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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14 (2013)

Chapter: 1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels

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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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1

Agent BZ (3-Quinuclidinyl Benzilate)1

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 Robert Young (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager Glenn Leach (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).

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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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 susceptible 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 susceptible individuals, could experience life-threatening health effects or death.

Airborne concentrations below the AEGL-1 represent exposure concentrations that could produce mild and progressively increasing but transient and non-disabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory 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 subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.

SUMMARY

Agent BZ (3-quinuclidinyl benzilate) is an odorless, environmentally stable, white crystalline powder with anticholinergic activity. Once considered a potential incapacitating agent for military applications, it is currently used as a pharmacological tool (a muscarinic antagonist known as QNB). It produces anticholinergic delirium, a non-specific syndrome of cognitive dysfunction, hallucinations, and inability to perform tasks. Inhalation exposure would likely involve an aerosolized solid.

No data on the lethality of BZ in humans after inhalation exposure were available. Lethal doses to humans were estimated by Ketchum (1963) using several methods, including extrapolation of data from animals on the basis of body weight, extrapolation of the lethality ratio of BZ and atropine in animals to humans, and extrapolation of the ratio of physiologic effectiveness (parasympatholytic effects) between BZ and atropine in humans. LD50 (lethal dose, 50% lethality) values estimated by these methods were 2-5 mg/kg, 0.3-1.4 mg/kg, and 0.2-1.2 mg/kg, respectively. Conversion of these doses to an air concentration of BZ was not provided.

Data on nonlethal effects of BZ in humans after inhalation exposure are from studies conducted by the military. Subjects in these studies were carefully screened, evaluated, and informed human volunteers (male military personnel). The results qualitatively demonstrated that BZ exerts its parasympatholytic effects (behavioral and cognitive dysfunction) regardless of exposure route.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

Inhalation exposure experiments were limited to those conducted by Ketchum and colleagues (Ketchum 1963, 2006; Ketchum et al. 1967), in which responses of test subjects were characterized using a scoring system that integrated various cognitive parameters, blood pressure, and heart rate. Exposures were of short duration (minutes) and were expressed as cumulative exposures (mg-min/m3). An ICt50 value (a concentration-time product causing incapacitation in 50% of the test subjects) of 60.1 mg-min/m3 (95% confidence interval [CI]: 41.3-87.5 mg-min/m3) was reported by Ketchum et al. (1967). Nonlethal effects of BZ are completely reversible.

Median lethal doses (LCt50) have been reported for several animal species (U.S. Department of the Army 1974). All exposures were of relatively short durations (5-40 min) but the LCt50 values ranged from 12,000 to 123,000 mg-min/m3 with no apparent relationship to body size. Results of animal experiments (Ketchum et al. 1967) showed that monkeys, dogs, and rabbits exhibited qualitatively similar responses to BZ. Mydriasis (excessive or prolonged dilation of the pupil) and cycloplegia (paralysis of the ciliary muscles of the eye) were consistently observed in all test species. Other effects included ataxia, lethargy, sedation, erratic behavior, weakness, and hyperactivity. Exposures were all of short duration (6-8 min).

AEGL-1 values for BZ could not be developed with scientific rigor. Although data on exposures to BZ resulting in no apparent effects in animals are available, the experiments could not assess possible cognitive and behavioral effects characteristic of BZ that are relevant to humans. Human data on BZ that define no-effect levels or that are consistent with the AEGL-1 definition were not available. Therefore, AEGL-1 values for BZ are not recommended.

For AEGL-2 values, a one-third reduction of the ICt50 value of 60.1 mg-min/m3 (60.1 mg-min/m3 ÷ 3 = 20 mg-min/m3 or 4 mg/m3) was considered an estimated threshold for incapacitating effects. The estimated threshold concentration is less than the lower limit of the ICt50 (41.3 mg-min/m3), which was considered too severe to serve as a point of departure because it could result in incapacitation. The threshold estimate is also lower than concentrations associated with clinical signs which may impair the ability to escape (e.g., progressive deterioration of normal gait and uncomfortable paresthesias of lower extremities reported by subjects exposed to BZ at 46.0-84.7 mg-min/m3 [or 9.2-16.4 mg/m3] for 5 min) (Ketchum et al. 1967). An interspecies uncertainty factor of 1 was used because the data are from human studies. An uncertainty factor of 10 was used to account for intraindividual variability. Effects in the human studies are likely due to the anticholinergic properties of BZ; structures of muscarinic receptors are highly conserved and, thus, receptor affinity is not likely to vary among individuals. However, individuals with pre-existing conditions may be more sensitive to the anticholinergic effects of BZ. Because of data limitations, particularly the short exposure duration of the critical study (5 min), a modifying factor of 3 was also applied. Data with which to assess the concentration-time relationship for BZ are not available. The concentration-time relationship for many irritant and systemically acting vapors and gases may be

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived exponent (n) and to obtain protective AEGL values, time scaling was performed using the default of n = 1 to extrapolate to the 10-min, 30-min, and 1-h durations. AEGL-2 values for the 4-h and 8-h durations are not recommended, because data on exposure to BZ for durations longer than a few minutes are lacking and the effects of longer exposures are uncertain.

No human data are available with which to develop AEGL-3 values for BZ. Several of the human exposures reported by Ketchum (1963) and Ketchum et al. (1967) were associated with high total response index (TRI) scores indicative of notable cognitive and behavioral effects and some motor-function effects but no apparent serious physiologic responses. Effects observed at all exposures were reversed 7-days post-exposure with no medical intervention. Other human studies have uncertainties inherent in the exposure-route extrapolations that would be required if using human LC50 estimates (Ketchum 1963) or if using the non-verifiable LCt50 of 200,000 mg-min/m3 estimated by Hoenig (2007). Thus, animal studies were used as the basis for deriving AEGL-3 values.

AEGL-3 values for BZ were derived using 3,700 mg-min/m3 as the point of departure. That value was determined by reducing the LCt50 for monkeys (37,000 mg-min/m3 for 6-25 min) 10-fold (U.S. Department of the Army 1974). The LCt50 for the monkey is neither the highest nor lowest value of the six species tested, but the monkey was considered a better model for aerosol inhalation exposure in humans than the other species. Although a one-third reduction of the LC50 is often considered an appropriate estimate of the lethality threshold for chemicals with steep concentration-response relationships (NRC 2001), little is known about the concentration-response curve for BZ. An intraspecies uncertainty factor of 10 was used to account for individual variability. A factor of 10 was applied for interspecies variability because no human lethality data were available and LCt50 values for five animal species varied 10-fold. A modifying factor of 3 was applied because of data deficiencies. Time scaling was performed as described for the AEGL-2 values. AEGL-3 values for the 4-h and 8-h durations are not recommended, because data on longer exposure durations are lacking.

AEGL values for BZ are presented in Table 1-1.

1. INTRODUCTION

Agent BZ (3-quinuclidinyl benzilate) is an odorless, environmentally stable, white crystalline powder with anticholinergic activity. It was investigated as a potential incapacitating agent for military applications (Ketchum 1963, 2006; Ketchum et al. 1967; USACHPPM 1996), and is currently used as a pharmacological tool (a muscarinic antagonist known as QNB) (Yamamura and Snyder 1974). In general terms, its activity (by any route of exposure) is that of producing anticholinergic delirium, a non-specific syndrome of cognitive dysfunction,

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

hallucinations, and inability to perform tasks. Most physiologic response data in humans exposed to BZ are for parenteral (intravenous and subcutaneous) or oral routes of administration, although some data on aerosol inhalation are available. Inhalation exposure would likely involve an aerosolized solid.

Chemical and physical data on BZ are presented in Table 1-2.

TABLE 1-1 AEGL Values for Agent BZ

Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference)
AEGL-1 (nondisabling)a NR NR NR NR NR Insufficient data.
AEGL-2 (disabling) 0.067 mg/m3 0.022mg/m3 0.011 mg/m3 NR NR Estimated threshold (20 mg-min/m3) for incapacitation in human volunteers (Ketchum et al. 1967).
AEGL-3 (lethal) 1.2 mg/m3 0.41 mg/m3 0.21 mg/m3 NR NR Estimated lethality threshold (3,700 mgmin/m3) in monkeys (U.S. Department of the Army 1974)

Abbreviations: NR, not recommended.

aAbsence of AEGL-1 values does not imply that exposure to concentrations less than the AEGL-2 values is without effect.

TABLE 1-2 Chemical and Physical Data for Agent BZ

Parameter Value Reference
Synonyms QNB; benzilic acid, 3-quinuclidinyl benzilate; EA2277; 3-quinuclindinyl ester; 3-hydroxyquinuclidine benzilate; agent buzz; 3-(2,2-diphenyl-2-hydroxyethanoyloxy)-quinuclidine USACHPPM 1996; HSDB 2008; NIST 2011
CAS registry no. 6581-06-2 Hoenig 2007
Chemical formula C21H23NO3 Hoenig 2007
Molecular weight 337.4 Hoenig 2007
Physical state Solid (white crystalline powder) Hoenig 2007
Melting point 167.5°C Hoenig 2007
Boiling point 320°C Hoenig 2007
Relative vapor density 11.6 Hoenig 2007
Solubility Slightly soluble in water; soluble in most organic solvents Hoenig 2007
Vapor pressure 0.03 mm Hg at 70°C Hoenig 2007
Conversion factors in air 1 ppm = 13.8 mg/m3 1 mg/m3 = 0.07 ppm
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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2. HUMAN TOXICITY DATA

2.1. Acute Lethality

No data regarding lethality in humans following inhalation exposure to BZ are available. Lethal exposures for humans were estimated by Ketchum (1963) using several methods, including extrapolation from animals on the basis of body weight, extrapolation of the lethality ratio of BZ and atropine in animals to humans, and extrapolation from the ratio of physiologic effectiveness (parasympatholytic effects) between BZ and atropine in humans. Estimated LD50 values for BZ were 2-5 mg/kg (by species weight), 0.3-1.4 mg/kg (by atropine lethality ratio), and 0.2-1.2 mg/kg (by relative effectiveness ratio of atropine and BZ). Conversion to a concentration of BZ in air was not provided. An estimated median lethal dose (LCt50) for BZ of 200,000 mg-min/m3 was reported by Hoenig (2007), but the basis for that value was not described.

2.2. Nonlethal Toxicity

Ketchum (1963) conducted research on the effects of BZ in male volunteers. Subjects were informed military personnel who underwent medical and psychological evaluations as a prerequisite for participation. Test candidates were also selected on the basis of their evaluation by the Minnesota Multiphasic Personality Inventory and results of psychological interviews. Experiments were conducted under continuous medical supervision. Severity of BZ-induced effects (criterion for incapacitation) was evaluated using a total response index (TRI), which was calculated using the equation: ([2 × performance index] + [2 × heart rate index] + blood pressure index) ÷ 5. Cognitive function was assessed by the performance index, which was based on serial performance scores in numerical facility and speed of closure tests. Physiologic effects were assessed by blood pressure and heart rate measurements. TRI levels were:

• TRI 4.0 (mild): subjects show peak heart rate of 80-85 beats/min, systolic blood pressure elevation <10 mm Hg, moderate pupillary dilatation, slight blurring of vision and dryness of mouth, some mental slowing, minimal loss of coordination, no loss of contact with reality, lowest performance score of 60% at 7 h; recovery at approximately 48 h.

• TRI 5.0 (moderate): subjects show peak heart rate of 80-95 beats/min, systolic blood pressure elevation <20 mm Hg, sedation might be marked at 4-16 h, transient illusions/hallucinations/confusion and lapses in concentration, some metal slowing, lowest performance score of 40% at 8 h; recovery complete at approximately 72 h.

• TRI 6.0 (severe): subjects show peak heart rate of 95-110 beats/min, hallucinations/confusion, hyperactive disorganized behavior, incoherent speech, memory and attention deficit, deep sleep/stupor, performance at zero within 6 h; recovery complete at approximately 96 h.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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• TRI 7.0 (maximal): peak heart rate of 110-140 beats/min within 3 h, systolic blood pressure increase of 20-60 mm Hg, onset of stupor within 3 h and performance decrement to zero within 4 h followed by protracted sleepiness, disorganized behavior, continual hallucinations, possible outbursts of fear and anger, delirium subsides within 72 h; complete recovery by 120 h.

Air concentrations were established to attain estimated doses of BZ ranging from 1.4 to 26 μg/kg. Doses were estimated based on body weight and on the difference between the amount of BZ presented to the subject and the amount remaining in the exposure system. Cumulative concentration values were reported as 24-397 mg-min/m3. Aerosol size mass median aerodynamic diameter (MMAD) ranged from <0.5 to 4.0 μm. The experiments were conducted using a series of suspensions and solutions of BZ, including an acetone solution, Freon 11 suspension, methylene chloride solution, pyrotechnic mix, and water solution. For the pyrotechnic mix (eight volunteers), breathing was regulated by reference to a visual feedback system that resulted in more uniform (± 10%) ventilation rates and tidal volumes. Cumulative exposures (CT; mg-min/m3) to BZ ranged from 155-261 mg-min/m3 and produced TRI values of 4.5 to 8.5.

Probit analysis for exposures associated with various TRI indices was reported by Ketchum (1963). The analysis provided an ED50 (a concentration-time product causing a specific TRI score in 50% of the test subjects) with 95% confidence limits for aerosol exposures (see Table 1-3) for groups of 36 volunteers. The exposure duration was not specified but was assumed to be of very short duration (<5 min) on the basis of other experiments and summaries provided in the report (U.S. Department of the Army 1974).

Ketchum et al. (1967) also reported the results of field-condition assessments (project DORK) for exposure to BZ aerosols. The assessments appeared to be an extension of the pyrotechnic exposures mentioned above. Two groups of eight volunteers (enlisted U.S. Army personnel under no coercion or enticement) participated with stringent medical safeguards in place. Subjects were evaluated using the number facility test (simple mathematics speed-accuracy test), speed of closure tests (ability to recognize words in a pseudo random array of letters), hand-eye coordination evaluations, and evaluations of ability to perform tasks typical of military situations (e.g., use of field glasses, sequential reporting of general activities, or completing tasks in routine military scenarios). Subjects were exposed to BZ aerosol generated by a Mars generator, and an ICt50 (concentration that will incapacitate 50% of exposed subjects) was estimated to be 60.1 mg-min/m3 (95% CI: 41.3-87.5 mg-min/m3) for a 165-pound man with a minute volume of 15 L (see Table 1-4). Incapacitation was determined by inability to perform at better than 10% on two consecutive tests of number facility. Neurologic signs were observed in seven of the eight subjects. Signs included symmetrical increase in deep tendon reflexes in the

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

TABLE 1-3 Probit Analysis for Response Criteria for Inhalation Exposure to Agent BZ

Response Criteria (TRI score) Sample Size ED50(mg-min/m3) 95% Confidence Limits (mg-min/m3)
4.0 36 90.5 66.2–123.6
5.0 36 124.8 102.8–151.5
6.0 36 134.8 110.3–164.7
7.0 36 183.1 132.9–252.0

Source: Ketchum 1963.

TABLE 1-4 Cumulative Exposures and TRI Scores for Male Volunteers Exposed to Agent BZ

Subject Number Minute Volume (L) Body Weight TRI Score BZ (CT, mg-min/m3)
1 12.4 160 4.4 64.8
2 16.8 165 7.1 84.7
3 13.8 145 6.3 68.3
4 11.9 190 4.2 46.0
5 13.8 145 4.6 71.2
6 18.8 200 5.4 82.2
7 14.8 160 6.3 54.0
8 23.1 190 6.8 72.9

Source: Ketchum et al. 1967.

lower extremities that progressed to ankle clonus and progressive deterioration of normal gait. Subjects also reported uncomfortable paresthesias of the lower extremities and diffuse, nonspecific weakness of all extremities which manifested as an unsteady gait, truncal weakness when sitting, and slow response to rebound testing. Additionally dysarthria (slow, slurred, and difficult to produce speech) was also noted in the subjects.

A maximum no-effect dose of 0.5-1.0 μg/kg for BZ in humans after intramuscular injection was reported by NRC (1982), and estimated median incapacitating inhalation concentrations of 101 mg-min/m3 (base) and 112 mg-min/m3 (hydrochloride) were reported by the U.S. Department of the Army (1974) for humans breathing rate at a rate of of 15 L/min.

2.3. Developmental and Reproductive Effects

No human developmental or reproductive toxicity data on BZ were available.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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2.4. Genotoxicity

No human genotoxicity data on BZ were available.

2.5. Carcinogenicity

No data were found regarding the carcinogenic potential of BZ in humans.

2.6. Summary

Data regarding the health effects of BZ in humans following inhalation exposure are limited to military application studies. No lethality data are available. Results of experiments using carefully screened and evaluated informed human volunteers (male military personnel) qualitatively demonstrated that BZ would exert parasympatholytic effects (behavioral and cognitive dysfunction). Inhalation exposure experiments are limited to those conducted by Ketchum and colleagues (Ketchum 1963, 2006; Ketchum et al. 1967) in which responses of test subjects were characterized using a scoring system expressed as a TRI value on the basis of various cognitive parameters, blood pressure, and heart rate. Exposures were of short duration (minutes) and expressed as cumulative exposures (mg-min/m3). An ICt50 of 60.1 mg-min/m3 (95% CI: 41.3-87.5 mg-min/m3) was reported by Ketchum et al. (1967).

3. ANIMAL TOXICITY DATA

3.1. Acute Lethality

3.1.1. Monkeys

An LCt50 of 37,000 mg-min/m3 for monkeys has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 6-25 min. No additional information is available.

3.1.2. Dogs

An LCt50 of 25,000 mg-min/m3 for dogs has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 6-16 min. No additional information is available.

3.1.3. Rats

An LCt50 of 64,000 mg-min/m3 for rats has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 5-30 min. No additional information is available.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

3.1.4. Mice

An LCt50 of 12,000 mg-min/m3 for mice has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 5-19 min. No additional information is available.

3.1.5. Rabbits

An LCt50 of 32,000 mg-min/m3 for rabbits has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 15-40 min. No additional information is available.

3.1.6. Guinea Pigs

An LCt50 of 123,000 mg-min/m3 for guinea pigs has been reported for BZ (U.S. Department of the Army 1974). The value was reportedly based on exposure durations of 5-30 min. No additional information is available.

3.1.7. Summary of Animal Lethality Data

LCt50 values have been reported for several species (U.S. Department of the Army 1974). Details of the experimental protocol and results are not available. All exposures were of relatively short durations (5-40 min), but the LCt50 values ranged from 12,000 to 123,000 mg-min/m3 with no apparent relationship to body size. The mouse and guinea pig were at the low end and high end, respectively, of the range of lethality values.

3.2. Nonlethal Toxicity

The only animal data on the effects of inhalation exposure to BZ are from a study by Ketchum et al. (1967). Studies of the effects of aerosol exposure of monkeys, dogs, rabbits, and rats were conducted prior to involvement of human volunteers. All species were exposed simultaneously, so exposure parameters were identical across species.

3.2.1. Monkeys

Five monkeys were exposed head only to aerosols of BZ at concentrations of 575 mg-min/m3 for 6 min and 10 seconds or at 164, 70, or 40 mg-min/m3 for 8 min (Ketchum et al. 1967). Information about the monkeys’ species, sex, and body weight were not reported. Effects were assessed at 4, 8, 16, 24, 32, 40, 48, 56, 64, and 72 h and at 7-days post-exposure (see Table 1-5). Aerosols were generated by a Mars generator as was done for the human experiments. A BZ concentration of 40 mg-min/m3 at 500 yards (equivalent to 5 mg/m3 for the 8-

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

min duration) was without detectable effect. Although qualitatively similar, the effects observed at 575 mg-min/m3 (equivalent to 93 mg/m3) tended to persist for longer periods (up to 7 days) compared with the lower exposures (40-164 mg-min/m3) where effects started to resolve by 72 h.

An RCt50 (response dose for 50% of animals tested) of less than 1,000 mg-min/m3 was reported by McNamara (1963; cited in Rosenblatt et al. 1977) on the basis of conditioned avoidance response testing. Exposure duration was not specified.

3.2.2. Dogs

Groups of six dogs (breed, sex, and body weight were not reported) were tested as described for the monkeys (Ketchum et al. 1967). Results of the experiments are summarized in Table 1-6.

McNamara (1963; cited in Rosenblatt et al. 1977) reported RCt50 values for BZ of <130 mg-min/m3 on the basis of mydriasis, 200 mg-min/m3 on the basis of sustained physical exercise, 250 mg-min/m3 on the basis of conditioned avoidance response, 25 mg-min/m3 on the basis of increased heart rate, and 500 mg-min/m3 on the basis of weakness in dogs. Exposure durations and details regarding the experimental protocol were not available.

3.2.3. Rabbits

Ketchum et al. (1967) also tested groups of six rabbits (strain, sex, and body weight were not reported) using the same protocol as for the monkeys and dogs. Effects were similar to those observed in those species (see Table 1-7).

TABLE 1-5 Effects of Agent BZ on Monkeys

Concentration (mg-min/m3) Duration Conditions Distance(yards) Effectsa
575 6 min, 10 sec 41°F, 67% relative humidity 100 Mydriasis, cycloplegia, tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia.
No datab 500 Mydriasis, cycloplegia.
No datab 1,000 Mydriasis, cycloplegia.
164 100 Mydriasis, cycloplegia.
70 8 min 32°F, 63% relative humidity 300 Mydriasis, cycloplegia.
40 500 No effects.

aAll effects occurring in monkeys at any time during the post-exposure observation period are noted, although not all monkeys exhibited all effects.

bStudy report indicated “no samples”.

Source: Ketchum et al. 1967.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

McNamara (1963; cited in Rosenblatt et al. 1977) reported RCt50 values of 10-50 mg-min/m3 on the basis of mydriasis in rabbits. Details of the experimental protocol were not provided.

TABLE 1-6 Effects of Agent BZ on Dogs

Concentration (mg-min/m3) Duration Conditions Distance (yards) Effectsa
575 6 min, 10 sec 41°F, 67% relative humidity 100 Mydriasis, cycloplegia, tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia, increased heart rate.
No datab     500 Mydriasis, cycloplegia, tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia, increased heart rate.
No datab     1,000 Mydriasis, cycloplegia, increased heart rate.
164 8 inin 32°F, 63% relative huimdity 100 Mydriasis, cycloplegia, tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia, increased heart rate, apprehension.
70     300 Mydriasis, cycloplegia, ataxia, lethargy, hyperactivity, increased heart rate.
40     500 No effects.

aAll effects occurring in dogs at any time during the post-exposure observation period are noted, although not all dogs exhibited all effects.

bStudy report indicated “no samples”.

Source: Ketchum et al. 1967.

TABLE 1-7 Effects of Agent BZ on Rabbits

Concentration (mg-min/m3) Duration Conditions Distance (yards) Effectsa
575 6 min, 10 sec 41°F, 67% relative humidity 100 Mydriasis, cycloplegia.
No datab     500 Mydriasis, cycloplegia, salivation.
No datab     1,000 Mydriasis, cycloplegia.
164     100 Mydriasis, cycloplegia, respiratory distress, ataxia.
70 8 min 32°F, 63% relative humidity 300 Mydriasis, cycloplegia, hyperpnea, ataxia.
40     500 Mydriasis, cycloplegia.

aAll effects occurring in rabbits at any time during the post-exposure observation period are noted, although not all rabbits exhibited all effects.

bStudy report indicated “no samples”.

Source: Ketchum et al. 1967.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

3.2.4. Rats

Groups of 20 rats (strain, sex, and body weight were not reported) were exposed simultaneously with the monkeys, dogs, and rabbits in the Ketchum et al. (1967) study. With the exception of dyspnea (4/20 rats) and ataxia (1/20 rats) at 4 h post-exposure, no effects were observed in any of the rats at any exposure.

3.2.5. Summary of Nonlethal Toxicity in Animals

Information on the nonlethal toxicity of BZ in animals is limited to data from Ketchum et al. (1967) and McNamara (1963). Results of the Ketchum et al. (1967) study showed that monkeys, dogs, and rabbits exhibited qualitatively similar responses to BZ. Mydriasis and cycloplegia were consistently observed in all species. Other effects varied and included ataxia, lethargy, sedation, erratic behavior, weakness, and hyperactivity. Generally, the effects were most pronounced at 4- and 8-h post-exposure and, with the exception of cycloplegia, tended to resolve within 24-48 h. Cycloplegia was frequently observed in all species through the 7-day post-exposure observation period. Exposures to BZ were all of short duration (6-8 min). McNamara (1963) reported that dogs, rabbits, and monkeys exhibited similar responses along with some behavioral modifications at cumulative exposures of 10 to 1,000 mg-min/m3.

3.3. Developmental and Reproductive Effects

Data regarding the developmental and reproductive toxicity of BZ following inhalation exposures were not available.

3.4. Genotoxicity

No information regarding the genotoxicity of BZ was available.

3.5. Carcinogenicity

No data with which to evaluate the carcinogenic potential of BZ were available.

3.6. Summary

Toxicity data on BZ are extremely limited. Both the human and animal data are from experiments with short exposure durations (minutes). The only available inhalation exposure data are expressed in cumulative exposure terms (mg-min/m3) and are not precisely characterized. Qualitatively, the effects of BZ

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

appear to be similar across species. The ability to detect, interpret, and quantify behavioral and cognitive dysfunction characteristic of BZ exposure in laboratory animals is difficult. On the basis of tests with human volunteers, Ketchum et al. (1967) estimated an ICt50 of 60.1 mg-min/m3 (95% CI: 41.3-87.5 mg-min/m3).

4. SPECIAL CONSIDERATIONS

4.1. Metabolism and Disposition

BZ hydrolyzes in aqueous environments to benzilic acid and 3-quinuclidinol. It is reportedly excreted primarily in the urine (Byrd et al. 1992). In rats, about 3% of a dose (route not specified) is excreted unchanged in the urine.

4.2. Mechanism of Toxicity

BZ is an anticholinergic agent similar in its pharmacologic action to atropine and scopolamine although more potent than both (Ketchum and Sidell 1997). It exhibits a preferential affinity for muscarinc cholinergic receptors in the brain, heart, and smooth muscle, resulting in inhibition of functions mediated through acetylcholine activation of these receptors. For both humans and animals, there is a latency period of about 30 min to several hours or more regardless of exposure route. Longer latency periods are associated with percutaneous exposures.

4.3. Structure-Activity Relationships

No data regarding structure-activity relationships that would be instrumental in developing AEGL values for BZ were available.

4.4. Species Variability

Ketchum et al. (1967) tested monkeys, dogs, rabbits, and rats in their studies. Results of their preliminary tests suggested that rats are less sensitive than the other species tested. The U.S. Department of the Army (1974) found that guinea pigs were even less sensitive than rats.

4.5. Concurrent Exposure Issues

No relevant data regarding concurrent exposure issues were available.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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5. DATA ANALYSIS FOR AEGL-1

5.1. Human Data Relevant to AEGL-1

No quantitative data on BZ relevant to AEGL-1 effects in humans were available.

5.2. Animal Data Relevant to AEGL-1

No animal data on BZ relevant to AEGL-1 effects in humans were available. No-effect levels in animals were reported, but assessment of cognitive and behavioral effects (major effects of BZ) were not possible.

5.3. Derivation of AEGL-1 Values

It is not possible to develop AEGL-1 values for BZ with scientific rigor. Although data on exposures resulting in no apparent effects in animals are available, the experiments could not assess possible cognitive and behavioral effects characteristic of BZ that are relevant to humans. Human data on BZ that define no-effect levels or that are consistent with the AEGL-1 definition are not available. Thus, AEGL-1 values for BZ are not recommended.

6. DATA ANALYSIS FOR AEGL-2

6.1. Human Data Relevant to AEGL-2

Studies by Ketchum and colleagues (Ketchum 1963, 2006; Ketchum et al. 1967) are relevant to developing AEGL-2 values. Effects of BZ were characterized in these studies by a scoring system expressed as TRI values, which were based on cognitive parameters, blood pressure, and heart rate. All exposures were of short duration (about 20 min) and were expressed as cumulative exposures (CT; mg-min/m3). An ICt50 of 60.1 mg-min/m3 (95% CI: 41.3-87.5 mg-min/m3) was reported by Ketchum et al. (1967). CT products of 46-261 mg-min/m3 were associated with high TRI scores, which are indicative of effects well exceeding the severity of an AEGL-2 threshold (see Section 2.2). No human lethality data are available, but lethal exposures to humans were estimated by Ketchum (1963). Estimates were made by extrapolation of animal data on the basis of body weight, extrapolation of the lethality ratio of BZ and atropine in animals to humans, and extrapolation of the ratio of physiologic effectiveness (parasympatholytic effects) between BZ and atropine in humans. LD50 values were estimated to be 2-5 mg/kg (on the basis of species weight), 0.3-1.4 mg/kg

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

(on the basis of atropine lethality ratio), and 0.2-1.2 mg/kg (on the basis of the relative effectiveness ratio of atropine and BZ). Conversion of the doses to concentrations of BZ in air was not provided.

6.2. Animal Data Relevant to AEGL-2

Results of studies with laboratory animals (monkeys, dogs, rabbits, and rats) showed that exposure to BZ at 40-575 mg-min/m3 for very short durations (6 and 8 min) generally produced nonlethal effects (mydriasis, cycloplegia, and salivation) consistent with exposure to a parasympatholytic agent. Rats appeared to be especially resistant, because none of the exposures resulted in notable effects. Monkeys and dogs also showed no effect when exposed to BZ at 40 mg-min/m3. Studies in animals could not assess cognitive and behavioral effects as evaluated for human volunteer subjects. No animal lethality data are available.

6.3. Derivation of AEGL-2 Values

On the basis of tests with human volunteers, Ketchum et al. (1967) estimated an ICt50 of 60.1 mg-min/m3 for a 165-pound human with a breathing rate of 15 L/min. A one-third reduction of the ICt50 (60.1 mg-min/m3 ÷ 3 = 20 mg-min/m3 or 4 mg/m3) was considered an estimated threshold for incapacitating effects. A one-third reduction is often used to estimate a no-effect level (in this case, the highest concentration that is not expected to cause incapacitation) from an effect level (in this case, a concentration that incapacitates 50% of exposed persons). Comparison of the estimated threshold level and other possible point of departures for AEGL-2 values suggests that this estimate is likely to be protective. The point of departure of 20 mg-min/m3 is less than the lower limit of the ICt50 (41.3 mg-min/m3), which was considered too severe to serve as a point of departure because it could result in incapacitation. The threshold level is also lower than the one associated with clinical signs that might impair the ability to escape (e.g., progressive deterioration of normal gait and uncomfortable paresthesias of lower extremities reported by subjects exposed to BZ at 46.0-84.7 mg-min/m3 [or 9.2-16.9 mg/m3] for 5 min) (Ketchum et al. 1967) and the median incapacitation concentration of 101 mg-min/m3 for humans breathing at a rate of 15 L/min (U.S. Department of the Army 1974). Additionally, experiments with four animal species indicated that 40 mg-min/m3 was a no-effect level in monkeys, dogs, and rats (Ketchum et al. 1967); cycloplegia and mydriasis were observed in rabbits exposed at that concentration. Applying an inter-species uncertainty factor of 3 to the animal no-effect levels results in a CT product of 13.3 mg-min/m3, which is similar but somewhat lower than the aforementioned point of departure of 20 mg-min/m3. In the absence of definitive concentration-response data, this comparison supports the point of departure for development of AEGL-2 values.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

Data with which to assess the concentration-time relationship for BZ are not available. Experiments conducted by Ketchum and colleagues were of short durations; 6-8 min in animal studies and possibly no more than 5 min in tests with human volunteers. 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). In the absence of an empirically derived exponent (n) and to obtain protective AEGL values, time scaling was performed using the default of n = 1 to extrapolate to the longer AEGL-specific exposure durations. Nonlethal effects of BZ are totally reversible. Because of the paucity of data for longer-term exposures, AEGL-2 values for the 4-h and 8-h durations were not developed and are not recommended. Effects observed in the human studies are likely due to the anticholinergic properties of BZ; structures of muscarinic receptors are highly conserved in humans and, thus, receptor affinity is not likely to vary among individuals. For example, very few polymorphisms in the M1 receptor (associated with learning and memory) have been detected and polymorphisms at highly conserved sites that might disrupt function of the receptor are rare (Lucas et al. 2001). However, individuals with pre-existing conditions may be more sensitive to the anticholinergic properties of BZ than the healthy men tested in the Ketchum studies. An intraspecies uncertainty factor of 10 accounts for possible pharmacokinetic differences and possible increased sensitivity between individuals. A modifying factor of 3 was applied to account for uncertainties in the overall database, particularly the short exposure duration (5 min) of the critical study.

AEGL-2 values for BZ are presented in Table 1-8 and their derivation is summarized in Appendix A.

7. DATA ANALYSIS FOR AEGL-3

7.1. Human Data Relevant to AEGL-3

No data regarding lethality in humans resulting from inhalation exposure to BZ are available. Ketchum and colleagues estimated human LD50 values of 2-5 mg/kg (extrapolation by species weight), 0.3-1.4 mg/kg (extrapolation by atropine lethality ratio), and 0.2-1.2 mg/kg (extrapolation by relative effectiveness ratio of atropine and BZ). Conversion of these doses to a concentration of BZ in air was not provided.

TABLE 1-8 AEGL-2 Values for Agent BZ

10 inin 30 mm lh 4h 8h
0.067 mg/m3 0.022 mg/m3 0.011 mg/m3 Not recommended Not recommended
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

7.2. Animal Data Relevant to AEGL-3

Lethality data for several laboratory species have been reported in the form of LCt50 values (U.S. Department of the Army 1974). These values had little or no accompanying information. The LCt50 was 37,000 mg-min/m3 in monkeys exposed for 6-25 min, 25,000 mg-min/m3 in dogs exposed for 6-16 min, 64,000 mg-min/m3 in rats exposed for 5-30 min, 12,000 mg-min/m3 in mice exposed for 5-19 min, 32,000 mg-min/m3 in rabbits exposed for 15-40 min, and 123,000 mg-min/m3 in guinea pigs exposed for 5-30 min. No information is available regarding the concentration-response relationship for inhaled BZ. In the Ketchum et al. (1967) study, even the highest concentration (575 mg-min/m3 for 8-min duration) was without serious effect.

7.3. Derivation of AEGL-3 Values

No human data with which to develop AEGL-3 values for BZ are available. Several of the human exposures reported by Ketchum (1963) and Ketchum et al. (1967) were associated with high TRI scores indicative of notable cognitive and behavioral effects and some motor function effects but no apparent serious physiologic responses. Effects were reversed 7-days post-exposure with no medical intervention. Other human studies have uncertainties inherent in the exposure-route extrapolations that would be required if using human LC50 estimates (Ketchum 1963) or if using the non-verifiable LCt50 of 200,000 mg-min/m3 estimated by Hoenig (2007). Thus, animal studies were used as the basis for deriving AEGL-3 values.

LCt50 values for animals are based on relatively short exposure durations (5-40 min). The LCt50 for the monkey (37,000 mg-min/m3) is neither the highest nor lowest value of the six species tested, but the monkey is a better model for aerosol inhalation exposure in humans than the other species. The monkey LCt50 was decreased 10-fold to 3,700 mg-min/m3, as an estimate of the lethality threshold and a point of departure for AEGL-3 derivation. Although a one-third reduction of the LC50 is often considered an appropriate estimate of the lethality threshold for chemicals with steep concentration-response relationships (NRC 2001), little is known about the concentration-response curve for BZ. Therefore, the 10-fold reduction is considered more defensible. Time scaling was performed using the equation Cn × t = k, with n = 1 to extrapolate to the longer AEGL-specific exposure durations. A factor of 10 was applied for interspecies differences because no lethality data are available for humans and LCt50 values for five animal species varied 10-fold. An intraspecies uncertainty factor of 10 was applied to account for possible pharmacokinetic differences and possible increased sensitivity between individuals. Effects observed in humans are likely due to the anticholinergic properties of BZ; structures of muscarinic receptors are highly conserved in humans and, thus, receptor affinity (and, therefore, toxicodynamics) is not likely to vary among individuals. For example, very few

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

polymorphisms in the M1 receptor (associated with learning and memory) have been detected and polymorphisms at highly conserved sites that might disrupt function of the receptor are rare (Lucas et al. 2001). However, individuals with pre-existing conditions may be sensitive to the anticholinergic effects of BZ. A modifying factor of 3 was applied because of uncertainties in the database, particularly a lack of incidence data (lethality studies only reported LCt50 values) which could be used to estimate a LC01 and a lack of studies involving longer exposure durations (longest duration was 40 min). AEGL-3 values for the 4- and 8-h durations are not recommended because data on exposure durations longer than 1 h are lacking.

AEGL-3 values for BZ are presented in Table 1-9 and their derivation is summarized in Appendix A.

8. SUMMARY OF AEGLs

8.1. AEGL Values and Toxicity End Points

AEGL values for BZ are presented in Table 1-10. The available data do not allow for assessing a minimal-effect threshold appropriate for developing AEGL-1 values. For AEGL-2 values, the point of departure was selected on the basis of preventing cognitive, behavioral, or physiologic effects. Cognitive and behavioral effects resulting from the anticholinergic activity of BZ are the most relevant effects (incapacitation) regarding human exposure to this chemical. Data for the AEGL-2 assessment are from extensive experiments using informed, human volunteers who underwent extensive screening prior to participation in the studies. AEGL-3 values were developed on the basis of LCt50 values in laboratory animals; the monkey was selected as the best animal model for humans. The anticholinergic (parasympatholytic) effects of BZ exhibit a notable latency (several hours or more) and are long-lasting (several days) following only brief exposure, but are reversible. Estimates of lethality thresholds for humans and lethality data in animals indicate a large margin between induction of incapacitating effects and lethality.

8.2. Comparisons with Other Standards and Guidelines

No guidelines or standards were available for BZ.

8.3. Data Adequacy and Research Needs

Human exposure data from controlled experiments adequately describe the incapacitating effects of BZ. Concentration-response data for inhalation exposures are lacking compared with data on other exposure routes. Data in animals are adequate for assessing lethality, although definitive lethality threshold data are lacking and effects of exposures for several hours are uncertain.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

TABLE 1-9 AEGL Values for Agent BZ

10 min 30 min l h 4 h 8 h
1.2 mg/m3 0.41 mg/m3 0.21 mg/m3 Not recommended Not recommended

TABLE 1-10 AEGL Values for Agent BZ

Classification 10 min 30 min 1 h 4 h 8 h
AEGL-1 (nondisabling)a NR NR NR NR NR
AEGL-2 (disabling) 0.067 mg/m3 0.022 mg/m3 0.011 mg/m3 NR NR
AEGL-3 (lethal) 1.2 mg/m3 0.41 mg/m3 0.21 mg/m3 NR NR

aAbsence of AEGL-1 values does not imply that exposure to concentrations less than the AEGL-2 values is without effect.

NR: not recommended because of data deficiencies.

9. REFERENCES

Byrd, G.D., R.C. Paule, L.C. Sander, L.T. Sniegoski, V.E. White, and H.T. Bausum. 1992. Determination of 3-quinuclidinyl benzilate (QNB) and its major metabolites in urine by isotope dilution gas chromatography/mass spectrometry. J. Anal. Toxicol. 16(3):182-187.

Haber, F.R. 1924. On the history of the gas war. Pp. 76-92 in Five Lectures from the Years 1920-1923 [in German]. Berlin, Germany: Verlag von Julius Springer.

Hoenig, S.L. 2007. Incapacitating Agents: Agent-BZ. Pp. 73-76 in Compendium of Chemical Warfare Agents. New York: Springer.

HSDB (Hazardous Substance Data Bank) 2008. BZ CAS No. (6581-06-2). TOXNET, Specialized Information Services, U.S. National Library of Medicine: Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Jan. 9, 2013].

Ketchum, J.S. 1963. The Human Assessment of BZ. CRDL Technical Memorandum 20-29. Human Investigations Facility, Directorate of Medical Research, U.S. Army Chemical Research and Development Laboratories, Edgewood Arsenal, MD.

Ketchum, J.S. 2006. Chemical Warfare Secrets Almost Forgotten: A Personal Story of Medical Testing of Army Volunteers. Santa Rosa, CA: ChemBooks.

Ketchum, J.S. and F.R. Sidell. 1997. Incapacitating agents. Pp. 287-306 in Medical Aspects of Chemical and Biological Warfare, F.R. Sidell, E.T. Takafuji, and D.R. Franz, eds. Office of the Surgeon General at TMM Publications, Borden Institute, Walter Reed Army Medical Center, Washington, DC.

Ketchum, J.S., B.R. Tharp, E.B. Crowell, D.L. Sawhill, and M.E. Vancil. 1967. The Human Assessment of BZ Disseminated Under Field Conditions. Edgewood Arsenal Technical Report EATR 4140. Medical Research Laboratory, Edgewood Arsenal, MD.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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Lucas, J.L., W. Sadee, and J.A. DeYoung. 2001. Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene. Pharm. Sci. 3(4):57-61.

McNamara, B.P. 1963. Toxicological Studies of Effects of BZ on Animals. CRCL Special Publication 2-50, U.S. Army Chemical Research and Development Laboratories, Edgewood Arsenal, MD (as cited in Rosenblatt et al. 1974).

NIST (The National Institute of Standards and Technology). 2011. 3-Quinuslidinyl benzilate. NIST Standard Reference Database 69: NIST Chemistry WebBook [online]. Available: http://webbook.nist.gov/cgi/cbook.cgi?ID=6581-06-2&Units=SI [accessed Jan. 9, 2013].

NRC (National Research Council). 1982. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. 1. Washington, DC: National Academy Press.

NRC (National Research Council). 1993. Guidelines for Developing Community Emergency 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: National Academy Press.

Rinehart, W.E., and T. Hatch. 1964. Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. Am. Ind. Hyg. Assoc. J. 25(6):545-553.

Rosenblatt, D.H., J.C. Dacre, R.N. Shiotuska, and C.D. Rowlett. 1977. Problem Definition Studies on Potential Environmental Pollutants, VIII. Chemistry and Toxicology of BZ (3-Quinuclindinyl Benzilate). Technical Report 7710. U.S. Army Medical Research and Development Laboratory, Fort Detrick, MD.

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. Hazard. Mater. 13(3):301-309.

USACHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 1996. Detailed facts about psychedelic agent 3- Quinuclidinyl benzilate (BZ). No. 218-16-1096 in Detailed and General Facts about Chemical Agents - TG218. U.S. Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, MD [online]. Available: https://safety.army.mil/LinkClick.aspx&fileticket=gdwCr8ynIao%3D&tabid=558 [accessed Jan. 9, 2013].

U.S. Department of the Army. 1974. Pp. 109-113 in Chemical Agent Data Sheets, Vol. 1. Edgewood Arsenal Special Report AD 0030. U.S. Department of the Army, Edgewood Arsenal, Aberdeen Proving Ground, MD.

Yamamura, H.I., and S.H. Snyder. 1974. Muscarinic cholinergic receptor binding in the longitudinal muscle of the guinea pig ileum with [3H] quinuclidinyl benzilate. Mol. Pharmacol. 10(6):861-867.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
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APPENDIX A

DERIVATION OF AEGL VALUES FOR AGENT BZ

Derivation of AEGL-1 Values

Although exposures to BZ resulting in no apparent effects in animals were available, the experiments could not assess possible cognitive and behavioral effects characteristic of BZ that are relevant to humans. Human data on BZ that define no-effect levels or that are consistent with the AEGL-1 definition were not available. Thus, AEGL-1 values for BZ are not recommended.

Derivation of AEGL-2 Values

Key study:

Ketchum, J.S., B.R. Tharp, E.B. Crowell, D.L. Sawhill, and M.E. Vancil. 1967. The Human Assessment of BZ Disseminated Under Field Conditions Edgewood Arsenal Technical Report EATR 4140.U.S. Department of the Army, Medical Research Laboratory, Edgewood Arsenal, MD.

Critical effect:

Point of departure is 20 mg-min/m3. Value was calculated as one-third of the ICt50 (a concentration-time product causing incapacitation of 50% of the test subjects) of 60.1 mg-min/m3 (95% CI: 41.3-87.5 mg-min/m3), and was considered an estimated threshold for incapacitating effects in humans. The one-third reduction was considered sufficient because it was well below the lower confidence limit of the ICt50, and is lower than concentrations (46.0-84.7 mg-min/m3) associated with clinical signs that might impair the ability to escape (e.g., progressive deterioration of normal gait and uncomfortable paresthesias of lower extremities).

Time scaling:

Data with which to assess the concentration-time relationship for BZ toxicity are not available. Experiments conducted by Ketchum and colleagues were of short durations; 6-8 min in animal studies and possibly no more than 5 min in tests with human volunteers. 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

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
 

Berge et al. 1986). In the absence of an empirically derived exponent (n) and to obtain protective AEGL values, time scaling was performed using a default of n = 1 for extrapolating from shorter exposures to longer duration.

Uncertainty factors:

1 for interspecies differences, because data were from human volunteers.

10 for intraspecies variability. The structures of muscarinic receptors are highly conserved in humans and, thus, receptor affinity is not likely to vary among individuals; however, some individuals with pre-existing conditions may be sensitive to the anticholingeric effects of BZ.

Total uncertainty factor of 10

Modifying factor:

3 because of deficiencies in overall data, particularly lack of longer duration studies

Calculation:

10-min AEGL-2:

C = 20 mg-min/m3 ÷ 10 min = 2 mg/m3
C = 2 mg/m3 ÷ 30 = 0.067 mg/m3

30-min AEGL-2:

C = 20 mg-min/m3 ÷ 30 min = 0.667 mg/m3
C = 0.667 mg/m3 ÷ 30 = 0.022 mg/m3

1-h AEGL-2:

C = 20 mg-min/m3 ÷ 60 min = 0.33 mg/m3
C = 0.33 mg/m3 ÷ 30 = 0.011 mg/m3

4-h AEGL-2:

Not recommended because of uncertainties regarding longer-term exposures.

8-h AEGL-2:

Not recommended because of uncertainties regarding longer-term exposures.

Derivation of AEGL-3 Values

Key study:

U.S. Department of the Army. 1974. Pp. 109-113 in Chemical Agent Data Sheets, Volume 1. Edgewood Arsenal Special Report AD 0030. U.S. Department of the Army, Edgewood Arsenal, Aberdeen Proving Ground, MD.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

Critical effect:

Lethality threshold estimated as one-tenth of the LCt50 of 37,000 mg-min/m3 for monkeys exposed to BZ for 6-25 min.

Time scaling:

Data with which to assess the concentration-time relationship for BZ toxicity are not available. The experiments conducted by Ketchum and colleagues were of short durations; 6-8 min in animal studies and possibly no more than 5 min in tests with human volunteers. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived exponent (n) and to obtain protective AEGL values, time scaling was performed using the default of n = 1 for extrapolating from shorter exposures to longer duration.

Uncertainty factors:

10 for interspecies differences; no lethality data are available for humans and LCt50 values for five animal species varied 10-fold. 10 for intraspecies variability; BZ toxicity is due to an anticholinergic mechanism and the structures of muscarinic receptors are highly conserved in humans, so receptor affinity (and, therefore, toxicodynamics) is not likely to vary among individuals; however, some individuals with pre-existing conditions may be sensitive to the anticholinergic effects of BZ.

Modifying factor:

3 because of deficiencies in overall data, in particular a lack of incidence data (the available lethality studies only reported LCt50 values) which could be used to estimate a LC01 and studies involving longer exposure durations (the longest duration exposure was 40 min).

Calculation:

10-min AEGL-3:

C = 3,700 mg-min/m3 ÷ 10 min = 370 mg/m3
C = 370 mg/m3 ÷ 300 = 1.2 mg/m3

30-min AEGL-3:

C = 3,700 mg-min/m3 ÷ 30 min = 123.3 mg/m3
C = 123.3 mg/m3 ÷ 300 = 0.41 mg/m3

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

1-h AEGL-3:

C = 3,700 mg-min/m3 ÷ 60 min = 61.67 mg/m3
C = 61.67 mg/m3 ÷ 300 = 0.21 mg/m3

4-h AEGL-3:

Not recommended because of uncertainties regarding longer-term exposures.

8-h AEGL-3:

Not recommended because of uncertainties regarding longer-term exposures.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

APPENDIX B

ACUTE EXPOSURE GUIDELINE LEVELS FOR AGENT BZ

Derivation Summary

AEGL-1 VALUES

Data on BZ were insufficient for deriving AEGL-1 values. Absence of AEGL-1 values does not imply that exposure below the AEGL-2 values are without adverse effects.

AEGL-2 VALUES

10 min 30 min 1 h 4 h 8 h
0.067 mg/m3 0.022 mg/m3 0.011 mg/m3 Not recommended Not recommended
Reference: Ketchum, J.S., B.R. Tharp, E.B. Crowell, D.L. Sawhill, and M.E. Vancil. 1967. The Human Assessment of BZ Disseminated Under Field Conditions. Edgewood Arsenal Technical Report EATR 4140.U.S. Department of the Army, Medical Research Laboratory, Edgewood Arsenal, MD.
Test species/Strain/Sex/Number: Human volunteers, males, n = 8
Exposure route/Concentrations/Durations: Aerosol inhalation
Effects: Cognitive and behavioral effects, mild effects on heart rate and blood pressure. ICt50 of 60.1 mg-min/m3 (95% CI: 41.3–87.5 mg-min/m3; presumably for 5 min) for a 165-pound human with a breathing rate of 15 L/min. An ICt50 is a concentration-time product causing incapacitation of 50% of the test subjects.
End point/Concentration/Rationale: Point of departure is 20 mg-min/m3 (one-third of the ICt50). One-third of the ICt50 was considered an estimated threshold for incapacitating effects in humans. The reduction was considered sufficient because it was well below the lower confidence limit of the ICt50 and concentrations associated with clinical signs which might impair the ability to escape (e.g., progressive deterioration of normal gait and uncomfortable paresthesias of lower extremities reported by subjects exposed to BZ at 46.0–84.7 mg-min/m3). BZ effects are totally reversible.
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies: 1, because data were from human volunteers
Intraspecies: 10, although the anticholinergic mechanism by which BZ operates is not likely to vary between individuals because the structure of muscarinic receptors are highly conserved in humans, individuals with pre-existing conditions may be sensitive to the antimuscarinic effects of BZ.
Modifying factor: 3, incomplete data base.
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Experimental data on BZ were expressed as CT products (mg-min/m3). For AEGL-specific exposure durations, all of which involved extrapolating to longer time frames, the concentrations were determined using the default of n = 1.
Data adequacy: Although definitive concentration-response information for inhalation exposure to BZ is lacking, data regarding human response to inhaled BZ aerosol are available and sufficient for developing AEGL-2 values.

AEGL-3 VALUES

10 min 30 min 1 h 4 h 8 h
1.2 mg/m3 0.41 mg/m3 0.21 mg/m3 Not recommended Not recommended
Reference: U.S. Department of the Army. 1974. Pp. 109–113 in Chemical Agent Data Sheets, Volume 1. Edgewood Arsenal Special Report AD 0030. U.S. Department of the Army, Edgewood Arsenal, Aberdeen Proving Ground, MD.
Test species/Strain/Sex/Number: Monkeys; species, gender, and number not reported.
Exposure route/Concentrations/Durations: Aerosol inhalation; LCt50 of 37,000 mg-min/m3 based on exposure durations of 6–25 min. Effects: LCt50 of 37,000 mg-min/m3 based on exposure durations of 6–25 min.
End point/Concentration/Rationale: Lethality threshold estimated as one-tenth of LCt50; definitive information regarding the concentration-response relationship for BZ is lacking.
Uncertainty factors/Rationale:
Total uncertainty factor: 100
Interspecies: 10, no lethality data are available for humans and LCt50 values for five animal species varied 10-fold.
Intraspecies: 10, the anticholinergic mechanism by which BZ operates is not likely to vary between individuals because the structure of muscarinic receptors are highly conserved in humans; however, individuals with pre-existing conditions may be sensitive to the anticholingeric effects of BZ.
Modifying factor: 3, incomplete data base (e.g., incidence data and studies involving longer exposure durations).
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Experimental data for BZ were consistently expressed as CT products (mg-min/m3). For AEGL-specific exposure durations, all of which involved extrapolating to longer time frames, the concentrations were determined using the default of n = 1.
Data adequacy: LCt50 values are available for five species but experimental details are lacking. Data are considered sufficient for deriving AEGL-3 values which can be compared with human exposure data.
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×

APPENDIX C

CATEGORY PLOT FOR AGENT BZ

title

FIGURE C-1 Category plot of animal and human data and AEGL values for Agent BZ. Response data for BZ were routinely expressed as a CT products (concentration × time) of mg-min/m3. Data points were derived for the lowest and highest exposure durations for which the CT values were determined, as well as for AEGL-specific durations within or near the respective range of the experimental exposure durations.

TABLE C-1 Data Used in Category Plot for Agent BZ

Source Species No. Exposures mg/m3 Minutes Category Comments
NAC/AEGL-1     NR 10 AEGL  
NAC/AEGL-1     NR 30 AEGL  
NAC/AEGL-1     NR 60 AEGL  
NAC/AEGL-1     NR 240 AEGL  
NAC/AEGL-1     NR 480 AEGL  
NAC/AEGL-2     0.067 10 AEGL  
NAC/AEGL-2     0.022 30 AEGL  
NAC/AEGL-2     0.011 60 AEGL  
NAC/AEGL-2     NR 240 AEGL  
NAC/AEGL-2     NR 480 AEGL  
NAC/AEGL-3     1.2 10 AEGL  
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Source Species No. Exposures mg/m3 Minutes Category Comments
NAC/AEGL-3     1.2 10 AEGL  
NAC/AEGL-3     0.41 30 AEGL  
NAC/AEGL-3     0.21 60 AEGL  
NAC/AEGL-3     NR 240 AEGL  
NAC/AEGL-3     NR 480 AEGL  
Ketchum 1963 Human 1 2 30 2  
  Human 1 5 30 2  
  Human 1 0.8 60 2  
  Human 1 1.2 60 2  
Department of the Army 1974 Monkey 1 6,167 6 SL LCt50
  Monkey 1 1,480 25 SL LCt50
  Dog 1 4,167 6 SL LCt50
  Dog 1 1,563 16 SL LCt50
  Rat 1 12,800 5 SL LCt50
  Rat 1 2,133 30 SL LCt50
  Mouse 1 2,400 5 SL LCt50
  Mouse 1 632 19 SL LCt50
  Rabbit 1 2,133 15 SL LCt50
  Rabbit 1 800 40 SL LCt50
  Guinea pig 1 24.600 5 SL LCt50
  Guinea pig 1 1 4,100 30 SL LCt50
Ketchum et al. 1967 Monkey 1 93 6.17 1 Mydriasis, cycloplegia. tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia
  Dog 1 93 6.17 1 Mydriasis, cycloplegia. tranquility, erratic behavior, lethargy, hyperactivity, sedation, ataxia, increased heart rate
  Dog 1 5 8 0  
  Rabbit 1 93 6.17 1 Mydriasis, cycloplegia
  Dog 1 1,000 8 SL RCt50
  Dog 1 25 8 1  
  Rabbit 1 10 8 1 RCt50
  Rabbit 1 1,000 8 SL  

For category: 0 = no effect; 1 = discomfort; 2 = disabling; SL = some lethality; 3 = lethal.

Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 15
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 19
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 23
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 24
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 25
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 26
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 27
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 28
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 29
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 38
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
Page 39
Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Suggested Citation:"1 Agent BZ (3-Quinuclidinyl Benzilate) Acute Exposure Guideline Levels." National Research Council. 2013. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington, DC: The National Academies Press. doi: 10.17226/18313.
×
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Extremely hazardous substances (EHSs) can be released accidentally as a result of result of chemical spills, industrial explosions, fires, or accidents involving railroad cars and trucks transporting EHSs. Workers and residents in communities surrounding industrial facilities where EHSs are manufactured, used, or stored and in communities along the nation's railways and highways are potentially at risk of being exposed to airborne EHSs during accidental releases or intentional releases by terrorists. Pursuant to the Superfund Amendments and Reauthorization Act of 1986, the U.S. Environmental Protection Agency (EPA) has identified approximately 400 EHSs on the basis of acute lethality data in rodents.

As part of its efforts to develop acute exposure guideline levels for EHSs, EPA and the Agency for Toxic Substances and Disease Registry (ATSDR) in 1991 requested that the National Research Council (NRC) develop guidelines for establishing such levels. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standard Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001, providing updated procedures, methodologies, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances and the Committee on Acute Exposure Guideline Levels (AEGLs) in developing the AEGL values.

Using the 1993 and 2001 NRC guidelines reports, the NAC—consisting of members from EPA, the Department of Defense (DOD), the Department of Energy (DOE), the Department of Transportation (DOT), other federal and state governments, the chemical industry, academia, and other organizations from the private sector—has developed AEGLs for more than 270 EHSs. In 1998, EPA and DOD requested that the NRC independently review the AEGLs developed by NAC. In response to that request, the NRC organized within its Committee on Toxicology (COT) the Committee on Acute Exposure Guideline Levels, which prepared this report. This report is the fourteenth volume in that series. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14 summarizes the committee's conclusions and recommendations.

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