hrs using Cn x t = k, where n = 2 as

described above. Because hydrazine is

extremely reactive and the effects are

considered to be concentration

dependent rather than time dependent,

the 0.1 ppm AEGL–1 value derived for

the 8-hr duration was also applied to the

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

The AEGL–2 was derived based upon

data from a study by Latendresse et al.

(1995) in which rats exposed to

hydrazine (750 ppm) for 1 hr exhibited

nasal lesions. Following a dosimetric

adjustment based upon regional gas

dose (U.S. EPA 1994), the values were

scaled to AEGL-specific durations as for

AEGL–1 and a total uncertainty factor of

30 applied. An uncertainty factor of 10

for interspecies variability was applied

to account for a deficiency in data

pertaining to species variability and also

variability in the data that are available.

An uncertainty factor of 3 was applied

for intraspecies variability because the

toxic response to hydrazine is not likely

to vary considerably among individuals

of the same species, including

susceptible individuals.

The AEGL–3 values were derived

based upon a rat inhalation study (HRC,

1993) that provided data to estimate a

lethality threshold (LC01 = 337 ppm).

Temporal scaling was again applied

using the exponential expression C2 x t

= k. Dosimetric conversion using a

regional gas dose methodology (U.S.

EPA 1994) was applied and resulting

exposure values adjusted by a total

uncertainty factor of 30. An uncertainty

factor of 10 for interspecies variability

was applied to account for a deficiency

in data pertaining to species variability

and also variability in the data that are

available. An uncertainty factor of 3 was

applied for intraspecies variability

because the toxic response to hydrazine

is not likely to vary considerably among

individuals of the same species.

An estimation of AEGLs based upon

carcinogenic potential resulting from a

one-time, short term exposure was

conducted using the inhalation cancer

slope factor for hydrazine. The

assessment revealed that AEGLs derived

from noncarcinogenic toxicity

endpoints were lower values and so the

AEGL–3 values were based on the

noncarcinogenic endpoint.

The proposed AEGLs, their respective

toxicity endpoints and references are

summarized below.

SUMMARY OF PROPOSED AEGL VALUES FOR HYDRAZINE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 0.1 ppm (0.1 mg/m3) 0.1 ppm (0.1 mg/m3) 0.1 ppm (0.1 mg/m3) 0.1 ppm (0.1 mg/m3) Eye and facial irritation inmonkeys

(House, 1964)a

AEGL–2 8 ppm (10 mg/m3) .. 6 ppm (8 mg/m3) .... 3 ppm (4 mg/m3) .... 2 ppm (3 mg/m3) .... Nasal lesions (Latendresse et al., 1995)

AEGL–3 47 ppm (61 mg/m3) 33 ppm (43 mg/m3) 17 ppm (22 mg/m3) 12 ppm (16 mg/m3) Lethality in rats (HRC, 1993)

a Because the contact irritation response to the extremely reactive hydrazine is concentration dependent rather than time-dependent, the

AEGL–1 is the same of all time periods.
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58849

2Each uncertainty factor of 3 is the geometric

mean of 10 which is 3.16; hence, 3.16. x 3.16 = 10.

References

1. House, W.B. 1964. Tolerance criteria for

continuous exposure inhalation exposure to

toxic materials. Part III. Effects on animals of

90-day exposure to hydrazine,

unsymmetrical dimethylhydrazine (UMDH),

decaborane, and nitrogen dioxide. ASD–TR–

61–519 (iii). Wright-Patterson AFB, OH. 84

pp.

2. HRC (Huntington Research Centre, Ltd.).

1993. Hydrazine 64% aqueous solution:

acute inhalation toxicity in rats 1-hr

exposure. Huntington Research Centre,

Cambridge, England. CMA 8/930523.

3. Latendresse, J.R., Marit, G.B., Vernot,

E.H., Haun, C.C., and Flemming, C.D. 1995.

Oncogenic potential of hydrazine in the nose

of rats and hamsters after 1 or 10 1-hr

exposures. Fundamental and Applied

Toxicology 27:33–48.

4. ten Berge, W.F., Zwart. A, and

Appelman, L.M. 1986. Concentration-time

mortality response relationship of irritant

and systemically acting vapours and gases.

Journal of Hazardous Materials 13:301–309.

5. U.S. EPA 1994. EPA/600/8–90/066F,

Methods for Derivation of Inhalation

Reference Concentrations and Application of

Inhalation Dosimetry.

Methylhydrazine

Methylhydrazine is a clear, colorless

liquid used extensively in military

applications as a missile and rocket

propellant, in chemical power sources,

and as a solvent and chemical

intermediate. Upon contact with strong

oxidizers (e.g., hydrogen peroxide,

nitrogen tetroxide, chlorine, and

fluorine) spontaneous ignition may

occur.

Human volunteers exposed to 90 ppm

methylhydrazine for 10 mins reported

minor irritation as the only effect of

exposure (MacEwen et al., 1970).

Toxicity data are available for

multiple laboratory species including,

rhesus monkeys, squirrel monkeys,

beagle dogs, rats, mice, and hamsters.

Nonlethal toxic effects include irritation

of the respiratory tract, hemolytic

responses, and some evidence of renal

and hepatic toxicity. Lethal exposures

are usually preceded by convulsions.

Lethal toxicity varies somewhat among

species. One-hour LC50 values of 162,

82, 96, 244, 122, and 991 ppm have

been determined for rhesus monkeys,

squirrel monkeys, beagle dogs, rats,

mice, and hamsters, respectively.

Concentration-time relationships appear

to follow Haber’s Law although there

appears to be a critical threshold for

lethality with little margin between

exposures causing only minor,

reversible effects, and those resulting in

lethality.

In a 1-year inhalation bioassay using

dogs, rats, mice, and hamsters,

methylhydrazine concentrations of 2

ppm and 5 ppm, there was no evidence

of treatment-related carcinogenicity in

dogs or rats even after a 1-year post

exposure observation period. However,

mice exposed to 2 ppm for the same

duration exhibited an increased

incidence of lung tumors, nasal

adenomas, nasal polyps, nasal osteomas,

hemangioma, and liver adenomas and

carcinomas. In hamsters exposed to 2 or

5 ppm, there was an increase in nasal

polyps and nasal adenomas (5 ppm

only), interstitial fibrosis of the kidney,

and benign adrenal adenomas.

It was the consensus of the NAC/

AEGL Committee that the setting of

AEGL–1 values for methylhydrazine

would be inappropriate. This

conclusion was based on the occurrence

of toxic effects at or below the odor

threshold, and a concentration-response

relationship for methylhydrazine that

indicated little margin between

exposures producing no toxic response

and those resulting in significant

toxicity.

The AEGL–2 values were derived by

applying a modifying factor of 3 to each

of the AEGL–3 values. This estimate of

a threshold for irreversible effects was

justified because of the absence of

exposure-response data related to

irreversible or other serious, long-lasting

effects and the steep dose-response

relationship indicated by the data that

was available on methylhydrazine. For

AEGL–3, lethality data (1-hr LC50 of 82

ppm) for squirrel monkeys (Haun et al.,

1970) was adjusted using a modifying

factor of 3 to estimate a lethality

threshold (27 ppm). The lethality data

for the species tested indicated a linear

relationship between concentration and

time. Therefore, temporal scaling to

obtain time-specific AEGL values was

described as C1 x t = k where the

exponent n = 1. The derived exposure

values were adjusted by a total

uncertainty factor of 10. An uncertainty

factor of 3 was applied for interspecies

variability because a sensitive

nonhuman primate was used to estimate

the lethality threshold, and an

uncertainty factor of 3 was used for

intraspecies variability due to the steep

exposure-response relationship.2

The AEGL values reflect the steep

exposure-response relationship

exhibited by the toxicity data.

Additional information regarding the

mechanism(s) of action and metabolism

of methylhydrazine may provide insight

into understanding and defining the

threshold between nonlethal and lethal

exposures.

An estimation of AEGLs based upon

carcinogenic potential resulting from a

one-time, short-term exposure was

conducted and the assessment revealed

that AEGLs derived from carcinogenic

toxicity for a 10-4 carcinogenic risk

exceeded AEGL–3 values based on non

cancer endpoints.

SUMMARY OF PROPOSED AEGL VALUES FOR METHYLHYDRAZINE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 NA ........................ NA ........................ NA ........................ NA ........................ Inappropriate because notable toxicity may occur

at concentrations below the odor threshold;

concentration-response relationships suggest

little margin between exposures causing minor

effects and those resulting in serious toxicity.a

AEGL–2 2 ppm (3.8 mg/m3) 1 ppm (1.9 mg/m3) 0.2 ppm (0.4 mg/

m3)

0.1 ppm (0.2 mg/

m3)

Three-fold reduction in AEGL–3.

AEGL–3 6 ppm (11.3 mg/

m3)

3 ppm (5.6 mg/m3) 0.7 ppm (1.1 mg/

m3)

0.3 ppm (0.6 mg/

m3)

1-hr LC50 of 82 ppm reduced 3-fold to estimate a

lethality threshold; UF–10

a Refer to AEGL–1 for hydrazine if hydrazine is also present.
58850 Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices

References

1. Haun, C.C., MacEwen, J.D., Vernot, E.H.,

and Egan, G.F. 1970. Acute inhalation

toxicity of monomethylhydrazine vapor.

American Industrial Hygiene Association

Journal 31:667–677.

2. MacEwen, J.D., Theodore, J., and Vernot,

E.H. 1970. Human exposure to EEL

concentrations of monomethylhydrazine.

Proceedings. First Annual Conference on

Environmental Toxicology. AMRL–TR–70–

102, Aerospace Medical Research Laboratory,

Wright-Patterson Air Force Base, OH.

Nitric Acid

Nitric acid is a highly corrosive,

strongly oxidizing acid. The course of

toxicity following inhalation exposure

to nitric acid is consistent between

humans and animals. Nitric acid fumes

may cause immediate irritation of the

respiratory tract, pain, and dyspnea

which are followed by a period of

recovery that may last several weeks.

After this time, a relapse may occur

with death caused by

bronchopneumonia and/or pulmonary

fibrosis. For exposure to nonlethal

concentrations, allergic or asthmatic

individuals appear to be a sensitive

subpopulation.

For derivation of the AEGL values,

both human and animal data were

utilized. For AEGL–1, humans exposed

to 1.6 ppm (4.13 mg/m3) for 10 mins

showed no changes in pulmonary

function (Sackner and Ford, 1981). An

uncertainty factor of 3 was applied to

account for sensitive populations, since

the mechanism of action of an irritant

gas is not expected to vary greatly

among individuals. Scaling to the 30-

min, 1-, 4-, and 8-hr exposure periods

was not performed because this was a

no effect level and irritation is generally

concentration dependent but not time

dependent. The derived AEGL–1 value

is above the odor threshold which

provides a warning of exposure before

an individual would experience notable

discomfort.

AEGL–2 values were derived from

data on human studies (Diem, 1907).

Individuals exposed to 12 ppm (31 mg/

m3) nitric acid for 1 hour experienced

respiratory irritation, pressure in the

chest, slight stabbing pains in the

trachea and larynx, coughing, marked

secretion from the nose and salivary

glands, burning of the eyes and

lacrimation, and burning and itching of

facial skin. An uncertainty factor of 3

was applied to the 1-hr exposure level

reported in this study and scaling of the

value to 30 mins, 4 hrs, and 8 hrs was

accomplished as described below.

Very little data were available for

determining AEGL–3 levels. Human

case reports of severe injury or death

did not contain exposure concentrations

and in most animal studies, nitric acid

was administered by intratracheal

instillation. Extrapolation from a

mortality versus concentration curve in

the published literature indicated that

the LC0 was approximately one-third the

LC50 value of 138 ppm (356 mg/m3) for

the rat. This concentration was reported

as nitrogen dioxide (NO2) instead of

total nitric acid. From the estimated LC0

an uncertainty factor of 3 was applied

to account for sensitive individuals. Due

to the steepness of the dose-response

curve for nitric acid, application of

additional uncertainty factors would

lower the AEGL–3 values below the

values derived for AEGL–2 which were

based on human data and, since the

mechanism of action appears to be the

same in both humans and animals with

the production of both pulmonary

edema and bronchiolitis obliterans,

additional uncertainty factors were not

used.

The concentration-exposure time

relationship is described by the

equation cn t = k. Although insufficient

data on nitric acid were available to

calculate the exponent n, structureactivity relationships indicated that

nitric acid and NO2 have parallel doseresponse curves for a 30-min exposure.

Therefore, for extrapolation to the

various time points for the AEGL–2 and

–3 levels, a previously published n of

3.5 derived from NO2 data was used.

The calculated values for the three

AEGL classifications for the four time

periods are listed in the table below.

SUMMARY TABLE OF PROPOSED AEGL VALUES FOR NITRIC ACID

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 0.5 ppm (1.3mg/

m3).

0.5 ppm (1.3mg/

m3).

0.5 ppm (1.3mg/

m3).

0.5 ppm (1.3mg/

m3).

No observed effect level (NOEL) for changes in

pulmonary function in humans (Sackner and

Ford, 1981); UF=3

AEGL–2 5 ppm (13mg/m3) 4 ppm (10mg/m3) 3 ppm (8mg/m3) 2 ppm (5mg/m3) Irritation with cough; burning of eyes and skin;

lacrimationand salivation (Diem, 1907); UF=3

AEGL–3 15 ppm (39mg/m3) 13 ppm (34mg/m3) 8 ppm (21mg/m3) 7 ppm (18mg/m3) LC0 estimated from a 30-min LC50 in the rat

(Gray et al., 1954); UF=3

References

1. Diem, L.1907. [Experimentelle

Untersuchungen u ̈ ber die Einatmung von

Saltpetersa ̈ure-Da ̈mpfen].Thesis, D-8700,

Wu ̈rzburg. (as cited in Henschler, 1991).

2. Gray, E.Le B., Patton, F.M., Goldberg,

S.B., and Kaplan, E.1954. Toxicity of the

oxides of nitrogen. Part II. Acute inhalation

toxicity of nitrogen dioxide, red fuming nitric

acid, and white fuming nitric acid. Archive

for Industrial Hygiene and Occupational

Medicine 10:418–422.

3. Henschler, D.1991. Occupational

Toxicants Critical Data Evaluation for MAK

Values and Classification of Carcinogens,

Vol. 3. VCH Publishers, New York (USA) and

Weinheim (FRG).

4. Sackner, M.A. and Ford, D. 1981. Effects

of breathing nitrate aerosols in high

concentrations for 10 mins on pulmonary

function of normal and asthmatic adults, and

preliminary results in normals exposed to

nitric acid fumes. American Review of

Respiratory Diseases 123:151.

Phosphine

Phosphine is a colorless gas used as

a fumigant against insects and rodents

in stored grain. The pesticide is usually

applied as a metal phosphide and reacts

with moisture to liberate phosphine gas.

Phosphine is also used in the

semiconductor industry. Information

concerning human exposure to

phosphine is of limited use in

derivation of AEGL values since

exposure duration and concentration are

not precisely reported. Appropriate

animal data are more abundant;

however, data consistent with the

definition of AEGL–1 values are not

available. Therefore, due to insufficient

data, AEGL–1 values were not derived.

The AEGL–2 was based on a NOEL for

renal and pulmonary pathology in

Fischer 344 rats exposed to 3.1 ppm

phosphine 6 hrs/day, 5 days/week for

13 weeks (Newton et al, 1993). Scaling

to the 30-min, 1-, 4-, and 8-hr exposures

was accomplished using the cn x t = k

relationship, where n = 2. The
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 / Notices 58851

concentration exposure time

relationship for many irritant and

systemically acting vapors and gases

may be described by cn x t = k, where

the exponent, n, ranges from 1 to 3.5

(ten Berge et al 1986). For scaling the

AEGL values for phosphine across time,

the mid-point value of 2 was used as the

exponent n because no exposure versus

time data were available. An uncertainty

factor of 3 was used for interspecies

extrapolation since the rat is the most

sensitive species. An uncertainity factor

of 10 was used for intraspecies

extrapolation since the data indicate

that children are more sensitive than

adults when exposed to phosphine.

The AEGL–3 was based on a NOEL for

lethality (18 ppm phosphine) in Sprague

Dawley rats exposed to phosphine for 6

hrs. Scaling to the 30-min, 1-, 4-, and 8-

hr exposures was accomplished using

the cn x t = k relationship, where n =

2. An uncertainty factor of 3 was used

for interspecies extrapolation since the

rat is the most sensitive species and an

uncertainity factor of 10 was used for

intraspecies extrapolation since data

indicate that children are more sensitive

than adults when exposed to phosphine.

The calculated values are listed in the

table below.

SUMMARY TABLE OF PROPOSED AEGL VALUES PHOSPHINE

Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL–1 (Nondisabling)............................. ............................. ........................... ............................. Appropriate data not available

AEGL–2 (Disabling) 0.36 ppm (0.52 mg/

m3).

0.25 ppm (0.35 mg/

m3).

0.13 ppm (0.18mg/

m3).

0.09 ppm (0.13 mg/

m3).

NOEL for renal and pulmonary pathology in rats

exposed to 3.1 ppm

phosphine, 6 hr/day, 5

days/week for 13 weeks

(Newton et al., 1993)

AEGL–3 (Lethality) .. 2.1 ppm (2.9 mg/m3) 1.5 ppm (2.1 mg/m3) 0.74 ppm (1.0 mg/

m3).

0.52 ppm (0.73 mg/

m3).

NOEL for lethality in rats exposed to 18 ppm

phosphine for 6

hr.(Newton, 1991)

References

1. Newton, P.E. 1991. Acute Inhalation

exposures of rats to phosphine. Biology

Dynamics, Inc. East Millstone, NJ. Project No.

90–8271.

2. Newton, P.E., Schroeder, R.E., Sullivan,

J.B., Busey, W.M., and Banas, D.A. 1993.

Inhalation toxicity of phosphine in the rat:

acute, subchronic, and developmental.

Inhalation Toxicology 5:223–239.

V. Public Record and Electronic

Submission

The official record for this notice, as

well as the public version, has been

established for this notice under docket

control number (OPPTS–00218; FRL–

5737–3) (including comments and data

submitted electronically as described

below). A public version of this record,

including printed, paper versions of

electronic comments, which does not

include any information claimed as CBI,

is available for inspection from 12 noon

to 4 p.m., Monday through Friday,

excluding legal holidays. The official

record is located in the TSCA

Nonconfidential Information Center,

Rm. NE–B607, 401 M St., SW.,

Washington, DC.

Electronic comments can be sent

directly to EPA at:

oppt.ncic@epamail.epa.gov

Electronic comments must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption. Comments and data will

also be accepted on disks in

WordPerfect in 5.1/6.1 file format or

ASCII file format. All comments and

data in electronic form must be

identified by the docket control number

(OPPTS–00218; FRL–5737–3).

Electronic comments on this notice may

be filed online at many Federal

Depository Libraries.

All comments which contain

information claimed as CBI must be

clearly marked as such. Three sanitized

copies of any comments containing

information claimed as CBI must also be

submitted and will be placed in the

public record for this notice. Persons

submitting information on any portion

of which they believe is entitled to

treatment as CBI by EPA must assert a

business confidentiality claim in

accordance with 40 CFR 2.203(b) for

each such portion. This claim must be

made at the time that the information is

submitted to EPA. If a submitter does

not assert a confidentiality claim at the

time of submission, EPA will consider

this as a waiver of any confidentiality

claim and the information may be made

available to the public by EPA without

further notice to the submitter.

List of Subjects

Environmental protection, Hazardous

substances.

Dated: October 20, 1997.

Lynn R. Goldman,

Assistant Administrator for Prevention,

Pesticides and Toxic Substances.

[FR Doc. 97–28642 Filed 10–29–97; 8:45 am]

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