3

Methacrylonitrile1

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), Gary Diamond (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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3 Methacrylonitrile1 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), Gary Diamond (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). 143

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144 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. SUMMARY Methacrylonitrile is a colorless liquid at ambient temperature and pressure. It has an odor similar to bitter almonds and may cause irritation or burning of the eyes and skin. It is metabolized to cyanide in the body and signs of exposure may include weakness, headache, confusion, nausea, vomiting, convulsion, di- lated pupils, weak pulse, shallow and gasping breathing, and cyanosis (HSDB 2005). The same signs have been reported in humans exposed to hydrogen cya- nide (Blanc et al. 1985). Transitory irritation was noted by humans exposed to methacrylonitrile at 2 or 14 ppm for 10 min (Pozzani et al. 1968); however, the study was designed to assess sensory end points and did not examine potential systemic effects. Ol- factory fatigue was also noted by the subjects exposed at 2 ppm or higher. Ani- mal studies demonstrate a steep dose-response for lethality. For example, no deaths were observed in mice exposed to methacrylonitrile at 19.7 ppm and the LC50 is 36 ppm (Pozzani et al. 1968). Similarly in rats, a two-fold increase in concentration resulted in a 33% increase in mortality. Because of the poor warn- ing properties of methacrylonitrile, AEGL-1 values are not recommended for this chemical. No inhalation data consistent with the definition of AEGL-2 were availa- ble. Therefore, the AEGL-2 values for methacrylonitrile were based on a three- fold reduction of the AEGL-3 values. These values are considered estimates of a

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Methacrylonitrile 145 threshold for irreversible effects and are considered appropriate given the steep concentration-response curve for methacrylonitrile. A comparison of the 4-h LC50 values for several species suggest that mice and rabbits are more sensitive than rats and guinea pigs (Pozzani et al. 1968). No deaths were observed in mice or rabbits exposed to methacrylonitrile at 19.7 ppm for 4 h, so that concentration was selected as the point of departure for cal- culating AEGL-3 values. 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). An interspecies uncertainty factor of 3 was applied because mice and rabbits are the most sensitive species. Thus, the total uncer- tainty factor is 10. The concentration-time relationship for many irritant and systemically-acting vapors and gases may 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 on methacrylonitrile were insufficient for deriving an empirical value for n. There- fore, default values of n = 3 to extrapolate to shorter durations (30 min and 1h) and n = 1 to extrapolate longer durations (8-h) were used to estimate AEGL val- ues that are protective of human health (NRC 2001). The 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value because of the uncertainty associated with time scaling a 4-h exposure to a 10-min value. AEGL values for methacry- lonitrile are presented in Table 3-1. 1. INTRODUCTION Methacrylonitrile is a colorless liquid at ambient temperature and pressure. It has an odor similar to bitter almonds and may cause irritation or burning of the eyes and skin. It is metabolized to cyanide in the body and signs of exposure may include weakness, headache, confusion, nausea, vomiting, convulsion, di- lated pupils, weak pulse, shallow and gasping breathing, and cyanosis (HSDB 2005). The acute toxicity of the organonitriles is due to the metabolic liberation of cyanide; cyanide interrupts cellular respiration by blocking electron transfer from cytochrome oxidase to oxygen (Smith 1996). Methacrylonitrile is produced by vapor-phase catalytic oxidation of me- thallylamine, dehydration of methacrylamide, or by vapor-phase ammoxidation of isobutylene with ammonia. Methacrylonitrile is used as a copolymer with styrene and butadiene; as an intermediate in the preparation of acids, amides, amines, esters, and nitriles; and in elastomers, coatings, and plastics (HSDB 2005). It is a highly reactive unsaturated alkyl nitrile that readily polymerizes in the absence of a stabilizer. The commercial product contains hydroquinone monomethyl ether (50 ppm) as a stabilizer (Farooqui and Mumtaz 1991). The estimated production capacity of methacrylonitrile in the United States in 1977 was 1-10 million pounds (EPA 1987). Approximately 425 work- ers were exposed annually to methacrylonitrile between 1980 and 1983 (NIOSH

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146 Acute Exposure Guideline Levels 1990). Methacrylonitrile has been identified as a component of mainstream ciga- rette smoke (3 μg/cigarette). The physical and chemical properties of methacrylonitrile are presented in Table 3-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Information concerning human fatalities following inhalation exposure to methacrylonitrile was not available. 2.2. Nonlethal Toxicity 2.2.1. Experimental Studies Groups of 8-9 volunteers (ages 22-57 years) were exposed to a series of concentrations of methacrylonitrile for 1-min periods (Pozzani et al. 1968). The inhalation trials were conducted in a glass-lined 12.8-m3 room from which air was exhausted at 2.5-3.2 m3/min. Concentrations of methacrylonitrile in cham- ber air were monitored by gas chromatography. The intervals between each ex- posure period were at least 45 min. The subjects inhaled the same concentrations twice in the following sequence: 24, 14, 0, 7, 14, 24, 7, 2, 0, and 2 ppm. The subjects were unaware of the concentrations they were inhaling. Olfactory fa- tigue was reported by most subjects at concentrations of 7 and 14 ppm and by two subjects at 24 ppm. Most subjects exposed at 24 and 14 ppm detected an odor initially, but only half of the subjects could detect an odor at 7 ppm. None of the subjects could differentiate between the 0- and 2-ppm exposures. Results of this study are summarized in Table 3-3. TABLE 3-1 AEGL Values for Methacrylonitrile End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient data (nondisabling) AEGL-2 1.3 ppm 1.3 ppm 1.0 ppm 0.67 ppm 0.33 ppm Three-fold (disabling) (3.5 (3.5 (2.7 (1.8 (0.89 reduction of mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 AEGL-3 3.9 ppm 3.9 ppm 3.1 ppm 2.0 ppm 0.99 ppm No effect level for (lethal) (11 (11 (8.5 (5.5 (2.7 lethality in mice and mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) rabbits exposed to 19.7 ppm for 4 h (Pozzani et al. 1968) a Not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

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Methacrylonitrile 147 TABLE 3-2 Physical and Chemical Properties of Methacrylonitrile Parameter Data Reference Synonyms 2-Methyl-2-propenenitile; methyl Cohrssen 2001 acrylonitrile; isoprene cyanide; isopropenylcarbonitrile; 2-cyano-1- propene; 2-cyanopropene; MAN; MeAN CAS registry no. 126-98-7 Cohrssen 2001 Chemical formula C4H5N Cohrssen 2001 Molecular weight 67.09 Cohrssen 2001 Physical state Colorless liquid Farooqui and Mumtaz 1991 Melting point -35.8°C Farooqui and Mumtaz 1991 Boiling point 90.3°C Farooqui and Mumtaz 1991 Flash point 13°C Farooqui and Mumtaz 1991 Specific gravity 0.800 at 20°C Farooqui and Mumtaz 1991 Solubility 2.5% in water; miscible with Farooqui and Mumtaz 1991; acetone, octane, and toluene Hartung 1994 Vapor density 2.31 (air = 1) Hartung 1994 Vapor pressure 65 mm Hg at 25°C Farooqui and Mumtaz 1991 3 Conversion factors in air 1 ppm = 2.74 mg/m Hartung 1994 1 mg/m3 = 0.365 ppm TABLE 3-3 Human Response to One-Minute Inhalation Exposures to Methacrylonitrile 24 ppm 14 ppm 7 ppm 2 ppm 0 ppm Number of subject inhalations 18 17 17 18 18 Incidence of odor detection, % 89 88 47 0 0 Incidence of throat irritation, % 22 0 0 0 0 Incidence of eye irritation, % 17 0 0 0 0 Incidence of nose irritation, % 6 0 0 0 0 Source: Pozzani et al. 1968. Reprinted with permission; copyright 1968, Journal of Oc- cupational and Environmental Hygiene. Two additional experiments were performed in a similar manner (Pozzani et al. 1968). Nine subjects were exposed to methacrylonitrile at 2 ppm for 10 min in one study, and seven subjects at 14 ppm for 10 min in the other study. Odor and irritation data were recorded at 1-min intervals during the exposures. These experiments indicate olfactory fatigue and irritation of a “transitory” na- ture. Results are summarized in Tables 3-4 and 3-5. Amoore and Hautala (1983) reported an odor threshold of 7 ppm for methacrylonitrile.

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148 Acute Exposure Guideline Levels TABLE 3-4 Effects in Nine Subjects from Exposure to Methacrylonitrile at 2 ppm for 10 Minutes Odor Eye Nose Throat Time (min) Detection Irritation Tears Irritation Irritation 1 4 2 1 0 0 2 4 1 0 0 1 3 3 0 0 0 1 4 0 0 0 0 0 5 0 0 0 0 0 6 0 0 0 0 0 7 0 0 0 2 0 8 0 1 0 1 0 9 0 0 0 0 0 10 0 0 0 0 0 Source: Pozzani et al. 1968. Reprinted with permission; copyright 1968, Journal of Oc- cupational and Environmental Hygiene. TABLE 3-5 Effects in Seven Exposed to Methacrylonitrile at 14 ppm for 10 Minutes Odor Eye Nose Throat Time (min) Detection Irritation Tears Irritation Irritation 1 7 0 0 0 1 2 6 1 0 0 0 3 1 1 0 0 0 4 0 1 0 0 0 5 0 1 0 0 0 6 0 1 0 0 1 7 0 1 0 1 0 8 0 1 0 1 0 9 0 1 0 1 0 10 0 0 1 0 0 Source: Pozzani et al. 1968. Reprinted with permission; copyright 1968, Journal of Oc- cupational and Environmental Hygiene. 2.3. Developmental and Reproductive Toxicity Developmental and reproductive studies of acute human exposure to methacrylonitrile were not available.

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Methacrylonitrile 149 2.4. Genotoxicity Genotoxic studies of acute human exposure to methacrylonitrile were not available. 2.5. Carcinogenicity Carcinogenicity studies of human exposure to methacrylonitrile were not available. 2.6. Summary Only one human exposure study of methacrylonitrile was available. Ap- proximately 6-22% of subjects exposed methacrylonitrile at 24 ppm for 1 min experienced nasal, throat, or ocular irritation. Irritation was also noted by a few subjects during the course of 10-min exposures at 2 or 14 ppm. No humans stud- ies of the developmental and reproductive toxicity, genotoxicity, or carcinogen- icity of methacrylonitrile were available. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats A group of four mature male rats (strain not specified) were exposed to a concentrated atmosphere of methacrylonitrile for up to 25 min (Younger Labs 1969). Vapors were produced by passing a stream of air through 106.0 g of methacrylonitrile in a 350-mL Erlenmeyer flask. Vapors from the flask passed into a 1-L bottle to remove droplets. The vapor then passed into the 35-L metal chamber. Air flow through the chamber was 4 L/min, the average chamber tem- perature was 74°F, and the average humidity was 58%. All animals died within 25 min after the start of exposure. Labored breathing, pawing at the face and nose, cyanosis, and collapse were observed during exposure. At necropsy, pul- monary and hepatic hyperemia, dilated coronary arteries, and aortic aneurysms were observed. Groups of 10 young adult male ChR-CD rats were exposed to methacrylo- nitrile (most concentrations not reported, highest concentration was 625 ppm) for 4 h and observed for up to 14 days (DuPont 1968a). The test sample was uniformly metered by a syringe drive into a stainless steel T-tube whose internal temperature was above the boiling point of methacrylonitrile. A metered stream of air passing through the T-tube carried the vapors to the exposure chamber where the atmosphere was analyzed every half-hour by gas chromatography. Irregular respiration and hyperemia, followed by pale ears, unresponsiveness, tremors, convulsions, face-pawing, and lacrimation (at 625 ppm only), were

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150 Acute Exposure Guideline Levels observed during exposure. Mild and erratic weight loss was initially observed, but was followed by normal weight gain after the exposure period. One animal died 1.5 h after the start of exposure and another died 15 min post-exposure. An LC50 of 440 ppm (380-510 ppm) was calculated. No other experimental details were reported. Pozzani et al. (1968) exposed groups of six female Harlan-Wistar rats to methacrylonitrile at approximately 85,500 ppm (essentially saturated vapor) for 14, 7.5, 3.75, 1.88, 0.93, or 0.47 min. Mortality was 6/6, 6/6, 6/6, 1/6, 0/6, and 0/6, respectively. Deaths occurred during the 14-min exposure, within 1.5 h after the 7.5-min exposure, and within 24 h following the 3.75- and 1.88-min expo- sures. Prostration and loss of consciousness always preceded death, but also appeared in many survivors exposed for 1.88 min. The rats exposed for 0.93 min appeared normal during the exposure period, but showed prostration 0.5 h after the exposure, and remained in this condition for 2 h. Rats exposed for 0.47 min showed no clinical signs during or after exposure. No convulsions were ob- served in this study, and survivors gained weight normally during the 14-day observation period. Pozzani et al. (1968) also exposed groups of six male and six female Har- lan-Wistar rats to unspecified concentrations of methacrylonitrile for 4 h. Con- centrations of methacrylonitrile in the inhalation chambers were determined by gas chromatography. Death was preceded by loss of consciousness and tonic- clonic convulsions. At necropsy, no discernible cause of death was found in animals that died, and no gross treatment-related effects were observed in ani- mals surviving the 14-day observation period. Calculated LC50 values (328-700 ppm) are presented in Table 3-6. In a repeated exposure, range-finding study, groups of six male and six female Harlan-Wistar rats were exposed to methacrylonitrile at 0, 20, 50, or 110 ppm for 7 h/day, 5 days/week for a total of 9 days (Pozzani et al. 1968). Concen- trations of methacrylonitrile in the inhalation chambers were determined by gas chromatography. Two male rats in the 110-ppm group died during the first day; no convulsions were noted in these animals. No other rats in any exposure group exhibited clinical signs during the 9-day exposure period. No gross lesions were observed in the decedents or survivors, and survivors had normal body weight gains and normal liver and kidney weights at necropsy. In an oral toxicity study, a 1% (w/v) solution of methacrylonitrile in water was intragastrically administered to groups of five non-fasted male Harlan- Wistar albino rats (Pozzani et al. 1968). An LD50 value of 0.24 g/kg was calcu- lated (0.16-0.36 g/kg). Four of five rats administered 0.4 g/kg died on the day of dosing, and the fifth rat died overnight. Doses of 0.1 and 0.2 g/kg resulted in mortality of one of five rats in each group; deaths occurred overnight after dos- ing. In animals that died, prostration and convulsions were noted within 1.5 h after dosing. Survivors showed the same clinical signs, but to a lesser degree, and gained weight normally over the 14-day observation period.

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Methacrylonitrile 151 3.1.2. Mice Pozzani et al. (1968) exposed groups of six male A/J mice to unspecified concentrations of methacrylonitrile for 4 h. Concentrations of methacrylonitrile in the inhalation chambers were determined by gas chromatography. Death was preceded by loss of consciousness and tonic-clonic convulsions. At necropsy, no discernible cause of death was noted in animals that died, and no gross treat- ment-related effects were noted in animals surviving the 14-day observation period. A 4-h LC50 of 36 ppm was calculated (see Table 3-6). 3.1.3. Guinea Pigs Pozzani et al. (1968) exposed groups of six male albino guinea pigs to un- specified concentrations of methacrylonitrile for 4 h. Concentrations of methac- rylonitrile in the inhalation chambers were determined by gas chromatography. Death was preceded by loss of consciousness and tonic-clonic convulsions. At necropsy, no discernible cause of death was noted in animals that died, and no gross treatment-related effects were noted in animals surviving the 14-day ob- servation period. A 4-h LC50 of 88 ppm was calculated (see Table 3-6). 3.1.4. Rabbits Pozzani et al. (1968) exposed groups of four male albino rabbits to un- specified concentrations of methacrylonitrile for 4 h. Concentrations of methac- rylonitrile in the inhalation chambers were determined by gas chromatography. Death was preceded by loss of consciousness and tonic-clonic convulsions. At necropsy, no discernible cause of death was noted in animals that died, and no gross treatment-related effects were noted in animals surviving the 14-day ob- servation period. A 4-h LC50 of 37 ppm was calculated (see Table 3-6). In a dermal toxicity study, undiluted methacrylonitrile was administered to groups of four male albino New Zealand white rabbits (Pozzani et al. 1968). The compound was kept in covered contact with clipped trunks for 24 h. An LD50 value of 0.32 mL/kg was calculated (0.19-0.51 mL/kg). All four rabbits treated with 0.5 mL/kg died within 3.45 h and were gasping or convulsing before to death. One rabbit administered 0.25 mL/kg gasped, convulsed, and died 2.66 h into the exposure. The three surviving rabbits treated with 0.25 mL/kg showed no clinical signs and gained weight normally over the 14-day observation peri- od. 3.1.5. Dogs Pozzani et al. (1968) exposed one female mongrel dog to methacrylonitrile at 106 ppm for 3 h. The concentration of methacrylonitrile in the inhalation chamber was determined by gas chromatography. Convulsions were observed

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152 Acute Exposure Guideline Levels followed by death in 3 h. The investigators also exposed one female mongrel dog to methacrylonitrile at 106 ppm for 7 h. Vomiting, diarrhea, and convul- sions were observed, and the dog died in 7 h. Finally, a female cocker spaniel was exposed to methacrylonitrile at 52.5 ppm for 7 h. Vomiting, convulsions, and loss of consciousness were observed within 7 h, and the dog died overnight. At necropsy, no discernible cause of death was apparent in any of the dogs. In another study, DuPont (1968b) exposed young adult female beagles (number not specified) to methacrylonitrile at 40 or 87.5 ppm for 7 h. The test sample was uniformly metered by a syringe drive into a stainless steel T-tube whose internal temperature was above the boiling point of methacrylonitrile. A metered stream of air passing through the T-tube carried the vapors to the expo- sure chamber where the atmosphere was analyzed every half-hour by gas chro- matography. No deaths or clinical signs were observed at 40 ppm. Vomiting, convulsions, unconsciousness, and irregular breathing were observed in dogs exposed at 87.5 ppm. Death occurred 5 h and 5 min post-exposure. No addition- al details were available. 3.2. Nonlethal Toxicity No deaths or clinical signs were observed in guinea pigs exposed to meth- acrylonitrile at 52.5 ppm, in rabbits exposed at 19.7 ppm, or in mice exposed at 19.7 ppm for 4 h (Pozzani et al. 1968). No further details were available. Data from this study are summarized in Table 3-6. TABLE 3-6 Effects in Animals Exposed to Methacrylonitrile for 4 Hours LC50 (Concentrations that Species (weight range) Sex Caused Death) (ppm) Comments Rat (213-317 g) Females 700 (213-2,327) Loss of consciousness within 3 h; no deaths at 176 ppm. Rat (95-72 g) Females 496 (250-993) Loss of consciousness within 3 h; no deaths at 176 ppm. Rat (344-510 g) Males 328 (208-516) Loss of consciousness within 3 h; one death with convul- sions at 176 ppm. Rat (123-207 g) Males 328 (231-594) Loss of consciousness within 3 h; no deaths at 176 ppm. Guinea Pig (585-1,035 g) Males 88 (62-124) No symptoms at 52.5 ppm. Rabbit (2,356-4,290 g) Males 37 (23-57) No symptoms at 19.7 ppm. Mouse (23-33 g) Males 36 (25-43) No symptoms at 19.7 ppm. Source: Adapted from Pozzani et al. 1968.

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Methacrylonitrile 153 3.3. Repeated-Dose Studies 3.3.1. Rats Groups of 12 male and 12 female Harlan-Wistar rats were exposed to methacrylonitrile vapor at 0, 19.3, 52.6, or 109.3 ppm (measured by gas chroma- tography) for 7 h/day, 5 days/week for 91 days (Pozzani et al. 1968). Seven males died during the first day of exposure at 109.3 ppm and one male died on day 2 of exposure at 52.6 ppm. Loss of consciousness with no convulsions pre- ceded death. Transient, decreased body-weight gain was observed at day 5 in mid-concentration females and high-concentration males and females. Relative liver weights were increased at the end of the study in mid-concentration males (10% increase) and high-concentration males (28% increase) and females (21% increase) compared with controls. However, no treatment-related effects were found in measurements of blood urea nitrogen, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), or alka- line phosphatase activities, and no correlative histopathology was observed. No other treatment-related effects were reported. Both lethal and nonlethal effects were reported in a preliminary repeated- dose, range-finding study (Pozzani et al. 1968). This information is discussed in Section 3.1.1. In a 13-week range-finding study, groups of 20 male and 20 female F344/N rats were administered methacrylonitrile at 0, 7.5, 15, 30, 60, or 120 mg/kg in de- ionized water by gavage 5 days/week (NTP 2000). Ten males and 10 females from each group were schedule to be killed on day 32 for interim evaluation. In this 32- day evaluation group, nine males exposed at 120 mg/kg died within the first week, but all high-dose female rats survived the 32-day period. Males in the 60-mg/kg group had decreased mean body weights (8% decrease compared with controls; p ≤ 0.01) at the end of the 32-day period. The one surviving high-dose male also showed a decreased body weight (10% decrease compared with controls). Clinical findings at the 32-day evaluation included lethargy, lacrimation, ataxia, tremors, convulsions, and abnormal breathing in all treatment groups in a dose-related manner; these effects appeared within minutes of dosing and resolved several hours after dosing. Minimal, normocytic, normochromic anemia was found in males and females, as evidenced by dose-related decreases in hematocrit, hemo- globin concentration, and erythrocyte counts. (This anemia resolved in the 13- week evaluation group.) Decreased (p ≤ 0.01) kidney and thymus weights were noted in males in the 60-mg/kg group at the 32-day evaluation. In females, stom- ach weights were increased (p ≤ 0.01) in the 60- and 120-mg/kg groups, thymus weights were decreased (p ≤ 0.01) in the 120-mg/kg group, and liver weights were increased (p ≤ 0.01) in the 120-mg/kg group on day 32. Male and female rats in the 60-mg/kg groups and females in the 120-mg/kg groups showed increased (p ≤ 0.05 or p ≤ 01) incidences of nasal olfactory epithelial metaplasia on day 32. In females exposed at 60 and 120 mg/kg, an increased (p ≤ 0.05) incidence of olfac- tory epithelial necrosis was also noted.

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Methacrylonitrile 169 Washington, DC, by DuPont, Wilmington, DE, with Cover Letter Dated October 15, 1992. EPA Document No. 88-920009945. Microfiche No. OTS0571603. EPA (U.S. Environmental Protection Agency). 1987. Health and Environmental Effects Document for Selected Nitriles. EPA500ECAOCING008. Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Cincinnati, OH. November 1987. Farooqui, M.Y., and M.M. Mumtaz. 1991. Toxicology of methacrylonitrile. Toxicology 65(3):239-250. Farooqui, M.Y., R.G. Diaz, and J.H. Deleon. 1992. Methacrylonitrile: In vivo metabolism to cyanide in rats, mice, and gerbils. Drug. Metab. Dispos. 20(2):156-160. George, J.D., C.J. Proce, M.C. Marr, C.B. Myers, B.A. Schwetz, J.J. Heindel, and E.S. Hunter, III. 1996. Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits. Fundam. Appl. Toxicol. 34(2):249-259. Ghanayem, B.I., and L.T. Burka. 1996. Excretion and identification of methacrylonitrile metabolites in the bile of male F344 rats. Drug Metab. Dispos. 24(4):390-394. Ghanayem, B.I., P.J. Boor, and A.E. Ahmed. 1985. Acrylonitrile-induced gastric mucosal necrosis: Role of gastric glutathione. J. Pharmacol. Exp. Therap. 232(2):570-577. Ghanayem, B.I., I.M. Sanchez, and L.T. Burka. 1992. Effects of dose, strain, and dosing vehicle on methacrylonitrile disposition in rats and identification of a novel ex- haled metabolite. Drug Metab. Dispos. 20(5):642-652. Ghanayem, B.I., I.M. Sanchez, and L.T. Burka. 1994. Investigation of methacrylonitrile metabolism and the metabolic basis for the differences in its toxicity in rats and mice. J. Pharmacol. Exp. Therap. 269(2):581-588. Ghanayem, B.I., J.M. Sanders, B. Chanas, L.T. Burka, and F.J. Gonzalez. 1999. Role of cytochrome P450 2E1 in methacrylonitrile metabolism and disposition. J. Pharma- col. Exp. Therap. 289(2):1054-1059. Guengerich, F.P., L.E. Geiger, L.L. Hogy, and P.L. Wright. 1981. In vitro metabolism of acrylonitrile to 2-cyanoethylene oxide, reaction with glutathione, and irreversible binding to proteins and nucleic acids. Cancer Res. 41(12Pt 1):4925-4933. Hartung, R. 1994. Cyanides and nitriles: Methacrylonitrile. Pp. 3139-3140 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. II, Part D. Toxicology, G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley &Sons. HSDB (Hazardous Substances Data Bank). 2005. Methylacrylonitrile (CAS Reg. No. 126-98-7). TOXNET Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ [accessed Nov. 25, 2013]. IARC (International Agency for Research on Cancer). 1987. Acrylonitrile (Group 2A). Pp. 79-80 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volume 1 to 42, Supplement 7. International Agency for Re- search on Cancer, Lyon, France [online]. Available: http://monographs.iarc.fr/ ENG/Monographs/suppl7/Suppl7.pdf [accessed Nov. 25, 2013]. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Methylacrylnitril. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Mar.1, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1990. National Occupa- tional Exposure Survey (NOES) Conducted from 1981-1983. Centers for Disease Control and Prevention, Atlanta, GA [online]. Available: http://www.cdc.gov/ noes/ [accessed Nov. 25, 2013].

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170 Acute Exposure Guideline Levels NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Methylacrylonitrile. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc. gov/niosh/npg/npgd0395.html [accessed Dec. 24, 2013]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2002. Hydrogen cyanide. Pp. 211-276 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: National Academies Press. NTP (National Toxicology Program). 2000. Toxicity Studies of Methacrylonitrile (CAS Reg. No. 126-98-7) Administered by Gavage to F344/N Rats and B6C3F1 Mice. Toxicity Reports Series No. 47. NIH Publication No. 00-4403. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/ht docs/ST_rpts/tox047.pdf [accessed Nov. 25, 2013]. NTP (National Toxicology Program). 2001. Toxicity and Carcinogenesis Studies of Methacrylonitrile (CAS Reg. No. 126-98-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Toxicity Reports Series No. 497. NIH Publication No. 02-4431. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC [online]. Available: http://ntp. niehs.nih.gov/ntp/htdocs/LT_rpts/tr497.pdf [accessed Nov. 25, 2013]. Nyska, A., and B.I. Ghanayem. 2003. Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 rats and B6C3F1 mice. Arch. Toxicol. 77(4):233-242. Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacry- lonitrile. Am. Ind. Hyg. Assoc. J. 29(3):202-210. Saillenfait, A.M., and J.P. Sabate. 2000. Comparative developmental toxicities of ali- phatic nitriles: In vivo and in vitro observations. Toxicol. Appl. Pharmacol. 163(2):149-163. Saillenfait, A.M., P. Bonnet, J.P. Gurnier, and J. de Ceaurriz. 1993. Relative developmen- tal toxicities of inhaled aliphatic mononitriles in rats. Fundam. Appl. Toxicol. 20(3):365-375. Shelby, M.D., G.L. Erexson, G.J. Hook, and R.R. Tice. 1993. Evaluation of a three- exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ. Mol. Mutagen. 21(2):160-179. Smith, R.P. 1996. Toxic responses of the blood. Pp. 335-354 in Casarett & Doull’s Toxi- cology: The Basic Science of Poisons, 5th Ed., C.D. Klaassen, ed. New York: Macmillan. Tanii, H., and K. Hashimoto. 1986. Influence of ethanol on the in vivo and in vitro me- tabolism of nitriles in mice. Arch. Toxicol. 58(3):171-176. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(1):301-309.

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Methacrylonitrile 171 Younger Laboratories. 1969. Initial Submission: Toxicological Investigation of Methycrylonitrile, July 21, 1969. Submitted to EPA, Washington, DC, by Monsan- to, St. Louis, MO, with Cover Letter Dated July 23, 1992. EPA Document No. 88- 920007902. Microfiche No. OTS0570516. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans, and W. Speck. 1987. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. En- viron. Mutagen. 9(suppl. 9):1-109. Zimmering, S., J.M. Mason, and R. Valencia. 1989. Chemical mutagenesis testing in Drospohila: VII. Results of 22 coded compounds tested in larval feeding experi- ments. Environ. Mol. Mutagen. 14(4):245-251.

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172 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR METHYACRYLONITRILE Derivation of AEGL-1 Values AEGL-1 values are not recommended due to the poor warning properties of methacrylonitrile. However, absence of AEGL-1 values does not imply that expo- sures below the AEGL-2 values are without adverse effects. Derivation of AEGL-2 Values In the absence of relevant data to derive AEGL-2 values for methacrylonitrile, AEGL-3 values were dived by 3 to estimate AEGL-2 values. Calculations: 10-min AEGL-2: 3.9 ppm ÷ 3 = 1.3 ppm 30-min AEGL-2: 3.9 ppm ÷ 3 = 1.3 ppm 1-h AEGL-2: 3.1 ppm ÷ 3 = 1.0 ppm 4-h AEGL-2: 2.0 ppm ÷ 3 = 0.67 ppm 8-h AEGL-2: 0.99 ppm ÷ 3 = 0.33 ppm Derivation of AEGL-3 Values Key study: Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacrylonitrile. Am. Ind. Hyg. Assoc. J. 29(3):202-210. Toxicity end point: No mortality in mice exposed for 4 h at 19.7 ppm Time scaling: Cn × t = k (default values of n =3 for extrapolating to shorter durations and n =1 for extrapolating to longer durations) (19.7 ppm)3 × 4 h = 30,581 ppm-h (19.7 ppm)1 × 4 h = 78.8 ppm-h Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability

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Methacrylonitrile 173 10-min AEGL-3: Set equal to the 30-min AEGL-3 value of 3.9 ppm 30-min AEGL-3: C3 × 0.5 h = 30,581 ppm-h C3 = 61,162 ppm C = 39.4 ppm 39.4 ÷ 10 = 3.9 ppm 1-h AEGL-3: C3 × 1 h = 30,581 ppm-h C3 = 30,581 ppm C = 31.3 ppm 31.3 ÷ 10 = 3.1 ppm 4-h AEGL-3: C × 4 h = 78.8 ppm-h C = 19.7 ppm 19.7 ÷ 10 = 2.0 ppm 8-h AEGL-3: C1 × 8 h = 78.8 ppm-h C1 = 9.9 ppm C = 9.9 ppm 9.9 ÷ 10 = 0.99 ppm

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174 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR METHACRYLONITRILE Derivation Summary AEGL-1 VALUES AEGL-1 values are not recommended due to the poor warning properties of methacrylonitrile. However, absence of AEGL-1 values does not imply that expo- sures below the AEGL-2 values are without adverse effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1.3 ppm 1.3 ppm 1.0 ppm 0.67 ppm 0.33 ppm (3.5 mg/m3) (3.5 mg/m3) (2.7 mg/m3) (1.8 mg/m3) (0.89 mg/m3) Data adequacy: Data consistent with the definition of AEGL-2 were not available. AEGL-2 values for methacrylonitrile were estimated by dividing the AEGL-3 values by 3. These values are considered estimates of thresholds for irreversible effects and are considered appropriate given the steep concentration-response curve for the chemical. For example, in the mouse, the 4-h no-effect level is 19.7 ppm and the LC50 is 36 ppm. In the rabbit, the 4-h no-effect level is 19.7 ppm and the LC50 is 37 ppm. In the guinea pig, the 4-h no-effect level is 52.5 ppm and the LC50 is 88 ppm (Pozzani et al. 1968). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3.9 ppm 3.9 ppm 3.1 ppm 2.0 ppm 0.99 ppm (11 mg/m3) (11 mg/m3) (8.5 mg/m3) (5.5 mg/m3) (2.7 mg/m3) Key reference: Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacrylonitrile. Am. Ind. Hyg. Assoc. J. 29(3):202-210. Test species/Strain/Sex/Number: Mouse, A/J, males, 6/group Exposure route/Concentrations/Durations: Inhalation, 19.7 ppm and other unspecified concentrations for 4 h End point/Concentration/Rationale: No deaths or symptoms at 19.7 ppm Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because mice are a sensitive species. Intraspecies: 3, because studies of accidental and occupational exposures to hydrogen cyanide (the metabolically-liberated toxicant) indicate that there are individual differences in sensitivity to this chemical but that the differences are not expected to exceed 3-fold (NRC 2002). Modifying factor: None

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Methacrylonitrile 175 Animal-to-human dosimetric adjustment: Insufficient data Time scaling: Cn × t = k, where default values of n = 3 for extrapolation to shorter durations and n = 1 for extrapolation to longer durations were used to calculate AEGL values that are protective of human health (NRC 2001). The 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 4-h exposure to a 10-min value. Data adequacy: End point consistently observed in numerous experiments.

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176 Ac cute Exposure Guideline Levels AP PPENDIX C CATEGO ORY PLOT FOR METHAC F CRYLONITR RILE FIGUR C-1 Category plot of toxicity data and AEGL values for meth RE y y L hacrylonitrile.

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TABLE C-1 Data Used in Category Plot for Methacrylonitrile 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 1.3 10 AEGL AEGL-2 1.3 30 AEGL AEGL-2 1.0 60 AEGL AEGL-2 0.67 240 AEGL AEGL-2 0.33 480 AEGL AEGL-3 3.7 10 AEGL AEGL-3 3.7 30 AEGL AEGL-3 3.1 60 AEGL AEGL-3 2.0 240 AEGL AEGL-3 0.99 480 AEGL Pozzani et al. 1968 Human 1 2 1 0 Human 1 7 1 0 Human 1 14 1 0 Human 1 2 10 1 Human 1 14 10 1 Human 1 24 1 1 (Continued) 177

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178 TABLE C-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Younger Labs 1969 Rat Males 1 625 240 SL Mortality (2/10) Pozzani et al. 1968 Rat Females 1 85,500 0.47 2 No mortality (0/6) Rat Females 1 85,500 0.93 2 No mortality (0/6) Rat Females 1 85,500 1.88 SL 17% mortality (1/6) Rat Females 1 85,500 3.75 3 100% mortality (6/6) Rat Females 1 85,500 7.5 3 100% mortality (6/6) Rat Females 1 85,500 14 3 100% mortality (6/6) Rat Females 1 85,500 25 3 100% mortality (4/4) Rat 1 176 240 2 Loss of consciousness, no mortality Rat 1 176 240 SL 1 male died Rat Females 1 700 240 SL LC50 Rat Females 1 496 240 SL LC50 Rat Males 1 328 240 SL LC50 Rat Males 1 328 240 SL LC50 Guinea pig Males 1 88 240 SL LC50 Rabbit Males 1 37 240 SL LC50 Mouse Males 1 36 240 SL LC50 Pozzani et al. 1968 Dog Females 1 106 180 3 Mortality (1/1) Dog Females 1 106 420 3 Mortality (1/1) Dog Females 1 52.5 420 3 Mortality (1/1)

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DuPont 1968b Dog Females 1 40 420 0 No mortality Dog Females 1 87.5 420 3 100% mortality Pozzani et al. 1968 Guinea pig 1 52.5 240 0 Rabbit 1 19.7 240 0 Mouse 1 19.7 240 0 Saillenfait et al. 1993 Rat Both 1 12 360 0 Rat Both 1 25 360 1 Rat Both 1 100 360 2 For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 179