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Aliphatic Nitriles1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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1 Aliphatic Nitriles1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 13

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14 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. 1. GENERAL INFORMATION FOR SELECTED ALIPHATIC NITRILES In this chapter, the bases of the AEGL values for the following five aliphatic nitriles are described: acetonitrile, isobutyronitrile, chloroacetonitrile, propi- onitrile, and malononitrile. Information relevant to all five compounds is first pre- sented, and is followed by separate sections on the individual chemicals. 1.1. Absorption, Distribution, Metabolism, and Excretion Aliphatic nitriles are readily absorbed from the lung and gastrointestinal tract, resulting in systemic toxicity. Most of the systemic toxicity of these ni- triles is mediated through hepatic and extrahepatic cytochrome P450 catalyzed oxidation of the carbon alpha to the cyano group producing a cyanohydrin and an aldehyde. The metabolically-liberated cyanide is then conjugated with thio- sulfate to form thiocyanate and is excreted in the urine (NTP 1996). Studies con- taining nitrile-specific metabolism information were available for acetonitrile, propionitrile, and chloroacetonitrile and are described below. No chemical- specific metabolism studies were available for isobutyronitrile or malononitrile.

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Aliphatic Nitriles 15 1.1.1. Acetonitrile In humans, studies of smokers suggested that 91 ± 4% of the acetonitrile inhaled in cigarette smoke was retained and that a significant portion may have been retained in the mouth (Dalhamn et al. 1968). Also, human poisoning cases suggest that acetonitrile is well absorbed by both inhalation and dermal routes but provide little quantitative data (see Section 2.3.1). Studies in monkeys, rats, and dogs have shown cyanide in the blood and thiocyanate in the urine following exposure to acetonitrile by injection or inhala- tion (Pozzani et al. 1959). The rate of cyanide release from acetonitrile is slower than for other nitriles (Ahmed and Farooqui 1982; see Section 1.4). Peak blood cyanide concentrations occurred 7.5-h after exposure to acetonitrile whereas peak levels occurred 1 h after exposure to comparable amounts of other nitriles or potassium cyanide. Also, the percentage of acetonitrile excreted in the urine as thiocyanate was lower than that for other nitriles, even when the initial dose was greater. These data suggest that the toxicity of acetonitrile is less than other nitriles because of its slower conversion to cyanide and thus more efficient de- toxification to thiocyanate (NTP 1996). Studies of male rats found free and conjugated cyanide and unchanged ace- tonitrile in various tissues after inhalation or intraperitoneal injection (Haguenoer et al. 1975). Ahmed et al. (1992) found acetonitrile and metabolites in the liver, kidney, gastrointestinal tract, gallbladder, and urinary bladder 5 min after admin- istration of 2-[14C]-acetonitrile to mice. At 24- and 48-h post-exposure, label was still detected in the liver and gastrointestinal tract, and delayed retention was noted in the male reproductive organs and brain. Elimination acetonitrile occurs mainly through urinary excretion of un- changed chemical and free and bound hydrogen cyanide. Urinary excretion is greatest during the initial 24 h after dosing. However, after intraperitoneal injec- tion, small amounts were detected in the urine of rats for up to 4 days post- exposure. Thiocyanate excretion was observed for up to 11 days post-exposure (Haguenoer et al. 1975). At high inhalation concentrations, unchanged acetoni- trile may be eliminated by exhalation. 1.1.2. Propionitrile Fromont et al. (1974) studied acute and repeated parenteral administration of propionitrile in relation to its distribution and biotransformation to cyanide in the rat. Lethal doses resulted in propionitrile accumulation in the kidneys, heart, testes, and liver, whereas cyanide concentrations were highest in the spleen, lungs, heart, and brain. Mumtaz et al. (1997) administered a tracer dose of 100 μCi/kg 14C-propionitrile intravenously to female Sprague-Dawley rats, and killed selected animals 1-, 8-, or 24-h post-exposure. Within 1 h of administra- tion, peak radioactivity was detected in the duodenum, kidneys, lungs, large intestine, plasma, erythrocytes, stomach, heart, and brain. The animals excreted approximately 5.3% of the dose within 24 h, with approximately equal amounts

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16 Acute Exposure Guideline Levels in the expired air and urine and only trace amounts in the feces. The presence of radioactivity in the gastrointestinal tract for up to 24-h post-exposure suggested enterohepatic recirculation of propionitrile or metabolites. Subcellular fractions of liver, duodenum, and brain showed significant accumulation of radioactivity. 1.1.3. Chloroacetonitrile Male Sprague-Dawley rats were administered chloroacetonitrile at 57 mg/kg by gavage (Pereira et al. 1984). Approximately 14% of the administered dose was excreted as thiocyanate in the urine within 24 h, suggesting that, as with other ni- triles, chloroacetonitrile is metabolized via P450 catalyzed oxidation of the carbon alpha to the cyano group producing a cyanohydrin which leads to hydrogen cya- nide. Male Sprague-Dawley rats were administered [2-14C]chloroacetonitrile in- travenously (Ahmed et al. 1991). Within 12-h post-exposure, 51% of the radio- activity was excreted in the urine, 2.7% in feces, and 12% in expired air as 14 CO2. Only 0.8% of the administered dose was exhaled as unchanged chloro- acetonitrile, and no unchanged chloroacetonitrile was excreted in the urine. Whole-body autoradiography for up to 48-h post-exposure showed persistent label in the thyroid, gastrointestinal tract, testes, brain, and eyes. In vivo and in vitro studies suggest that chloroacetonitrile reacts extensive- ly with glutathione and causes significant decreases in glutathione concentra- tions in treated rats (Ahmed et al. 1989) and mice (Jacob et al. 1998). 1.2. Mechanism of Toxicity The toxicity of the aliphatic nitriles is due to the metabolic release of cya- nide. Cyanide interrupts cellular respiration by blocking the terminal step of electron transfer from cytochrome c oxidase to oxygen. Tissue concentrations of oxygen rise, resulting in increased tissue oxygen tension and a decreased un- loading of oxyhemoglobin. Increased oxyhemoglobin in the venous blood may impart a flush to the skin and mucous membranes. As a consequence, oxidative metabolism may slow to a point where it cannot meet metabolic demands. This is particularly critical in the brain stem nuclei where lack of an energy source results in central respiratory arrest and death. Cyanide also stimulates chemore- ceptors of the carotid and aortic bodies to produce a brief period of hyperpnea. Cardiac irregularities may occur, but death is due to respiratory arrest (Smith 1996). 1.3. Concurrent Exposure Issues As noted in Section 1.2, the selected aliphatic nitriles reviewed in this doc- ument share a common mechanism of toxicity through their biotransformation to cyanide. Therefore, caution should be noted regarding cumulative effects of expo- sure to multiple aliphatic nitriles.

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Aliphatic Nitriles 17 Tanii and Hashimoto (1986) studied the effect of ethanol on the metabo- lism of 20 nitriles, including acetonitrile, isobutyronitrile, propionitrile, and chloroacetonitrile. Male ddY mice were dosed orally with either ethanol (4.0 g/kg) or glucose (7.0 g/kg), killed by cervical dislocation 13 h later, and micro- somes were then prepared from the livers. (A preliminary study indicated that hepatic microsomal metabolizing activity for nitriles reached a maximum 13 h after oral administration of ethanol at 4.0 g/kg. Glucose at 7.0 g/kg was isocalor- ic to the ethanol dosage). The nitrile was added to the reaction mixture and the amount of cyanide released per minute per milligram of protein was determined. None of the nitriles were metabolized when incubation mixtures lacked nicotin- amide adenine dinucleotide phosphate (NADPH). Ethanol treatment stimulated the metabolic rate of most nitriles compared with the glucose control, suggesting that ethanol consumption may enhance the acute toxicity of nitriles. The etha- nol-to-glucose ratios ranged from 1.00 to 1.83 for the 20 nitriles tested. The rati- os were 1.83 for acetonitrile, 1.20 for isobutyronitrile, 1.62 for propionitrile, and 1.54 for chloroacetonitrile. Willhite and Smith (1981) found that subcutaneous pretreatment of mice with carbon tetrachloride (at a dose that effectively destroyed the metabolic ca- pacity of the liver) protected mice against the lethal and toxic effects of intraper- itoneally administered acetonitrile, propionitrile, and malononitrile. Survival of the carbon tetrachloride-treated mice compared with controls was attributed to decreased brain cyanide concentrations. Tanii and Hashimoto (1984) also found that mice pretreated intraperitoneally with carbon tetrachloride were less suscep- tible to the toxic effects of orally administered acetonitrile and propionitrile. In another study, Tanii and Hashimoto (1985) pretreated male ddY mice with olive oil or carbon tetrachloride and then orally administered malononitrile at doses 3-5 times greater than the LD50. Mean survival times were increased and brain cyanide concentrations were decreased in the carbon tetrachloride-pretreated mice. 1.4. Structure-Activity Relationships Because the acute toxicity of nitriles depends on their ability to undergo cytochrome P450 mediated hydroxylation, on the carbon alpha to the cyano group (α-carbon), and because the hydroxylation is a radical-based reaction, acute toxicity of nitriles is related to the structural features that influence α- carbon radical stability. Generally, the nitriles that are metabolized most quickly or easily at the α-carbon are more toxic than nitriles metabolized more slowly at the α-carbon. Thus, the toxicity pattern, in decreasing order, with regard to the type of α-carbon radical formed following α-hydrogen abstraction is benzylic ≈ 3° > 2° > 1°. The presence of a hydroxy or a substituted or unsubstituted amino group on the α-carbon increases toxicity, and the presence of these moieties at other carbon positions decreases acute toxicity (DeVito 1996). Dahl and Waruszewski (1987, 1989) examined the in vitro metabolism of acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, acrylonitrile, succinoni-

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18 Acute Exposure Guideline Levels trile, and benzyl cyanide. Nasal maxilloturbinate, ethmoturbinate, and liver micro- somes were prepared from 10-16-week-old male F344 rats. The microsomes and selected nitriles were incubated at 37°C for 30 min, the reaction was stopped by the addition of potassium hydroxide, and cyanide concentrations were measured. The rate of cyanide production varied with both the nitrile side chain and tissue source of the microsomes. Except in the case of acrylonitrile with maxilloturbinate microsomes, the maximum rate of cyanide production increased as the number of carbon atoms in the side chain increased. For ethmoturbinates, the rate of cyanide production was the lowest for acetonitrile and acrylonitrile (which had almost equal rates), followed by propionitrile, butyronitrile, isobutyronitrile, and suc- cinonitrile (which had similar rates), and then benzyl cyanide. For maxilloturbi- nates, the rates were the lowest for acetonitrile, followed by propionitrile, isobu- tyronitrile and succinonitrile (which had similar rates), butyronitrile, benzyl cyanide, and acrylonitrile. For liver, rate were lowest for succinonitrile, followed by acetonitrile, propionitrile and butyronitrile (which had similar rates), isobu- tyronitrile, acrylonitrile, and benzyl cyanide. Ahmed and Farooqui (1982) orally administered aliphatic nitriles or potas- sium cyanide at a single LD50 to male Sprague-Dawley rats. Animals were killed 1 h later and tissue and blood cyanide concentrations were measured. Hepatic and blood cyanide concentrations were highest for malononitrile, followed by propionitrile, potassium cyanide, butyronitrile, acrylonitrile, allylcyanide, fu- maronitrile, and acetonitrile. The pattern in the brain differed in that potassium cyanide preceded malononitrile and propionitrile. Hepatic and brain cytochrome c oxidase were decreased and the decreases corresponded to measured cyanide concentrations. Intraperitoneal LD50 values from studies of mice have been reported for several nitriles (Lewis 1996), allowing for the comparison of the relative toxicity of these compounds (see Table 1-1). These data are consistent with the infor- mation described above showing that the predicted rate of cyanide production (Dahl and Waruszewski1987, 1989; Devito 1996) and measured blood cyanide concentrations (Ahmed and Farooqui 1982) correlate with the intraperitoneal LD50 values. TABLE 1-1 Intraperitoneal LD50 Values for Mice Chemical LD50 Acetonitrile 521 mg/kg Isobutyronitrile Not available Chloroacetonitrile 100 mg/kg Propionitrile 34 mg/kg Malononitrile 13 mg/kg Molar ratio of LD50 values: Acetonitrile/Chloroacetonitrile 10 Acetonitrile/Propionitrile 21 Acetonitrile/Malononitrile 65

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Aliphatic Nitriles 19 1.5. Species Sensitivity Data on the aliphatic nitriles suggest that mice, guinea pigs, rabbits, dogs, and monkeys are more sensitive than rats to the effects of acetonitrile. Interspe- cies differences in acetonitrile toxicity may be due to the relative speed of cya- nide formation and detoxification (NTP 1996). Thus, a slow rate of cyanide pro- duction that enables more efficient detoxification may account for the decreased sensitivity of the rat to acetonitrile. Although much metabolism data are availa- ble for rats and mice, direct comparisons of the rates between species are not possible because of differences in cyanide detection methods, different routes of administration, and units used in reporting data (for example, nmol/106 cells vs. ng/mg protein when comparing cyanide formed from isolated hepatocytes from rats vs. mice). No studies that rigorously compared the acute toxicity of isobutyronitrile, propionitrile, or chloroacetonitrile in different species were found. However, available data suggest that mice are more sensitive to the toxic effects of these nitriles than rats. In an acute inhalation study of saturated atmospheres of isobu- tyronitrile (Tsurumi and Kawada 1971), 0/10 rats died after 4 min of exposure, 1/10 after 5 min, 4/10 after 6 min, 6/10 after 8 min, and 10/10 after 10 min. In studies with mice, 3/10 animals died after 0.5 min, 5/10 after 1 min, 7/10 after 1.5 min, and 10/10 after 2 min. No deaths occurred in rats exposed to propionitrile at 690 ppm for 4 h, and the 4-h LC50 was 1,441 ppm (Younger Labs 1978). The 1-h mouse LC50 of 163 ppm (Willhite 1981) is approximately six times less than the concentration caus- ing no deaths in rats exposed for 4 h. Finally, rat oral LD50 values for chloroace- tonitrile are in the range of 180 to 220 mg/kg (Younger Labs 1976; Lewis 1996), whereas, the reported mouse oral LD50 is 139 mg/kg (Tanii and Hashimoto 1984). 1.6. Temporal Extrapolation The concentration-exposure duration relationship for many irritant and systemically-acting vapors and gases can be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data were available to derive an empirical value for n for acetonitrile only. An analy- sis of the acute inhalation lethality data for rats was conducted using the dose- response software of ten Berge (2006). This analysis used the concentration- specific data presented in the summary tables of lethal and sublethal effects of acetonitrile presented later in this chapter in Section 2.4.6, which allowed for the inclusion of all rat data except the DuPont (1968) study for which dose-specific data were not available. The value of n was estimated to be 1.550, with confi- dence limits of 0.539 and 2.560. Details of this analysis are presented in Appen- dix A. The exponent was rounded to 1.6, and was considered valid for scaling across time only for rat data because the rate of cyanide release from acetonitrile may vary between species.

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20 Acute Exposure Guideline Levels Data were unavailable to determine an empirical value of n for isobu- tyronitrile, propionitrile, chloroacetonitrile, or malononitrile. In the absence of chemical-specific data, default values of n = 3 for extrapolation shorter durations and n = 1 for extrapolation to longer durations were used to provide AEGL val- ues that are protective of human health (NRC 2001). 2. ACETONITRILE 2.1. Summary Acetonitrile is a volatile, colorless liquid at ambient temperature and pres- sure (WHO 1993). It has a sweet, ether-like odor, with a reported odor threshold of 42 ppm (Ruth 1986). Mean ambient air concentrations of 0.000048 to 0.007 ppm have been reported, and slightly higher values were obtained for urban than for rural air. Single measurements taken before and after burning of brush and straw indicated a 10-fold increase in acetonitrile concentrations in air (WHO 1993). The major use for acetonitrile is as an extraction and processing solvent in the pharmaceutical industry. Acetonitrile is also used as a process, extraction, and formulation solvent for agricultural chemicals, and in the extractive distilla- tion of butadiene. It is also used as a mobile phase in high-performance liquid chromatography and in the separation of chiral systems. It also has minor uses as an intermediate in chemical manufacturing and in photographic applications. The toxicity of acetonitrile is due to the metabolic liberation of cyanide and signs and symptoms are similar to those observed after cyanide exposure. Slight chest tightness and cooling sensation in the lungs reported by one of three male volunteers exposed to acetonitrile at 40 ppm for 4 h (Pozzani et al. 1959) were used as the basis for AEGL-1 values. An interspecies uncertainty factor of 1 was applied because the critical study was conducted in humans. A factor of 1 was also applied for intraspecies variability, because the mild effects were judged to have occurred in a sensitive subject. No symptoms were reported by two other subjects exposed in the same manner, nor when the same subjects were exposed at 80 ppm for 4 h. A modifying factor of 3 was applied to account for the sparse database for effects relevant to AEGL-1. The 4-h AEGL-1 value of 13 ppm was held constant across the 10-min, 30-min, and 1-h durations be- cause no human data were available exposure durations of less than 4 h; thus, time scaling to shorter durations could result in values that would eliciting symptoms above those defined by AEGL-1. A calculated value for an 8-h dura- tion was 14 ppm, which is essentially equal to the 4-h AEGL-1 value of 13 ppm, so an 8-h AEGL-1 value was not recommended. At nonlethal exposures, AEGL-2 effects, described as less than “moderate to marked pulmonary hemorrhage or congestion” were observed in rats (Pozzani et al. 1959). Since no-effect levels for AEGL-2 effects were not identified, AEGL-2 values could not be derived from the available data. Therefore, AEGL- 2 values were estimated by dividing AEGL-3 values by 3.

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Aliphatic Nitriles 21 The no-effect level for maternal and fetal mortality in pregnant rats ex- posed to acetonitrile at 1,500 ppm for 6 h/day on gestational days 6-20 (Saillen- fait et al. 1993) was used as the point of departure for deriving AEGL-3 values. Although the study involved repeated exposures, fetal death can occur during a narrow developmental window and does not necessarily require repeated expo- sures (Van Raaij et al. 2003). Therefore, the observation of increased fetal death after repeated gestational exposure was considered an appropriate end point for deriving AEGL-3 values. In addition, maternal lethality after repeated exposure during pregnancy is also relevant to AEGL-3 derivation, as pregnant animals may have increased sensitivity to acetonitrile compared with nonpregnant ani- mals. An interspecies uncertainty factor of 10 was applied because no compara- ble data for similar exposures (repeated inhalation exposure during gestation) in other species were found. An intraspecies uncertainty factor of 3 was applied because studies of accidental and occupational exposures to hydrogen cyanide (the metabolically-liberated toxicant) indicate that there are individual differ- ences in sensitivity to this chemical but that the differences are not expected to exceed 3-fold (NRC 2002). Thus, the total uncertainty factor is 30. Time scaling was performed using the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). This equation has been shown to describe the concentration-exposure duration relationship for many irritant and systemically acting vapors and gases. An empirical value for n of 1.6 was determined on the basis of rat lethality data that involved exposures to acetonitrile ranging from 15 min to 8 h. Time scaling was not performed for the 10-min AEGL-3 value, be- cause of the uncertainty associated with time scaling a 6-h exposure to a 10-min value. Therefore, the 10-min AEGL-3 value was set equal to the 30-min AEGL- 3 value. AEGL values for acetonitrile are presented in the Table 1-2. TABLE 1-2 AEGL Values for Acetonitrile Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 13 ppm 13 ppm 13 ppm 13 ppm NRa Slight chest tightness (nondisabling) (22 (22 (22 (22 and cooling sensation mg/m3) mg/m3) mg/m3) mg/m3) in lung (Pozzani et al. 1959) AEGL-2 80 ppm 80 ppm 50 ppm 21 ppm 14 ppm One-third of (disabling) (130 (130 (84 (35 (24 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 240 ppm 240 ppm 150 ppm 64 ppm 42 ppm No-effect level for (lethal) (400 (400 (250 (110 (71 maternal and fetal mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) lethality in rats (Saillenfait et al. 1993) a Not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 is without adverse effects.

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22 Acute Exposure Guideline Levels 2.2. Introduction Acetonitrile is a volatile, colorless liquid at ambient temperature and pres- sure (WHO 1993). It has a sweet, ether-like odor, with a reported odor threshold of 42 ppm (Ruth, 1986). Mean ambient air concentrations of 0.000048 to 0.007 ppm have been reported, and slightly higher values were obtained for urban than for rural air. Single measurements taken before and after burning of brush and straw indicated a 10-fold increase in acetonitrile concentrations in air (WHO 1993). Acetonitrile is a combustion product of wood, straw, and other vegetation (WHO 1993). Commercially, most, if not all, acetonitrile produced in the United States is a byproduct of acrylonitrile synthesis by propylene ammoxidation. The amount of acetonitrile produced in an acrylonitrile plant is depends on the am- moxidation catalyst that is used; however, the ratio of acetonitrile:acrylonitrile is typically 2-3:100. Acetonitrile is then recovered as the water azeotype, dried, and purified by distillation. Current acetonitrile production information was not found. Acetonitrile can also be synthesized by other methods such as dehydra- tion of an acetic acid and ammonia mixture, acetamide, or ammonium acetate; reaction of ethanol and ammonia at moderate temperatures in the presence of a metal catalyst; or the reaction of cyanogen chloride with methane, ketones, eth- anol, alkylene epoxides, and paraffins or olefins (WHO 1993). The major use for acetonitrile is as an extraction and processing solvent in the pharmaceutical industry. Acetonitrile is also used as a process, extraction, and formulation solvent for agricultural chemicals, and in the extractive distilla- tion of butadiene. It is also used as a mobile phase in high-performance liquid chromatography and in the separation of chiral systems. It also has minor uses as an intermediate in chemical manufacturing and in photographic applications. The chemical and physical properties of acetonitrile are presented in Table 1-3. 2.3. Human Toxicity Data 2.3.1. Acute Lethality Case reports of lethality from acetonitrile exposure exist; however, specif- ic information about exposure concentrations and durations are not available. Symptoms from acute exposure to acetonitrile before death include chest pain, gastric distress, skin discoloration, tachypnea, hypotension, general weakness, and absence of deep reflexes. Grabois (1955) reported on 16 workers accidentally exposed to acetoni- trile vapors while painting the inside walls of a storage tank. One worker died after two days exposure, two were seriously ill, and other workers experienced

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Aliphatic Nitriles 23 TABLE 1-3 Chemical and Physical Data on Acetonitrile Parameter Data Reference Common name Acetonitrile HSDB 2009 Synonyms Cyanomethane; ethanenitrile; nitrile of WHO 1993 acetic acid; methyl cyanide; ethyl nitrile; methanecarbonitrile CAS registry no. 75-05-8 HSDB 2009 Chemical formula CH3CN HSDB 2009 Molecular weight 41.05 HSDB 2009 Physical state Colorless liquid HSDB 2009 Boiling point 81.6°C WHO 1993 Freezing point -45°C HSDB 2009 Flash point 5.6°C (open cup) WHO 1993 Density/Specific gravity 0.78745 at 15°C/4°C HSDB 2009 Solubility Infinitely soluble in water; WHO 1993, readily miscible with ethanol, HSDB 2009 ether, acetone, chloroform, carbon tetrachloride, and ethylene chloride; immiscible with saturated hydrocarbons (petroleum fractions) Vapor density 1.42 (air = 1) HSDB 2009 Vapor pressure 88.8 mm Hg at 25°C HSDB 2009 Conversion factors in air 1 ppm = 1.68 mg/m3 WHO 1993 1 mg/m3 = 0.595 ppm less serious symptoms. In a follow-up report to this incident, Amdur (1959) re- ported that the tank capacity was 22,730 L (6 meters high and 2.75 meters at its greatest diameter). Due to the viscosity of the paint, it was thinned and heated to 25°C on the second work day; also, ventilation to the tank was stopped. The paint consisted of 30-40% acetonitrile and the thinner was 90-95% acetonitrile. Other components of the paint and thinner included phenolic resin primer, di- ethylene triamine, and mica. The one fatality was a 23-year-old male who had painted inside the tank for 12 h. He was asymptomatic when he returned home; however, he awakened shortly after midnight with malaise and chest pain. Nau- sea, vomiting, and spitting up blood preceded convulsions and coma. He was admitted to the hospital at 9:15 AM with shallow, irregular, and infrequent res- piration; he died within 1 h of admission. Autopsy revealed cerebral, thyroid, hepatic, and splenic, and renal congestion, and a peach-pit odor of all tissues. Cyanide was detected in his blood, urine, gastric fluid, spleen, kidney, and lung. No cyanide was detected in his liver. The two workers who became seriously ill included a 35-year-old male who had painted inside the tank for 3 h and a 28- year-old male who had painted outside of the tank for 12 h. Both men felt well

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110 TABLE D-1 Data Used in Category Plot for Acetonitrile Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 13 10 AEGL AEGL-1 13 30 AEGL AEGL-1 13 60 AEGL AEGL-1 13 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 80 10 AEGL AEGL-2 80 30 AEGL AEGL-2 50 60 AEGL AEGL-2 21 240 AEGL AEGL-2 14 480 AEGL AEGL-3 240 10 AEGL AEGL-3 240 30 AEGL AEGL-3 150 60 AEGL AEGL-3 64 240 AEGL AEGL-3 42 480 AEGL Pozzani et al. 1959 Dog Male 1 2,000 240 2 Pulmonary congestion or hemorrhage Pozzani et al. 1959 Dog Male 1 16,000 240 3 100% mortality (3/3) Pozzani et al. 1959 Guinea pig 1 4,000 240 2 Pulmonary congestion or hemorrhage Pozzani et al. 1959 Guinea pig 1 5,655 240 SL LC50 Pozzani et al. 1959 Guinea pig 1 8,000 240 3 100% mortality (6/6) Willhite 1983 Hamster Female 1 1,800 60 0 No maternal death Willhite 1983 Hamster Female 1 3,800 60 SL Mortality (1/6); no signs of toxicity in others

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Willhite 1983 Hamster Female 1 3,800 60 0 No embryo lethality Pozzani et al. 1959 Human Male 1 40 240 1 n = 3, no subjective symptoms, slight chest tightness followed by a cooling sensation in lungs Pozzani et al. 1959 Human Male 1 80 240 0 n = 2, no subjective symptoms Pozzani et al. 1959 Human Male 1 160 240 1 n = 2, slight transitory flushing of the face, slight bronchial tightness MPI 1998 Mouse Both 1 3,039 240 SL 20% mortality (2/10) Willhite 1981 Mouse 1 2,693 60 SL LC50 Willhite 1981 Mouse 1 5,000 60 3 100% mortality (10/10) Pozzani et al. 1959 Rabbit 1 2,000 240 2 Pulmonary congestion or hemorrhage Pozzani et al. 1959 Rabbit 1 2,828 240 SL LC50 Pozzani et al. 1959 Rabbit 1 4,000 240 3 100% mortality (4/4) DuPont 1968 Rat Male 1 17,100 240 SL LC50 Haguenoer et al. 1975 Rat 1 25,000 30 3 100% mortality (3/3) Monsanto 1986 Rat 1 10,100 240 2 Hemorrhagic lungs Monsanto 1986 Rat 1 13,600 240 SL Mortality (1/10), hemorrhagic lungs, corneal opacity Northview Pacific Rat Both 1 4,760 60 0 1/5 females lost weight, no mortality or Labs 1989 gross abnormalities Mast et al. 1994 Rat Female 14 1,200 360 0 No embryo lethality Mast et al. 1994 Rat Female 13 1,200 360 SL 6% (2/33) in dams NTP 1996 Rat Male 65 400 360 0 No death NTP 1996 Rat Female 65 800 360 0 No death NTP 1996 Rat Male 65 800 360 SL 10% mortality (1/10) (Continued) 111

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112 TABLE D-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Pozzani et al. 1959 Rat Both 1 1,000 480 2 Pulmonary congestion or hemorrhage Pozzani et al. 1959 Rat Both 1 2,000 480 SL Mortality (1/24), pulmonary congestion or hemorrhage Pozzani et al. 1959 Rat Both 1 4,000 240 2 Pulmonary congestion or hemorrhage Pozzani et al. 1959 Rat Both 1 4,000 480 SL Mortality (2/24), pulmonary congestion or hemorrhage Pozzani et al. 1959 Rat Male 1 7,551 480 SL LC50 Pozzani et al. 1959 Rat Both 1 8,000 240 SL Mortality (7/12) Pozzani et al. 1959 Rat Female 1 12,435 480 SL LC50 Pozzani et al. 1959 Rat Both 1 32,000 240 3 100% mortality (24/24) Pozzani et al. 1959 Rat Female 1 32,000 480 3 100% mortality (24/24) Pozzani et al. 1959 Rat 1 53,000 15 2 No death Pozzani et al. 1959 Rat 1 53,000 30 SL 50% mortality (3/6) Saillenfait et al. 1993 Rat Female 14 1,500 360 0 No maternal death or embryo lethality Saillenfait et al. 1993 Rat Female 14 1,800 360 3 40% (8/20) mortality in dams, embryo lethality UCC 1965 Rat 1 4,000 240 SL 10% mortality (3/30) For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal

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TABLE D-2 Data Used in Category Plot for Isobutyronitrile Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 2.5 10 AEGL AEGL-2 2.5 30 AEGL AEGL-2 2.0 60 AEGL AEGL-2 1.3 240 AEGL AEGL-2 0.83 480 AEGL AEGL-3 7.6 10 AEGL AEGL-3 7.6 30 AEGL AEGL-3 6.1 60 AEGL AEGL-3 3.8 240 AEGL AEGL-3 2.5 480 AEGL Katz 1986 Rat Male 1 1,248 60 SL Mortality (1/5) Katz 1986 Rat Male 1 2,709 60 3 Mortality (5/5) Katz 1986 Rat Female 1 1,248 60 0 No clinical signs Katz 1986 Rat Female 1 1,778 60 SL Mortality (1/5) (Continued) 113

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114 TABLE D-2 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Eastman Kodak 1986a Rat Male 1 1,200 60 2 “Appreciable” differences noted in expiratory reserve volume, residual volume, dynamic compliance (up to 76% decrease), and FEV 10% Eastman Kodak 1986a Rat Male 1 1,800 60 SL Mortality (2/4) Eastman Kodak 1986a Rat Male 1 2,700 60 3 Mortality (4/4) Eastman Kodak1986b Rat Male 1 1,233 60 SL Mortality (1/5) Smyth et al. 1962 Rat 1 500 240 2 No mortality, no details provided Tsurumi and Rat 1 37,000 4 0 Mortality (0/10), no other effects described Kawada 1971 Tsurumi and Rat 1 37,000 5 SL Mortality (1/10), no other effects described Kawada 1971 Tsurumi and Rat 1 37,000 10 3 Mortality (10/10), no other effects described Kawada 1971 Tsurumi and Mouse 1 37,000 0.25 2 Mortality (0/10), no other effects described Kawada 1971 Tsurumi and Mouse 1 37,000 0.5 SL Mortality (3/10), no other effects described Kawada 1971 Tsurumi and Mouse 1 37,000 2 3 Mortality (10/10), no other effects described Kawada 1971 AIHA 1992 Human 1 25 3 0 An exposure of a few minutes to estimated concentrations of 20-25 ppm from a isobutyronitrile spill did not produce symptoms of cyanide poisoning

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Saillenfait et al. 1993 Rat Female 15 50 360 1 Gestation days 6-20 Saillenfait et al. 1993 Rat Female 15 100 360 1 Gestation days 6-20 Saillenfait et al. 1993 Rat Female 15 200 360 SL Gestation days 6-20, mortality (1/21), decrease in fetal weight Saillenfait et al. 1993 Rat Female 15 300 360 SL Gestation days 6-20, mortality (3/21), increased embryonic resorptions, decreased fetal weight, unilateral hydronephrosis For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 115

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116 Ac cute Exposure Guideline Levels FIGUR D-3 Category plot of toxicity data and AEGL values for prop RE y y L pionitrile. FIGUR D-4 Category plot of AEGL values for chloro RE y v oacetonitrile.

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TABLE D-3 Data Used in Category Plot for Propionitrile Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 3.7 10 AEGL AEGL-2 3.7 30 AEGL AEGL-2 3.0 60 AEGL AEGL-2 1.9 240 AEGL AEGL-2 1.3 480 AEGL AEGL-3 11 10 AEGL AEGL-3 11 30 AEGL AEGL-3 9.1 60 AEGL AEGL-3 5.7 240 AEGL AEGL-3 3.8 480 AEGL Saillenfait et al. 1993 Rat Female 14 150 360 0 No maternal or fetal death Saillenfait et al. 1993 Rat Female 14 200 360 SL Maternal death (2/23) and increased embryo lethality (increased mean % non-surviving implants/litter, increased mean % resorption sites/litter) (Continued) 117

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118 TABLE D-3 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Younger Labs 1978 Rat Both 1 690 240 2 Salivation, lethargy, weakness, tremors, convulsions Younger Labs 1978 Rat Male 1 1,100 240 SL Mortality (5/10), salivation, lethargy, weakness, tremors, convulsions, collapse and death Younger Labs 1978 Rat Male 1 1,700 240 SL Mortality (5/10), salivation, lethargy, weakness, tremors, convulsions, collapse, death Younger Labs 1978 Rat Male 1 2,800 240 SL Mortality (8/10), salivation, lethargy, weakness, tremors, convulsions, collapse, death Younger Labs 1978 Rat Both 1 4,400 240 3 Mortality (10/10), salivation, lethargy, weakness, tremors, convulsions, collapse, death Younger Labs 1978 Rat Both 1 6,900 240 3 Mortality (10/10), salivation, lethargy, weakness, tremors, convulsions, collapse, death Younger Labs 1979 Rat Male 1 39,432 75 3 Mortality (6/6) Lewis 1996 Mouse 1 34 SL Intraperitoneal LD50 Tanii and Mouse Male 1 36 SL Oral LD50 Hashimoto 1984 Willhite and Smith Mouse Male 1 163 60 SL LC50 1981 Scolnick et al. 1993 Human Male 1 33.8 120 2 Headache, nausea, dizziness Scolnick et al. 1993 Human Male 1 33.8 420 2 Coma, seizures, bilateral interstitial infiltrates (lungs), lethargy, headaches, dizziness For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal

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Aliphat Nitriles tic 1 119 TABLE D-4 Data Us in Category Plot for Chlo E sed y oroacetonitrile No. Source Species Sex Exposures ppm M Minutes Categ gory Comment ts AEGL-1 NR 10 0 AEGLL AEGL-1 NR 30 0 AEGL L AEGL-1 NR 60 0 AEGL L AEGL-1 NR 24 40 AEGL L AEGL-1 NR 48 80 AEGL L AEGL-2 8.0 10 0 AEGL L AEGL-2 8.0 30 0 AEGL L AEGL-2 5.0 60 0 AEGL L AEGL-2 2.1 24 40 AEGL L AEGL-2 1.4 48 80 AEGL L AEGL-3 24 10 0 AEGL L AEGL-3 24 30 0 AEGL L AEGL-3 15 60 0 AEGL L AEGL-3 6.4 24 40 AEGL L AEGL-3 4.2 48 80 AEGL L For cate egory: 0 = no eff fect, 1 = discomf fort, 2 = disablin SL = some le ng, ethality, 3 = lethal FIGUR D-5 Category plot of AEGL values for malon RE y v nonitrile.

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120 Acute Exposure Guideline Levels TABLE D-5 Data Used in Category Plot for Malononitrile No. Source Species Sex Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 1.2 10 AEGL AEGL-2 1.2 30 AEGL AEGL-2 0.77 60 AEGL AEGL-2 0.32 240 AEGL AEGL-2 0.22 480 AEGL AEGL-3 3.7 10 AEGL AEGL-3 3.7 30 AEGL AEGL-3 2.3 60 AEGL AEGL-3 0.98 240 AEGL AEGL-3 0.65 480 AEGL For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal.