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Arsine1
Acute Exposure Guideline Levels

UPDATE OF ARSINE AEGLS TO INCLUDE 10-MINUTE VALUES

In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min), and 1, 4, and 8 hours (h). Since that time, AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The Summary below is from Volume 1 and contains additional discussion to address the development of 10-min values.

SUMMARY

Arsine is a colorless gas used in the semiconductor industry. It is also used in mining and manufacturing processes involving arsenicals and in paints and herbicides containing arsenicals.

Arsine is an extremely toxic potent hemolytic agent, ultimately causing death from renal failure. Numerous human case reports are available, but these reports lack definitive quantitative exposure data. The reports do affirm, however, the extreme toxicity and the latency period for toxic effects of arsine in humans.

1

This document was prepared by AEGL Development Team member Richard Thomas of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Robert Young of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC Committee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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4 Arsine1 Acute Exposure Guideline Levels UPDATE OF ARSINE AEGLS TO INCLUDE 10-MINUTE VALUES In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min), and 1, 4, and 8 hours (h). Since that time, AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The Summary below is from Vol- ume 1 and contains additional discussion to address the development of 10-min values. SUMMARY Arsine is a colorless gas used in the semiconductor industry. It is also used in mining and manufacturing processes involving arsenicals and in paints and herbicides containing arsenicals. Arsine is an extremely toxic potent hemolytic agent, ultimately causing death from renal failure. Numerous human case reports are available, but these reports lack definitive quantitative exposure data. The reports do affirm, how- ever, the extreme toxicity and the latency period for toxic effects of arsine in humans. 1 This document was prepared by AEGL Development Team member Richard Thomas of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Robert Young of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC Committee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines re- ports (NRC 1993, 2001). 119

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120 Acute Exposure Guideline Levels Exposure-response data from animal studies were used to derive AEGL values for arsine. AEGL values derived with animal data that had complete ex- posure data were more scientifically valid than AEGLs estimated from limited anecdotal human data. The greater conservatism afforded by the animal data is justified by the incomplete and often equivocal data for human exposures, the documented extreme toxicity of arsine, and the known latency involved in ar- sine-induced lethality. The AEGL values for the various exposure periods of concern (10 min, 30 min, 1 h, 4 h, and 8 h) were scaled from the experimental exposure duration using exponential scaling (Cn × t = k, where C is exposure concentration, t is exposure duration, and k is a constant). Data were unavailable to empirically derive a scaling factor (n) for arsine. The concentration exposure- time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived exponent, and to obtain conservative and protective AEGL values, temporal scaling was per- formed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. Based upon the available data, derivation of AEGL-1 values was consid- ered inappropriate. The continuum of arsine-induced toxicity does not appear to include effects consistent with the AEGL-1 definition. The available human and animal data affirm that there is little margin between exposures that result in little or no signs of toxicity and those that result in lethality. The mechanism of arsine toxicity (hemolysis that results in renal failure and death) and the fact that toxicity in humans and animals has been reported at concentrations at or below odor detection levels (0.5 part per million [ppm]) also support such a conclusion. The use of analytical detection limits (0.01-0.05 ppm) was considered as a basis for AEGL-1 values but was thought to be inconsistent with the AEGL-1 defini- tion. The AEGL-2 values were based on exposure levels that did not result in significant alterations in hematologic parameters in mice exposed to arsine for 1 h (Peterson and Bhattacharyya 1985). Uncertainty factor application included a factor of 10-fold interspecies variability because of uncertainties regarding spe- cies-specific sensitivity to arsine-induced hemolysis. Uncertainty regarding in- traspecies variability was limited to a factor of 3-fold, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the assumption that physiologic parameters (e.g., absorption, distribution, metabolism, structure of the erythrocyte and its response to arsine, renal responses) would not vary among individuals of the same species to such an extent that the response severity to arsine would be al- tered by an order of magnitude. Additionally, individual variability (i.e., vari- ability in erythrocyte structure/function or response of the kidney to hemolysis) is not likely to have a significant impact on any of the proposed subcellular mechanisms of arsine toxicity. The steep exposure-response curves from animal data also affirm the limited variability in response. Furthermore, the AEGL-2

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121 Arsine values were developed using an exposure resulting in no significant hemolysis in mice exposed to arsine at 5 ppm for 1 h, and, therefore, additional reduction of the values was unwarranted. The AEGL-3 values were based on lethality and hemolysis in mice ex- posed to arsine for 1 h (Peterson and Bhattacharyya 1985). A 1-h exposure to 15 ppm resulted in significant hemolysis, and a 1-h exposure at 26 ppm produced 100% lethality. A total uncertainty factor application of 30 was applied as was done for AEGL-2 values using identical rationale. Because the AEGL-3 values were developed based on an exposure producing hemolysis but no lethality in mice, no further reduction in the values was warranted. The derivation of AEGL-3 values using limited data in monkeys affirmed the values derived based on the mouse data. Although the information on the human experience was of qualitative value, the absence of definitive verifiable exposure terms severely limited its usefulness as a valid quantitative measure for AEGL-3 development. Time scaling was performed as previously described for the AEGL-2 tier. The three AEGL exposure levels reflect the narrow range between exposures resulting in minor effects and those producing lethality. A conservative ap- proach in the development of AEGLs for arsine was justified by the confirmed steep dose-response curve, the induction of hemolysis by arsine at extremely low concentrations, and the potential of hemolysis to progress to life-threatening renal failure. It is also noted that all of the AEGL values are near or below the odor threshold for arsine. A summary of AEGL values is shown in Table 4-1. TABLE 4-1 Summary of AEGL Values for Arsine Classification 10 min 30 min 1h 4h 8h End Point (Reference) NRa NRa AEGL-1 NR NR NR Not recommended due to steep dose-response relationship and mechanism of toxicity and because toxicity occurs at or below the odor threshold AEGL-2 0.30 0.21 0.17 0.04 0.020 Absence of significant ppm ppm ppm ppm ppm hematological alterations in (0.9 (0.7 (0.5 (0.1 (0.06 mice consistent with the mg/m3 mg/m3) mg/m3) mg/m3) mg/m3) known continuum of arsine toxicity (Peterson and Bhattacharyya 1985) AEGL-3 0.91 0.63 0.50 0.13 0.06 Estimated threshold for ppm ppm ppm ppm ppm lethality in mice (Peterson (2.9 (2.0 (1.6 (0.4 (0.2 and Bhattacharyya 1985) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) NR: not recommended. Numeric values for AEGL-1 are not recommended (1) because ofthe lack of available data, (2) because an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (3) because the derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.

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122 Acute Exposure Guideline Levels REFERENCES NRC (National Research Council). 2000. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 1. Washington, DC: National Academy Press. Peterson, D.P., and M.H. Bhattacharyya. 1985. Hematological responses to arsine expo- sure: Quantitation of exposure response in mice. Fundam. Appl. Toxicol. 5(3):499- 505. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309.