Thirteenth Interim Report of the Subcommittee on Acute Exposure Guideline Levels (2005) / Chapter Skim
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Thirteenth Interim Report of the Subcommittee on Acute Exposure Guideline Levels
Thirteenth Interim Report of the Subcommittee on Acute Exposure Guideline Levels
Pages 1-24
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This interim report presents the subcommittee's comments concerning the NAC's draft AEGL documents for 10 chemicals: 1, 4-dioxane; chloroform; carbon tetrachloride; sulfur dioxide; cis, trans 1,-2 dichloroethylene; monochloroacetic acid; carbon monoxide; fluorine; methanol; and phenol. COMMENTS ON 1, 4-DIOXANE At its February 21-23, 2005, meeting, the subcommittee reviewed the AEGL document on 1,4dioxane.
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In the section titled Intraspecies Variability, revise to read "Due to the lack of data, there was no basis for reducing the default intraspecies uncertainty factor." Page 32, lines 1287-1288. "A total uncertainty factor of 3 was used because for local effects, the toxi cokinetic differences do not vary considerably within and between species." The NAC needs to break this down to inter- and intra-, not combine them.
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Stick with the CNS depression effect. For solvents that cause CNS effects, the AEGL-2 and AEGL-3 values should remain relatively constant over a time exceeding 1 h due to blood equilibrium concentrations.
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The delayed response of the liver and kidneys apparently forms a greater risk than initial CNS depression. Lines 207 and 241.
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Line 992. Apart from a moderate CNS depression, other CNS effects have not been reported.
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The proper abbreviation for milliliters is mL, not ml. COMMENTS ON CHLOROFORM At its February 21-23, 2005, meeting, the subcommittee reviewed the AEGL document on chloroform.
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2000. Physiologically based pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water ex posures.
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COMMENTS ON CARBON TETRACHLORIDE At its February 21-23, 2005, meeting, the subcommittee reviewed the AEGL document on carbon tetrachloride (CCl4)
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were exposed subchronically, not acutely, to CC14. Peak vapor concentrations were likely much higher than the range of 20-85 ppm proposed by Elkins.
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the primary focus, longer-term exposures with observations at 24 hours or less are included as well as longer-term ex posures that may provide useful perspective in assessing the effects of inhalation exposure to carbon tetrachloride." The table should be reorganized so that the acute studies that are germane to the derivation of AEGL values are identified separately from the (1) longer-term studies with observa tions at 24 h or less that may be relevant to the derivation of AEGLs and (2)
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It should also be pointed out here that rats will receive a greater internal dose than humans upon equivalent inhalation exposures because of rats' higher respiratory rate, cardiac out put, and blood:air partition coefficient. More importantly, rats metabolize substantially more CC14 than do humans because of rats' higher hepatic blood flow and higher cytochrome P4502E1 (CYP2E1)
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to longer and shorter times would be preferable to extrapolation from 30 min to the longer exposure times. The scientific validity of using Cn × t = K under such circumstances for volatile organic chemicals (VOCs)
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Davis (1934) reported no CNS depression nor kidney injury in humans inhaling 76 ppm for 4 h, but one worker exposed to 200 ppm for 8 h exhibited compromised kidney function.
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. The possibility remains, nev ertheless, that molecular mechanisms of narcosis could vary among different species resulting in heretofore unrecognized interspecies pharmacodynamic differences in sensitivity to halocarbon induced CNS depression.
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2004. PBPK modeling of the metabolic interactions of carbon tetrachloride and tetrachloroethylene in B6C3F1 mice.
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2000. Comparative metabolism of carbon tetrachloride in mice, rats, and ham sters using gas uptake and PBPK modeling.
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The subcommittee recommends a value of 0.2 ppm at the highest. The subcommittee recommends that the AEGL values should be held constant for various exposure durations.
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The document was presented by Cheryl Bast of Oak Ridge National Laboratory. The subcommittee recommends minor revisions to the document.
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Derivation of AEGL-2 and AEGL-3: The argument given for the choice of the magni tude of the interspecies UF considers only pharmacodynamics: "because data suggest that the criti cal brain concentration of a halocarbon required to produce a given level of narcosis is relatively constant across species." Upon equivalent inhalation exposures, rats receive a substantially larger internal dose of VOCs than do humans. This is attributable to rats' higher respiratory rate and car diac output.
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The document was presented by Peter Griem of Clariant, Germany. The subcommittee recommends minor revisions to the document.
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Perhaps there are human data that support this decision in addition to the animal data cited in the text. COMMENTS ON FLUORINE At its February 21-23, 2005, meeting, the subcommittee reviewed the AEGL document on fluorine.
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As related in the subcommittee's initial review of this document, "A person who inhales ethanol vapor cannot attain blood levels sufficient to impair his/her ability to drive a motor vehicle. Methanol is less lipophilic and is therefore a less potent CNS depressant than ethanol." It is very unlikely that substantial CNS depression will result from the inhalation of methanol.
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that show little effect of folate deficiency on blood metha nol concentrations. CNS depression, of course, is directly dependent upon blood/brain methanol concentration.
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The document was presented by Peter Griem of Clariant, Germany. The subcommittee recommends minor revisions.
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