Toxic and hazardous substances control: Acute Exposure Guideline Levels for Hazardous Substances National Advisory Committee; proposed AEGL values,
[Federal Register: December 13, 2000 (Volume 65, Number 240)]
[Notices]
[Page 77866-77874]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13de00-51]
ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-00302; FRL-6752-5]
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 7 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 record for these 7 chemicals.
DATES: Comments, identified by the docket control number OPPTS-00302, must be received by EPA on or before January 12, 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-00302 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, Office of Pollution Prevention and Toxics (7408), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (202) 554-1404 and TDD: (202) 554-055; 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:
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General Information
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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 technical person listed under FOR FURTHER INFORMATION CONTACT.
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How Can I Get Additional Information, Including Copies of this Document or Other Related Documents?
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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,'' ``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/.
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In person. The Agency has established an official record for this action under docket control number OPPTS-00302. 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.
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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.
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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-00302 in the subject line on the first page of your response.
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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 this unit).
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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.
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Electronically. You may submit your comments electronically by e-mail
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to: oppt.ncic@epa.gov, or mail your computer disk to the address identified above. Do not submit any information electronically that you consider to be CBI. Electronic comments must be submitted as an ASCII file avoiding the use of special characters and any form of encryption. Comments and data will also be accepted on standard disks in WordPerfect 6.1/8.1 or ASCII file format. All comments in electronic form must be identified by docket control numbers OPPTS-00302. Electronic comments may also be filedonline at many Federal Depository Libraries.
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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 technical person listed under FOR FURTHER INFORMATION CONTACT.
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What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your comments:
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Explain your views as clearly as possible.
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Describe any assumptions that you used.
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Provide copies of any technical information and/or data that you used that support your views.
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If you estimate potential burden or costs, explain how you arrived at the estimate that you provide.
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Provide specific examples to illustrate your concerns.
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Offer alternative ways to improve this notice.
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Make sure to submit your comments by the deadline in this document.
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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.
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Background
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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 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 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.
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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 cube (mg/m\3\) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory 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/m\3\) 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/m\3\) 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.
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Development of the AEGLs
The NAC/AEGL Committee develops the AEGL values on a chemical-by- chemical basis. Relevant data and information are gathered from all known sources including published scientific literature, State and Federal agency publications, private industry, public databases, and individual experts in both the public and private sectors. All key data and information are summarized for the NAC/AEGL
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Committee in draft form by Oak Ridge National Laboratories together with ``draft'' AEGL values prepared in conjunction with NAC/AEGL Committee members. Both the ``draft'' AEGLs and ``draft'' technical support documents are reviewed and revised as necessary by the NAC/AEGL Committee members prior to formal 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 document, the NAC/AEGL Committee is publishing proposed AEGL values and the accompanying scientific rationale for their development for 7 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); and for 14 chemicals in the Federal Register of June 23, 2000 (65 FR 39263-39277) (FRL-6591-2) 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 (NRC/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.
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List of Chemicals
On behalf of the NAC/AEGL Committee, EPA is providing an opportunity for public comment on the AEGLs for the 7 chemicals identified in Table 1. Table 1 also provides the fax-on-demand item number for the chemical specific documents, which may be obtained as described in Unit 1.B.
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Fax-On-Demand Table
Table 1.--Fax-On-Demand
Fax-On-Demand item CAS No.
Chemical name
no.
75-44-5......................... Phosgene.......... 4862 78-82-0......................... Isobutyronitrile.. 4869 107-12-0........................ Propionitrile..... 4877 126-98-7........................ Methacrylonitrile. 4888 7790- 91-2...................... Chlorine
4922 trifluoride. 151-56-4........................ Ethylenimine...... 4890 75-55-8......................... Propylenimine..... 4863
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Executive Summaries
The following are executive summaries from the chemical specific Technical Support Documents (which may be obtained as described in Unit 1.B. and III.) that support the NAC/AEGL Committee's development of AEGL values for each chemical substance. This information provides the following information: A general description of each chemical, including its properties and principle uses; a summary of the rationale supporting the AEGL-1, -2, and -3 concentration levels; a summary table of the AEGL values; and a listing of key references that were used to develop the AEGL values. More extensive toxicological information and additional references for each chemical may be found in the complete Technical Support Documents. Risk managers may be interested in reviewing the complete Technical Support Document for a chemical when deciding issues related to use of the AEGL values within various programs.
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Phosgene--i. Description. Phosgene is a colorless gas at ambient temperature and pressure. Its odor has been described as similar to new-mown hay. Phosgene is manufactured from a reaction of carbon monoxide and chlorine gas in the presence of activated charcoal. The production of dyestuffs, isocyanates, carbonic acid esters (polycarbonates), acid chlorides, insecticides, and pharmaceutical chemicals requires phosgene.
Appropriate data were not available for deriving AEGL-1 values for phosgene.
AEGL-2 values were based on chemical pneumonia in rats (2 ppm for 90 minutes) (Gross et al., 1965). An uncertainty factor (UF) of 3 was applied for interspecies extrapolation since little species variability is observed both with lethal and non lethal endpoints after exposure to phosgene. An UF of 3 was applied to account for sensitive human subpopulations since the mechanism of phosgene toxicity (binding to macromolecules and irritation) is not expected to vary greatly between individuals (total UF = 10). The 1.5 hour value was then scaled to the 30-minute, 1-hour, 4-hour, and 8-hour AEGL exposure periods, using C\n\ x t = k, where n = 1 (Haber's Law) since Haber's Law has been shown to be valid for phosgene within certain limits. Haber's Law was originally derived from phosgene data (USEPA, August 1986). The 30-minute value was also adopted as the 10-minute value since extrapolation would yield a 10-minute AEGL-2 value close to concentrations producing alveolar edema in rats exposed for 10-minutes (Diller et al., 1985) and may not be protective.
The 30-minute, 1-hour, 4-hour, and 8-hour AEGL-3 values were based on a 30-minute no-effect-level for death in rats (15 ppm) (Zwart et al., 1990). An UF of 3 was applied for interspecies extrapolation since little species variability is observed both with lethal and non-lethal endpoints after exposure to phosgene. An UF of 3 was applied to account for sensitive-human subpopulations since the mechanism of phosgene toxicity (binding to macromolecules and irritation) is not expected to vary greatly between individuals (total UF = 10). The value was then scaled to the 1-, 4-, and 8-hour AEGL periods, using C\n\ x t = k, where n = 1 (Haber's Law) since Haber's Law has been shown to be valid for phosgene within certain limits. Haber's Law was originally derived from phosgene data (USEPA, August 1986). The 10-minute AEGL-3 value was based on a 10-minute no-effect-level for death in rats and mice (Zwart et al., 1990). An UF of 3 was applied for interspecies extrapolation since little species variability is
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observed both with lethal and non lethal endpoints after exposure to phosgene. An UF of 3 was applied to account for sensitive human subpopulations since the mechanism of phosgene toxicity (binding to macromolecules and irritation) is not expected to vary greatly between individuals (total UF = 10).
The calculated values are listed in Table 2 below:
Table 2.--Phosgene
Summary of Proposed Aegl Values for Phosgene [ppm (mg/m\3\)]
Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours Endpoint/Reference
AEGL-1 (Nondisabling)
NA
NA
NA
NA
NA
NA
AEGL-2 (Disabling)
0.60 (2.5)
0.60 (2.5)
0.30 (1.2)
0.080 (0.33)
0.040 (0.16)
Chemical pneumonia rats (Gross et al., 1965)
AEGL-3 (Lethal)
3.6 (15)
1.5 (6.2)
0.75 (3.1)
0.20 (0.82 )
0.090 (0.34 ) 30-minute r 10- minute no-effect- level for death in rats (Zwart et al., 1990)
NA means not applicable
ii. References. a. Diller, W. F., Bruch, J., and Dehnen, W. 1985. Pulmonary changes in rats following low phosgene exposure. Archives of Toxicology. 57:184-190.
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Gross, P., Rinehart, W.E., and Hatch, T. 1965. Chronic pneumonitis caused by phosgene. Archieves of Environmental Health. 10:768-775.
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USEPA, August 1986. Health Assessment Document for Phosgene. EPA/600/8-86/022A. p. 1-4 to 1-5.
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Zwart, A., Arts, J.H.E., Klokman-Houweling, J.M., and Schoen, E.D. 1990. Determination of concentration-time-mortality relationships to replace LC50values. Inhalation Toxicology. 2:105-117. November 1977.
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Isobutyronitrile--i. Description. Isobutyronitrile is a colorless liquid at ambient temperature and pressure. It has an almond- like odor and may cause irritation or burning of the eyes and skin. It is metabolized to cyanide in the body and signs of exposure may include weakness, headache, confusion, nausea, vomiting, convulsion, dilated pupils, weak pulse, shallow and gasping breathing, and cyanosis (EPA, 1985).
Data were insufficient for derivation of AEGL-1 values for isobutyronitrile.
The AEGL-2 was based on a no-effect-level from a developmental toxicity study in rats (100 ppm, 6 hour/day, days 6-20 of gestation) (Saillenfait et al., 1993). Although no interspecies information concerning isobutyronitrile toxicity was available, data from another nitrile (methacrylonitrile) suggest that the rat is not the most sensitive species. Therefore, an interspecies UF of 10 will be applied. In the absence of chemical-specific data and since much of the acute toxicity of nitriles is due to cyanide, the intraspecies UF will be the same as that used in the derivation of hydrogen cyanide AEGL-2 values (NAC/AEGL Committee, 1997). Thus, an UF of 3 will be applied to account for sensitive individuals since human accidental and occupational exposures suggest little intraindividual variability of hydrogen cyanide toxicity (NAC/AEGL Committee, 1997). Therefore, the total UF is 30. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by C\n\ x t = k (ten Berge et al., 1986). Since much of the acute toxicity of isobutyronitrile is thought to be due to cyanide, the empirically derived chemical-specific value of n = 2.6 derived from cyanide rat lethality data) (NAC/AEGL Committee, 1997) will be used for scaling the AEGL values for isobutyronitrile across time.
The AEGL-3 was based on a estimated no-effect-level for death in rats (1/3 of the 1-hour LC50: 1,800 ppm 3 = 600 ppm) (Eastman Kodak Co., 1986a). Although no interspecies information concerning isobutyronitrile toxicity was available, data from another nitrile (methacrylonitrile) suggest that the rat is not the most sensitive species. Therefore, an interspecies UF of 10 will be applied. In the absence of chemical-specific data and since much of the acute toxicity of nitriles is due to cyanide, the intraspecies UF will be the same as that used in the derivation of hydrogen cyanide AEGL-3 values (NAC/AEGL Committee, 1997). Thus, an UF of 3 will be applied to account for sensitive individuals since human accidental and occupational exposures suggest little intraindividual variability of hydrogen cyanide toxicity (NAC/AEGL Committee, 1997). Therefore, the total UF is 30. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by C\n\ x t = k (ten Berge et al., 1986). Since much of the acute toxicity of isobutyronitrile is thought to be due to cyanide, the empirically derived chemical-specific value of n = 2.6 (derived from cyanide rat lethality data, (NAC/AEGL Committee, 1997) will be used for scaling the AEGL values for isobutyronitrile across time.
The calculated values are listed in Table 3 below:
Table 3.--Isobutyronitrile
Summary of Proposed AEGL Values for Isobutyronitrile [ppm (mg/m\3\)]
Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours Endpoint/Reference
AEGL-1 (Nondisabling)
ID
ID
ID
ID
ID
Insufficient data to derive AEGL-1 values
AEGL-2 (Disabling)
13 (36)
8.7 (24)
6.6 (18)
3.9 (11)
3.0 (8.4)
No-effect-level in rats (Saillenfait et al., 1993)
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AEGL-3 (Lethal)
40 (112)
26 (73)
20 (56)
12 (34)
9.0 (23)
Estimated no- observed-effect level (NOEL) for death in rats (Eastman Kodak, 1986a)
ID Insufficient data.
ii. References. a. Eastman Kodak Company. 1986a. Acute inhalation toxicity and one-hour LC10value of isobutyronitrile in the rat. (Study No. TX-86-193) Eastman Kodak Company, Rochester, NY 14650.
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NAC/AEGL Committee. 1997. Acute Exposure Guideline Levels for Hydrogen Cyanide. NAC Pro Draft 3:11/97.
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Saillenfait, A. M., Bonnet, P., Gurnier, J. P., and de Ceaurriz, J. 1993. Relative developmental toxicities of inhaled aliphatic mononitriles in rats. Fundamental Applied Toxicology. 20:365-375.
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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 Hazardous Materials. 13:301-309.
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USEPA. 1985. Chemical Profile. Isobutyronitrile. Washington, DC. December, 1985.
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Propionitrile--i. Description. Propionitrile is a colorless liquid at ambient temperature and pressure. It has a pleasant, ethereal, sweetish odor and may cause irritation or burning of the eyes and skin. It is metabolized to cyanide in the body and signs of exposure may include weakness, headache, confusion, nausea, vomiting, convulsion, dilated pupils, weak pulse, shallow and gasping breathing, and cyanosis (Hazardous Substances Data Bank (HSDB), 1998).
Data were insufficient for derivation of AEGL-1 values for propionitrile.
The AEGL-2 was based on headache, nausea, dizziness, vomiting, confusion, and disorientation in a 34-year-old male worker exposed to approximately 33.8 ppm propionitrile for 2 hours (Scolnick et al., 1993). In the absence of chemical-specific data and since much of the acute toxicity of propionitrile appears to be due to cyanide, an UF of 3 was applied to account for sensitive individuals since human accidental and occupational exposures suggest little intraindividual variability of hydrogen cyanide toxicity (NAC/AEGL Committee, 1997). A modifying factor of 2 was also applied to account for the poor database. Thus, the total uncertainty/modifying factor is 6. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by C\n\ x t = k (ten Berge et al., 1986). Since much of the acute toxicity of proprionitrile is thought to be due to cyanide, the empirically derived chemical-specific value of n = 2.6 (derived from cyanide rat lethality data, (NAC/AEGL Committee, 1997) was used for scaling the AEGL-2 values for 30-minutes, 1-, 4-, and 8-hours. The 30-minute AEGL-2 value was also adopted as the 10-minute value due to the fact that reliable data are limited to durations 2 hours, and it is considered inappropriate to extrapolate back to 10-minutes.
The AEGL-3 was based on a 4-hour no-effect-level for death in rats of 690 ppm (Younger Labs, 1978). An interspecies UF of 10 was applied since toxicity information suggests that the rat is not the most sensitive species. In the absence of chemical-specific data and since much of the acute toxicity of proprionitrile appears to be due to cyanide, an UF of 3 was applied to account for sensitive individuals since human accidental and occupational exposures suggest little intraindividual variability of hydrogen cyanide toxicity (NAC/AEGL Committee, 1997). Thus, the total UF is 30. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by C\n\ x t = k (ten Berge et al., 1986). Since much of the acute toxicity of propionitrile is thought to be due to cyanide, the empirically derived chemical-specific value of n = 2.6 (derived from cyanide rat lethality data, (NAC/AEGL Committee, 1997) was used for scaling the AEGL values for values for 30-minutes, 1-hour, and 8- hours. The 30-minute AEGL-3 value was also adopted as the 10-minute value due to the fact that the values are derived from a 4 hour exposure, and it is considered inappropriate to extrapolate back to 10- minutes.
The calculated values are listed in the Table 4 below:
Table 4.--Propionitrile
Summary of Proposed AEGL Values for Propionitrile [ppm (mg/m\3\)]
Endpoint/Reference Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours
AEGL-1 (Nondisabling)
ID
ID
ID
ID
ID
Insufficient data to derive AEGL-1 values
AEGL-2 (Disabling)
9.6 (22)
9.6 (22)
7.4 (17)
4.3 (9.8)
3.3 (7.6)
Headache, nausea, vomiting, dizziness, confusion in a human subject (Scolnick et al., 1993)
AEGL-3 (Lethal)
51 (120)
51 (120)
39 (89)
23 (53)
18 (41)
No-effect-level for death in rats (Younger Labs, 1978)
ID Insufficient data.
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ii. References. a. HSDB. 1998. Propionitrile. Reviewed 9/24/92. Updated 6/2/98. Retrieved 6/16/98.
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NAC/AEGL Committee. 1997. Acute Exposure Guideline Levels for Hydrogen Cyanide. NAC Pro Draft 3:11/97.
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Scolnick, B., Hamel, D., and Woolf, A.D. 1993. Successful treatment of life threatening propionitrile exposure with sodium thiosulfate followed by hyperbaric oxygen. Journal of Occupational Medicine. 35:577-580.
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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.
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Younger Labs. 1978. Initial Submission: Toxicological Investigation of Propionitrile with Cover Letter Dated 081992. OTS0546148.
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Methacrylonitrile--i. Description. Methacrylonitrile is a colorless liquid at ambient temperature and pressure. It has an odor similar to bitter almonds and may cause irritation or burning of the eyes and skin. It is metabolized to cyanide in the body and signs of exposure may include weakness, headache, confusion, nausea, vomiting, convulsion, dilated pupils, weak pulse, shallow and gasping breathing, and cyanosis (HSDB, 1998).
Data were insufficient for derivation of AEGL-1 values for methacrylonitrile.
The AEGL-2 values were set as 1/3 of the AEGL-3 values. The values obtained from this approach are supported by a repeated-exposure study in which dogs were exposed to 13.5 ppm methacrylonitrile, 7 hours/day, 5 days/week for 90 days (Pozzani et al., 1968). Convulsions and loss of motor control of the hindlimbs were observed starting at day 39 of exposure.
The AEGL-3 was based on a no-effect-level for death in mice (19 ppm for 4 hours) (Pozzani et al., 1968). An interspecies UF of 3 will be applied since the mouse is the most sensitive species. In the absence of chemical-specific information on intraspecies variability and since much of the acute toxicity of nitriles is due to cyanide, the intraspecies UF will be the same as that used in the derivation of hydrogen cyanide AEGL-3 values (NAC/AEGL Committee, 1997). Thus, an UF of 3 will be applied to account for sensitive individuals since human accidental and occupational exposures suggest little intraindividual variability of hydrogen cyanide toxicity (NAC/AEGL Committee, 1997). Thus, the total UF is 10. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by C\n\ x t = k (ten Berge et al., 1986). In the absence of chemical- specific information and since much of the acute toxicity of methacryonitrile is thought to be due to cyanide, the empirically derived chemical-specific value of n = 2.6 (derived from cyanide rat lethality data, (NAC/AEGL Committee, 1997) will be used for scaling the 30-minute, 1-, and 8-hour AEGL values for propionitrile across time. The 30-minute AEGL-3 value was also adopted as the 10-minute value due to the fact that reliable data are limited to durations 4 hours, and it is considered inappropriate to extrapolate back to 10- minutes.
The calculated values are listed in Table 5 below:
Table 5.--Methacrylonitrile
Summary of Proposed AEGL Values for Methacrylonitrile [ppm (mg/m\3\)]
Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours Endpoint/Reference
AEGL-1 (Nondisabling)
ID
ID
ID
ID
ID
Insufficient data to derive AEGL-1 values
AEGL-2 (Disabling)
1.5 (4.1)
1.5 (4.1)
1.1 (3.0)
0.70 (1.9)
0.50 (1.4)
1/3 of the AEGL-3 values
AEGL-3 (Lethal)
4.5 (12)
4.5 (12)
3.4 (9.3)
2.0 (5.5)
1.5 (4.1)
4-hr. no-effect- level for death in mice (Pozzani et al., 1968)
ID Insufficient data.
ii. References. a. HSDB. 1998. Methacrylonitrile. Reviewed 9/24/92. Updated 6/3/98. Retrieved 6/16/98.
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NAC/AEGL Committee. 1997. Acute Exposure Guideline Levels for Hydrogen Cyanide. NAC Pro Draft 3: 11/97.
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Pozzani, U.C., Kinkead, E.R., and King, J.M. 1968. The mammalian toxicity of methacrylonitrile. American Industrial Hygiene Association Journal. 29:202-210.
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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.
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Chlorine trifluoride--i. Description. Chlorine trifluoride is an extremely reactive and corrosive oxidizing agent used in nuclear reactor fuel processing, as a fluorinating agent, as an incendiary, igniter and propellant for rockets, and as a pyrolysis inhibitor for fluorocarbon polymers. It is unstable in air and rapidly hydrolyses to hydrogen fluoride (HF) and a number of chlorine-containing compounds including chlorine dioxide (ClO2). The toxic effects of ClF3are likely due to HF and ClO2.
Chlorine trifluoride is a mucous membrane irritant. Contact with the skin and eyes produces burns and inhalation causes pulmonary irritation and edema. Inhalation studies with the monkey, dog, rat, and mouse for several endpoints and exposure durations were located. Data on irritant effects were available for the dog and rat; data on sublethal and lethal concentrations were available for the monkey, rat, and mouse. Although human exposures have occurred, no data on exposure concentrations were located.
The AEGL-1 was based on the threshold for notable discomfort (lacrimation) that was observed in dogs after 3 hours during a 6-hour exposure to an average concentration of 1.17 ppm (Horn and Weir, 1956). The only other sign of exposure was mild sensory irritation (nasal discharge) that usually occurred within 45 minutes. Nasal discharge in the sensitive nose of the dog was considered below the definition of the AEGL-1. No effects were observed in rats exposed to this concentration for 6 hours. The 1.17 ppm concentration for an exposure duration of 3 hours was divided by a combined interspecies and intraspecies UF of 10 (3 for interspecies differences [the dog was more sensitive than the rat] and 3 for intraspecies differences in sensitivity [the mechanism of toxicity is irritation; response to such a basic chemical effect on tissue is not expected to vary
[[Page 77872]]
significantly among individuals]). Scaling across time was based on C\n\ x t = k where n = 1 (Haber's Law); this concentration-exposure duration relationship was determined from several lethality studies. Because of the long exposure duration of the key study, the 10-minute AEGL-1 was set equal to the 30-minute AEGL-1.
The AEGL-2 was based on signs of strong irritation (salivation, lacrimation, rhinorrhea, and blinking of the eyes) in dogs exposed to a concentration of 5.15 ppm for 6 hours (Horn and Weir, 1955). Although these effects appeared reversible by the end of the day, they may impair the ability to escape. Rats exposed to this concentration for 6 hours appeared unaffected. The 6-hour concentration of 5.15 ppm was divided by a combined interspecies and intraspecies UF of 10 and scaled across time using the same reasons and relationships as for the AEGL-1 in this unit. Because of the long exposure duration of the key study, the 10-minute AEGL-2 was set equal to the 30-minute AEGL-2.
Lethality data (1-hour LC50values) were available for the monkey, rat, and mouse. The AEGL-3 was based on the calculated 1- hour LC01for the mouse, the most sensitive species based on LC50values (MacEwen and Vernot, 1970). This concentration, 135 ppm, was divided by a combined interspecies and intraspecies UF of 10 and scaled across time using the same reasons and relationships as for the AEGL-1 in this unit. Death was due to extreme irritation resulting in massive lung hemorrhaging. Data from another study in which dogs exposed to a concentration of 21 ppm for 6 hours showed extreme signs of irritation but no deaths resulted in essentially the same AEGL-3 values when adjusted by an UF of 10 and scaled across time using Haber's Law.
The calculated values are listed in Table 6 below:
Table 6.--Chlorine Trifluoride
Summary of Proposed AEGL Values for Chlorine Trifluoride [ppm (mg/m\3\)]
Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours Endpoint/Reference
AEGL-1 (Nondisabling)
0.70 (2.7)
0.70 (2.7)
0.35 (1.3)
0.090 (0.34)
0.040 (0.15) Threshold, notable discomfort--dog (Horn and Weir, 1956)
AEGL-2 (Disabling)
6.2 (24)
6.2 (24)
3.1 (12)
0.77 (2.9)
0.39 (1.5)
Strong irritation-- dog (Horn and Weir, 1955)
AEGL-3 (Lethal)
81 (308)
27 (103)
14 (53)
3.4 (13)
1.7 (6.5)
Lethality (LC01)-- mouse (MacEwen and Vernot, 1970)
ii. References. a. Horn, H.J. and R.J. Weir. 1955. Inhalation toxicology of chlorine trifluoride. I. Acute and subacute toxicity. A.M.A. Archives of Industrial Health. 12:515-521.
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Horn, H.J. and R.J. Weir. 1956. Inhalation toxicology of chlorine trifluoride. II. Chronic toxicity. A.M.A. Archives of Industrial Health. 13:340-345.
-
MacEwen, J.D. and E.H. Vernot. 1970. Toxic Hazards Research Unit Annual Technical Report: 1970. AMRL-TR-70-77, Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH; National Technical Information Service, Springfield,VA
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Ethyleneimine--i. Description. Ethylenimine is a volatile, clear, colorless, flammable explosive liquid that has an odor similar to that of ammonia and an odor detection level of 2 ppm. It is a very reactive direct-acting alkylating agent, the activity of which is similar to that of nitrogen mustards. It is also very caustic, attacking numerous substances including plastics, metals, and glass that does not contain carbonate or borax. Estimates of domestic production of ethylenimine range between 3.3 and 4.85 million pounds. Ethylenimine is used in the manufacture of products, such as triethylenemelamine, paper, textile chemicals, adhesive binders, and petroleum refining chemicals. Ethylenimine is stored in 320-pound cylinders, but shipping quantities are unknown.
Relevant data on ethylenimine consisted of only a few case studies in humans and acute inhalation lethality studies in laboratory animals. One individual died after a brief exposure to an unknown concentration of ethylenimine. Death was preceded by eye irritation, salivation, vomiting, respiratory tract irritation, breathlessness, and pulmonary edema; death may have been due to medical treatment. Individuals exposed to ethylenimine at estimated concentrations of 235-353 ppm and N-ethylethylenimine at 722 to 1,084 ppm for 11/2 to 2 hours suffered severe eye and respiratory tract irritation and vomiting that were delayed for 1 to 5 hours after exposure, followed by hemoglobinemia, eosinophilia, and albuminuria. Effects reported for occupational exposure to ethylenimine included skin sensitization, slow-healing dermatitis, rapidly reversible irritation to the eyes and respiratory tract, and blistering, reddening, and edema of the scrotum. Direct contact of liquid ethylenimine to the tongue caused delayed inflammation and edematous swelling of the oral cavity and inflammation of eyes, and direct contact of liquid with the skin causes necrotizing painless burns. Ethylenimine was genotoxic in all test systems investigated including bacteria, fungi, plants, insects, and mammalian cells in vitro. It is clastogenic in cultured human cells. Subcutaneous injection of rats with ethylenimine produced sarcomas at the injection site.
Acute inhalation LC50values were 2,558, 1,407, 545, 268, 259, 58, and 35 ppm for rats exposed to ethylenimine for 5, 10, 15, 60, 120, 240, or 480 minutes, respectively; 2,906, 2,824, 1,283, 364, 235, 158, 45, and 27 ppm for guinea pigs exposed for 5, 10, 15, 30, 60, 120, 240, or 480 minutes, respectively; and 2,236 ppm for mice exposed for 10 minutes. In all studies, death and other signs of toxicity were delayed depending on exposure concentration. Signs of toxicity included eye irritation, respiratory tract irritation, respiratory difficulty, prostration, complete loss of muscular coordination (mouse only), and convulsions (mouse only). Systemic effects included lung damage, congestion in lungs and all internal organs, damage to the kidney tubules, and albuminuria in rats and guinea pigs.
AEGL-1 values were not derived, because ethylenimine is an insidious agent (effects are delayed) that has an odor similar to that of ammonia, and an odor detection limit at 2 ppm; consequently, ethylenimine has no specific warning properties (sensory irritation or odor). The odor detection level is similar to or higher than the
[[Page 77873]]
AEGL-2 values for 4-hour and 8-hour exposures; therefore, it is not valid nor would it be a benefit to the public to propose AEGL-1 values.
No animal studies designed specifically to examine nonlethal effects of ethylenimine were located in the literature, and the human study involved exposure to another substance that could have contributed to the observed toxic effects. Therefore, the AEGL-2 values were based on a NOEL for extreme respiratory difficulty in guinea pigs (10 ppm for 240 minutes) in the study by Carpenter et al. (1948). An UF of 3 was applied for intraspecies variability because of the insidious nature of ethylenimine, and effects of exposure may not become apparent before exposure is terminated. Under these conditions; individuals with respiratory or heart diseases are not expected to respond differently from the general population. The very reactive alkylating activity of ethylenimine also suggests that it would be similarly effective in all individuals. A UF of 3 was also applied for interspecies sensitivity because of the reactive alkylating activity of ethylenimine and the similarity of the mode of action in different species. Further, the available evidence suggests that humans may be less sensitive than rodents. The total UF is 10. Scaling across the pertinent time frames was based on the equation C\0.91\ x t = k, where n was derived from the LC50data for guinea pigs. The AEGL-2 values do not take into account the potential carcinogenicity of ethylenimine.
AEGL-3 values were based on the acute inhalation study in rats (Carpenter et al. , 1948). The LC01(lethality threshold) of 15 ppm for the 8-hour exposure duration was estimated by probit analysis. The 8-hour LC01was selected because it had the smallest standard error. A total UF of 10 (3 for intraspecies variability and 3 for interspecies sensitivity) was applied to the LC01value. Scaling across the pertinent time frames was based on the equation C\1.1\ x t = k, where n was derived from LC50data for rats.
The calculated values are listed in Table 7 below:
Table 7.--Ethylenimine
Summary of Proposed AEGL Values for Ethylenimine\a,b\ [ppm (mg/m\3\)]
Classification
10-minutes
30-minutes
1-hour
4-hours
8-hours Endpoint/Reference
AEGL-1 (Nondisabling)
No values derived for AEGL-1
AEGL-2 (Disabling)
33 (59)
9.8 (185)
4.6 (8.2)
1.0 (1.8)
0.47 (0.84 )
NOEL for extreme respiratory difficulty (Carpenter et al., 1948)
AEGL-3 (Lethal)
51 (91)
19 (34)
9.9 (18)
2.8 (5.0)
1.5 (2.7)
Threshold for lethality (Carpenter et al., 1948)
a AEGL-2 and -3 values do not take into consideration the potential cancer risk due to exposure to ethylenimine. b Effects at these concentrations may be delayed until sometime after exposure; toxic levels may be absorbed through the skin.
ii. Reference. Carpenter, C. P.; Smyth, H. F., Jr.; Shaffer, C. B. 1948. The acute toxicity ethyleneimine to small animals. Journal of Industrial Hygiene and Toxicology. 30:2-6.
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Propyleneimine--i. Description. Propylenimine is an aziridine compound used to modify latex surface coating resins to improve adhesion and to modify bonding properties of textiles, paper, and dyes; it is also used in photography, in the pharmaceutical industry, in gelatins, and in organic syntheses. Propylenimine is a colorless oily liquid that has an odor similar to that of ammonia. It is flammable and is an explosion hazard. Propylenimine is similar in structure and toxicity to ethylenimine.
No data were found in the literature concerning toxicity or the odor detection threshold for exposure to propylenimine in humans. A time-response study conducted in rats and guinea pigs showed that 1/6 guinea pigs died after exposure to 500 ppm for 60 minutes and 0/6 died after exposure to the same concentration for 30 minutes (Carpenter et al., 1948). In rats, 5/6 died after exposure to 500 ppm for 240 minutes and 0/6 died after exposure to the same concentration for 120 minutes. No concentration-response data were available for deriving AEGL values from animal studies. Therefore, a relative potency approach was used to derive AEGL-2 values, because the toxicity of propylenimine is considered to be qualitatively similar to that of ethylenimine. The study of Carpenter et al. (1948) showed that propylenimine is 4 to 8 times less toxic than ethylenimine depending on the species: 4 or 5 times less toxic to the guinea pig and 8 times less toxic to the rat. Tumors developed at multiple sites in rats treated orally with propylenimine for 28 or 60 weeks; therefore, International Agency for Research on Cancer (IARC) has classified propylenimine as Group 2B (possibly carcinogenic to human). Propylenimine is mutagenic in salmonella and drosophila.
No AEGL-1 values were proposed for ethylenimine, and no values are proposed for propylenimine. Propylenimine has an odor similar to that of ammonia, the odor detection and irritation thresholds are not known, and propylenimine is probably an insidious agent similar to ethylenimine. It would not be valid nor beneficial to propose AEGL-1 values for propylenimine.
The derivation of AEGL-2 values is based on the relative toxicity approach. The AEGL values proposed for ethylenimine based on a no- effect-level for extreme respiratory difficulty were as follows: 33, 9.8, 4.6, 1.0, and 0.47 ppm for 10 minutes, 30 minutes, 1 hour, 4 hours, and 8 hours, respectively. The NAC/AEGL Committee selected 5 as the appropriate relative toxicity value for deriving AEGL-2 values for propylenimine. The NAC/AEGL Committee also proposed that a modifying factor of 2 should be applied to account for a deficient database. Therefore, the resulting values for propylenimine based on a relative toxicity value of 5 and a modifying factor of 2 are 83, 25, 12, 2.5, and 1.2 ppm for exposure durations of 10 minutes, 30 minutes, 1 hour, 4 hours, and 8 hours, respectively.
It was the consensus of the NAC/AEGL Committee to consider a 500 ppm exposure for 30 minutes as the no-effect-level for lethality and to use this concentration to derive AEGL-3 values. An UF of 10 (3 for intraspecies sensitivity and 3 for interspecies sensitivity) was applied to the no-effect-levels for lethality. Propylenimine is an insidious agent and signs of toxicity may not become apparent until after exposure. Propylenimine a very reactive direct-acting alkylating agent, and its mode of action is not expected to vary
[[Page 77874]]
considerably across species or within the population. Time extrapolation was based on the equation, C\n\ x t = k, where n = 0.91 derived by probit analysis of LC50data for guinea pigs exposed to ethylenimine.
The calculated values are listed in Table 8 below:
Table 8.--Propylenimine
Summary of Proposed AEGL Values for Propylenimine\a,b\ [ppm (mg/m\3\)]
ppm (mg/m\3\) Classification
---------------------------------------------------------------------------------------------------- Endpoint/Reference 10-minutes
30-minutes
1-hour
4-hours
8-hours
AEGL-1
No values derived for AEGL-1
AEGL-2\c\
83 (200)
25 (58)
12 (28)
2.5 (5.8)
1.2 (2.8)
NOEL for extreme respiratory difficulty (Carpenter et al., 1948)
AEGL-3
167 (390)
50 (120 )
23 (54 )
5.1 (12)
2.4 (5.6 )
Lethality threshold (Carpenter et al., 1948)
a AEGL-2 and -3 values do not take into consideration the potential cancer risk due to inhalation exposure to propylenimine. b Effects including lethality, irritation to eyes, and irritation to the respiratory tract may be delayed until after exposure; toxic levels of propylenimine may be absorbed through the skin. c AEGL values for propylenimine = AEGL for ethylenimine x 5 (relative potency factor) 2 (modifying factor).
ii. Reference. Carpenter, C.P., Smyth, H.F., Jr., Shaffer, C.B. 1948. The acute toxicity of ethylenimine to small animals. Journal of Industrial Hygiene and Toxicology. 30:2-6.
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Next Steps
The NAC/AEGL Committee plans to publish ``Proposed'' AEGL values for five-exposure periods for other chemicals on the priority list 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: December 6, 2000. Stephen L. Johnson, Acting Assistant Administrator for Prevention, Pesticides and Toxic Substances.
[FR Doc. 00-31730Filed12-12-00; 8:45 am]
BILLING CODE 6560-50-S
