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Acrylonitrile
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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

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1This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager Susan Ripple (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 Acrylonitrile1 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 1 This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager Susan Ripple (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 re- viewed by the National Research Council (NRC) Committee on Acute Exposure Guide- line Levels. The NRC committee has concluded that the AEGLs developed in this docu- ment 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 experience notable discomfort, irritation, or certain asymptomatic, nonsensory 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. SUMMARY Acrylonitrile is a monomer used in the manufacture of acrylic fibers, syn- thetic rubber, resins, plastics, adhesives, and acrylamide. Acrylonitrile has a sharp onion-garlic odor. Worldwide production is estimated at 4-4.5 million metric tons. The odor threshold for acrylonitrile ranges from 1.6 to 36.3 ppm. A level of distinct odor awareness of 145 ppm was calculated for acrylonitrile. Nonlethal effects of occupational exposure to acrylonitrile include head- ache, nasal and ocular irritation, thoracic discomfort, nervousness, and irritabil- ity. Information from occupational studies indicates that these effects have oc- curred at exposures of 16-100 ppm for 20-45 min. Workers routinely exposed to acrylonitrile at 5 ppm experienced initial conjunctival irritation followed by some degree of accommodation, and routine exposure at 5-20 ppm resulted in complaints of headache, fatigue, nausea, and insomnia. No signs or symptoms were reported by informed male volunteers after exposure to acrylonitrile at up to 4.6 ppm for 8 h. Lethality following acute inhalation exposure to acrylonitrile has been reported, but exposures were not defined. Acute exposure data are available for several laboratory species (monkey, rat, dog, rabbit, guinea pig, and cat) and demonstrate qualitatively similar re- sponses between species, ranging from mild irritation (redness of exposed skin, lacrimation, and nasal discharge) and mild effects on ventilation and cardiovas-

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Acrylonitrile 15 cular responses to severe respiratory effects, convulsions, and death. A 4-h ex- posure to acrylonitrile at 30-100 ppm produced little or no effect in most species tested, but dogs appeared to be notably more sensitive, exhibiting severe effects at the 100 ppm. Developmental toxicity studies conducted in rats found nonle- thal effects on fetal development that included decrements in fetal body weight without fetal malformations (25-100 ppm) (Saillenfait et al. 1993a) and nonle- thal fetal malformations (40 and 80 ppm) (Murray et al. 1978). Murray et al. (1978) found three malformations in two of 33 liters from dams exposed at 40 ppm and 11 malformations in six of 35 litters from dams exposed at 80 ppm. The most serious malformation was one omphalocele at 40 and 80 ppm. These malformations were not confirmed in the Saillenfait et al. (1993a) study at expo- sures up to 100 ppm. A two-generation study found weight decrements in F1 offspring of the 90-ppm group, but no other evidence of exposure-related mor- talities in adult animals, effects on reproduction or reproductive organs, or tox- icity in developing offspring at exposures up to 90 ppm (Nemec et al. 2008). No effects on resorptions or live births were found in the single-generation or two- generation studies. Lethality in rats appears to occur at cumulative exposure of 1,800-1,900 ppm-h for 30 min to 6 h, although for nose-only exposures it was notably higher (about 3,800 ppm-h). Analysis of exposure concentration-duration data suggest a near linear relationship (Cn × t = k, where n = 1.1; ten Berge et al. 1986). Re- sults of studies in animals showed that lethality may be delayed especially at the lower limits of lethal exposures. One study provided evidence of teratogenic effects in rats following gestational exposure of dams to acrylonitrile at 80 ppm but not at 40 ppm. Another study showed an exposure-related decrease in fetal weight following gestational exposure of dams at 25, 50, or 100 ppm; no other reproductive or developmental effects were detected. Acrylonitrile toxicity ap- pears to be directly related to its metabolism. Two major metabolic pathways have been described: conjugation with glutathione and epoxidation by microso- mal cytochrome P450 2E1, which forms 2-cyanoethylene oxide (CEO). Metabo- lites from both pathways are subject to additional biotransformation. The gluta- thione conjugate may form a mercapturic acid which is excreted in urine. CEO is further metabolized via conjugation with glutathione (catalysis with cytosolic glutathione S-transferase [GST] or nonenzymatically) resulting in additional conjugates and via hydrolysis by microsomal epoxide hydrolase (EH). The sec- ondary metabolites of CEO may also be further metabolized. Cyanide may be generated via the EH pathway and by one of the glutathione (GSH) conjugation products. Cyanide, in turn, is detoxified to thiocyanate via rhodanese-mediated reactions with thiosulfate. Results of genotoxicity studies are mixed, but provide evidence that acry- lonitrile is genotoxic, with positive results in in vitro (DNA strand breaks, sister chromatid exchange [SCE], chromosomal aberrations, and cell transformations) and in vivo (DNA damage, SCE, chromosomal aberrations, and micronuclei) models. The overall weight of evidence supports the conclusion that acryloni- trile is genotoxic. Results of long-term inhalation exposure cancer bioassays

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16 Acute Exposure Guideline Levels have shown that acrylonitrile is carcinogenic in rats, with brain, spinal cord, Zymbal’s gland, tongue, small intestines and mammary glands identified as tar- gets. Available data are sufficient for considering acrylonitrile to be carcinogen- ic in animals following chronic inhalation exposure. The AEGL-1 values for acrylonitrile are based on the absence of effects in informed human volunteer (six males) exposed to acrylonitrile at 4.6 ppm for 8 h (Jakubowski et al. 1987), supported by observations of mild effects (initial conjunctival irritation, for which there was some accommodation) in workers routinely exposed at approximately 5 ppm (Sakurai et al. 1978). Therefore, the 8-h exposure at 4.6 ppm is considered a no-effect level for notable discomfort and a point-of-departure for deriving AEGL-1 values. That concentration is ap- proximately 3-fold lower than concentrations reported by Wilson et al. (1948) to be associated with more severe effects in occupational settings (16-100 ppm for 20-45 min: headache, nasal and ocular irritation, discomfort of the chest, nerv- ousness, and irritability). Pharmacokinetic variability is not likely to be signifi- cant for mild effects (ocular irritation) of low-level exposure. However, the point-of-departure is based on studies of healthy adults and, in the occupational studies, subjects who experienced repeated exposures to acrylonitrile, which may have resulted in some accommodation to the ocular irritation. Therefore, an intraspecies uncertainty factor of 3 was applied. No data are available on the relationship between exposure duration and severity of responses to acryloni- trile. Typically, in the absence of this information, AEGL-1 values based on an 8-h point-of-departure would be time scaled. However, in this case, the effect is ocular irritation, which would not be expected to have a response threshold that varies with exposure duration. Therefore, it is prudent to not time scale and the AEGL-1 values were held constant at 1.5 ppm for exposure durations of 10 and 30 min. However, 1.5 ppm exceeds AEGL-2 values for longer exposure dura- tions; therefore, AEGL-1 values for 1 h, 4 h, and 8 h are not recommended. The AEGL-2 values for acrylonitrile are based a developmental toxicity study conducted in rats, which showed that 12 ppm (6 h/day, gestation days 6- 20) was a no-effect level for fetal toxicity, indicated by decrements in fetal body weight at higher concentrations (25-100 ppm). Support for the point-of- departure is provided from studies conducted in rats and monkeys. In monkeys, slight or modest reversible effects (transient skin flushing and elevation of respi- ration rates) were observed from 4-h exposures to acrylonitrile at 65 or 90 ppm (Dudley and Neal 1942). Slight transient effects were found in rats exposed to acrylonitrile at 305 ppm for 2 h (Dudley and Neal 1942). The effects resolved within 12 h postexposure. At higher concentrations or longer exposure dura- tions, effects were more severe (rapid respiration, tremors, convulsions, and death). A threshold for these more severe effects in the rat appears to be above 305 ppm and below the threshold for lethality (the 2-h BMCL05 [benchmark concentration, 95% lower confidence limit at the 5% response rate] is 491 ppm) in the rat. An interspecies uncertainty factor of 6 (3 × 2) was applied; a factor of 3 accounts for possible species differences in toxicodynamics of acrylonitrile and a factor of 2 accounts for interspecies differences in toxicokinetics. On the

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Acrylonitrile 17 basis of BPK modeling, Sweeney et al. (2003) predicted a 2-fold difference the concentrations of acrylonitrile and its metabolite, cyanoethylene oxide (the met- abolic precursor to cyanide), in blood and brain during 8-h exposures at 2 ppm. Higher cyanoethylene oxide concentrations were predicted in human blood and brain than in rats. A PBPK model developed by Takano et al. (2010) used data on in vitro metabolism of acrylonitrile in rat and human liver microsomes to estimate hepatic clearance of cyanoethylene oxide. The model predicted that repeated oral exposures to acrylonitrile at 30 mg/kg/day for 14 days would result in peak blood acrylonitrile concentrations that were approximately 2-fold higher in rats than humans. Although the Takano et al. (2010) model was evaluated using oral exposure data, experimental data for metabolism were obtained from in vitro microsome studies. Taken together, the Sweeney et al. (2003) and Taka- no et al. (2010) PBPK models support application of an interspecies uncertainty factor of 2 to account for differences in toxicokinetics. An intraspecies uncer- tainty factor of 6 (3 × 2) was applied; a factor of 3 for possible variation in toxi- codynamics of acrylonitrile in the human population and a factor of 2 for varia- bility in toxicokinetics. On the basis of PBPK modeling, Sweeney et al. (2003) predicted that human variability in toxicokinetics of acrylonitrile would result in the 95th percentile individual having acrylonitrile or cyanoethylene oxide con- centrations in blood 1.8-fold higher than the average (mean) individual. This suggests that an intraspecies uncertainty factor of 2 would account for toxicoki- netics variability in the human population. The total uncertainty factor was 36 (6 × 6). Time scaling from the 6-h experimental point-of-departure to AEGL- specific exposure durations was performed using the equation Cn × t = k, where n = 1.1 (ten Berge et al. 1986). Analysis of occupational exposures and effects indicated that routine exposure to acrylonitrile at 5-20 ppm resulted in com- plaints of headache, fatigue, nausea, and insomnia, which were neither irreversi- ble nor escape-impairing effects. The concentrations range is approximately 20- to-80 fold higher than the 8-h AEGL-2, which suggests that 8-h AEGL-2 is suf- ficiently protective. The AEGL-3 values were derived using 30-min, 1-h, 4-h, and 8-h BMCL05 estimates of lethality thresholds. Data for several AEGL-specific expo- sure periods were available from the reports by Appel et al. (1981a) and Dudley and Neal (1942). A 30-min BMCL05 of 1,748 ppm was calculated from the Ap- pel et al. (1981a) data. The 1-, 2-, 4-, and 8-h BMCL05 values derived from rat lethality data published by Dudley and Neal (1942) are 1,024.4, 491.3, 179.5, and 185.8 ppm, respectively. With the exception of the 4-h value, the data show a consistent duration-dependent relationship; therefore, the 30-min, 1-h, and 8-h estimates were used to derive corresponding AEGL-3 values. Because the 4-h BMCL05 was essentially equivalent to the 8-h BMCL05, the 4-h AEGL-3 value was derived by time-scaling the 8-h BMCL05. The 10-min AEGL-3 value was derived by time-scaling from the 30-min rat BMCL05. Time scaling was per- formed using the equation Cn × t = k, where n = 1.1 (ten Berge et al. 1986). Alt- hough the dog appeared to be the most sensitive species, the overall database for

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18 Acute Exposure Guideline Levels rats is more robust. The same uncertainty factors that were used to derive the AEGL-2 values were applied to the AEGL-3 values because the same toxicody- namic and toxicokinetic factors apply to both AEGl-2 and AEGL-3 dose- response relationships. An interspecies uncertainty factor of 6 (3 × 2) and an intraspecies uncertainty factor of 6 (3 × 2) were applied, for a total uncertainty factor of 36 (6 × 6). The AEGL values for acrylonitrile are presented in Table 1-1. 1. INTRODUCTION Acrylonitrile is a monomer used in the manufacture of acrylic fibers, syn- thetic rubber, resins, plastics, adhesives, and acrylamide. Acrylonitrile has a sharp onion-garlic odor. Worldwide production has been estimated at 4-4.5 mil- lion metric tons (Collins et al. 2003; NPI 2006). Production of acrylonitrile in the United States was 3.4 billion pounds in 1996 (NTP 2011). Chemical and physical data for acrylonitrile is presented in Table 1-2. AIHA (1997) lists an odor threshold range of 1.6-21 ppm for acrylonitrile, and Ruth (1986) reported a range of 3.7-36.3 ppm. A level of distinct odor awareness of 145 ppm was calculated for acrylonitrile (see Appendix A). TABLE 1-1 AEGL Values for Acrylonitrile End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 1.5 ppm 1.5 ppm NRa NRa NRa No-effect level for (nondisabling) (3.3 (3.3 notable discomfort mg/m3) mg/m3) (ocular irritation) in human subjects, 4.6 ppm for 8 h (Sakurai et al. 1978; Jakubowski et al. 1987). AEGL-2 8.6 ppm 3.2 ppm 1.7 ppm 0.48 ppm 0.26 ppm No-effect level for fetal (disabling) (19 (6.9 (3.7 (1.0 (0.56 toxicity (fetal body mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) weight) in rats, 12 ppm for 6 h (Saillenfait et al. 1993a). AEGL-3 130 ppm 50 ppm 28 ppm 9.7 ppm 5.2 ppm No-effect level for (lethal) (280 (110 (61 (21 (11 lethality (30-min, 1-h, mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) and 8-h BMCL05) in rats (Dudley and Neal 1942; Appel et al. 1981a). a Not recommended. Absence of an AEGL-1 value does not imply that exposure at con- centrations below the AEGL-2 value is without effect.

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Acrylonitrile 19 TABLE 1-2 Chemical and Physical Data for Acrylonitrile Parameter Value Reference Synonyms 2-propenenitrile; vinyl cyanide; acrylonitrile HSDB 2013 monomer; cyanoethylene CAS registry no. 107-13-1 HSDB 2013 Chemical formula C3H3N HSDB 2013 Molecular weight 53.06 HSDB 2013 Physical state Liquid HSDB 2013 Melting point -82°C HSDB 2013 Boiling point 77.3°C HSDB 2013 Density/specific gravity 0.8 at 23°C/4°C HSDB 2013 Solubility in water 74.5 g/L at 25°C HSDB 2013 Vapor density 1.8 (air = 1) HSDB 2013 Vapor pressure 109 mmHg at 25°C HSDB 2013 Conversion factors in air 1ppm = 2.17 mg/m3 NIOSH 2011 1 mg/m3 = 0.46 ppm 2. HUMAN TOXICITY DATA 2.1. Acute Lethality A child exposed overnight in a room fumigated with acrylonitrile died. Vomiting, lacrimation, convulsions, respiratory difficulty, cyanosis, and tachy- cardia were present. Five adults also in the room experienced little or no effect (see Section 2.2.) (Grunske 1949). No exposure concentration-duration infor- mation was reported. Another case study involved the death of a 10-year-old girl who had a delousing agent containing acrylonitrile applied to her scalp (Lorz 1950). Following dermal application of the delousing agent, the girl’s head was wrapped in a cloth and she went to bed. Symptoms of nausea, headache, and dizziness were followed by repeated vomiting and coma. Cramps and increasing cyanosis were followed by death 4 h after application. Loss of consciousness, convulsions, and respiratory arrest have been re- ported as outcomes of severe acute inhalation exposure to acrylonitrile (Buchter and Peter 1984). However, no exposure details were available. The death of a worker cleaning an acrylonitrile-containing wagon at a train depot was attributed to exposure to the chemical (Bader and Wrbitzky 2006). No exposure data were available, although liquid acrylonitrile was pre- sent on the clothing of the individual. Cause of death was reportedly “blood cir- culation collapse”. 2.2. Nonlethal Toxicity Wilson et al. (1948) reported that exposure of workers handling “polymer- izers” at concentrations of 16-100 ppm for 20-45 min experienced dull head-

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20 Acute Exposure Guideline Levels aches, nasal and ocular irritation, discomfort in the chest, nervousness, and irri- tability. Workers with notable poisoning (exposures not reported) experienced nausea, vomiting, and weakness. Some developed mild jaundice, low-grade anemia, and leukocytosis. No exposure details were provided for the workers with these more serious effects, but all recovered upon removal from exposure. Five adults who spent the night in the room in which a child died of acry- lonitrile poisoning (see Section 2.1.) had no signs of poisoning and complained only of ocular irritation (Grunske 1949). No exposure concentration-duration information was reported. Lacrimation and visual disturbance were reported in some nonfatal expo- sures to acrylonitrile (Davis et al. 1973). Although exposure concentrations were not reported, these effects were likely associated with very high acrylonitrile concentrations. In an analysis of 144 case reports of acute acrylonitrile poisoning, Chen et al. (1999) estimated that 60 cases were exposed to concentrations in the range of 18-258 ppm (40-560 mg/m3) and the remaining 84 cases were exposed at con- centrations greater than 460 ppm (1000 mg/m3). Air measurements were not made at the time of the accident and were estimated from accident simulations and postaccident measurements (5 h after the accident). Subjective symptoms reported for 92-100% of the cases included dizziness, headache, chest tightness, feebleness, and hyperactive knee jerk. Sore throat, dyspnea, vomiting, ab- dominal pain, fainting, and congestion of the pharynx were reported in 60-87% of cases. Other less frequently reported symptoms or effects (5-32% of cases) included numbness of limbs, convulsion, rapid heart rate, cough, hoarseness, rough breathing sound, coma, and abnormal liver function (Chen et al. 1999). Subchronic (about 3 years) occupational exposure to acrylonitrile at con- centrations ranging from 0.6 to 6.0 mg/m3 (0.3 to 3 ppm) produced headaches, insomnia, general weakness, decreased working capacity, and irritability (Baba- nov et al. 1959). In a report by Sakurai and Kusumoto (1972), the health records of 576 workers working in five acrylonitrile fiber plants over a 10-year period were examined. The report analyzed 4,439 examinations acquired over 10 years be- fore 1970. Two cohorts, one exposed to concentrations of acrylonitrile below 11 mg/m3 (5 ppm) and the other exposed to less than 45 mg/m3 (20 ppm), were considered. Workers exposed to acrylonitrile at concentrations of 11 mg/m3 (5 ppm) complained of headache, fatigue, nausea, and insomnia. There was a posi- tive correlation with exposure duration but not with the exposure concentration or age of workers. In a later report, however, Sakurai et al. (1978) stated that the study lacked adequate epidemiologic design, the findings were based on routine health examinations, and the “exposure levels were not reliably reported” and may have been much higher. In this later appraisal it was noted that many of the symptoms reported in Sakurai and Kusumoto (1972) were associated with expo- sures well in excess of 5 ppm. Sakurai et al. (1978) examined health records for 608 acrylonitrile fiber factory workers. Subjects were grouped into three cohorts that had median air concentrations (from spot samples) of approximately

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Acrylonitrile 21 <1 ppm, 1 ppm, and 5 ppm. They reported that “many workers” complained of initial conjunctival irritation and respiratory irritation and for which there was some accommodation; however, these effects were not attributed to specific exposure cohorts. Sakurai et al. (1978) stated that their findings were not contra- dictory to those of Wilson et al. (1948), because they reflected the older and less controlled workplace environment where concentrations could have been up to 20 ppm. Taken together, the Sakurai and Kusumoto (1972) and Sakurai et al. (1978) studies suggest mild and transient ocular irritation in association with exposures at 5 ppm (or less), with more severe outcomes (headache, fatigue, nausea, and insomnia) in association with higher exposures (5-20 ppm). In cross-sectional studies of acrylonitrile-exposed workers, subjective symptoms reported with increased prevalence compared with unexposed work- ers included dizziness, headache, chest tightness, poor memory, irritation, and neurologic effects. Average workplace air concentrations associated with in- creased prevalence of these subjective symptoms were 1.13 ppm (Muto et al. 1992), 1.8 ppm (Kaneko and Omae 1992), and 0.48 ppm (Chen et al. 2000). Rongzhu et al. (2005) reported statistically significant deficits in several neuro- behavioral tests measured in exposed workers in a Chinese acrylic fiber manu- facturing plant with mean workplace air concentrations of 0.11 ppm (0-1.70 ppm) and 0.91 ppm (range 0-8.34 ppm) in two different process areas. Deficits in exposed workers compared with nonexposed workers were noted in a profile of mood states test (20-68% higher for negative moods such as anger and confu- sion), a simple reaction time test of attention and response speed (10-16% defi- cits), and the backward sequence of the digit span test of auditory memory (21- 24% deficits). Ocular irritation was a primary effect in a 24-year old man whose face, eyes, and body were sprayed by acrylonitrile (no concentration data) explosively released from a defective valve (Vogel and Kirkendall 1984). Mild conjunctivi- tis with no corneal clouding was reported. Results of fundascopic examination were normal. A study was conducted to evaluate the metabolism and excretion of acry- lonitrile in informed volunteer subjects (Jakubowski et al. 1987). The six volun- teers (including the investigators) were all males aged 28-45 years. Being toxi- cologists, they were all aware of the toxic properties of acrylonitrile. The subjects were exposed for 8 h to acrylonitrile vapors generated by a saturator immersed in a thermostat-controlled water bath and diluted with carrier air to produce the desired acrylonitrile concentrations (5 or 10 mg/m3; equivalent to 2.3 and 4.6 ppm, respectively). Airflow in the 11.7-m3 chamber was approxi- mately 200 m3/h. There were three 10-min breaks from the exposure at 2, 4, and 6 h. Gas chromatography was used to monitor the acrylonitrile concentration every 15 min. No symptoms were reported by any of the subjects. Limitations of the Jakubowski et al. (1987) study are that the objective of the study was to col- lect data on the toxicokinetics of acrylonitrile and not to evaluate health effects. All of the subjects were informed toxicologists who worked in the laboratory in

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22 Acute Exposure Guideline Levels which the study was performed (stakeholders) and may have been more tolerant of mild irritant effects than less motivated individuals. The World Health Organization (WHO 1983) summarized various work- place studies (Zotova 1975; Enikeeva et al. 1976; Delivanova et al.1978; Ivanov, State Medical Institute, Krasnoyarsk, USSR, personal commun. 1983). Blepharo- conjunctivitis was reported following exposure to acrylonitrile at 5 ppm. Other nonocular symptoms were also reported. Gincheva et al. (1977) reported no changes in the health status for a group of 23 men occupationally exposed to acrylonitrile at 1.9-3.3 ppm for 3-5 years. 2.3. Developmental and Reproductive Effects Xu et al. (2003) reported that workers exposed to mean acrylonitrile con- centration of 0.8 mg/m3 (0.37 ppm) had a significant decrease (46%) in sperm density when compared with unexposed controls. In addition, DNA strand breakage and sex chromosome aneuploidy were significantly increased in the sperm cells of exposed workers. Xu et al. (2003) stated that aneuploidy transmit- ted via germ cells is a major contributor to infertility, spontaneous abortion, stillbirths, and infant death. Reproductive outcomes in workers exposed to acrylonitrile were evaluated by Dong and Pan (1995) and Dong et al. (2000). Several inconsistencies were noted in the reports. The following incidence values correct for inconsistencies between tables and text in the original study reports. Dong and Pan (1995) re- ported statistically significantly increased incidences of adverse reproductive outcomes in acrylic fiber workers exposed to an average acrylonitrile concentra- tion of 3.7 ppm for 3.2-10.2 years when compared with unexposed controls. These adverse outcomes included premature delivery (10.7% vs. 3.5%) and ste- rility (5.0% vs. 1.8%) in exposed males compared with controls and stillbirths (4.5% vs. 0%) in exposed females compared with controls. Dong et al. (2000) reported statistically significantly increased incidences of adverse reproductive outcomes in female acrylic fiber workers exposed to an average acrylonitrile concentration of 3.7 ppm for 10.4 years. Adverse outcomes included increased stillbirths (2.66% vs. 0.68%), birth defects (1.93% vs. 0.45%), and premature deliveries (8.23% vs. 3.87%) compared with controls. A reported decreased in testosterone in acrylonitrile factory workers (Iva- nescu et al. 1990) was confounded by concurrent exposure to other chemicals. No adverse effect was detected for gynecological health of 410 women occupa- tionally exposed to acrylonitrile (no exposure details) compared with 436 unex- posed women (Dorodnova 1976). Czeizel et al. (1999) reported on the rate and type of congenital abnormalities in 46,326 infants born to mothers living within a 25-km radius of an acrylonitrile factory in Hungary. Significant clusters of pectus excavatum (depressed sternum), undescended testes, and clubfoot were noted. The authors, however, reported that the overall results supported the null hypothesis of no effects of acrylonitrile in people living in the vicinity of the acrylonitrile factory.

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Acrylonitrile 23 2.4. Genotoxicity 2.4.1. In Vitro Studies In experiments with human lymphocytes, Perocco et al. (1982) showed that exposure of human lymphocytes to acrylonitrile at 0.5 mM (26.5 μg/mL) resulted in a significant increase in sister chromatid exchange (SCE). Obe et al. (1985), however, was unable to demonstrate SCE-induction by acrylonitrile in human lymphocytes exposed for 24 h to acrylonitrile at concentrations of 1 or 10 μg/mL in the absence of S9 and for 1 h in the presence of S9 from Arochlor- induced rat livers. Rizzi et al. (1984) examined the incorporation of [3H]TdR into DNA in HeLa cells. The test groups included a control and acrylonitrile-treated cells without hydroxyurea (-HU), and control and treated cells treated with hy- droxyurea (+HU). The -HU/+HU relationship between treated and control cells and the value of +HU between treated and control cells were statistically signifi- cant at acrylonitrile concentrations of 0.18 (p < 0.01) and 0.036 mM (p < 0.09). It was concluded that acrylonitrile is mutagenic and genotoxic at very low con- centrations. Contrary to this, Martin and Campbell (1985) failed to demonstrate unscheduled DNA repair in HeLa cells. Acrylonitrile produced positive results in tests with human lymphoblasts (TK6, TK locus) both with and without metabolic activation (Crespi et al. 1985). Tests were conducted at acrylonitrile concentrations of 5-50 μg/mL for 3 h in the presence of S9 (from Arochlor-induced rat livers) or for 20 h without S9. There was a 3.5-fold increase in mutational frequency in the presence of S9 at 40 and 50 μg/mL. In the absence of S9, mutational frequency was increased 2-fold at 15 μg/mL and 1.3-fold at 20 μg/mL (compared with controls). Crespi et al. (1985) also conducted tests using the AHH-1 cell line (HGPRT locus). Concentrations of acrylonitrile were 5-25 μg/mL for 28 h. Tests were conducted with metabolic activation and an expression period of 6 days. An approximate 4.5-fold increase in mutation frequency at 25 μg/mL was de- tected relative to controls which was similar to the response obtained with the benzo(a)pyrene (3.1 μg/mL, positive control). The mutagenic potential of both acrylonitrile and its metabolite 2- cyanoethylene oxide (CEO) was examined using the TK human lymphoblast cell line (with and without S9) with heterozygous thymidine kinase (tk) locus as the marker (Recio et al. 1989). Cells were exposed for 2 h with an expression period of 6-8 days. Acrylonitrile was not mutagenic in the absence of S9 (less than a 2-fold increase in mutation frequency) over a concentration range of 0.4 to 1.5 mM (21 to 80 μg/mL). With S9, there was a statistically significant (p < 0.05) 4-fold mutagenic response at the highest concentration 1.5 mM (74 μg/mL). Survival was only 10% at 1.5 mM. The metabolite produced a 17-fold increase in mutation frequency without S9 at 100 μM. The results indicated ac- rylonitrile to be weakly mutagenic in mammalian cells, while the mutagenic response induced by CEO suggests that it may be the primary mutagenic metab-

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Acrylonitrile 85 Analysis of Deviance Table Model Log (likelihood) Deviance Test d.f. P-value Full model -9.93738 Fitted model -9.93738 2.60525e-007 1 0.9996 Reduced mode -32.8951 45.9154 2 <0.0001 AIC: 23.8748 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 130.0000 0.0000 0.000 0 16 -3.783e-008 315.0000 0.3125 5.000 5 16 -3.304e-006 635.0000 1.0000 16.000 16 16 0.0003609 Chi-square =0.00 d.f. = 1 P-value = 0.9997 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 276.026 BMCL = 179.532 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 100 200 300 400 500 600 dose 10:26 07/11 2007 FIGURE F-4 Probit model with 0.95 confidence level.

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86 Acute Exposure Guideline Levels BMCL05 8-h Exposure of Rats (Dudley and Neal 1942) Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ Input Data File: C:\BMDS\UNSAVED1.(d) Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt Thu Mar 01 08:46:12 2007 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 5 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -13 Slope = 2.37276 Asymptotic Correlation Matrix of Parameter Estimates (*** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix) Intercept Slope Intercept 1 -1 Slope -1 1 Parameter Estimates Variable Estimate Standard Error Background 0 NA Intercept 40.1969 9.34116 Slope 7.18845 1.66722 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.

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Acrylonitrile 87 Analysis of Deviance Table Model Log (likelihood) Deviance Test d.f. P-value Full model -18.4464 Fitted model -18.9141 0.935409 3 0.8169 Reduced mode -47.991 59.091 4 <0.0001 AIC: 41.8281 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 90.0000 0.0000 0.000 0 16 -1.822e-007 135.0000 0.0000 0.000 0 16 -0.002528 210.0000 0.0392 0.628 1 16 0.479 270.0000 0.5188 8.300 7 16 -0.6506 320.0000 0.8977 14.363 15 16 0.5257 Chi-square = 0.93 d.f. = 3 P-value = 0.8184 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 213.376 BMCL = 185.797 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 50 100 150 200 250 300 dose 10:06 07/11 2007 FIGURE F-5 Probit model with 0.95 confidence level.

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88 Acute Exposure Guideline Levels APPENDIX G LITCHFIELD AND WILCOXON LC50 CALCULATION Dudley and Neal (1942): Lethality in Rats Exposed for 1 Hour to Acrylonitrile Dose Mortality Observed% Expected% Observed Expected Chi-Square 665.000 0/16 0 (0.30) 0.28 0.02 0.0000 1,270.000 0/16 0 (3.80) 9.95 -6.15 0.0422 1,490.000 4/16 25.00 21.53 3.47 0.0071 2,445.000 13/16 81.25 82.13 -0.88 0.0005 Values in parentheses are corrected for 0 or 100 percent Total = 0.0499 LC50 = 1870.153(1621.558-2156.859)* Slope = 1.34(1.22-1.47)* *These values are 95% confidence limits Total animals = 64 Total doses = 4 Animals/dose = 16.00 Chi-square = total chi-square × animals/dose = 0.7986 Table value for Chi-square with 2 Degrees of Freedom = 5.9900 LC84 = 2502.530 LC16 = 1397.574 FED = 1.15 FS = 1.10 A = 1.07 99.99+ | 99.94+ | 99.60+ | 97.56+ | PERCENT 86.35+ EFFECT | **o 50.06+ *** | *** 13.71+ * *o* | *** 2.46 + * * * o | *** 0.40 + * * * o* 0.06 + | 0.01 +---+----+----+----+----+----+----+----+----+----+ 665 757 863 983 1119 1275 1452 1654 1884 2147 2445 DOSE

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Acrylonitrile 89 Expected Lethal Dose Values LC0.1 555.726 LC1.0 834.159 LC5.0 1,114.816 LC10 1,271.215 LC25 1,541.871 LC50 1,870.153 LC75 2,268.330 LC90 2,751.283 LC99 4,192.812

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90 Ac cute Exposure Guideline Levels AP PPENDIX H CATE EGORY PLO FOR ACRY OT YLONITRILE E FIGUR H-1 Category plot of toxicity data and AEGL values for acry RE y y L ylonitrile.

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TABLE H-1 Data Used in Category Plot for Acrylonitrile Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 1.5 10 AEGL AEGL-1 1.5 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 8.6 10 AEGL AEGL-2 3.2 30 AEGL AEGL-2 1.7 60 AEGL AEGL-2 0.48 240 AEGL AEGL-2 0.26 480 AEGL AEGL-3 130 10 AEGL AEGL-3 50 30 AEGL AEGL-3 28 60 AEGL AEGL-3 9.7 240 AEGL AEGL-3 5.2 480 AEGL Appel et al. 1981a Rat m 1 2400 10 2 No mortality. Dudley and Neal 1942 Rat 1 665 30 1 Moderate transitory effects. Dudley and Neal 1942 Rat 1 1270 30 1 Marked; no residual effects in 24 h. Dudley and Neal 1942 Rat 1 1490 30 1 Marked; no residual effects in 24 h. Appel et al. 1981a Rat m 1 1600 30 2 No mortality. Dudley and Neal 1942 Rat 1 2445 30 1 Marked; slight residual effects to 24 h. Appel et al. 1981a Rat m 1 2600 30 SL 33% mortality. (Continued) 91

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92 TABLE H-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Appel et al. 1981a Rat m 1 3000 30 3 100% mortality. Dudley and Neal 1942 Rat 1 665 60 2 Marked transitory effects. Vernon et al. 1990 Rat b 1 1008 60 2 Rapid shallow breathing, decreased activity, nasal discharge, salivation, lacrimation, and coma (in 3 of 10 animals). Dudley and Neal 1942 Rat 1 1270 60 2 Marked effects; slight effects at 24 h; normal at 48 h. Dudley and Neal 1942 Rat 1 1490 60 SL 25% mortality; deaths in 4 h; slight effects at 24 h in survivors. Dudley and Neal 1942 Rat 1 2445 60 SL 81% mortality; deaths in 4 h; slight effects at 24 h in survivors. Dudley and Neal 1942 Rat 1 305 120 2 Slight transitory effects. Dudley and Neal 1942 Rat 1 595 120 SL 6% mortality; marked transitory effects. Appel et al. 1981a Rat m 1 950 120 SL 33% mortality. Appel et al. 1981a Rat m 1 1100 120 3 100% mortality. Dudley and Neal 1942 Rat 1 1260 120 3 100% mortality; deaths within 4 h. Appel et al. 1981a Rat m 1 650 180 SL 33% mortality. Dudley and Neal 1942 Dog b 1 30 240 1 Slight salivation by end of exposure period; no other effects. Dudley and Neal 1942 Dog 1 30 240 1 Dudley and Neal 1942 Monkey 1 56 240 0 Dudley and Neal 1942 Cat 1 56 240 SL Dudley and Neal 1942 Monkey 1 65 240 1 Dudley and Neal 1942 Dog 1 65 240 2

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Dudley and Neal 1942 Dog b 1 65 240 SL Mortality (1/2). Dudley and Neal 1942 Monkey 1 90 240 1 Dudley and Neal 1942 Guinea Pig 1 100 240 0 Slight to no effect. Dudley and Neal 1942 Cat 1 100 240 1 Dudley and Neal 1942 Rabbit 1 100 240 1 Dudley and Neal 1942 Rabbit 1 100 240 1 Dudley and Neal 1942 Rat m 1 100 240 2 Slight transitory effects. Dudley and Neal 1942 Dog b 1 100 240 2 Dudley and Neal 1942 Dog 1 100 240 2 Dudley and Neal 1942 Dog b 1 110 240 SL Mortality (2/3). Dudley and Neal 1942 Rat 1 130 240 0 Slight transitory effects. Dudley and Neal 1942 Rat 1 130 240 0 Slight transitory effects. Dudley and Neal 1942 Rabbit 1 135 240 1 Dudley and Neal 1942 Dog b 1 165 240 3 Mortality (2/2). Dudley and Neal 1942 Rabbit 1 260 240 SL Mortality (1/2). Dudley and Neal 1942 Guinea Pig 1 265 240 1 Slight transitory effect; reduced feed consumption for 4 d. Dudley and Neal 1942 Cat 1 275 240 2 Dudley and Neal 1942 Rat 1 315 240 SL 31% mortality; marked; no effects in survivors at 24 h. Dudley and Neal 1942 Rat 1 315 240 SL 31% mortality; marked; no residual effects in survivors. Wil Research Laboratories, 2005 Rat b 1 539 240 1 No mortality. (Continued) 93

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94 TABLE H-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Dudley and Neal 1942 Guinea Pig 1 575 240 SL 63% mortality. Dudley and Neal 1942 Rabbit 1 580 240 3 100% mortality. Dudley and Neal 1942 Cat 1 600 240 3 100% mortality. Dudley and Neal 1942 Rat 1 635 240 3 100% mortality. Dudley and Neal 1942 Rat 1 635 240 3 100% mortality. Wil Research Laboratories 2005 Rat b 1 775 240 1 No mortality. Wil Research Laboratories 2005 Rat b 1 871 240 SL Mortality (4/10). Wil Research Laboratories 2005 Rat b 1 1006 240 SL Mortality (7/10). Dudley and Neal 1942 Guinea Pig 1 1160 240 3 100% mortality. Wil Research Laboratories 2005 Rat b 1 1181 240 SL Mortality (9/10). Haskell Laboratory 1942 Dog 1 25 360 1 Haskell Laboratory 1942 Dog 1 50 360 1 Jakubowski et al. 1987 Human m 1 2.3 480 0 Jakubowski et al. 1987 Human 4.6 480 0 Dudley and Neal 1942 Rat 1 90 480 1 Slight discomfort. Dudley and Neal 1942 Rat 1 135 480 1 Moderate transitory effects. Dudley and Neal 1942 Rat 1 210 480 SL 6% mortality; marked transitory effects. Dudley and Neal 1942 Rat 1 270 480 SL 44% mortality; marked; no effects in survivors at 24 h. Dudley and Neal 1942 Rat 1 320 480 SL 94% mortality. Haskell Laboratory 1942 Dog 1 225 105 2 Ocular and nasal irritation, vomiting, incoordination, and “noisy” respiration.

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Saillenfait et al. 1993a Rat f 15 12 6 0 Fetal toxicity (fetal body weight). Saillenfait et al. 1993a Rat f 15 25 6 2 Fetal toxicity (fetal body weight). Murray et al. 1978 Rat f 10 40 6 2 Fetal malformations. For Category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 95