2

Benzonitrile1

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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2 Benzonitrile1 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). 121

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122 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 Benzonitrile is a colorless liquid at ambient temperature and pressure and has an odor of volatile almond oil. The liquid is irritating to the skin and eyes, and the vapor is irritating to the eyes, nose, and throat (HSDB 2003). Information on the toxicity of benzonitrile in humans is limited to a single case study of a nonle- thal dermal and inhalation exposure (HSDB 2003). Symptoms included severe respiratory distress, tonic convulsions, and periods of unconsciousness which last- ed for 75 min. The benzonitriles ioxynil (4-hydroxy-3,5-diiodobenzonitrile) and bromoxynil (4-hydroxy-3,5-dibromodobenzonitrile) are uncoupling agents (Ellen- horn 1997); however, the mechanism of toxicity of benzonitrile has not been es- tablished. AEGL-1 values are not recommended for benzonitrile because of insuffi- cient data. Data on benzonitrile were also insufficient for calculating AEGL-2 values. Therefore, values were estimated by dividing the AEGL-3 values by 3. The steepness of the dose-response relationship makes it difficult to discern thresh- olds for impairment of escape (AEGL-2) and lethality (AEGL-3) from the avail- able data. A study of mice exposed to benzonitrile at 890 ppm for 2 h was used as the basis of AEGL-3 values. Because one of seven mice died, further adjustment to estimate the lethal threshold was warranted. Typically, a 3-fold reduction of

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Benzonitrile 123 the LC50 (lethal concentration, 50% lethality) would be used to extrapolate to a lethal threshold. However, an LC50 value was not available for benzonitrile. The 2-h study reported 14% mortality, which suggests the test concentration of 890 ppm is below the LC50; therefore, a 2-fold adjustment was applied. The resulting adjusted value of 445 ppm was considered an estimate of the lethality threshold and used as the point of departure for deriving AEGL-3 values. An interspecies uncertainty factor of 10 was applied. Mortality data reported by Agaev (1977) on benzonitrile suggest that rats and mice have similarly steep dose-response relationships (e.g., similar oral LD16, LD50, and LD84), but the reported lack de- tails about the methods, and no data on other species are available. An intraspe- cies uncertainty factor of 3 was applied to account for sensitive individuals. This value is supported by the steep concentration-response curve for benzonitrile, which implies little individual variability. For example, the steepness of the curve is evident in mice exposed by inhalation to benzonitrile (10% mortality at 890 ppm for 2 h [ct = 1,780 ppm-h] vs. 100% mortality at 700 ppm for 4 h [ct = 2,800 ppm-h]) (MacEwen and Vernot 1974), in rats exposed orally (no mortality at 0.6 g/kg vs. 100% mortality at 2.0 g/kg) (Industrial Bio-Test 1970), and in rabbits exposed dermally (no mortality at 0.9 g/kg vs. 100% mortality at 1.4 g/kg) (Industrial Bio-Test 1970). The total uncertainty factor is 30. The concen- tration-exposure time relationship for many irritant and systemically acting va- pors 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). Insufficient data were available to derive an empirical value for n. Therefore, time scaling was performed using default values of n = 3 to extrapolate to shorter durations and n = 1 to extrapo- late to longer durations to provide AEGL values that are protective of human health (NRC 2001). AEGL values for benzonitrile are presented Table 2-1. TABLE 2-1 AEGL Values for Benzonitrile End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient data (nondisabling) AEGL-2 11 ppm 7.8 ppm 6.2 ppm 2.5 ppm 1.2 ppm One-third of (disabling) (48 (33 (26 (10 (5.2 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 34 ppm 24 ppm 19 ppm 7.4 ppm 3.7 ppm Estimated lethal (lethal) (140 (99 (79 (31 (16 threshold in mice mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (MacEwen and Vernot 1974) a Not recommended. Absence of AEGL-1 values does not imply that exposures below AEGL-2 values are without adverse effects.

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124 Acute Exposure Guideline Levels 1. INTRODUCTION Benzonitrile is produced by vapor-phase catalytic ammoxidation of tolu- ene, dehydrogenation of the Diels-Alder adduct of butadiene and acrylonitrile, or by reaction of benzoic acid with urea at 220-240°C in the presence of a metal- lic catalyst. It is used as an intermediate for rubber chemicals, and as a solvent for nitrile rubber, lacquers, and resins and polymers. It is also used as an addi- tive in nickel-plating baths, for separating naphthalene and alkylphthalenes from nonaromatics by azeotropic distillation, as a jet fuel additive, in cotton bleaching baths, as a drying additive for acrylic fibers, and in the removal of titanium tet- rachloride and vanadium oxytrichloride from silicon tetrachloride (HSDB 2003). The physical and chemical properties of benzonitrile are presented in Ta- ble 2-2. TABLE 2-2 Physical and Chemical Data on Benzonitrile Parameter Data Reference Common name Benzonitrile IPCS 1999 Synonyms Cyanobenzene, benzoic acid nitrile; IPCS 1999 phenyl cyanide CAS registry no. 100-47-0 IPCS 1999 Chemical formula C6H5 (CN) IPCS 1999 Molecular weight 103.1 IPCS 1999 Physical state Colorless liquid HSDB 2003 Melting point -12.8°C IPCS 1999 Boiling point 190.7°C IPCS 1999 Flash Point 75°C IPCS 1999 Density/Specific gravity 1.010 at 25°C/15°C HSDB 2003 Solubility Poor solubility in water; miscible with HSDB 2003 organic solvents, soluble in alcohol, ether and acetone Vapor density 3.6 (air = 1) HSDB 2003 Vapor pressure 0.768 mm Hg at 25°C HSDB 2003 3 Conversion factors in air 1 ppm = 4.22 mg/m

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Benzonitrile 125 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Information on the toxicity of benzonitrile in humans is limited to a single occupational case study (HSDB 2003). A male worker was accidentally drenched (head and clothing) with benzonitrile. He was subsequently doused with water, but his clothing was not immediately removed. Immediately thereaf- ter the worker collapsed into unconsciousness. He was subsequently bathed to remove dermal exposure, and became responsive for a short period, but exhibit- ed respiratory distress. He then fell into deep unconsciousness and exhibited tonic contractions in the muscles of his arms and face. The tonic muscle contrac- tions were alleviated following treatment with phenobarbitol and sodium thio- sulfate. Under supplemental oxygen, he remained unconscious for approximate- ly 75 min and gradually recovered and was released without apparent symptoms the following day. Air concentrations of benzonitrile experienced during the exposure were not reported. Dermal exposure to benzonitrile probably contrib- uted to the absorbed dose. 2.2. Nonlethal Toxicity An odor threshold of 2.9 × 10-5 mg/L (0.007 ppm) has been reported for benzonitrile (HSDB 2003). 2.3. Developmental and Reproductive Toxicity Developmental and reproductive studies of acute human exposure to ben- zonitrile were not available. 2.4. Genotoxicity Genotoxic studies of acute human exposure to benzonitrile were not avail- able. 2.5. Carcinogenicity Carcinogenicity studies of human exposure to benzonitrile were not avail- able. 2.6. Summary No reports regarding lethality, nonlethal toxicity, developmental and re- productive toxicity, genotoxicity, or carcinogenicity on benzonitrile were avail- able.

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126 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats A group of six male CFE rats was exposed to benzonitrile at 900 ppm (saturated atmosphere) in a 30-L glass exposure chamber for 4 h and observed for 14 days (MacEwen and Vernot 1974). The benzonitrile atmosphere was pro- duced by passing air through a fritted disc bubbler immersed in 200 mL of test material. The airflow through the bubbler was 10 L/min, and 9 min was neces- sary to achieve 95% saturation in the exposure chamber. The chamber concen- tration of benzonitrile was continuously analyzed using a total hydrocarbon ana- lyzer initially calibrated with several standard gas bags containing benzonitrile at 450 and 900 ppm in air. Irritation of the extremities was observed during the first hour of exposure, followed by poor coordination and labored breathing after 3 h. Prostration occurred at 3.5 h. Following the 14-day observation period, five of the six rats had weight gain that was below normal (data not presented). No treatment-related deaths occurred; however, microscopic examinations of the rats at the end of the 14-day observation period revealed multifocal areas of lymphoid hyperplasia with macrophage-containing foamy accumulations. Groups of five male and five female young adult Charles River rats were exposed to benzonitrile at 0.8 or 8 mg/L (190 or 1,900 ppm) in a 70-L Plexiglas inhalation chamber for 4 h and observed for 14 days (Industrial Bio-Test 1970). An aerosol of undiluted benzonitrile was generated with an Ohio Ball-Jet Nebu- lizer. A stream of clean dry air was passed through the nebulizer and the result- ing aerosol stream was mixed with additional dry air to obtain the final desired concentration. The test atmosphere was then introduced into the top of the expo- sure chamber, dispersed with a baffle plate, and exhausted at the bottom of the chamber. Air flow rates were measured with rotameters connected to the air supply line upstream of the aerosol; temperature and pressure of the test atmos- phere were also measured. Average nominal concentrations were calculated by dividing the nebulizer weight loss by the total volume of air used during each exposure. No deaths, clinical signs, or effects on body weight were observed in the 0.8-mg/L group. At necropsy, no gross treatment-related effects were found in this group. Three females died after exposure at 8 mg/L; two deaths occurred 2 h after the end of the exposure period and one occurred on day 6. Six of the eight surviving rats lay prostrate 18 h after exposure; this effect persisted in two animals through day 4 and in one animal through day 6 (when death occurred). No adverse effects on body weight were noted. Necropsy of animals that died on the day of exposure showed minimal pulmonary hyperemia. Agaev (1977) reported the following lethal concentrations of benzonitrile in white rats: LC84 = 1,071 ppm, LC50 = 929 ppm, and LC16 = 738 ppm. Expo- sure duration and other experimental details were not reported.

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Benzonitrile 127 In an acute oral toxicity study, two male and two female albino Charles River rats were administered undiluted benzonitrile by gavage at single doses of 0.6, 0.9, 1.4, or 2.0 g/kg and observed for 14 days (Industrial Bio-Test 1970). Dose-related clinical signs included hypoactivity, muscular weakness, ruffled fur, prostration, dyspnea, and lacrimation. Mortality was 0/4 at 0.6 g/kg, 2/4 at 0.9 g/kg, 3/4 at 1.4 g/kg, and 4/4 at 2.0 g/kg. An oral LD50 of 1.0 ± 0.2 g/kg was calculated. Agaev (1977) reported the following lethal doses for a one-time exposure to a 50% solution of benzonitrile in sunflower oil in white rats: LD84 = 2,350 mg/kg, LD50 = 1,500 mg/kg, and LD16 = 650 mg/kg. No other experimental de- tails were reported. 3.1.2. Mice Groups of seven or 10 male CF-1 mice were exposed to benzonitrile at target concentrations of 900 ppm (saturated atmosphere) in a 30-L glass expo- sure chamber for 2 or 4 h and observed for 14 days (MacEwen and Vernot 1974). Measured concentrations were 890 ppm for the 2-h exposure and 700 ppm for the 4-h exposure. The benzonitrile atmosphere was produced by passing air through a fritted disc bubbler immersed in 200 mL of test material. The air- flow through the bubbler was 10 L/min, and 9 min was necessary to achieve 95% saturation in the exposure chamber. The benzonitrile chamber concentra- tion was continuously analyzed using a total hydrocarbon analyzer initially cali- brated with several standard gas bags containing benzonitrile at 450 and 900 ppm in air. Irritation of the extremities was observed during the first hour of exposure, followed by poor coordination and labored breathing after 60-90 min. Prostration occurred at 2.5 h. All mice in the 4-h group died; three died on the day of exposure (including one during exposure at 3.5 h), three on day 1, and four on day 2. Only one mouse in the 2-h group died on day 2. Congestion ac- companied by edema was found in the lungs of both exposure groups at necrop- sy. Mice exposed for 4 h also had hepatic congestion and sinusoidal dilation. Agaev (1977) reported the following lethal concentrations for benzonitrile in white mice: LC84 = 595 ppm, LC50 = 429 ppm, and LC16 = 167 ppm. Expo- sure duration and other experimental details were not reported. Agaev (1977) reported the following lethal doses for a one-time exposure to a 50% solution of benzonitrile in sunflower oil in white mice: LD84 = 2,350 mg/kg, LD50 = 1,400 mg/kg, and LD16 = 650 mg/kg. No other experimental de- tails were reported. 3.1.3. Rabbits In an acute dermal toxicity study, two male and two female New Zealand white rabbits were administered undiluted benzonitrile at doses of 0.9, 1.4, 2.0,

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128 Acute Exposure Guideline Levels or 3.0 g/kg and observed for 14 days (Industrial Bio-Test 1970). The test sub- stance was applied to the clipped skin, covered with impervious plastic sheeting, and allowed to remain in contact with the skin for 24 h. The rabbits were fitted with collars to prevent oral ingestion of the benzonitrile. Local skin irritation was characterized as barely perceptible to pale red erythema and slight edema at the end of the 24-h exposure period; the dermal irritation subsided during the first week. Dose-related clinical signs included salivation, muscular weakness, ataxia, prostration, tremors, and loss of righting reflex. Mortality was 0/4 at 0.9 g/kg and 4/4 at 1.4, 2.0, and 3.0 g/kg, suggesting a very steep dose-response curve. An acute dermal LD50 of 1.2 ± 0.1 g/kg was calculated. Necropsy of ani- mals that died from treatment found consolidation of the lungs, watery fluid in the peritoneal cavity, and hyperemia of kidneys. In an ocular irritation study, 0.1 mL of undiluted benzonitrile was instilled into the right eye of five New Zealand white rabbits; the left eyes served as scor- ing controls (Industrial Bio-Test 1970). The cornea, iris, and palpebral conjunc- tiva were graded according to the Draize method after 1 min, after 1, 24, and 72 h, and after 7 days following instillation. Benzonitrile was graded as mildly irri- tating. Transient iridal and conjunctival irritation (redness grade 2, swelling grade 1, and discharge grade 2) was observed within 1 min after instillation. Irritation peaked at 1 min and subsided over the following 24-72 h. In a primary skin irritation study, 0.5 mL of undiluted benzonitrile was applied to the shaved abraded or unabraded skin of four New Zealand white rabbits (Industrial Bio-Test 1970). The test sites were covered with gauze and plastic sheeting and remained in place for 24 h. No irritation was found 24- or 72-h post-treatment. 3.2. Nonlethal Toxicity No nonlethal toxicity studies of benzonitrile in animals were found. 3.3. Developmental and Reproductive Toxicity Developmental and reproductive toxicity studies of animal exposure to benzonitrile were not available. 3.4. Genotoxicity Genotoxicity studies of animal exposure to benzonitrile were not available. 3.5. Carcinogenicity Carcinogenicity studies of animal exposure to benzonitrile were not avail- able.

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Benzonitrile 129 3.6. Summary Animal toxicity data are limited to acute lethality studies in rats, mice, and rabbits. The data suggest that mice are more sensitive than rats to the effects of benzonitrile administered by inhalation; however, oral lethality data suggest that mice and rats have similar sensitivities. Clinical signs included labored breath- ing, poor coordination, hypoactivity, salivation, lacrimation, muscular weakness, and dyspnea. No developmental and reproductive, genotoxicity, or carcinogenic- ity data on benzonitrile were available. Animal data on benzonitrile are summa- rized in Table 2-3. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism Hydrogen cyanide is not a metabolite of benzonitrile. The major metabolic pathway for benzonitrile is aromatic hydroxylation to cyanophenols. A small amount of the cyanophenol may then be hydrolyzed to benzoic acid. In rabbits, 50% of an orally administered dose of benzonitrile at 150 mg/kg was conjugated to cyanophenols, and 10% was excreted as benzoic acid. In rats, the in vivo mi- crosomal hydroxylation of deuterated benzonitrile yielded primarily 4- hydroxybenzonitrile with 41% retention of deuterium (HSDB 2003). Although not documented, the structure of benzonitrile suggests that formation of an epox- ide intermediate may occur; this may account for the hepatotoxicity observed in mice at necropsy by MacEwen and Vernot (1974). 4.2. Mechanism of Toxicity No information regarding the mechanism of toxicity of benzonitrile was found. The benzonitriles, ioxynil (4-hydroxy-3,5-diiodobenzonitrile) and bro- moxynil (4-hydroxy-3,5-dibromodobenzonitrile), are uncoupling agents (Ellen- horn 1997); however, the mechanism of toxicity of benzonitrile has not been established. 4.3. Concurrent Exposure Issues Tanii and Hashimoto (1984) studied the acute toxicity and effect of carbon tetrachloride on the metabolism of 20 nitriles, including benzonitrile, in male ddY mice. All of the test nitriles liberated cyanide in vivo and in vitro except for ben- zonitrile. Groups of 10 male ddY mice were dosed orally with either carbon tetra- chloride or olive oil, and then treated with the nitrile 24 h later. Pretreatment with carbon tetrachloride clearly enhanced the toxicity of benzonitrile (100% mortality with carbon tetrachloride vs. no mortality with olive oil). However, pretreatment with carbon tetrachloride either reduced or had little effect on the toxicity of ni- triles that metabolically liberate cyanide.

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130 TABLE 2-3 Summary of Animal Toxicity Data on Benzonitrile Species Concentration or Dose Exposure Duration Effect Reference Inhalation Studies Rat 190 ppm 4h No-observed-effect level Industrial Bio-Test 1970 Rat 900 ppm 1h Irritation of extremities MacEwen and Vernot 1974 Rat 900 ppm 3h Labored breathing, poor coordination MacEwen and Vernot 1974 Rat 900 ppm 4h No mortality (0/6), decreased weight gain MacEwen and Vernot 1974 Rat 1,900 ppm 4h 30% mortality (3/10); two died after 2 h, one Industrial Bio-Test 1970 died on day 6 post-exposure Mouse 700 ppm 4h 100% mortality (10/10) MacEwen and Vernot 1974 Mouse 890 ppm 2h 14% mortality (1/7) MacEwen and Vernot 1974 Oral Studies Rat 0.6 g/kg Single gavage No mortality (0/4); hypoactivity, ruffled Industrial Bio-Test 1970 fur, muscular weakness, prostration, dyspnea, lacrimation Rat 0.9 g/kg Single gavage 50% mortality (2/4); hypoactivity, ruffled Industrial Bio-Test 1970 fur, muscular weakness, prostration, dyspnea, lacrimation Rat 1.4 g/kg Single gavage 75% mortality (3/4); hypoactivity, ruffled Industrial Bio-Test 1970 fur, muscular weakness, prostration, dyspnea, lacrimation Rat 2.0 g/kg Single gavage 100% mortality (4/4); hypoactivity, ruffled Industrial Bio-Test 1970 fur, muscular weakness, prostration, dyspnea, lacrimation Rat 650 mg/kg Single gavage LD16 Agaev 1977 Rat 1,500 mg/kg Single gavage LD50 Agaev 1977

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Rat 2,350 mg/kg Single gavage LD84 Agaev 1977 Mouse 650 mg/kg Single gavage LD16 Agaev 1977 Mouse 1,400 mg/kg Single gavage LD50 Agaev 1977 Mouse 2,350 mg/kg Single gavage LD84 Agaev 1977 Dermal Studies Rabbit 0.9 g/kg 4h 0% mortality (0/4); muscular weakness, Industrial Bio-Test 1970 prostration, salivation, ataxia, tremors, loss of righting reflex Rabbit 1.4 g/kg 24 h 100% mortality (4/4); muscular weakness, Industrial Bio-Test 1970 prostration, salivation, ataxia, tremors, loss of righting reflex Rabbit 2.0 g/kg 24 h 100% mortality (4/4); muscular weakness, Industrial Bio-Test 1970 prostration, salivation, ataxia, tremors, loss of righting reflex Rabbit 3.0 g/kg 24 h 100% mortality (4/4); muscular weakness, Industrial Bio-Test 1970 prostration, salivation, ataxia, tremors, loss of righting reflex 131

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132 Acute Exposure Guideline Levels 4.4. Structure-Activity Relationships Because the acute toxicity of most nitriles is dependent 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 reac- tion, acute toxicity of nitriles is related to the structural features that influence α- carbon radical stability. Generally, 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). Benzonitrile is not metabolized to cyanide in vivo or in vitro (Tanii and Hashimoto 1984). 4.5. Species Differences One study of inhalation exposure to benzonitrile suggests that rats are more resistant than mice to its lethal effects (MacEwen and Vernot 1974). Another study of the oral lethality of benzonitrile suggests that mice and rats have similar sensitivities (Agaev 1977), but details of the study methods were lacking. 4.6. Concentration-Exposure Duration Relationship The concentration-exposure time relationship for many irritant and sys- temically-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 were inadequate to derive an empirical value of n for benzonitrile. To obtain con- servative and protective AEGL values in the absence of a chemical-specific scaling exponent, temporal scaling was performed using default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations. 5. RATIONALE FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 No human data on benzonitrile consistent with the definition of AEGL-1 were available.

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Benzonitrile 133 5.2. Animal Data Relevant to AEGL-1 No animal data on benzonitrile consistent with the definition of AEGL-1 were available. 5.3. Derivation of AEGL-1 Values Data on benzonitrile are insufficient to derive AEGL-1 values; therefore, AEGL-1 values are not recommended. Absence of AEGL-1 values does not imply that exposures below AEGL-2 values are without adverse effects. 6. RATIONALE FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data on benzonitrile consistent with the definition of AEGL-2 were available. 6.2. Animal Data Relevant to AEGL-2 Studies conducted in rats and mice show steep dose-response relationships which makes it difficult to discern thresholds for AEGL-2 and AEGL-3 effects from the sparse data (MacEwen and Vernot 1974). For example, in mice, expo- sure to benzonitrile at 890 for 2 h (Cn × t = 1,780 ppm-h) resulted in 14% (1/7) mortality whereas exposure at 700 ppm for 4 h (2,800 ppm-h) resulted in 100% mortality, with prostration occurring at 2.5 h and 10% (1/10) mortality at 3.5 h. In rats, exposure at 900 ppm for 3 h (2,700 ppm-h) resulted in labored breathing and impaired coordination; however, an additional 30 min of exposure at 900 ppm resulted in prostration, but no deaths in rats. 6.3. Derivation of AEGL-2 Values Given the steepness of the dose-response relationship and uncertainty in distinguishing the threshold for AEGL-2 and AEGL-3 effects, AEGL-2 values were derived based on a 3-fold reduction of the AEGL-3 values. The AEGL-2 values for benzonitrile are presented in Table 2-4, and the calculations for these AEGL-2 values are presented in Appendix A. TABLE 2-4 AEGL-2 Values for Benzonitrile 10 min 30 min 1h 4h 8h 11 ppm 7.8 ppm 6.2 ppm 2.5 ppm 1.2 ppm (48 mg/m3) (33 mg/m3) (26 mg/m3) (10 mg/m3) (5.2 mg/m3)

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134 Acute Exposure Guideline Levels 7. RATIONALE FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data on benzonitrile consistent with the definition of AEGL-3 were available. 7.2. Animal Data Relevant to AEGL-3 Animal data on benzonitrile consistent with the definition of AEGL-3 are sparse. No deaths were observed in rats exposed to benzonitrile at 190 ppm for 4 h (Industrial Bio-Test 1970) or at 900 ppm for 4 h (MacEwen and Vernot 1974). One of 10 mice died when exposed at 890 ppm for 2 h (MacEwen and Vernot 1974). 7.3. Derivation of AEGL-3 Values The available data offer two options for deriving the AEGL-3 value. One option is to use the 3.5-h exposure at 900 ppm that resulted in prostration but no deaths in rats as the point of departure. The second option is to base the AEGL-3 values on the 2-h exposure at 890 ppm that resulted in 14% (1/7) mortality in mice. The second option was chosen because it results in lower AEGL-3 values. Because some lethality in mice was observed at 890 ppm, the concentration was adjusted to estimate the lethal threshold. Typically, a 3-fold reduction of the LC50 would be used to extrapolate to a lethality threshold. However, an LC50 value for benzonitrile is not available. The 2-h study reported 14% mortality, which suggests the test concentration of 890 ppm is below the LC50; therefore, a 2-fold adjustment was applied. The resulting adjusted value of 445 ppm was considered an estimate of the lethality threshold and used as the point of depar- ture for deriving AEGL-3 values. An interspecies uncertainty factor of 10 was applied. Mortality data re- ported by Agaev (1977) on benzonitrile suggest that rats and mice have similarly steep dose-response relationships (e.g., similar oral LD16, LD50, and LD84), but the reported lack details about the methods, and no data on other species are available. An intraspecies uncertainty factor of 3 was applied to account for sen- sitive individuals. Application of this value, rather than a default of 10, is sup- ported by the steep concentration-response curve for benzonitrile, which implies little individual variability. For example, the steepness of the curve is evident in mice exposed by inhalation to benzonitrile (10% mortality at 890 ppm for 2 h [ct = 1,780 ppm-h] vs. 100% mortality at 700 ppm for 4 h [ct = 2,800 ppm-h]) (MacEwen and Vernot 1974), in rats exposed orally (no mortality at 0.6 g/kg vs. 100% mortality at 2.0 g/kg) (Industrial Bio-Test 1970), and in rabbits exposed dermally (no mortality at 0.9 g/kg vs. 100% mortality at 1.4 g/kg) (Industrial Bio-Test 1970). The total uncertainty factor is 30. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may

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Benzonitrile 135 be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Insufficient data were available to derive an empiri- cal value for n. Therefore, time scaling was performed using default values of n = 3 to extrapolate to shorter durations and n = 1 to extrapolate to longer dura- tions to provide AEGL values that are protective of human health (NRC 2001). AEGL-3 values for benzonitrile are presented in Table 2-5, and the calculations are presented in Appendix A. 8. SUMMARY OF AEGL VALUES 8.1. AEGL Values and Toxicity End Points AEGL values for benzonitrile are presented in Table 2-6. AEGL-1 values are not recommended due to insufficient data. AEGL-2 values were estimated by dividing the corresponding AEGL-3 values by 3, and AEGL-3 values were based on lethality data from studies of mice. 8.2. Other Standards and Guidelines No other standards and guidelines for short-term exposures to benzonitrile were found. 8.3. Data Adequacy and Research Needs No human data on benzonitrile were found and animal data were sparse. AEGL-1 values were not derived. AEGL-2 and AEGL-3 values were derived; however, it was necessary to apply a modifying factor, partly because of the sparse data base. TABLE 2-5 AEGL-3 Values for Benzonitrile 10 min 30 min 1h 4h 8h 34 ppm 24 ppm 19 ppm 7.4 ppm 3.7 ppm (140 mg/m3) (99 mg/m3) (79 mg/m3) (31 mg/m3) (16 mg/m3) TABLE 2-6 AEGL Values for Benzonitrile Classification 10 min 30 min 1h 4h 8h AEGL-1 NRa NRa NRa NRa NRa (nondisabling) AEGL-2 11 ppm 7.8 ppm 6.2 ppm 2.5 ppm 1.2 ppm (disabling) (48 mg/m3) (33 mg/m3) (26 mg/m3) (10 mg/m3) (5.2 mg/m3) AEGL-3 34 ppm 24 ppm 19 ppm 7.4 ppm 3.7 ppm (lethal) (140 mg/m3) (99 mg/m3) (79 mg/m3) (31 mg/m3) (16 mg/m3) a Not recommended. Absence of AEGL-1 values does not imply that exposures below AEGL-2 values are without adverse effects.

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136 Acute Exposure Guideline Levels 9. REFERENCES Agaev, F.B. 1977. Experimental basis of the maximum allowable concentration of ben- zonitrile in the air of the workplace [in Russian]. Gig. Tr. Prof. Zabol. (6):34-37. DeVito, S.C. 1996. Designing safer nitriles. Pp. 194-223 in Designing Safer Chemicals, S.C. DeVito, and R.L. Garrett, eds. American Chemical Society Symposium Series Vol. 640. Washington, DC: American Chemical Society. Ellenhorn, M.J. 1997. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Hu- man Poisoning, 2nd Ed., M.J. Ellenhorn, S. Schonwald, G. Ordog, and J. Wasser- berger, eds. Baltimore, MD: Williams and Wilkins. HSDB (Hazardous Substances Data Bank). 2003. Benzonitrile (CAS Reg. No. 100-47-0). TOXNET Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ [accessed June 5, 2013]. Industrial Bio-Test. 1970. Acute Toxicity Studies on Benzonitrile. Report to Velsicol Chemical Corporation, by Industrial Bio-Test Laboratories, Inc., Northbrook, IL. Submitted to EPA, by Sherwin-Williams Company, Washington, DC with Cover Letter Dated September 9, 1992. EPA Document No. 88-920009445. Microfiche No. OTS0571101. IPCS (International Programme on Chemical Safety). 1999. Benzonitrile (CAS Reg. No. 100-47-0). International Chemical Safety Card No. 1103 [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics1103.htm [accessed Feb. 4, 2014]. MacEwen, J.D. and E.H. Vernot. 1974. Acute inhalation toxicity of benzonitrile. Pp. 77- 80 in Toxic Hazards Research Unit Annual Technical Report: 1974. AMRL-TR- 74-78. ADA011559. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Resource Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. Tanii, H., and K. Hashimoto. 1984. Studies on the mechanism of acute toxicity of nitriles in mice. Arch. Toxicol. 55(1):47-54. 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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Benzonitrile 137 APPENDIX A DERIVATION OF AEGL VALUES FOR BENZONITRILE Derivation of AEGL-1 Values The data on benzonitrile were insufficient for deriving AEGL-1 values. Derivation of AEGL-2 Values In the absence of relevant data to derive AEGL-2 values for benzonitrile, AEGL-3 values were divided by 3 to estimate AEGL-2 values. 10-min AEGL-2: 34 ppm ÷ 3 = 11 ppm 30-min AEGL-2: 24 ppm ÷ 3 = 7.8 ppm 1-h AEGL-2: 19 ppm ÷ 3 = 6.2 ppm 4-h AEGL-2: 7.4 ppm ÷ 3 = 2.5 ppm 8-h AEGL-2: 3.7 ppm ÷ 3 = 1.2 ppm Derivation of AEGL-3 Values Key study: MacEwen, J.D., and E.H. Vernot. 1974. Acute inhalation toxicity of benzonitrile. Pp. 77-80 in Toxic Hazards Research Unit Annual Technical Report: 1974. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH. Toxicity end point: Estimated 2-h lethality threshold in mice of 445 ppm Time scaling: Cn × t = k (default values of n = 3 for extrapolating to shorter durations and n =1 for extrapolating to longer durations) (445 ppm)3 × 2 h = 176,242,250 ppm-h (445 ppm)1 × 2 h = 890 ppm-h Uncertainty factors: 10 for interspecies differences 3 for intraspecies variability Modifying factor: None

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138 Acute Exposure Guideline Levels 10-min AEGL-3: C3 × 0.167 h = 176,242,250 ppm-h C3 = 1,055,342,814 ppm C = 1,018 ppm 1,018 ÷ 30 = 34 ppm 30-min AEGL-3: C3 × 0.5 h = 176,242,250 ppm-h C3 = 352,484,500 ppm C = 706 ppm 706 ÷ 30 = 24 ppm 1-h AEGL-3: C3 × 1 h = 176,242,250 ppm-h C3 = 176,242,250 ppm C = 561 ppm 561 ÷ 30 = 19 ppm 4-h AEGL-3: C1 × 4 h = 890 ppm-h C1 = 223 ppm C = 223 ppm 223 ÷ 30 = 7.4 ppm 8-h AEGL-3: C1 × 8 h = 890 ppm-h C1 = 111 ppm C = 111 ppm 111 ÷ 30 = 3.7 ppm

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Benzonitrile 139 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR BENZONITRILE Derivation Summary AEGL-1 VALUES The data on benzonitrile were insufficient for deriving AEGL-1 values. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 11 ppm 7.8 ppm 6.2 ppm 2.5 ppm 1.2 ppm (48 mg/m3) (33 mg/m3) (26 mg/m3) (10 mg/m3) (5.2 mg/m3) Data adequacy: In the absence of specific data on benzonitrile to determine AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. These values are considered estimates of the threshold for impaired ability to escape and are considered appropriate given the steep concentration-response curve for benzonitrile. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 34 ppm 24 ppm 19 ppm 7.4 ppm 3.7 ppm (140 mg/m3) (99 mg/m3) (79 mg/m3) (31 mg/m3) (16 mg/m3) Key reference: MacEwen, J.D., and E.H. Vernot. 1974. Acute inhalation toxicity of benzonitrile. Pp. 77-80 in Toxic Hazards Research Unit Annual Technical Report: 1974. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH. Test species/Strain/Number: Mouse, CF-1, 7 or 10 males/group Exposure route/Concentrations/Durations: Inhalation, 700 ppm for 4 h or 890 ppm for 2 h Effects: 700 ppm for 4 h: 100% mortality (10/10) 890 ppm for 2 h: 14% mortality (1/7) End point/Concentration/Rationale: Estimated lethality threshold of 445 ppm. Typically, a 3-fold reduction of the LC50 would be used to estimate a lethal threshold. However, an LC50 value for benzonitrile was not available. The 2-h exposure to benzonitrile at 890 ppm resulted in 14% lethality, which suggests this concentration is below the LC50; therefore, a 2-fold adjustment was applied to estimate a 2-h lethality threshold of 445 ppm. (Continued)

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140 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 10, even though mortality data suggest that rats and mice have similarly steep dose-response relationships (e.g., similar oral LD16, LD50, and LD84) (Agaev 1977), details of the study methods are lacking and no data on other species are available. Intraspecies: 3, because steep concentration-response curves imply little individual variability. The steepness of the curve is evident in mice exposed by inhalation to benzonitrile (10% mortality at 890 ppm for 2 h [ct = 1,780 ppm-h] vs. 100% mortality at 700 ppm for 4 h [ct = 2,800 ppm-h]) (MacEwen and Vernot 1974), in rats exposed orally (no mortality at 0.6 g/kg vs. 100% mortality at 2.0 g/kg) (Industrial Bio-Test 1970), and in rabbits exposed dermally (no mortality at 0.9 g/kg vs. 100% mortality at 1.4 g/kg) (Industrial Bio-Test 1970). Animal-to-human dosimetric adjustment: Insufficient data Time scaling: Cn × t = k; default values of n = 3 to extrapolate to shorter durations (10 min, 30 min, and 1 h) and n = 1 to extrapolate to longer durations (4 and 8 h) to provide AEGL values that would be protective of human health (NRC 2001). Data adequacy: Sparse data set.

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Benzonitrile 141 APPENDIX C CATEGORY PLOT FOR BENZONITRILE FIGURE C-1 Category plot of toxicity data and AEGL values for benzonitrile.

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142 TABLE C-1 Data Used in Category Plot for Benzonitrile 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 11 10 AEGL AEGL-2 7.8 30 AEGL AEGL-2 6.2 60 AEGL AEGL-2 2.5 240 AEGL AEGL-2 1.2 480 AEGL AEGL-3 34 10 AEGL AEGL-3 24 30 AEGL AEGL-3 19 60 AEGL AEGL-3 7.4 240 AEGL AEGL-3 3.7 480 AEGL Industrial Bio-Test 1970 Rat 1 190 240 0 No-observed-effect level MacEwen and Vernot 1974 Rat 1 900 60 1 Irritation of extremities MacEwen and Vernot 1974 Rat 1 900 180 2 Labored breathing, poor coordination MacEwen and Vernot 1974 Rat 1 900 240 2 No mortality (0/6), decreased weight gain Industrial Bio-Test 1970 Rat 1 1,900 240 SL 30% mortality (3/10) MacEwen and Vernot 1974 Mouse 1 700 240 3 100% mortality (10/10) MacEwen and Vernot 1974 Mouse 1 890 120 SL 14% mortality (1/7) For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal