2

Arsine1
Acute Exposure Guideline Levels

SUMMARY

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

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

Exposure-response data from animal studies were used to derive acute exposure guideline level (AEGL) values for arsine. AEGL values derived with animal data which had complete exposure data were more scientifically valid than AEGLs estimated from limited anecdotal human data. The greater conser

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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) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee 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; NRC in press).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 2 Arsine1 Acute Exposure Guideline Levels SUMMARY ARSINE is a colorless gas used in the semiconductor industry. Arsine also is used in mining and manufacturing processes involving arsenicals and paints and herbicides containing arsenicals. Arsine is extremely toxic and a potent hemolytic agent, ultimately causing death via renal failure. Numerous human case reports are available, but these reports lack definitive quantitative exposure data. The reports, however, affirm the extreme toxicity and latency period for the toxic effects of arsine in humans. Exposure-response data from animal studies were used to derive acute exposure guideline level (AEGL) values for arsine. AEGL values derived with animal data which had complete exposure data were more scientifically valid than AEGLs estimated from limited anecdotal human data. The greater conser 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) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee 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; NRC in press).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 vatism 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 arsine-induced lethality. The AEGL values for the various exposure periods of concern (0.5, 1, 4, and 8 h) were scaled from the experimental exposure duration using exponential scaling (Cn×t=k, where C=exposure concentration, t=exposure duration, and k=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 (n), temporal scaling was performed 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 considered 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 a very narrow margin between exposures that result in little or no signs or symptoms 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 parts per million (ppm)) also support such a conclusion. The use of analytical detection limits (0.01 to 0.05 ppm) was considered as a basis for AEGL-1 values but was considered to be inconsistent with the AEGL-1 definition. The AEGL-2 values were based upon exposures 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 10-fold interspecies variability because of uncertainties regarding species-specific sensitivity to arsine-induced hemolysis. The 10-min LC50 (lethal concentration for 50% of the animals) value for the monkey was approximately 60% of the rat value and one-third the rabbit value. A less sensitive species, the rat, was used to calculate the AEGL levels because the data exhibited clear exposure-response relationships and the reduced hematocrit can be considered a sensitive indicator of arsine toxicity. Uncertainty regarding intraspecies 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 (such as absorption, distribution and metabolism of arsine, as well as renal responses and the structure of the erythrocyte and its response to arsine) would not vary among individuals of the same species by an order of magnitude. Additionally, individual variability (i.e.,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 variability 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 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. Arsine data were not available to determine a concentration-exposure time relationship. The concentration-exposure time relationship for many irritant and systemically acting vapors 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 chemical-specific data, temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. The AEGL-3 values were based upon lethality and hemolysis in mice exposed to arsine for 1 h (Peterson and Bhattacharyya 1985). A 1-h exposure at 15 ppm resulted in significant hemolysis, and a 1-h exposure at 26 ppm produced 100% lethality. A total uncertainty factor of 30 was applied, as was done for AEGL-2 values using identical rationale. Because the AEGL-3 values were developed based upon 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 upon the mouse data. Although the human experience was of qualitative value, the absence of definitive verifiable exposure terms severely limited its utility as a valid quantitative measure for AEGL-3 development. Time scaling for AEGL-3 development 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. The approach used 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 for arsine is shown in Table 2–1.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 2–1 Summary of AEGL Values for Arsine Classification 30 min 1 h 4 h 8 h Endpoint (Reference) AEGL-1 (Non-disabling) NRa NR NR NR Not recommended due to steep dose-response relationship, mechanism of toxicity, and because toxicity occurs at or below the odor threshold AEGL-2 (Disabling) 0.21 ppm 0.7 mg/m3 0.17 ppm 0.5 mg/m3 0.04 ppm 0.1 mg/m3 0.02 ppm 0.06 mg/m3 Absence of significant hematologic alterations in mice consistent with the known continuum of arsine toxicity (Peterson and Bhattacharyya 1985) AEGL-3 (Lethal) 0.63 ppm 2.0 mg/m3 0.50 ppm 1.6 mg/m3 0.13 ppm 0.4 mg/m3 0.06 ppm 0.2 mg/m3 Estimated threshold for lethality in mice (Peterson and Bhattacharyya 1985) Numeric values for AEGL-1 are not recommended because (1) data are not available, (2) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (3) 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. Abbreviations: NR, not recommended, ppm, parts per million; mg/m3, milligrams per cubic meter.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 2–2 Chemical and Physical Data Parameter Value Reference Synonyms arsenic trihydride; hydrogen arsenide; arsenious trihydride; arsenic hydride; arsenic hydrid; arsineuretted hydrogen Budavari et al. 1989; AIHA 1993; Hesdorffer et al. 1986 Chemical formula AsH3 Budavari et al. 1989 Molecular weight 77.93 Budavari et al. 1989 CAS Registry No. 7784–42–1 Budavari et al. 1989 Physical state gas Budavari et al. 1989 Solubility in water 20% at 20°C AIHA 1993 Vapor pressure 14.95 atm @ 21.1°C Braker and Mossman 1980 Density 2.695 g/cm3 USAF 1990 Melting/boiling/flash point −117°/−55°C/ND Budavari et al. 1989 Odor threshold 0.5 ppm; garlic-like odor NAPCA 1969 Conversion factors in air 1 mg/m3=0.31 ppm 1 ppm=3.19 mg/m3 AIHA 1993 1. INTRODUCTION Arsine is an extremely toxic, colorless gas used extensively in the semiconductor industry. Arsine also is used in mining and manufacturing processes involving arsenicals and in paints and herbicides containing arsenicals (Risk and Fuortes 1991). Annual production has been estimated at over 10,000 pounds and is likely increasing with greater use in the semiconductor industry (U.S. EPA 1980). The physical and chemical data for arsine are shown in Table 2–2. 2. HUMAN TOXICITY DATA Human data for arsine are compromised by deficiencies in exposure concentration and duration data and by concurrent exposures to other materials. It has been reported that exposure to 3–100 ppm for several hours may result in slight symptoms, and exposure to 16–30 ppm arsine for 0.5–1 h is dangerous (Coles

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 et al. 1969). These estimates, however, reflect uncertainties in the human data and are not necessarily consistent with all the available data. The odor threshold for arsine ranges from 0.5 to 1 ppm. The clinical aspects of arsine poisoning have been reviewed by Fowler and Weissberg (1974) and Dreisbach (1983). 2.1. Acute Lethality Human LClo values of 25 ppm (30 min) and 300 ppm (5 min) have been reported (RTECS 1986). Henderson and Haggard (1943) (as cited in AIHA 1993) noted that exposure of humans to arsine at 250 ppm for 30 min was fatal. Early reports, summarized by Flury and Zernik (1931), provided the following anecdotal information regarding human responses to arsine exposure: immediately fatal following exposure at 1,530 ppm (no duration specified), fatal within 30 min following exposure at 250 ppm, immediately fatal following exposure at 15.5 ppm for 30–60 min, dangerous to life following exposure at 6.25 ppm for 30–60 min. Contrary to the above estimates, the following were also reported in Flury and Zernik (1931): no immediate or delayed effects following exposure at 6.25 ppm for 30–60 min, no symptoms following 6-h exposure at 3.1 ppm. 2.1.1. Case Reports Case reports are available regarding lethal effects of acute exposure to arsine (Pinto et al. 1950; Morse and Setterlind 1950; Hesdorffer et al. 1986). However, no definitive quantitative exposure data accompany these reports. Signs and symptoms varied depending on the exposure situation but usually included abdominal and muscle pain, nausea and diarrhea, hematuria, and oliguria. Delayed lethality, common in arsine poisoning, varied considerably. Levinsky et al. (1970) reported on three men exposed to an unknown concentration of arsine for an estimated, 2, 3, and 15 min. Signs and symptoms of exposure (malaise, headache, abdominal pain, chills, nausea, vomiting, oliguria/ anuria, hematuria, bronze skin color) developed within 1–2 h. All three individuals required extensive medical intervention to save their lives. Clinical findings were indicative of massive hemolysis and repeated blood exchange transfusions were necessary for the survival of these individuals. Pinto (1976) also reported similar characteristics regarding acute arsine poisoning. Although, an exposure concentration was unavailable, exposure to newly formed arsine for less than 1 h resulted in severe (likely fatal without medical intervention of exchange transfusion) signs and symptoms, including

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 abdominal pain, chest pain, and hematuria within hours of exposure. A successive reduction in hematocrit (42.2 to 27.7) and hemoglobin (14.1 to 9.6 g %) occurred within 3 d. Cardiac involvement indicative of left ventricular ischemia was detected within 1 d of exposure. 2.2. Nonlethal Toxicity Human TClo values of 3 ppm (no duration specified) and 325 micrograms per cubic meter (µg/m3) (0.1 ppm) (no duration specified) have been reported (RTECS 1987). Henderson and Haggard (1943) (as cited in AIHA1993) noted that exposure of humans to arsine at 3–10 ppm for a few hours may result in signs and symptoms of poisoning. Similar to the data set for acute lethality, most information on nonlethal effects of arsine exposure in humans are case reports representing exposure estimates. 2.2.1. Case Reports Numerous cases of arsine poisoning have been reported (Elkins and Fahy 1967; DePalma 1969). However, these reports lack definitive exposure concentration data and usually lack exposure duration data as well. Some of the more recent and complete reports involving nonlethal consequences are described in the following section. These reports do not provide quantitative data suitable for AEGL derivations, but they do provide valuable insight into the nature and progression of arsine poisoning in humans. In most cases, the severity of the effects was usually sufficient to necessitate medical intervention to prevent lethality. Some of the more prominent reports and those with the best descriptive data have been summarized, but the overview is by no means exhaustive. Three cases of arsine poisoning were reported by DePalma (1969). One day after exposure, the blood arsenic levels were 0.66, 0.25 and 2.2 milligram per liter (mg/L). Hemoglobin levels at 1 d after exposure were 5.9, 7.8, and 11.7 grams per deciliter (g/dL) but tended to fluctuate considerably over several weeks. Although no quantitative exposure data were provided, the case reports serve to identify the hemolysis, abdominal pain and tenderness, hematuria, nausea and vomiting that appears to be characteristic signs and symptoms of acute arsine poisoning. Additionally, the case reports attest to the prolonged nature of arsine-induced toxicity; recovery frequently requires many weeks even with medical intervention. A case of oliguric renal failure following acute exposure to arsine was reported by Uldall et al. (1970). The concentration of arsine was not available,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 but the duration of exposure was approximately 7 h. Within hours of the exposure, the subject experienced episodic hot and cold sensation, abdominal pain and cramping, hematuria, and confusion. On admission to the hospital (3 d post-exposure), the subject was disoriented, abdominal pain had increased, and his skin was discolored (yellowish-brown), and mucous membranes were pale. Hemoglobin was 6.1 g/dL, hematocrit was 18%, and urine samples contained protein and erythrocytes and erythrocyte casts. The victim required peritoneal dialysis and considerable medical intervention prior to a long-term moderate recovery. Two additional workers were also exposed in a similar fashion but for only 1 h. Hemoglobin values for these individuals (admitted to the hospital 3 and 4 d post-exposure) was 8.9 and 12 g/dL, respectively, and hematocrit was 27% and 36%, respectively. Both exhibited hematuria and mild proteinuria, and both recovered without sequelae. A case report of acute arsine poisoning in which a 27-y-old man was exposed to arsine during chemical manufacturing was reported by Pinto (1976). The subject was exposed to arsine as a result of arsine production via a reaction between a galvanized bucket and an arsenic-containing sulfuric acid solution. The exposure (duration not specified) produced toxic effects characterized by abdominal cramping, thoracic discomfort, and hematuria. Over the next week, the patient’s hematocrit declined from 42.5 to 27.1 and hemoglobin dropped from 14.1 to 9.5 g/dL even with medical intervention (blood transfusions and mannitol diuresis). Nine hours after exposure, blood arsenic was 159 µg/dL and urinary arsenic was 1862 µg/L. Kleinfeld (1980) reported a case of arsine poisoning in a 31-y-old man. The exposure to arsine occurred from a leaking canister thought to be empty. The exposure duration was estimated to be 1–2 min, but no actual or estimated arsine concentrations were available. The victim presented with hematuria. On hospital admission, no intact erythrocytes were present in the urine, hematocrit was 43%, and hemoglobin was 9.8 g/dL. The hematocrit dropped to as low as 18%, the correction of which required one unit of packed cells. Based upon the exposure history and the subject's note of a "garlicky" odor, the diagnosis was arsine-induced hemolytic anemia. Urinary arsenic was 7.2 mg/L on admission and 0.1 mg/L 4 d later. The patient was subsequently discharged. The occupational exposure of five workers to arsine was reported by Phoon et al. (1984). All cases involved hematuria and, except for one patient, abdominal pain and jaundice. One worker was exposed for approximately 1 3/4 h, while the others were exposed for approximately 2 1/4 h. The latency in appearance of toxic effects was unusually short (≈3 h). The following day, the arsine level in the workers’ breathing zone was 0.055 mg/m3 (0.017 ppm), although no processing of arsenic-containing material was taking place at the time of measurement. It was hypothesized by the report authors that the arsine

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 concentration at the time of exposure was much higher, thus accounting for the very short latency period. Mora et al. (1992) reported on two cases of acute arsine poisoning in workers shoveling scories at a ferrous metal foundry. One case involved acute hemolysis followed by acute renal failure requiring dialysis, and the other involved acute hemolysis and cytolytic hepatitis; a definitive etiology for the hepatitis was not found but was thought to be possibly related to the arsine exposure. Arsine levels were subsequently found to be at or below the ACGIH Threshold Limit Value (TLV) (0.05 ppm) during dry conditions but increased to 60 ppm when water was added to the scories. It was not known if the exposures occurred during wet or dry conditions. Data from case reports indicated that there is usually a 1- to 24-h delay between exposure and onset of signs and symptoms of poisoning. Additionally, hematologic parameters (e.g., hemoglobin, hematocrit levels) appear to be progressively affected for several days after the exposure. Hence although the exposure is acute, the most serious adverse effect may be delayed by several hours or days. Bulmer et al. (1940) (as cited in Elkins 1959) reported on eight workers in a gold extraction plant who were exposed to arsine for up to 8 mon. During this period, major medical findings were jaundice and anemia. Based upon urinary arsine levels (0.7–4 mg/L), a 50% absorption factor, and an inhalation rate of 5 m3/8 h, the arsine concentration was estimated at 0.12 ppm. It was suggested that a maximum allowable concentration of 0.05 ppm would not be unreasonable. The estimation of exposure levels provides some insight into arsine toxicity in humans but it is unclear if the effects observed were the result of long-term, repeated exposure or would have been observed after a single exposure. 2.2.2. Epidemiologic Studies Landrigan et al. (1982) conducted an epidemiologic survey to evaluate occupational exposure to arsine in a lead-acid battery manufacturing plant. Arsine concentrations ranged from nondetectable to 49 µg/m3 (≈0.02 ppm) in 177 breathing zone samples. A high correlation was found between urinary arsenic concentration and arsine exposure (r=0.84; p=0.0001 for an n of 47). Additionally, arsine levels above 15.6 µg/m3 (≈0.005 ppm) were associated with urinary arsenic concentrations in excess of 50 µg/L. The investigators concluded that exposure to a 200 µg/m3 arsine exposure standard would not prevent chronic increased absorption of trivalent arsenic.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 2.3. Developmental and Reproductive Toxicity No definitive, quantitative data were available regarding the potential reproductive and developmental toxicity of arsine in humans. 2.4. Genotoxicity Genotoxicity data relevant to the derivation of AEGLs for arsine were not available. 2.5. Carcinogenicity Although some forms of inorganic arsenic are considered known human carcinogens, there are no data available regarding the carcinogenic potential of arsine or its conversion to carcinogenic forms. The extreme acute toxicity of arsine gas precludes the relevance of carcinogenic potential for acute exposures. Therefore, a carcinogenicity assessment based upon elemental equivalence has not been carried out. 2.6. Summary Numerous case reports are available regarding the lethal and nonlethal toxicity of arsine in humans, but definitive exposure concentration or duration data are lacking. Although the case reports are of limited use for quantitative estimates of exposure limits, they do provide qualitative information about the nature of arsine poisoning in humans. Some estimated human toxicity values are available and are summarized in Table 2–3. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Acute lethality data for several laboratory species are summarized in the following sections. Lethal concentrations for various species are shown in Table 2–4. Cumulative exposures (C×t) exhibit notable variability even within species.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 2–3 Acute Toxicity Values for Arsine Poisoning in Humans Estimated Toxicity Value C×t (ppm·min) Comments Reference 30-min LClo: 25 ppm 750 Fatal within 30 min RTECS 1987 5-min LClo: 300 ppm 1,500 RTECS 1987 30-min LClo: 250 ppm 7,500 Henderson and Haggard 1943 (as cited in AIHA 1993) 30-min LClo: 250 ppm 7,500 Flury and Zernik 1931 30 to 60-min LClo: 15.5 ppm 465–930 Flury and Zernik 1931 30 to 60-min LClo: 6.25 ppm 188–375 "Dangerous to life"a Flury and Zernik 1931 6-h NOAEL: 3.1 ppm 19 No symptoms reported following this 6-h exposure Flury and Zernik 1931 aFlury and Zernik (1931) also reported no immediate or delayed effects in a human exposed at 6.25 ppm for 30–60 min. Abbreviation: NOAEL, no-observed-adverse-effect level. 3.1.1. Nonhuman Primates A 30-min LC50 of 250 mg/m3 for monkeys was reported by RTECS (1987). Effects included hemolysis without anemia and abnormal erythrocytes. Kensler et al. (1946) exposed three monkeys (species not specified) to arsine at a concentration of 0.45 mg/L (450 mg/m3 or 140 ppm) for 15 min. One monkey died in 24 h and exhibited marked intravascular hemolysis and hematuria. Delayed lethality (3 d post-exposure) in a monkey exposed to arsine at approximately 190,000 ppm for 1 h was reported by Joachimoglu (1924) (as cited in Flury and Zernik 1931). Four hours after the exposure, the monkey was vomiting and hematuria was evident. 3.1.2. Dogs Dubitski (1911) (as cited in Flury and Zernik 1931) noted that the dog was similar to the cat regarding arsine toxicity. Exposure to 10 ppm was without

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 This page in the original is blank.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Key study: Blair et al. (1990a). Male and female B6C3F1 mice exposed to arsine at 0.5 ppm for 6 h exhibited no change in relative spleen weights or hematologic parameters and exhibited no overt signs of toxicity. Uncertainty factors: An uncertainty factor of 10 was used for interspecies variability to account for possible variability in arsine-induced hemolysis and progression to renal effects. An uncertainty factor of 3 was used for intraspecies variability assuming limited individual variability in hemolytic response (described more fully under AEGL-2 and AEGL-3). Calculations: 0.5 ppm/30=0.0167 ppm C3×t=k (0.0167 ppm)3×30 min=0.00167 ppm3·min Time scaling: Cn×t=k; data were unavailable for empirical derivation of a scaling factor. 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 chemical-specific data, temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. NOTE: The following analysis served as an initial estimate for the AEGL-1. However, it is believed that it is not appropriate to derive AEGL-1 values for arsine because of the steep dose-response and the inability of available data to justify an exposure that would result in little or no toxic effect. 30-min AEGL-1: C3×30 min=0.00167 ppm3·min C=0.04 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 1-h AEGL-1: C3×60 min=0.00167 ppm3·min C=0.03 ppm 4-h AEGL-1: C3×240 min=0.00167 ppm3·min C=0.02 ppm 8-h AEGL-1: C3×480 min=0.00167 ppm3·min C=0.01 ppm. Derivation of AEGL-2 Key study: Peterson and Bhattacharyya (1985). NOAEL of 5 ppm based upon absence of hematologic changes in mice following 1-h exposure. At 15 ppm, hematologic changes were significant, and at 26 ppm there was 100% mortality. Uncertainty factors: An uncertainty factor of 10 was used for interspecies variability to account for possible variability in arsine-induced hemolysis and progression to renal effects. Uncertainty regarding intraspecies variability was limited to 3, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the consideration that physiologic parameters (e.g., absorption, distribution, metabolism, structure of the erythrocyte and its response to arsine, and renal responses) are not likely to vary among individuals of the same species to such an extent that the response severity to arsine would be altered by an order of magnitude. Individual variability (i.e., variability in erythrocyte structure/function or response of the kidney to hemolysis) would not likely have a significant impact on any of the proposed subcellular mechanisms of arsine toxicity. The steep exposure-response relationships from animal data also affirm the limited variability in response. Because of the forgoing considerations and the fact that the AEGL-2 values were developed from a data point showing no significant indication of hemolysis in mice exposed for 1 h to arsine at 5 ppm, the additional reduction of the values would seem unwarranted. Calculations: 5 ppm/30=0.167 ppm C3×t=k

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1   (0.167 ppm)3×60 min=0.278 ppm3·min C1×t=k 0.167 ppm×60 min=10 ppm·min Time scaling: Cn×t=k; data were unavailable for empirical derivation of a scaling factor. 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 chemical-specific data, temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. 30-min AEGL-2: C3×30 min=0.278 ppm3·min C=0.21 ppm 1-h AEGL-2: C3×60 min=0.278 ppm3·min C=0.17 ppm 4-h AEGL-2: C1×240 min=10 ppm·min C=0.04 ppm 8-h AEGL-2: C1×480 min=10 ppm·min C=0.02 ppm. Derivation of AEGL-3 Key study: Peterson and Bhattacharyya (1985), based upon an estimate of a lethality threshold (15 ppm) in mice exposed for 1 h. Hematologic changes were significant at 15 ppm, and at 26 ppm there was 100% mortality. Uncertainty factors: An uncertainty factor of 10 was retained for interspecies variability to account for possible variability in arsine-induced hemolysis and progression to renal effects. An uncertainty factor for intraspecies variability of 3 was used, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the consideration that physiologic parameters (e.g., absorption, distribution, metabolism, structure of

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1   the erythrocyte and its response to arsine, and renal responses) would not vary among individuals of the same species to such an extent that the response severity to arsine would be altered by an order of magnitude. Individual variability (i.e., variability 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 relationships from animal data also affirm the limited variability in response. Because of the aforementioned considerations and the fact that the AEGL-3 values were developed based on a nonlethal toxic response (hemolysis in the absence of lethality), any additional reduction of the values would seem unwarranted. Calculations: 15 ppm/30=0.5 ppm C3×t=k (0.5 ppm)3×60 min=7.5 ppm3·min C1×t=k 0.5 ppm×60 min=30 ppm·min Time scaling: Cn×t=k; data were unavailable for empirical derivation of a scaling factor. 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 chemical-specific data, temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. 30-min AEGL-3: C3×30 min=7.5 ppm3·min C=0.63 ppm 1-h AEGL-3: C3×60 min=7.5 ppm3·min C=0.50 ppm 4-h AEGL-3: C1×240 min=30 ppm·min C=0.13 ppm 8-h AEGL-3: C1×480 min=30 ppm·min C=0.06 ppm.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX B TIME SCALING CALCULATIONS FOR ARSINE 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 (n), and to obtain AEGL values, temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINES FOR ARSINE (CAS No. 7784–42–1) AEGL-1 Values-Arsine 30 min 1 h 4 h 8 h Not Not Not Not recommended recommended recommended recommended Reference: The available human and animal data indicate that there is very little margin between seemingly inconsequential exposures and lethal exposures. The mechanism of arsine toxicity (hemolysis and subsequent renal failure) and the fact that toxicity has been demonstrated at or below the odor threshold justify the inappropriateness of AEGL-1 values for any exposure period. Test Species/Strain/Number: Not applicable Exposure Route/Concentrations/Durations: Not applicable Effects: Not applicable Endpoint/Concentration/Rationale: Not applicable Uncertainty Factors/Rationale: Not applicable Modifying Factor: Not applicable (1) Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Not applicable Data Adequacy: Numeric values for AEGL-1 are not recommended, because (1) data are not available, (2) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (3) 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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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-2 Values-Arsine 30 min 1 h 4 h 8 h 0.21 ppm 0.17 ppm 0.04 ppm 0.02 ppm Reference: Peterson, D.P., and M.H.Bhattacharyya. 1985. Hematological responses to arsine exposure: quantitation of exposure response in mice. Fundam. Appl. Toxicol. 5:499–505 Test Species/Strain/Sex/Number: Female B6C3F1 mice, 8/group Exposure Route/Concentrations/Durations: Inhalation: 0, 5, 9, 11, 15, or 26 ppm for 1 h Effects: hematocrit level (as % of controls) 5 ppm no significant effects (determinant for AEGL-2) 9 ppm 80.2% 11 ppm 79.7% 15 ppm 61.4% 26 ppm 21.7% (100% mortality at 4 d post-exposure) Endpoint/Concentration/Rationale: 5 ppm for 1 h considered as a no-observed-effect level (NOEL) for decreased hematocrit levels. A NOEL was used because of an extremely steep dose-response curve and the fact that the ultimate toxic effect, renal failure, is delayed for several days. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. Intraspecies: 3—An uncertainty factor of 3-fold was used, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the consideration that physiologic parameters (e.g., absorption, distribution, metabolism, structure of the erythrocyte and its response to arsine, and renal responses) are not likely to vary among individuals of the same species to such an extent that the response severity to arsine would be altered by an order of magnitude. Individual variability (i.e., variability in erythrocyte structure/function or response of the kidney to hemolysis)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 also is not likely have a significant impact on any of the proposed subcellular mechanisms of arsine toxicity. The steep exposure-response curves derived from animal data also affirm the limited variability in response. Because of these considerations and the fact that the AEGL-2 values were developed using a toxic response indicative of no significant hemolysis in mice exposed for 1 h to arsine at 5 ppm, an additional reduction of the values would seem unwarranted. Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 or 3. 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). Temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. Data Adequacy: The study was considered adequate for AEGL-2 derivation. It was carefully designed and performed, used adequate numbers of animals, used an appropriate exposure regimen, and identified an endpoint consistent with the AEGL-2 definition and with the known effects of arsine.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-3 Values-Arsine 30 min 1 h 4 h 8 h 0.63 ppm 0.50 ppm 0.13 ppm 0.06 ppm Reference: Peterson, D.P., and M.H.Bhattacharyya. 1985. Hematological responses to arsine exposure: quantitation of exposure response in mice. Fundam. Appl. Toxicol. 5:499–505 Test Species/Strain/Sex/Number: Female B6C3F1 mice, 8/group Exposure Route/Concentrations/Durations: Inhalation: 0, 5, 9, 11, 15, or 26 ppm for 1 h Effects: hematocrit level (as % of controls) and lethality 5 ppm no significant effects 9 ppm 80.2 % (no mortality) 11 ppm 79.7% (no mortality) 15 ppm 61.4% (no mortality) (determinant for AEGL-3) 26 ppm 21.7% (3/8 immediately following exposures; 100% mortality at 4 d post-exposure) Endpoint/Concentration/Rationale: 15 ppm for 1 h induced a significant decrease in hematocrit levels that may be approaching a degree of hemolysis that can lead to renal failure. Given the steepness of the dose-response relationship this is justified as an estimate of the lethality threshold. An exposure of 26 ppm for 1 h resulted in 100% lethality. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship curve, and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship giving little margin between no effects and lethality. Intraspecies: 3—Uncertainty regarding intraspecies variability was limited to 3, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the consideration that physiologic parameters (e.g., absorption, distribution, metabolism, structure of the erythrocyte and its

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 response to arsine, and renal responses) are not likely to vary among individuals of the same species to such an extent that the response severity to arsine would be altered by an order of magnitude. Individual variability (i.e., variability in erythrocyte structure/function or response of the kidney to hemolysis) also is not likely to have a significant impact on any of the proposed subcellular mechanisms of arsine toxicity. The steep exposure-response curves derived from animal data also affirm the limited variability in response. Because of these considerations and the fact that the AEGL-2 values were developed using a toxic response indicative of no significant hemolysis in mice exposed for 1 h to arsine at 5 ppm, additional reduction of the values would seem unwarranted. Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 or 3. 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). Temporal scaling was performed using n=3 when extrapolating to shorter time points and n=1 when extrapolating to longer time points using the Cn×t=k equation. Data Adequacy: The study was considered adequate for AEGL-3 derivation. It was carefully designed and performed, used adequate numbers of animals, used an appropriate exposure regimen, and identified an endpoint consistent with AEGL-3 definition and with the known effects of arsine. The available data indicate that the exposure-response relationship for arsine is very steep, thereby justifying the approach taken to derive the AEGL-3 values.