65 FR 51 pgs. 14186-14197 - National Advisory Committee for Acute Exposure Guideline Levels (AEGLs) forHazardous Substances; Proposed AEGL Values
Type: NOTICEVolume: 65Number: 51Pages: 14186 - 14197
Docket number: [OPPTS-00289; FRL-6492-4]
FR document: [FR Doc. 00-6397 Filed 3-14-00; 8:45 am]
Agency: Environmental Protection Agency
Official PDF Version: PDF Version
ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-00289; FRL-6492-4]
National Advisory Committee for Acute Exposure Guideline Levels (AEGLs) forHazardous Substances; Proposed AEGL Values
AGENCY:
Environmental Protection Agency (EPA).
ACTION:
Notice and request for comments.
SUMMARY:
The National Advisory Committee for Acute Exposure GuidelineLevels for Hazardous Substances (NAC/AEGL Committee) is developing AEGL values on an ongoingbasis to provide Federal, State, and local agencies with information on short-term exposures tohazardous chemicals. This notice provides "Proposed" AEGL values and Executive Summaries for 10chemicals for public review and comment. Comments are welcome on both the "Proposed" AEGL values in this notice and the Technical Support Documents placed in the public version of the official record in the TSCA Docket for these 10 chemicals.
DATES:
Comments, identified by the docket control number OPPTS-00289,must be received by EPA on or before April 14, 2000.
ADDRESSES:
Comments may be submitted by mail, electronically, or in person.Please follow the detailed instructions for each method as provided in Unit I. of the"SUPPLEMENTARY INFORMATION." To ensure proper receipt by EPA, it is imperative thatyou identify docket control number OPPTS-00289 in the subject line on the first page of yourresponse.
FOR FURTHER INFORMATION CONTACT:
For general informationcontact: Joseph S. Carra, Deputy Director, Office of Pollution Prevention and Toxics (7401),Environmental Protection Agency, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., Washington,DC 20460; telephone numbers: (202) 554-1404 and TDD: (202) 554-055; e-mailaddress: TSCA-Hotline@epa.gov.
For technical information contact: Paul S. Tobin, Designated Federal Officer (DFO), Office of Pollution Prevention and Toxics (7406), Environmental Protection Agency, Ariel Rios Bldg., 1200Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (202) 260-1736; e-mail address: tobin.paul@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the general public to provide an opportunity for review andcomment on "Proposed" AEGL values and their supporting scientific rationale. This action maybe of particular interest to anyone who may be affected if the AEGL values are adopted bygovernment agencies for emergency planning, prevention, or response programs, such as EPA'sRisk Management Program under the Clean Air Act and Amendments Section 112r. It is possiblethat other Federal agencies besides EPA, as well as State and local agencies and privateorganizations, may adopt the AEGL values for their programs. As such, the Agency has notattempted to describe all the specific entities that may be affected by this action. If you have anyquestions regarding the applicability of this action to a particular entity, consult the DFO listedunder "FOR FURTHER INFORMATION CONTACT."
B. How Can I Get Additional Information, Including Copies of this Document or OtherRelated Documents?
1. Electronically . You may obtain electronic copies of this document, andcertain other related documents that might be available electronically, from the EPA InternetHome Page at http://www.epa.gov/. To access this document, on the Home Page select "Lawsand Regulations" and then look up the entry for this document under the " FederalRegister -Environmental Documents." You can also go directly to the FederalRegister listings at http://www.epa.gov/fedrgstr/.
2. In person . The Agency has established an official record for this actionunder docket control number OPPTS-00289. The official record consists of the documentsspecifically referenced in this action, any public comments received during an applicablecomment period, and other information related to this action, including any information claimedas Confidential Business Information (CBI). This official record includes the documents that arephysically located in the docket, as well as the documents that are referenced in thosedocuments. The public version of the official record does not include any information claimed asCBI. The public version of the official record, which includes printed, paper versions of anyelectronic comments submitted during an applicable comment period, is available for inspectionin the TSCA Nonconfidential Information Center, North East Mall Rm. B-607, WatersideMall, 401 M St., SW., Washington, DC. The Center is open from noon to 4 p.m., Mondaythrough Friday, excluding legal holidays. The telephone number of the Center is (202) 260-7099.
3. Fax-on-Demand . Using a faxphone call (202) 401-0527 and select item4800 for an index of items in this category. For a more specific item number, see the table inUnit III.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or electronically. To ensureproper receipt by EPA, it is imperative that you identify docket control number OPPTS-00289 in the subject line on the first page of your response.
1. By mail . Submit your comments to: Document Control Office (7407),Office of Pollution Prevention and Toxics (OPPT), Environmental Protection Agency, ArielRios Bldg., 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier . Deliver your comments to: OPPT DocumentControl 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, excludinglegal holidays. The telephone number for the DCO is (202) 260-7093.
3. Electronically . You may submit your comments electronically by e-mail to: "oppt.ncic@epa.gov," or mail your computer disk to the address identified above. Donot submit any information electronically that you consider to be CBI. Electronic commentsmust be submitted as an ASCII file avoiding the use of special characters and any form ofencryption.Comments and data will also be accepted on standard disks in WordPerfect 6.1/8.1 or ASCII fileformat. All comments in electronic form must be identified by docket control number OPPTS-00289. Electronic comments may also be filed online at many Federal Depository Libraries
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to be CBI. You mayclaim information that you submit to EPA in response to this document as CBI by marking anypart or all of that information as CBI. Information so marked will not be disclosed except inaccordance with procedures set forth in 40 CFR part 2. In addition to one complete version ofthe comment that includes any information claimed as CBI, a copy of the comment that does notcontain the information claimed as CBI must be submitted for inclusion in the public version ofthe official record. Information not marked confidential will be included in the public version ofthe official record without prior notice. If you have any questions about CBI or the proceduresfor claiming CBI, please consult the technical person identified under "FOR FURTHERINFORMATION CONTACT."
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used that supportyour views.
4. If you estimate potential burden or costs, explain how you arrived at the estimatethat you provide.
5. Provide specific examples to illustrate your concerns.
6. Offer alternative ways to improve the proposed rule or collection activity.
7. Make sure to submit your comments by the deadline in this document.
8. To ensure proper receipt by EPA, be sure to identify the docket control numberassigned to this action in the subject line on the first page of your response. You may alsoprovide the name, date, and Federal Register citation.
II. Background
Since its first meeting on June 19-21, 1996, the NAC/AEGL Committee has beenevaluating scientific data and developing "Proposed" AEGLs for 76 of the first 85 prioritychemicals initially scheduled for development of AEGL values. This first list of 85 chemicals waspublished in the Federal Register of May 21, 1997 (62 FR 27733-27734) (FRL-5718-9). EPA published the first "Proposed" AEGL values for 12 chemicals from the initial priority list in the Federal Register of October 30, 1997 (62 FR 58839-58851) (FRL-5737-3) in order to provide an opportunity for public review and comment. That Federal Register notice also provides the AEGL Program's history and developmentprocess. Since then, the NAC/AEGL Committee continues to develop AEGL values for other chemicals from the initial priority list and continues to establish greater consistency in the procedures and methodologies used in their development. Additionally, the NAC/AEGL Committee hasexpanded the number of exposure periods to include AEGL values for 10 minute exposure periods to cover a wider range of potential exposures to hazarous chemicals. The NAC/AEGL Committee plans to publish "Proposed" AEGL values for 10 minute exposure periods for other chemicals on the priority list of 85 in groups of approximately 10 to 20 chemicals in future Federal Register notices.
The NAC/AEGL Committee will review and consider all public comments receivedon this notice, with revisions to the "Proposed" AEGL values, as appropriate. The resultingAEGL values will be established as "Interim" AEGL values and will be forwarded to the NationalResearch Council, National Academy of Sciences (NRC/NAS), for review and comment. The"Final" AEGL values will be published under the auspices of the NRC/NAS following concurrence onthe values and the scientific rationale used in their development.
III. 10 Chemicals for Public Notice and Comment
A. Fax-On-Demand Table
| CAS No. | Chemical name | Fax-On-Demand item no. |
|---|---|---|
| 71-55-6 | 1,1,1-Trichloroethane | 4937 |
| 74-90-8 | Hydrogen cyanide | 4858 |
| 156-59-2 | Cis-1,2-Dichloroethylene | 4895 |
| 156-60-5 | Trans-1,2-Dichloroethylene | 4895 |
| 505-60-2 | Agent HD (sulfur mustard) | 4936 |
| 811-97-2 | HFC-134a (1,1,1,2-tetrafluoroethane) | 4899 |
| 1717-00-6 | HCFC-141b (1,1-dichloro-1-fluoroethane) | 4902 |
| 7664-39-3 | Hydrogen fluoride | 4909 |
| 7783-06-4 | Hydrogen sulfide | 4917 |
| 106602-80-6 | Otto Fuel II (main component propylene glycol dinitrate; CAS No. 6423-43-4) | 4935 |
B. Executive Summaries
1. Cis-1,2-Dichloroethylene and 2. Trans-1,2-Dichloroethylene -i. Description . 1,2-Dichloroethylene 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 anintermediate in the production of chlorinated solvents and as a low-temperature extractionsolvent for decaffeinated coffee, dyes, perfumes, lacquers, and thermoplastics. The compound isa 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 forderivation of the three AEGL classifications.
The AEGL-1 was based on a human exposure concentration of 825 parts per million (ppm) trans -1,2-dichloroethene for 5 minutes (Lehmann and Schmidt-Kehl 1936). Thisconcentration is a no-effect-level for eye irritation. Because the mechanism of irritation is notexpected to differ greatly among individuals (including sensitive individuals), this value wasdivided by an uncertainty factor (UF) of 3 to protect sensitive individuals. This UF of 3 was applied for AEGL-1 values for both the cis - and trans -isomers. Sinceanimal data suggest that the cis -isomer is approximately twice as toxic as the trans -isomer, a modifying factor of 2 was applied in the derivation of the cis -isomer values only. The same value was applied across the 10- and 30-minute and 1-, 4-, and 8-hour exposure time points since mild irritantancy is a threshold effect and generally does notvary greatly over time. Thus, prolonged exposure will not result in an enhanced effect.
The AEGL-2 for the 4- and 8-hour time points was based on narcosis observed inpregnant rats exposed to 6,000 ppm of the trans -isomer for 6 hours (Hurtt et al., 1993).Uncertainty factors of 3 each (total UF = 10) were applied for both inter- and intraspeciesdifferences because the endpoint, narcosis, is unlikely to vary greatly among individuals orspecies. This total UF of 10 was applied for AEGL-2 values for both the cis - and trans -isomers. The concentration-exposure time relationship for manyirritant and systemically acting vapors and gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). To obtain protectiveAEGL values in the absence of an empirically derived chemical-specific scaling exponent, aconservative approach to temporal scaling was performed using n = 3 when extrapolating toshorter time points and n = 1 when extrapolating to longer time points using theC n x t = k equation. The AEGL-2 for the 10- and 30-minute and 1-hourtime points was set as a ceiling based on a plateau for anesthetic effects in humans (Lehman andSchmidt-Kehl, 1936). Since data suggest that the cis -isomer is approximately twice astoxic as the trans -isomer, a modifying factor of 2 was applied in the derivation of the cis -isomer values only.
The AEGL-3 for the 4- and 8-hour time points was based on a 4-hour no-effect-levelfor death in rats of 12,300 ppm trans -1,2-dichloroethene (Kelly, 1999). Uncertaintyfactors of 3 each (total UF = 10) were applied for both inter- and intraspecies differences. Rat andmouse lethality data indicate little species variability with regard to death. This total UF of 10 was applied for AEGL-3 values for both the cis - and trans -isomers. The concentration-exposure time relationship for many irritant and systemically actingvapors and gases may be described by C n x t = k, where the exponent, n,ranges from 0.8 to 3.5 (ten Berge et al., 1986). To obtain protective AEGL values in the absenceof an empirically derived chemical-specific scaling exponent, a conservative approach to temporalscaling was performed using n = 3 when extrapolating to shorter time points and n = 1 whenextrapolating to longer time points using the C n x t = k equation. TheAEGL-3 for the 10- and 30-minute and 1-hour time points was set as a ceiling based on a plateaufor intracranial pressure, nausea, and severe dizziness in humans (Lehman and Schmidt-Kehl,1936). Since data suggest that the cis -isomer is approximately twice as toxic as the trans -isomer, a modifying factor of 2 was applied in the derivation of the cis -isomer values only.
The calculated values are listed in the tables below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 280(1,109) | 280(1,109] | 280(1,109) | 280(1,109) | 280(1,109) | Ocular irritation in humans(Lehman and Schmidt-Kehl, 1936) |
| AEGL-2 (Disabling) | 1,000(3,960) | 1,000(3,960) | 1,000(3,960) | 690(2,724) | 450(1,782) | Narcosis in rats: 4- and 8-hour (Hurtt etal., 1993); Anesthetic effects in humans(Lehman and Schmidt-Kehl, 1936) |
| AEGL-3 (Lethality) | 1,700(6,732) | 1,700(6,732) | 1,700(6,732) | 1,200(4,752) | 620(2,455) | No-effect-level for death in rats: 4- and 8-hour (Kelly, 1999); Nausea,intracranial pressure, and dizziness inhumans (Lehman and Schmidt-Kehl,1936) |
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 140(554) | 140(554) | 140(554) | 140(554) | 140(554) | Ocular irritation in humans(Lehman and Schmidt-Kehl, 1936) |
| AEGL-2 (Disabling) | 500(1,980) | 500(1,980) | 500(1,980) | 340(1,346) | 230(911) | Narcosis in rats: 4- and 8-hour (Hurtt etal., 1993); Anesthetic effects in humans(Lehman and Schmidt-Kehl, 1936) |
| AEGL-3 (Lethality) | 850(3,366) | 850(3,366) | 850(3,366) | 620(2,455) | 310(1,228) | No-effect-level for death in rats: 4-and 8-hour (Kelly, 1999); Nausea,intracranial pressure, and dizziness inhumans (Lehman and Schmidt-Kehl,1936) |
ii. References .
Hurtt, M.E., Valentine, R., and Alvarez, L. 1993. Developmental toxicity of inhaled trans -1,2-dichloroethylene in the rat. Fundamental and Applied Toxicology . 20:225-230.
Kelly, D. P. 1999. Trans -1,2-dichloroethylene and cis -1,2-dichloroethylene: Inhalationmedian lethal concentration (LC 50 ) study in rats. E.I. du Pont de Nemours andCompany, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. LaboratoryProject ID: DuPont-2806.
Lehman, K.B. and Schmidt-Kehl, L. 1936. The thirteen most important chlorinatedaliphatic hydrocarbons from the standpoint of industrial hygiene. Archiv Fuer Hygiene und Bakteriologie . 116:9-268.
ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986. Concentration-time mortalityresponse relationship of irritant and systemically acting vapours and gases. Journal ofHazardous Materials . 13:301-309.
3. Agent HD (sulfur mustard) -i. Description . Sulfur mustard (Agent HD) is an alkylating chemical vesicant developed as a warfare agent that affects any epithelialsurface it contacts. The active component is bis (2-chloroethyl)sulfide (CAS No. 505-60-2). Although the chemical is a liquid at ordinary ambient temperatures, itsvolatility results in rapid generation of vapors with a garlic-like odor. Due to its low aqueoussolubility, it is persistent in the environment. Odor thresholds of 1 mg-min/m 3 (milligram-minute/meter) and0.6 mg/m 3 have been reported.
Exposure to sulfur mustard vapor may result in irritation and damage to the eyes,respiratory tract, and skin. The toxic effects of sulfur mustard are temperature and humiditydependent; for a given exposure, the effects may be greater with increasing temperature andhumidity. An exposure-dependent latency period of hours to days is documented for the toxiceffects of sulfur mustard and is relevant for all routes of exposure but may be less for ocular andupper respiratory tract effects than for dermal and systemic responses. Both human and animaldata indicate that the eyes are the most sensitive organ/tissue although deaths resulting fromsulfur mustard exposure are likely the result of respiratory tract involvement. Because the toxiceffects of sulfur mustard (at least for short-time periods) appear to be a linear function ofexposure duration and exposure concentration, most of the available exposure-response data areexpressed as cumulative exposures (Ct).
Minor ocular irritation (conjunctival injection in the absence of irritation) is reportedto occur in humans following exposures to 12-30 mg-min/m 3 and more severeeffects at 60-75 mg-min/m 3 (conjunctivitis, irritation, photophobia) and 100mg-min/m 3 (severe ocular irritation). Exposure estimates for human lethality rangefrom 900-1,500 mg-min/m 3 .
Animal lethality following acute exposure to sulfur mustard occurs at cumulativeexposures ranging from approximately 600-1,500 mg-min/m 3 . Nonlethal effectswere similar to those observed in humans and included effects on the eyes, respiratory tract, andskin. Long-term exposure of dogs, rats, and guinea pigs to concentrations of 0.03mg/m 3 produced only minor signs of ocular and respiratory tract irritation. 1-hour exposure of mice to concentrations up to 16.9 mg/m 3 resulted in notable butnot serious effects on respiratory parameters and acute exposures of rabbits (20 minutes to 12hours) to concentrations ranging from 58-389 mg/m 3 (Ct "2,300 mg-min/m 3 ) resulted in severe respiratory tract damage.
Because exposure-response data were unavailable for all of the AEGL-specificexposure durations, temporal extrapolation was used in the development of AEGL values for theAEGL-specific time periods. The concentration-exposure time relationship for many irritant andsystemically acting vapors and gases may be described by C n x t = k, where theexponent n ranges from 0.8 to 3.5 (ten Berge, 1986). Analysis of available dataregarding AEGL-1 type effects reported by Reed (1918), Reed et al. (1918), Guild et al. (1941),and Anderson (1942) indicate that, for exposure periods up to several hours, the concentration-exposure time relationship is a near-linear function (i.e., Haber's Law where n = 1 forC n x t = k) as shown by n values of 1.11 and 0.96 for various data sets analyzedthat were consistent with AEGL-1 effects. Therefore, an empirically derived, chemical-specificestimate of n = 1 was used for derivation of most of the AEGL values rather than a default valuebased upon the ten Berge (1986) analysis. Due to uncertainty regarding linear extrapolation toa time duration notably shorter than that for which empirically derived lethality data wereavailable, the 10-minute AEGL-3 values utilized exponential time scaling where n was 3.
The AEGL-1 values were based upon data from Anderson (1942) who found that anexposure concentration-time product of 12 mg-min/m 3 represented a threshold forocular effects (conjunctival injection and minor discomfort with no functional decrement) inhuman volunteers acutely exposed to sulfur mustard. An UF adjustment was limited to a factor of 3 for protection ofsensitive individuals. This adjustment was considered appropriate for acute exposures tochemicals whose mechanism of action primarily involves surface contact irritation of ocularand/or respiratory tract tissue rather than systemic activity that involves absorption anddistribution of the parent chemical or a biotransformation product to a target tissue. Anderson(1942) noted that there was little variability in the ocular responses among the subjects in hisstudy, thereby providing additional justification for the intraspecies UF of 3.
The AEGL-2 values for sulfur mustard were also developed using the data fromAnderson (1942). Anderson reported that a Ct value of approximately 60 mg-min/m 3 represented the lowest concentration-time product for which ocular effectscould be characterized as military casualties. The 60 mg-min/m 3 exposure wasused as the basis for developing the AEGL-2 values because it represented an acute exposurecausing an effect severe enough to impair escape and, although not irreversible, would certainlyresult in potential for additional injury. Anderson (1942) characterized the 60 mg-min/m 3 Ct as representing the lower margin of the concentration-effect zone thatwould result in ineffective military performance (necessary to complete a mission), and that mayrequire treatment for up to 1 week. The ocular irritation and damage were also consideredappropriate as a threshold estimate for AEGL-2 effects because the eyes are generally consideredthe most sensitive indicator of sulfur mustard exposure and would likely occur in the absence ofvesication effects and severe pulmonary effects. The fact that the AEGL-2 is based upon humandata precludes the use of an interspecies UF. A factor of 3 was applied forintraspecies variability (protection of sensitive populations). This factor was limited to threeunder the assumption that the primary mechanism of action of sulfur mustard involves a directeffect on the ocular surface and that this response will not vary greatly among individuals.Anderson also noted little variability in the ocular responses among the subjects in his study. Amodifying factor of 3 was applied to accommodate potential onset of long-term ocular orrespiratory effects. This was justified by the fact that there was no long-term follow-up reportedby Anderson with which to confirm or deny the development of permanent ocular or respiratorytract damage. The total uncertainty/modifying factor adjustment was 10 [The total adjustment is10 because the factors of 3 each represent a logarithmic mean (3.16) of 10, therefore 3.16 x 3.16 = 10].
For development of the AEGL-3, a 1-hour exposure of mice to 21.2mg/m 3 was used as an estimated lethality threshold (Kumar and Vijayaraghavan,1998). This value is also near the lower bound of the 95% confidence interval for the 1-hourmouse LC 50 of 42.5 mg/m 3 reported by Vijayaraghavan (1997). AnUF for intraspecies variability of 3 was used because the lethality resulting fromacute inhalation exposure to sulfur mustard appears to be a function of pulmonary damageresulting from direct contact of the agent with epithelial surfaces and would not likely exhibit anorder-of-magnitude variability among individuals. An UF of 3 was also applied toaccount for possible interspecies variability in the lethal response to sulfur mustard. Theresulting total UF adjustment was 10. The modifying factor of 3 utilized forAEGL-2 development to account for uncertainties regarding the latency and persistence of theirritant effects of low-level exposure to sulfur mustard was not applied for AEGL-3 becauselethality of the mice was assessed at 14 days post exposure in a study by Vijayaraghavan (1997).Application of any additional UFs or modifying factors was not warrantedbecause the proposed AEGL-3 values are equivalent to exposures in humans that are known toproduce only ocular and respiratory tract irritation.
The AEGL values for sulfur mustard are based upon noncancer endpoints. Sulfurmustard is genotoxic and has induced carcinogenic responses in humans following single highexposures and following multiple exposures that were sufficient to produce adverse effects.Carcinogenic responses, however, are not known to occur with asymptomatic exposures.Limitations on the currently available data do not allow for a definitive quantitative cancer risk assessment, especially for an acute, once-in-a-lifetime, exposure.
The AEGL-1 and AEGL-2 values are based upon human exposure data and areconsidered to be defensible estimates for exposures representing thresholds for the respectiveAEGL effect levels. The ocular irritation upon which the AEGL-1 and AEGL-2 values are basedis the most sensitive response to sulfur mustard vapor. The AEGL-3 values provide Ct products(approximately 60-130 mg-min/m 3 ) that are known to cause only moderate tosevere ocular irritation and possible respiratory tract irritation in human subjects but not life-threatening health effects or death. Although, the overall database for acute inhalation exposureto sulfur mustard is not extensive, the AEGL values appear to be supported by the available dataand in some cases, similar values obtained using somewhat differing approaches.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 0.06(0.40) | 0.02(0.13) | 0.01(0.067) | 0.003(0.017) | 0.001(0.008) | Conjunctival injectionand minor discomfortwith no functionaldecrement in humanvolunteers (Anderson,1942) |
| AEGL-2(Disabling) | 0.09(0.60) | 0.03(0.20) | 0.02(0.10) | 0.004(0.025) | 0.002(0.013) | Well marked, generalizedconjunctivitis, edema,photophobia, and eyeirritation in humanvolunteers (Anderson,1942) |
| AEGL-3(Lethality) | 0.91(6.1) | 0.63(4.2) | 0.32(2.1) | 0.08(0.53) | 0.04(0.27) | Lethality estimate in mice(Kumar andVijayaraghavan, 1998) |
ii. References .
Anderson, J.S. 1942. The effect of mustard gas vapour on eyes under Indian hot weatherconditions. CDRE Report No. 241. Chemical Defense Research Establishment (India).
Guild, W.J., Harrison, K.P., Fairly, A., and Childs, A.E. 1941. The effect of mustard gasvapour on the eyes. Porton Report No. 2297, Serial No. 12. November 8, 1941.
Kumar, O. and Vjayaraghavan, R. 1998. Effect of sulphur mustard inhalation exposure onsome urinary variables in mice. Journal of Applied Toxicology . 18:257-259.
Reed, C.I. 1918. The minimum concentration of mustard gas effective for man.Preliminary Report. Report 318. War Department, Medical Division, Chemical Warfare Section, Pharmacological Research Section, American University Experiment Station. October 26, 1918.
Reed, C.I., Hopkins, E.F., and Weyand, C.F. 1918. The minimum concentration of mustardgas effective for man. Final Report. Report 329. War Department, Medical Division, Chemical Warfare Section, Pharmacological Research Section, American University Experiment Station. December 2, 1918.
ten Berge, W.F. 1986. Concentration-time mortality response relationship of irritant andsystemically acting vapours and gases. Journal of Hazardous Materials . 13:301-309.
Vijayaraghavan, R. 1997. Modifications of breathing pattern induced by inhaled sulphurmustard in mice. Archives of Toxicology . 71:157-164.
4. HCFC-141b (1,1-dichloro-1-fluoroethane) or hydrochlorofluorocarbon-141b -i. Description . 1,1-Dichloro-1-fluoroethane has been developed as a replacementfor fully halogenated chlorofluorocarbons as its residence time in the atmosphere is shorter andits ozone depleting potential is lower than that of presently used chlorofluorocarbons. HCFC-141b may be used in the production of rigid polyurethane and polyisocyanurate or phenolicinsulation foams for residential and commercial buildings. It may also be used as a solvent inelectronic and other precision cleaning applications.
HCFC-141b is of low inhalation toxicity. Its effects have been studied with humansubjects and several animal species including the monkey, dog, rat, mouse, and rabbit. Inaddition, studies addressing repeated and chronic exposures, genotoxicity, carcinogenicity,neurotoxicity, and cardiac sensitization were also available. At high concentrations, halogenatedhydrocarbons may produce cardiac arrhythmias; this sensitive endpoint was considered indevelopment of AEGL values.
Adequate data were available for development of the three AEGL classifications.Inadequate data were available for determination of the relationship between concentration andexposure duration for a fixed effect. However, based on the rapidity with which bloodconcentrations in humans approached equilibrium, the similarity in lethality values in ratsexposed for 4 or 6 hours, and the fact that the cardiac sensitization effect is based on aconcentration threshold rather than exposure duration, all AEGL values were flat-lined acrosstime. The fact that some experimental exposure durations in both human and animal studieswere generally long, 4 to 6 hours, lends confidence to flat-lining the values for the shorterexposure durations.
The AEGL-1 value was based on the observation that exercising human subjectscould tolerate exposure to concentrations of 500 or 1,000 ppm for 4 hours with no effects onlung functions, respiratory symptoms, irritation of the eyes, or cardiac symptoms (Utell et al., 1997). Results of exposures of two subjects for an additional 2 hours to the 500 ppmconcentration and one of the subjects to the 1,000 ppm concentration for an additional 2 hoursdid not indicate a clear effect on neurobehavioral parameters. Because the 4- or 6-hour 1,000ppm concentration is a no-observed-effect-level (NOEL), there were no indications of responsedifferences among tested subjects, and animal studies indicate that adverse effects occur only atconsiderably higher concentrations, the value was not adjusted by an UF to protectsensitive individuals. Because blood concentrations of HCFC-141b rapidly approachedequilibrium and did not greatly increase after 55 minutes of exposure, the value of 1,000 ppmwas used for all time periods.
The AEGL-2 value was based on the lowest concentration that caused cardiacsensitization in dogs exposed to HCFC-141b for 10 minutes (Mullin, 1977). This value of 5,200ppm is far below the lowest concentrations that caused death from cardiac fibrillation (10,000ppm in this study and 20,000 ppm in a similar study [Hardy et al., 1989a]). Because the cardiacsensitization test is supersensitive as the response to epinephrine is optimized (the epinephrinedose is greater than the physiological level in stressed animals by up to a factor of 10), a single intraspecies UF of 3 was applied to protect sensitive individuals. Cardiacsensitization is concentration dependent; duration of exposure did not influence theconcentration at which this effect occurred. Using the reasoning that the concentration is thedetermining factor in cardiac sensitization and exposure duration is of lesser importance, theresulting value of 1,700 ppm is proposed for all time periods.
The AEGL-3 values were based on the concentration of 9,000 ppm, the highestvalue that resulted in mild to marked cardiac responses but did not cause death in a cardiacsensitization study with the dog (Hardy et al., 1989a). Because the cardiac sensitization test issupersensitive as the response to epinephrine is optimized, a single intraspecies UF of 3 was applied to protect sensitive individuals. Using the reasoning that theconcentration is the determining factor in cardiac sensitization and exposure duration is of lesserimportance, the resulting value of 3,000 ppm is proposed for all time periods.
Based on the extensive database involving both human and animal exposures anduse of the most sensitive endpoint in the studies, confidence in the AEGL values is high. Valuesare summarized in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 1,000(4,850) | 1,000(4,850) | 1,000(4,850) | 1,000(4,850) | 1,000(4,850) | No effect-humans(Utell et al., 1997) |
| AEGL-2(Disabling) | 1,700(8,245) | 1,700(8,245) | 1,700(8,245) | 1,700(8,245) | 1,700(8,245) | Threshold for cardiacarrhythmia-dog1 (Mullin, 1977) |
| AEGL-3(Lethality) | 3,000(14,550) | 3,000(14,550) | 3,000(14,550) | 3,000(14,550) | 3,000(14,550) | Threshold for severecardiac response-dog1 (Hardy et al., 1989a) |
| 1 Response to challenge dose of epinephrine (cardiac sensitization test). | ||||||
ii. References .
Hardy, J.C., Sharman, I.J., and Chanter, D.O. 1989a. Assessment of cardiac sensitizationpotential in dogs and monkeys. Comparison of I-141b and F11. PWT 86/89437, HuntingdonResearch Centre Ltd., Huntingdon, Cambridgeshire, England.
Mullin, L.S. 1977. Cardiac sensitisation. Haskell Laboratory Report 957-77, E.I. duPont de Nemours and Co., Newark, DE.
Utell, M.J., Anders, M.W., and Morrow, P.E. 1997. Clinical inhalation studies with HCFC-141b. Final Report: December 4, 1997. MA-RR-97-2406, Departments of Medicine,Environmental Medicine, and Pharmacology and Physiology, University of Rochester MedicalCenter, Rochester, NY.
5. HFC-134a (1,1,1,2-tetrafluoroethane) or hydrofluorocarbon-134a -i. Description . 1,1,1,2-Tetrafluoroethane has been developed as a replacement for fully halogenated chlorofluorocarbons because its residence time in the atmosphere is shorter and itsozone depleting potential is insignificant. HFC-134a may be used in refrigeration and airconditioning systems, as a blowing agent for polyurethane foams, and as a propellant for medicalaerosols. Yearly production is estimated at 175,000 tons.
HFC-134a has a very low acute inhalation toxicity. Its acute inhalation effects havebeen studied with human subjects and several animal species including the monkey, dog, rat, andmouse. In addition, studies addressing repeated and chronic exposures, genotoxicity,carcinogenicity, neurotoxicity, and cardiac sensitization were also available. At highconcentrations, halogenated hydrocarbons may produce cardiac arrhythmias; this sensitiveendpoint was considered in development of AEGL values.
Adequate data were available for development of the three AEGL classifications.Inadequate data were available for determination of the relationship between concentration andtime for a fixed effect. Based on the observations that:
a. Blood concentrations in humans rapidly approach equilibrium with negligiblemetabolism and tissue uptake.
b. The endpoint of cardiac sensitization is a blood concentration-related thresholdphenomenon, derived values for each AEGL classification were flat-lined across time.
The AEGL-1 concentration was based on a 1-hour no-effect concentration of 8,000ppm in human subjects (Emmen and Hoogendijk, 1998). This concentration was without effectson lung functions, respiratory parameters, the eyes (irritation), or the heart (cardiac symptoms).Because this concentration is considerably below that causing any effect in animal studies, no intraspecies UF was applied. Based on the fact that blood concentrations inthis study appeared to be approaching equilibrium following 55 minutes of exposure and effectsare determined by blood concentrations, the value of 8,000 ppm was used across all time periods.
The AEGL-2 concentration was based on the no-effect concentration of 40,000 ppmfor cardiac sensitization in dogs (Hardy et al., 1991). Because the cardiac sensitization test issupersensitive as the response to epinephrine is optimized (the epinephrine dose is greater thanthe physiological level in stressed animals by up to a factor of 10), a single intraspeciesUF of 3 was applied to protect sensitive individuals. Cardiac sensitization isconcentration dependent; duration of exposure does not influence the concentration at which thiseffect occurs. Using the reasoning that the concentration is the determining factor in cardiacsensitization and exposure duration is of lesser importance, the resulting value of 13,000 ppm isproposed for all time periods.
The AEGL-3 concentration was based on the concentration of 80,000 which causedmarked cardiac effects but no deaths in dogs (Hardy et al., 1991). Because the cardiacsensitization test is supersensitive as the response to epinephrine is optimized (the epinephrinedose is greater than the physiological level in stressed animals by up to a factor of 10), a singleintraspecies UF of 3 was applied to protect sensitive individuals. Cardiacsensitization is concentration dependent; duration of exposure does not influence theconcentration at which this effect occurs. Using the reasoning that the concentration is thedetermining factor in cardiac sensitization and exposure duration is of lesser importance, theresulting value of 27,000 ppm is proposed for all time periods.
Based on the extensive database involving both human and animal exposures and useof the most sensitive endpoint in the studies, confidence in the AEGL values is high. Values aresummarized in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint(Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 8,000(34,000) | 8,000(34,000) | 8,000(34,000) | 8,000(34,000) | 8,000(34,000) | No effects-humans(Emmen andHoogendijk, 1998) |
| AEGL-2(Disabling) | 13,000(55,250) | 13,000(55,250) | 13,000(55,250) | 13,000(55,250) | 13,000(55,250) | No effect, cardiacsensitization-dogs(Hardy et al., 1991) |
| AEGL-3(Lethality) | 27,000(114,750) | 27,000(114,750) | 27,000(114,750) | 27,000(114,750) | 27,000(114,750) | Markedeffect, cardiacsensitization-dogs(Hardy et al.,1991) |
ii. References .
Emmen, H.H. and Hoogendijk, E.M.G. 1998. Report on an ascending dose safety study comparing HFA-134a with CFC-12 and air, administered by whole-body exposure to healthyvolunteers. MA-250B-82-306, TNO Report V98.754, The Netherlands Organization Nutritionand Food Research Institute, Zeist, The Netherlands.
Hardy, C.J., Sharman, I.J., and Clark, G.C. 1991. Assessment of cardiac sensitisationpotential in dogs: Comparison of HFA 134a and A12. Report No. CTL/C/2521. HuntingdonResearch Centre, Huntingdon, Cambridgeshire, U.K.
6. Hydrogen cyanide (HCN) -i. Description . Hydrogen cyanide is acolorless, rapidly acting, highly poisonous gas or liquid having an odor of bitter almonds. MostHCN is used as an intermediate at the site of production. Major uses include the manufacture ofnylons, plastics, and fumigants; it is also used in electroplating and mining. Exposures to HCNmay occur in industrial situations as well as from cigarette smoke, combustion products, andnaturally occurring cyanide compounds in foods.
HCN is a systemic poison; toxicity is due to inhibition of cytochrome oxidase whichprevents cellular utilization of oxygen. Lack of oxygen supply to the brain results in loss ofconsciousness, respiratory arrest, and, ultimately, death. Stimulation of the chemoreceptors ofthe carotid and aortic bodies produces a brief period of hyperpnea; cardiac irregularities mayalso occur. These mechanisms of action are the same for all species.
Inhalation studies resulting in sublethal effects such as incapacitation and changes inrespiratory and cardiac parameters were described for the monkey, rat, and mouse; lethalitystudies were available for the rat, mouse, and rabbit. Exposure durations ranged from a fewseconds to 24 hours. Regression analyses of the exposure duration-concentration relationshipsfor both incapacitation and lethality for the monkey determined that the relationship isC 2 x t = k and that the relationship for lethality (based on rat data) is C 2.6 x t = k. Although human exposures have occurred, no reliable data on exposureconcentrations were available.
The AEGL-1 was not determined because serious effects may occur atconcentrations below those causing irritation or notable discomfort. In addition, the onset ofserious effects is very rapid.
The AEGL-2 was based on a concentration of 60 ppm for 30 minutes which resultedin a slight depressive effect on the central nervous system of monkeys as evidenced by changesin electroencephalograms; there was no physiological response (Purser, 1984; Purser et al.,1984). The mechanism of action of HCN is the same for all mammalian species, but the rapidityof the toxic effect may be related to relative respiration rates as well as pharmacokineticconsiderations. The monkey is an appropriate model for extrapolation to humans as the respiratory systems of monkeys and humans are similar. Because the monkey is an appropriate modeland the mechanism of action of HCN is the same for all species, an interspecies UF of 2 was applied. Humans may differ in their sensitivity to HCN but no data regardingspecific differences were located in the available literature. Therefore, an intraspecies UF of 3 was applied. The 30-minute concentration of 60 ppm was divided by acombined interspecies and intraspecies UF of 6 and scaled across time for theAEGL specified exposure periods using the relationship C 2 x t = k. The safety ofthe 10- and 30-minute values are supported by monitoring studies in which concentrations of10-15 ppm produced central nervous system effects in some workers.
The rat provided the only data set for calculation of LC 01 values fordifferent time periods (E.I. du Pont de Nemours and Company, 1981). The LC 01 values were considered the threshold for lethality and were used as the basis for deriving AEGL-3 values. The mouse, rat, and rabbit were equally sensitive to the lethal effects of HCN asdetermined by similar LC 50 values for the same time periods. In an earlier study,times to death for several animal species showed that mice and rats may be slightly moresensitive to HCN than monkeys (and presumably humans). The differences in sensitivity wereattributed, at least partially, to the more rapid respiratory rate of the rodent species. BecauseLC 50 values for several species were within a factor of 1.5 of each other, aninterspecies UF of 2 was applied. Humans may differ in their sensitivity to HCNbut no data regarding specific differences were located in the available literature. Therefore, anintraspecies UF of 3 was applied to protect sensitive individuals. The 15- and 30-minute and 1-hour LC 01 values, 138, 127, and 88 ppm, respectively, were dividedby a total UF of 6. The 15-minute value was time scaled to 10 minutes to derivethe 10-minute AEGL-3, the 30-minute LC 01 was used for the 30-minute AEGL-3value, and the 60-minute LC 01 was used to calculate the 1-, 4-, and 8-hour AEGL-3concentrations. For the AEGL-3 values, scaling across time utilized the lethal concentration-exposure duration relationship for the rat, C 2.6 x t = k.
The proposed values appear in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint(Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | NA1 | NA | NA | NA | NA | Serious effects mayoccur below detectableconcentrations orconcentrations causingdiscomfort |
| AEGL-2(Disabling) | 17(19) | 10(11) | 7.1(7.8) | 3.5(3.9) | 2.5(2.8) | Slight central nervoussystem depression-monkey(Purser, 1984) |
| AEGL-3(Lethality) | 27(30) | 21(23) | 15(17) | 8.6(9.7) | 6.6(7.3) | Lethality(LC 01 )-rat(E.I. du Pont de Nemours,1981) |
| 1 Not appropriate. | ||||||
ii. References .
E.I. du Pont de Nemours and Company. 1981. Inhalation Toxicity of CommonCombustion Gases. Haskell Laboratory Report No. 238-81. Haskell Laboratory, Newark, DE.
Purser, D.A. 1984. A bioassay model for testing the incapacitating effects of exposure tocombustion product atmospheres using cynomolgus monkeys. Journal of Fire Sciences . 2:20-36.
Purser, D.A., Grimshaw, P., and Berrill, K.R. 1984. Intoxication by cyanide in fires: Astudy in monkeys using polyacrylonitrile. Archives of Environmental Health . 39:394-400.
7. Hydrogen fluoride (HF) -i. Description . Hydrogen fluoride is acolorless, highly irritating and corrosive gas. Reaction with water is rapid, producing heat andhydrofluoric acid. Hydrogen fluoride is used in the manufacture of artificial cryolite; in theproduction of aluminum, fluorocarbons, and uranium hexafluoride; as a catalyst in alkylationprocesses in petroleum refining; in the manufacture of fluoride salts; and in stainless steel picklingoperations. It is also used to etch glass and as a cleaner in metal finishing processes.
Hydrogen fluoride is a severe irritant to the eyes, skin, and nasal passages; highconcentrations may penetrate to the lungs resulting in edema and hemorrhage. Data on irritanteffects in humans and lethal and sublethal effects in six species of mammals (monkey, dog, rat,mouse, guinea pig, and rabbit) were available for development of AEGLs. The data wereconsidered adequate for derivation of the three AEGL classifications for five exposure periods.Regression analyses of the reported concentration-exposure durations for lethality for the animalspecies determined that the relationship between concentration and time is C 2 x t = k.
The AEGL-1 values were based on the observation that human volunteers couldtolerate exposure to a concentration of 2 ppm for 6 hours with only mild irritation of the eyes,skin, and upper respiratory tract (Largent, 1960, 1961). This concentration was adjusted by anUF of 3 to protect sensitive individuals and scaled to the 30-minute and 1-, 4-, and 8-hourexposure durations using C 2 x t = k. The factor of 3 was selected because hydrogenfluoride reacts chemically with the tissues of the respiratory tract; the adverse effects are unlikelyto differ among individuals. The resulting derived values, 2.3, 1.6, 0.82, and 0.58 ppm, wererounded to the nearest whole integers of 2.0, 2.0, 1.0, and 1.0, respectively, by the NAC/AEGLCommittee. Because irritant properties would not change greatly between the 10-minute and 30-minute time frames, the 10-minute AEGL-1 was set at the same value of 2.0 ppm as the 30-minute AEGL-1.
The 10-minute AEGL-2 value was based on an absence of serious pulmonary orother adverse effects in rats during direct delivery of HF to the trachea for an exposure period of10 minutes (Dalbey, 1996; Dalbey et al., 1998). This reported concentration-exposure value of950 ppm for 10 minutes was adjusted by a combined UF of 10: 3 for interspecies variation sincethe rat was not the most sensitive species in other studies (but direct delivery to the trachea is asensitive model) and an intraspecies UF of 3 since HF reacts chemically and indiscriminately withthe tissues of the respiratory tract and adverse effects are unlikely to differ among individuals.
The 30-minute and the 1-, 4- and 8-hour AEGL-2 values were based on a study inwhich dogs exposed to 243 ppm for 1 hour showed signs of more than mild irritation, includingblinking, sneezing, and coughing (Rosenholtz et al., 1963). The 1-hour value of 243 ppm wasadjusted by a total UF of 10: 3 for intraspecies variation since the dog is a sensitive species forsensory irritation and 3 for intraspecies variation since HF reacts chemically and indiscriminatelywith the tissues of the respiratory tract and effects are unlikely to differ among individuals. Thevalues were scaled across time using C 2 x t = k where the value of n = 2 was derivedfrom concentration: Exposure duration relationships based on lethality.
The 10-minute AEGL-3 value was based on the reported 10-minute lethal thresholdin orally cannulated rats of 1,764 ppm (Dalbey, 1996; Dalbey et al., 1998). This value wasrounded down to 1,700 ppm and adjusted by UFs of 3 for interspecies differences(LC 50 values differ by a factor of approximately 2-4 between the mouse and rat)and 3 for intraspecies differences since HF reacts chemically and indiscriminately with tissues ofthe respiratory tract and effects are unlikely to differ among individuals. The total adjustment forUFs for the 10-minute AEGL-3 value was 10.
The 30-minute and the 1-, 4-, and 8-hour AEGL-3 values were derived from areported 1-hour exposure resulting in no deaths in mice (Wohlslagel et al., 1976). The dataindicated that the value of 263 ppm was the threshold for lethality. A comparison ofLC 50 values among species in several studies determined that the mouse was the mostsensitive species in lethality studies. The 1-hour value of 263 ppm was adjusted by an interspeciesUF of 1 since the mouse was the most sensitive species and intraspecies UF of 3 since HF reactschemically and indiscriminately with tissues of the respiratory tract and effects are unlikely todiffer among individuals. A modifying factor of 2 was applied to account for the steepness of thelethal dose-response curve and the value was scaled to the other AEGL-specified exposureperiods using a value of n = 2.
Based on the extensive database involving both human and animal exposures (six species of mammals) for various exposure durations, confidence in the AEGL values is high.Values are summarized in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 2(1.6) | 2(1.6) | 2(1.6) | 1(0.8) | 1(0.8) | Irritation inhumans (Largent,1960; 1961) |
| AEGL-2(Disabling) | 95(78) | 34(28) | 24(20) | 12(9.8) | 8.6(7.0) | NOAEL for lungeffects in cannulatedrats (Dalbey, 1996;Dalbey et al., 1998);1 sensory irritation indogs (Rosenholtz et al.,1963)2 |
| AEGL-3(Lethality) | 170(139) | 62(51) | 44(36) | 22(18) | 15(12) | Lethality thresholdin cannulated rats(Dalbey, 1996; Dalbeyet al., 1998);3 Lethality threshold inmice (Wohlslagel et al.,1976)4 |
| 1 10-minute AEGL-2 value. | ||||||
| 2 30-minute and 1-, 4-, and 8-hour AEGL-2 values. | ||||||
| 3 10-minute AEGL-3 value. | ||||||
| 4 30-minute and 1-, 4-, and 8-hour AEGL-3 values. | ||||||
ii. References .
Dalbey, W. 1996. Evaluation of the toxicity of hydrogen fluoride at short exposure times.Petroleum Environmental Research Forum Project 92-09, performed at StonybrookLaboratories Inc., Pennington, NJ.
Dalbey, W., Dunn, B., Bannister, R., Daughtrey, W., Kirwin, C., Reitman, F., Steiner, A., and Bruce, J. 1998. Acute effects of 10-minute exposure to hydrogen fluoride in rats and derivation ofa short-term exposure limit for humans. Regulatory Toxicology and Pharmacology . 27:207-216.
Largent, E.J. 1960. The metabolism of fluorides in man. American Medical Association Archives of Industrial Health . 21:318-323.
Largent, E.J. 1961. Fluorosis: The Health Aspects of Fluorine Compounds. Ohio StateUniversity Press, Columbus, OH.
Rosenholtz, M.J., Carson, T.R., Weeks, M.H., Wilinski, F., Ford, D.F., and Oberst, F.W. 1963. A toxicopathologic study in animals after brief single exposures to hydrogen fluoride. American Industrial Hygiene Association Journal . 24:253-261.
Wohlslagel, J., DiPasquale, L.C., and Vernot, E.H. 1976. Toxicity of solid rocket motorexhaust: Effects of HCl, HF, and alumina on rodents. Journal of Combustion Toxicology . 3:61-69.
8. Hydrogen sulfide ( H 2 S)-i. Description . The AEGL-1was based on persistent odors, eye and throat irritation, headache, and nausea in six workersexposed to a mean concentration of 0.09 ppm H 2 S for approximately 5 hours in amonitoring van downwind from an oil refinery (TNRCC, 1998). An UF of 3 was applied toaccount for intraspecies variability since minor irritation is not likely to vary greatly betweenindividuals. The value was flat-lined across the 10- and 30-minute and 1-, 4-, and 8-hour exposuretime points. The flat-lining approach was considered appropriate since mild irritant effectsgenerally do not vary greatly over time.
The AEGL-2 was based on focal areas of perivascular edema and an increase inprotein and lactic acid dehydrogenase (LDH) in bronchioalveolar lavage fluid in rats exposed to 200 ppm hydrogen sulfide for4 hours (Green et al., 1991; Khan et al., 1991). An UF of 3 was used to extrapolate fromanimals to humans since rat and mouse data suggest little interspecies variability. An UF of 3was also applied to account for sensitive individuals since data suggest little strain variability ofhydrogen sulfide toxicity among rats (total UF = 10). The 4-hour experimental value was thenscaled to the 10- and 30-minutes and 1- and 8-hour time points, using C 4.36 x t = k. Theexponent of 4.36 was derived from rat lethality data ranging from 10-minutes to 6-hour exposureduration.
The AEGL-3 was based on a 1-hour no-effect-level for death in rats (504 ppm)(MacEwen and Vernot, 1972). An UF of 3 was used to extrapolate from animals to humanssince rat and mouse data suggest little interspecies variability. An UF of 3 was also applied toaccount for sensitive individuals since data suggest little strain variability of hydrogen sulfidetoxicity among rats (total UF = 10). The value was then scaled to the 10- and 30-minutes and 1-, 4-, and 8-hour time points, using C 4.36 x t = k. The exponent of 4.36 was derived from ratlethality data ranging from 10 minutes to 6 hours exposure duration.
The calculated values are listed in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint(Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 0.03(0.04) | 0.03(0.04) | 0.03(0.04) | 0.03(0.04) | 0.03(0.04) | Persistent odor,eye, and throatirritation, headache,nausea (TNRCC, 1998) |
| AEGL-2(Disabling) | 42(59) | 32(45) | 28(39) | 20(28) | 17(24) | Perivascularedema, increasedprotein, and LDH inlavage fluid in rats(Green et al., 1991;Khan et al., 1991) |
| AEGL-3(Lethality) | 76(106) | 60(85) | 50(71) | 37(52) | 31(44) | 1 hour no-effect-level for death inrats(MacEwen and Vernot,1972) |
ii. References .
Green, F. H. Y., Schurch, S., and DeSanctis, G. T., et al. 1991. Effects of hydrogen sulfideexposure on surface properties of lung surfactant. Journal of Applied Physiology . 70:1943-1949.
Khan, A. A., Yong, S., and Prior, M. G., et al. 1991. Cytotoxic effects of hydrogen sulfide onpulmonary alveolar macrophages in rats. Journal of Toxicology and EnvironmentalHealth . 33:57-64.
MacEwen, J. D. and Vernot, E. H. 1972. Toxic Hazards Research Unit Annual Report.Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson AirForce Base, Ohio. Report No. ARML-TR-72-62. pp. 66-69.
TNRCC (Texas Natural Resources Conservation Commission). 1998. Memo from TimDoty to JoAnn Wiersma. Corpus Christi Mobile Laboratory Trip, January 31-February 6,1998; Real-Time Gas Chromatography and Composite Sampling, Sulfur Dioxide, HydrogenSulfide, and Impinger Sampling. April 20, 1998.
9. Otto Fuel II (main component propylene glycol dinitrate; CAS No. 6423-43-4) -i. Description . Otto Fuel II, a liquid propellant used exclusively by theU.S. Navy in torpedoes and other weapon systems, is a mixture of three synthetic compounds: 1,2-Propylene glycol dinitrate (PGDN), which is a nitrate ester explosive, dibutyl sebacate (a desensitizer), and 2-nitrodiphenylamine (a stabilizer). The primary component and the oneresponsible for the toxicity of Otto Fuel II is PGDN, a volatile liquid with a disagreeable odor.Because PGDN is the primary and most toxic component of Otto Fuel II and because onlyPGDN is relatively volatile compared with the other components, AEGLs have been derived interms of PGDN with the notation that the values are appropriate for Otto Fuel II.
PGDN is a systemic toxicant with effects on the cardiovascular and central nervoussystems. Its vasodilatory action results in headaches during human exposures. Symptoms ofdizziness, loss of balance, nasal congestion, eye irritation, palpitations, and chest pains have alsobeen reported. Methemoglobinemia has been reported at the high concentrations used in studieswith animals.
Few data were available that met the definitions of AEGL endpoints. Oneinhalation study with 20 human subjects described effects of headaches and slight loss of balanceat exposure concentrations of 0.1 to 1.5 ppm for exposure durations up to 8 hours (Stewart et al.,1974). Acute exposure of monkeys to concentrations of 70-100 ppm for 6 hours resulted insevere signs of toxicity including convulsions but no deaths (Jones et al., 1972). In the samestudy, exposure of rats to a higher concentration ( # 199 ppm for 4 hours) resulted in no toxicsigns. Examination of the relationship between exposure duration and concentration for bothmild and severe headaches in humans over periods of time of 1 to 8 hours determined that therelationship is C 1 x t = k.
The AEGL-1 values were based on concentrations of 0.5 ppm and 0.1 ppm whichwere the thresholds for mild headaches at exposure durations of 1 and 6 hours, respectively(Stewart et al., 1974). This effect can be considered the threshold for mild discomfort (only onesubject was affected at each exposure) which falls within the definition of an AEGL-1. The 0.5ppm concentration was used to derive the 30-minutes and 1-hour AEGL-1 values and the 0.1 ppmconcentration was used for the 4- and 8-hour values. Because the time and concentration valueswere based on the most sensitive subject, these concentrations were adjusted by an UF of 3 toaccount for additional differences in human sensitivity and scaled to the appropriate time periodsusing the C 1 x t = k relationship. An UF of 3 was considered sufficient as nosusceptible populations were identified (the headache effect is the same as that experienced byheart patients medicated with nitroglycerin for angina and these concentrations are far belowthose inducing methemoglobinemia in infants); the vasodilatory effects of PGDN, responsiblefor the headaches, are not expected to vary greatly among individuals. The 10-minute AEGL-1value was made equal to the 30-minute value.
The AEGL-2 values were based on a concentration of 0.5 ppm which caused severeheadaches accompanied by dizziness in one subject and slight loss of equilibrium in two subjectsin one of several sensitive equilibrium tests after 6 hours of exposure (Stewart et al., 1974). Thisconcentration-exposure duration was considered the threshold for impaired inability to escape asdefined by the AEGL-2. The 0.5 ppm concentration was adjusted by an intraspecies UF of 3 toprotect sensitive individuals and scaled across time using the C 1 x t = k relationship as for the AEGL-1 in Unit III.B.9.
The AEGL-3 values were based on the exposure of squirrel monkeys toconcentrations of 70-100 ppm for 6 hours which resulted in vomiting, pallor, coldextremities, semiconscousness, and clonic convulsions; these signs disappeared upon removalfrom the exposure chamber (Jones et al., 1972). The lower concentration, 70 ppm, was adjustedby a total UF of 10. An interspecies UF of 3 was chosen because both the monkey and humansubjects showed changes in electrical activity of the brain at similar PGDN concentrations, thethreshold for central nervous system depressants does not vary widely among mammalianspecies, and the monkey is an appropriate model for extrapolation to humans. Anintraspecies UF of 3 was chosen because the threshold for central nervous system depression alsodoes not vary greatly among individuals. Because the endpoint for the AEGL-3 values isdifferent than the endpoint for the AEGLs-1 and -2 and no data on the relationship betweenconcentration and exposure duration is available for the endpoint of central nervous systemdepression, the more conservative values of n = 3 and n = 1 were used to scale from 6 hours tothe shorter- and longer-time periods, respectively.
The proposed values appear in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1\a\(Nondisabling) | 0.33(2.3) | 0.33(2.3) | 0.17(1.1) | 0.05(0.34) | 0.03(0.17) | Mild headachesin humans(Stewart et al., 1974) |
| AEGL-2(Disabling) | 6.0(43) | 2.0(14) | 1.0(6.8) | 0.25(1.7) | 0.13(0.8) | Severeheadaches and slightimbalance in humans(Stewart et al., 1974) |
| AEGL-3(Lethality) | 23(165) | 16(114) | 13(93) | 8.0(57) | 5.3(38) | Convulsions inmonkeys(Jones et al., 1972) |
| a The distinctive odor of PGDN will be noticeable to most individuals at the 0.33 and 0.17 ppmconcentrations. | ||||||
ii. References .
Jones, R.A., Strickland, J.A., and Siegel, J. 1972. Toxicity of propylene glycol 1,2-dinitrate in experimental animals. Toxicology and Applied Pharmacology . 22:128-137.
Stewart, R.D., Peterson, J.E., Newton, P.E., Hake, C.L., Hosko, M.J., Lebrun, A. J., and Lawton, G.M. 1974. Experimental human exposure to propylene glycol dinitrate. Toxicologyand Applied Pharmacology . 30:377-395.
10. 1,1,1-Trichloroethane -i. Description . 1,1,1-Trichloroethane is acolorless, nonflammable liquid used primarily as an industrial metal degreasing agent. It is alsoused as a solvent for adhesives, inks, and coatings and as an aerosol propellant (Nolan et al.,1984). Solvent vapor is readily absorbed from the respiratory tract and distributed throughoutthe body, accumulating in tissues with high lipid content. In both humans and animals, theprimary response to acute inhalation exposures involve effects on the central nervous system (CNS). This chemical isarrhythmogenic and there is some evidence that it produces transient hepatotoxicity (Mcleod etal., 1987; Stahl et al., 1969; Hodgson et al., 1989). It has little effect on other organs and doesnot seem to be a developmental toxin although reliable epidemiological data for humans areunavailable. 1,1,1-Trichloroethane does not seem to have carcinogenic activity based on theavailable animal studies. A considerable amount of human and animal data are available forderivation of AEGLs. Rat ataxia and lethality data were used for the regression analyses of theconcentration-exposure durations. The relationship between time and concentration wasC n x t = k, where n = 3.3 or 3.
The AEGL-1 was based on consistent complaints of eye irritation and slightdizziness experienced by humans in an atmosphere controlled setting with exposures of 450 ppm for two 4-hour sessions separated by a 1.5-hour interval (Salvini et al., 1971). Stewart et al., 1969, exposed human subjects to time-weighted average (TWA) concentration of 500 ppm for 7 hour repeatedly for 5 days, the only consistent complaint was mild sleepiness and failure of the Romberg test by two of the subjects which had trouble with this test initially. Torkelson et al. (1958) reported a NOAEL for the Romberg test in humans after exposure to a TWA of 506 ppm for 7.5 hour. For derivation of the AEGL-1, the observations of Salvini et al. (1971) were used as the starting point for the threshold of eye irritation and very subtle CNS effects in humans at a concentration of 450 ppm for 4 hour. An UF of 2 was chosen based on the observation that the severity of the eye irritation did not increase with time and the threshold for mild CNS effects does not vary bymore than two-three fold which should be protective of sensitive individuals. The resulting figure of 230 ppm was used at all time points based on the information reported by Salvini et al. (1971) indicating that this exposure represented a threshold for these effects and the severity didnot increase with duration of exposure.
The AEGL-2 was based on more serious CNS effects which might impede escape.Mullin and Krivanek (1982) calculated EC 50 values for ataxia in rats at 30-minute and 1-, 2-, and 4-hour exposures to be 6,740; 6,000; 4,240; and 3,780 ppm. These values were usedas the basis for AEGL-2 derivation using an UF of 10 and extrapolations were made to the 10-minute and 8-hour time points using the equation C n x t = k, where n = 3.3 based onthe data presented by Mullin and Krivanek (1982). An UF of 10 was applied which includes afactor of 3 to account for sensitive individuals and a factor of 3 for interspecies extrapolation.These UFs were based on the two-three fold variation of minimum alveolar concentration for anesthesia (MAC) values among humans and thesimilarities in toxicity, metabolism, and excretion of 1,1,1-trichloroethane in rats compared tohumans. The resulting concentrations are similar to the concentration exposure durations applied in experimental human studies which resulting in effects that could impede escape, i.e., CNSintoxication.
The AEGL-3 values were derived from a lethality concentration-effect curve in the rat for a 6-hour exposure duration (Bonnet et al., 1980). The LC 0 wasconservatively estimated from this curve as a concentration of about 7,000 ppm for a 6-hour exposure duration. An extrapolation was made to the 30-minute and 1-, 4-, and 8-hour time points usingthe equation C n x t = k, where n = 3 based on the rat lethality data. An UF of 10was applied. An intraspecies factor of 3 was used to account for sensitive individuals based onthe two-three fold variation of MAC values observed among humans and an interspecies factorof 3 was used because of the similarities in toxicity, metabolism, and excretion of 1,1,1-trichloroethane in rats compared to humans. The resulting concentrations were multiplied by amodifying factor of 3 in order to achieve a reasonable concentration at which humans mightexperience life-threatening toxic effects. This factor is justified by the existence of a higherblood: Air partition coefficient for rats compared to humans. This principle determines therelative blood concentration for a vapor and because it is higher for rats, a higher bloodconcentration is achieved.
The proposed values appear in the table below.
| Classification | 10-min. | 30-min. | 1-hour | 4-hour | 8-hour | Endpoint (Reference) |
|---|---|---|---|---|---|---|
| AEGL-1(Nondisabling) | 230(1,252) | 230(1,252) | 230(1,252) | 230(1,252) | 230(1,252) | Eye irritation and slightdizziness in humans observed(Salvini et al., 1971) |
| AEGL-2(Disabling) | 930(5,064) | 670(3,650) | 600(3,270) | 380(2,070) | 310(1,688) | EC 50 for ataxia inrats (Mullin and Krivanek, 1982) |
| AEGL-3(Lethality) | 4,8001 (26,135) | 4,800(26,135) | 3,800(20,690) | 2,400(13,067) | 1,900(10,345) | LC 0 extrapolated(Bonnet et al., 1980) |
| 1 The 30-minute value was used as the 10-minute value so as not to exceed the threshold for cardiacsensitization observed in dogs (Reinhardt et al., 1973). | ||||||
ii. References .
Bonnet, P., Francin, J.M., Gradiski, D., Raoult, G., and Zissu, D. 1980. Determination of themedian lethal concentration of principle chlorinated aliphatic hydrocarbons in the rat Archives des Maladies Professionelles . 41:317-321.
Mullin, L.S. and Krivanek, N.D. 1982. Comparison of unconditioned avoidance tests inrats exposed by inhalation to carbon monoxide, 1,1,1-trichloroethane, and toluene or ethanol. Neurotoxicology . 1:126-137.
Reinhardt, C.F., Mullin, L.S., and Maxfield, M.E. 1973. Epinephrine-induced cardiacarrhythmia potential of some common industrial solvents. Journal of OccupationalMedicine . 15(12):953-955.
Salvini, M. S. and Binaschi, M. Riva. 1971. Evaluation of the psychophysiologicalfunctions in humans exposed to the threshold limit value of 1,1,1-trichloroethane. BritishJournal of Industrial Medicine . 28(3):286-292.
List of Subjects
Environmental protection, Hazardous substances.
Dated: March 8, 2000.
Susan H. Wayland,
Deputy Assistant Administrator for Prevention, Pesticides and Toxic Substances.
[FR Doc. 00-6397 Filed 3-14-00; 8:45 am]
BILLING CODE 6560-50-F