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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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8

Trimethylbenzenes1

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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

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1This document was prepared by the AEGL Development Team composed of Carol Wood (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager John P. Hinz (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:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

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 nondisabling 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

Trimethylbenzene (TMB) isomers, including 1,3,5-, 1,2,4-, and 1,2,3-TMB, are common components of fuels and mixed hydrocarbon solvents (Delic et al. 1992). Together with other compounds of the same empirical formula, these flammable and explosive hydrocarbons are referred to as the C9 aromatics. TMB isomers are clear, colorless liquids that are insoluble in water (O’Neil et al. 2001). Little difference in toxicity has been observed between the TMB isomers. Because occupational exposures are likely to involve more than one isomer, regulatory standards are for the individual isomers and any mixture thereof.

For derivation of AEGL values, all available data on the individual TMB isomers were considered. The most appropriate end point was used as the point of departure for deriving values for each AEGL tier. Therefore, even though the point of departure might be based on data from an individual isomer, the resulting AEGL values are considered applicable to all three TMB isomers.

Human data were not available for derivation of AGEL values. No symptoms were reported at the concentrations tested in pharmacokinetic studies, and no case reports of human intoxication with the pure materials were found.

The most appropriate animal data for deriving AEGL-1 values were from neurotoxicity studies in rats exposed to 1,2,4-, 1,3,5-, or 1,2,3-TMB for 4 h (Korsak et al. 1995; Korsak and Rydzyński 1996). The effective concentration (EC50) values calculated on the basis of decrements in rotarod performance were 954, 963, and 768 ppm, respectively, indicating little difference in the effect level between the isomers. The average EC50 of 900 ppm for mild neurologic effects for the three isomers was chosen as the point of departure. A total uncer-

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

tainty factor of 10 was used. A factor of 3 for interspecies differences was used because the mechanism of action for hydrocarbon narcosis is not expected to differ between rats and humans, and a factor of 3 was applied for intraspecies variability because the threshold for narcosis differs by no more than 2- to 3-fold among the general population (NRC 2001). Because the point of departure is based on a systemic effect, values were scaled using the equation Cn × t = k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n = 3 for extrapolating to the 30-min and 1-h durations and n = 1 for the 8-h duration. According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), 10-min values should not be scaled from experimental exposure durations of 4 h or longer. Therefore, the 30-min AEGL-1 value was adopted as the 10-min value.

Few data were available for deriving AEGL-2 values. Rats repeatedly exposed to 1,2,4-TMB at 2,000 ppm for 6 h exhibited irritation, respiratory difficulty, lethargy, and tremors (Gage 1970); therefore, 2,000 ppm was chosen as the basis for deriving the AEGL-2 values. That point of departure also is supported by the weight of evidence on neurologic deficits measured at this concentration (Korsak et al. 1995; Korsak and Rydzyński 1996). The point of departure might not be a no-effect-level for AEGL-2 values, because the effects could lead to an impaired ability to escape. However, because the study involved repeated exposures, 2,000 ppm was considered a conservative estimate of effects for a single exposure. A total uncertainty factor of 10 was applied, which included a factor 3 for interspecies differences and 3 for intraspecies variability. Use of larger uncertainty factors was unnecessary because the mechanisms for irritation and narcosis are not expected to differ between humans and animals. Values were scaled using the same method used to derive AEGL-1 values, and the 30-min AEGL-2 value was adopted as the 10-min value.

Data were insufficient to derive AEGL-3 values for TMB. AEGL values for TMB are presented in Table 8-1.

1. INTRODUCTION

Trimethylbenzene (TMB) isomers include 1,3,5-, 1,2,4-, and 1,2,3-TMB, which are common components of motor vehicle and aviation fuels and mixed hydrocarbon solvents (Delic et al. 1992). Together with other compounds of the same empirical formula, these substances are referred to as the C9 aromatics. The primary hazards associated with these compounds are fire and explosion. TMB isomers are clear, colorless liquids that are insoluble in water (O’Neil et al. 2001). 1,2,4-TMB is purified by superfractionation and is used as a component of liquid scintillation cocktails (Earhart and Komin 2000). The 1,3,5- and 1,2,3-TMB isomers are produced synthetically and the derivatives are used in specialty solvents (Delic et al. 1992; Earhart and Komin 2000).

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

TABLE 8-1 AEGL Values for Trimeth lbenzenes

Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference)
AEGL-1 (nondisabling) 180 ppm (890 mg/m3) 180 ppm (890 mg/m3) 140 ppm (690 mg/m3) 90 ppm (440 mg/m3) 45 ppm (220 mg/m3) Average ED50 for rotarod performance after 4 h (Korsak et al. 1995; Korsak and Rydzyński 1996).
AEGL-2 (disabling) 460 ppm (2,300 mg/m3) 460 ppm (2,300 mg/m3) 360 ppm (1,800 mg/m3) 230 ppm (1,100 mg/m3) 150 ppm (740 mg/m3) Ocular and nasal irritation and lethargy in rats exposed at 2,000 ppm for 6 h (Gage 1970).
AEGL-3 (lethal) NR NR NR NR NR

Abbreviations: NR = not recommended

Chemical and physical properties of the TMB isomers are presented in Table 8-2.

2. HUMAN TOXICITY DATA

2.1. Acute Lethality

No reports of human fatalities or acute poisoning from TMB were found.

2.2. Nonlethal Toxicity

2.2.1. Odor Threshold and Awareness

AIHA (1995) reported odor detection levels or “concentrations” of 2.4 ppm for 1,2,4-TMB and 2.2 ppm for 1,3,5-TMB from acceptable sources after a critique of the data. No odor threshold value for 1,2,3-TMB was found.

2.2.2. Case Reports

No reports of injury or illness from accidental or intentional exposure to TMB isomers were found.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

TABLE 8-2 Chemical and Ph sical Pro erties of Trimeth lbenzenes

Parameter 1,3,5-TMB 1,2,4-TMB 1,2,3-TMB Reference
Synonyms Mesitylene Pseudocumene Hemimellitene Delic et al. 1992
CAS registry no. 108-67-8 95-63-6 526-73-8
Chemical formula C9H12 C9H12 C9H12 Delic et al. 1992
Molecular weight 120.19 120.19 120.19 Earhart and Komin 2000
Physical state Liquid Liquid Liquid Delic et al. 1992
Melting point -44.8°C -43.78°C O’Neil et al. 2001
Boiling point 164°C 169°C 176°C Delic et al. 1992
Density
Vapor (air =1) -0.8651 g/cm3 at 20°C 4.15 4.1 Delic et al. 1992
Liquid (water =1) 0.8758 g/cm3 at 20°C 0.8944 g/cm3 at 20°C Earhart and Komin 2000
Solubility in water Practically insoluble Practically insoluble O’Neil et al. 2001
Vapor pressure 1.5 mm Hg 25°C 2.03 mm Hg 25°C 2.5 mm Hg 25°C EPA 1987
Flash point 43.0°C 46.0°C 51.0°C Earhart and Komin 2000
Flammability limits (% in air) 0.88 0.88 0.88 Henderson 2001
Conversion factors 1 ppm = 4.92 mg/m3 1 ppm = 4.92 mg/m3 1 ppm = 4.92 mg/m3 Delic et al. 1992
1 mg/m3 = 0.203 ppm 1 mg/m3 = 0.203 ppm 1 mg/m3 = 0.203 ppm
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

2.2.3. Epidemiologic Studies and Occupational Exposures

No epidemiologic data specifically on TMB exposure were found. Occupational exposures usually involve a complex mixture of hydrocarbons including dozens of related aromatic and aliphatic organic chemicals.

Concentrations of a variety of compounds were measured in six areas of an offset printing shop to estimate emission of volatile organic compounds (Wadden et al. 1995). Concentrations of 1,3,5-, 1,2,4-, and 1,2,3-TMB ranged from 1.63-3.68 mg/m3 (0.33-0.75 ppm), 2.27-5.07 mg/m3 (0.46-1.03 ppm), and 0.23-0.53 mg/m3 (0.05-0.11 ppm), respectively. No attempt was made to correlate these area measurements with breathing zone concentrations. In a similar workplace monitoring study, workers were exposed to concentrations ranging from none detected to 25.3 ppm (total of all three isomers) as an 8-h time weighted average (Jones et al. 2006). TMB concentrations in breath and urinary metabolite concentrations were positively correlated with personal and ambient air samples, but no symptoms were reported.

Concentrations of combined 1,2,4- and 1,2,3-TMB measured in the breathing zone of a painter were 0.4-4.6 mg/m3 (0.08-0.93 ppm). The painter used paint diluted with white spirit (C9 aromatics) and worked for 11-21 min (van der Wal and Moerkerken 1984).

Exposure to organic compounds was monitored and complaints recorded over several days in asphalt workers involved in road repair and construction (Norseth et al. 1991). Organic compounds were collected by personal samplers and measured by gas chromatography. Fatigue, reduced appetite, laryngeal and pharyngeal irritation, cough, and ocular irritation were found more often in asphalt workers than in a reference group. When symptoms were converted to a numeric scale for calculation of a “symptom sum,” a positive correlation was found between symptom sum and concentration of 1,2,4-TMB (r = 0.31). Mean concentrations of the 1,2,4-, 1,3,5-, and 1,2,3-TMB isomers were 1.50, 0.14, and 0.38 ppm, respectively. The most prevalent compounds were m- and p-xylene (12.4 ppm) and the C9-C13 aliphatics (39.6 ppm).

Bättig et al. (1956) reported on the health status of workers in a painting workshop. A total of 27 individuals with average ages of 48-55, depending on job type, had worked with the solvent “Fleet-X” for an average of 7 years. “Fleet-X” contains 50% 1,2,4-TMB, 30% 1,3,5-TMB, and 20% other solvents. Concentrations of total hydrocarbons in workshop air were 10-60 ppm. Up to 80% of the exposed workers complained of nervousness, tension, and anxiety and 70% had asthmatic bronchitis. Hematology showed a tendency to hyperchromic anemia and coagulation disorders. Gerarde (1960) subsequently noted that the hematology changes reported by Bättig et al. (1956) might have been due to trace amounts of benzene. Hematopoietic toxicity has not been reported in animal studies with pure TMB (Gage 1970).

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

2.2.4. Experimental Studies

In pharmacokinetic studies with all three TMB isomers, no irritation or central nervous system effects were reported in volunteers exposed at up to 25 ppm for 2 h (Järnberg et al. 1996) or 4 h (Jones et al. 2006) or at up to 30 ppm for 8 h (Kostrzewski et al. 1997).

2.3. Neurotoxicity

No information was found regarding the potential neurotoxicity of pure TMB in humans.

2.4. Developmental and Reproductive Toxicity

No information was found regarding the potential reproductive or developmental toxicity of pure TMB in humans.

2.5. Genotoxicity

No information was found regarding the potential genotoxicity of pure TMB in humans.

2.6. Carcinogenicity

No information was found regarding the potential carcinogenicity of pure TMB in humans. None of the TMB isomers have been classified by U.S. Environmental Protection Agency or the International Agency for Research on Cancer.

2.7. Summary

Very little information is available concerning human exposure to pure TMB isomers despite the wide use of these materials. No deaths have been reported from exposure to TMB. Occupational studies involved exposure to mixtures of hydrocarbon solvents.

3. ANIMAL TOXICITY DATA

3.1. Acute Lethality

3.1.1. Rats

Adult male and female Wistar rats (number per sex not specified) were exposed in whole body inhalation chambers to 1,3,5-TMB (purity not reported)

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

(Cameron et al. 1938). Atmospheres were generated by bubbling air through a saturation unit, and the chamber atmospheres were described as being accurate during a continuous run. Four of 16 rats exposed continuously to 1,3,5-TMB at 2,240 ppm for 24 h died. Narcosis developed and the animals died of respiratory failure; pulmonary congestion was observed at necropsy.

3.2. Nonlethal Toxicity

3.2.1. Rats

Groups of six male Wistar rats were exposed to 1,3,5-TMB at 0, 61, 305, 609, or 1,218 ppm for 6 h. No details were provided on the purity of 1,3,5-TMB, exposure apparatus, atmosphere generation, or monitoring (Wiglusz et al. 1975a,b). Blood was collected at various times after exposure for analyses of hematology and serum enzyme activity. No changes were found in hemoglobin concentration, erythrocyte and leukocyte count, or the activity of aspartate aminotransferase, alanine amino transferase, or glutamate dehydrogenase. However, a concentration-related slight increase in the percentage of segmented neutrophils and a slight reduction in the percentage of lymphocytes were observed immediately after exposure, and alkaline phosphatase activity was significantly higher on day 7 post exposure (at 609 ppm only). Clinical findings and body weight were not mentioned.

Male and female Wistar rats (number per sex not specified) were exposed in whole body inhalation chambers (Cameron et al. 1938). Atmospheres were generated by bubbling air through a saturation unit, and the chamber atmospheres were described as being accurate during a continuous run. No adverse clinical signs, deaths, or necropsy findings occurred in animals (n = 4-8) exposed to 1,2,4-TMB at 1,800-2,000 ppm for up to 48 h or for 8 h/day for 14 days. No animals died in groups (n = 10) exposed at 560 ppm for 24 h or for 8 h/day for 14 days.

3.2.2. Mice

The RD50 values (concentrations of a substance that reduces the respiratory rate by 50%) for 1,2,4-, 1,3,5-, and 1,2,3-TMB (purities of >97, 99, and 90-95%, respectively) in male Balb/C mice were 578, 519, and 541 ppm, respectively (Korsak et al. 1995, 1997). Groups of animals (n = 8-10) were exposed at 253-1,928 ppm for 6 min, followed by a 6-min recovery period. Each animal was placed in a plethysmograph for measurement of respiratory pattern. Chamber atmospheres were generated by heating the liquid solvent in washers and diluting with air to the desired concentration. Concentration was monitored by a gas chromatograph with a flame-ionization detector. The maximum reduction in respiratory rate occurred during the first 2 min of exposure with each isomer. Clinical signs were not mentioned.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

Male and female mice (strain and number per sex not specified) were exposed in whole body inhalation chambers to 1,2,4- or 1,3,5-TMB (Cameron et al. 1938). Atmospheres were generated by bubbling air through a saturation unit, and the chamber atmospheres were described as being accurate during a continuous run as measured by “chemical analysis.” No adverse clinical signs, deaths, or necropsy findings occurred in animals (n = 10) exposed to 1,3,5-TMB at 560 ppm for 24 h or for 8 h/day for 14 days. Likewise, no effects were seen in animals (n = 10) exposed to1,2,4-TMB at 1,800-2,000 ppm for 12 h.

Lazarew (1929) exposed white mice (strain and number per sex not specified) to 1,2,4- or 1,3,5-TMB in whole body inhalation chambers for 2 h. Details of atmosphere generation were not provided. Mice exposed to 1,2,4-TMB at 8,100 ppm or to 1,3,5-TMB at 5,000-7,000 ppm exhibited lateral position during exposure. Slightly higher concentrations of 8,100-9,100 ppm and 7,000-9,000 ppm for 1,2,4- and 1,3,5-TMB, respectively, resulted in loss of reflexes.

3.3. Neurotoxicity

Groups of 10 male Wistar rats were exposed in whole-body chambers to 1,2,4-, 1,3,5-, or 1,2,3-TMB at 250-2,000 ppm for 4 h (purity >97, 100, and 90-95%, respectively) (Korsak et al. 1995; Korsak and Rydzyński 1996). Chamber atmospheres were generated by heating the liquid and diluting it with air to the desired concentration. Chamber concentrations were monitored by a gas chromatograph equipped with a flame-ionization detector. Immediately after exposure each animal was tested either for rotarod performance or hot-plate reaction. Clinical signs were not mentioned; all animals survived the exposures, but no observations other than results of neurotoxicity testing were mentioned. A concentration-dependent increase in the number of failures in rotarod performance and decrease in pain sensitivity (measured as latency to the paw-lick response) occurred. Following exposure to either 1,2,4-, 1,3,5- or 1,2,3-TMB, the effective concentration for a 50% response (EC50) for rotarod performance were calculated to be 954 (95% confidence interval [CI]: 791-1,113), 963 (95% CI: 750-1,113), and 768 (95% CI: 578-942) ppm, respectively. EC50 values for pain sensitivity were 1,155 (95% CI: 552-1,544), 1,212 (95% CI: 1,086-1,329), and 848 (95% CI: 694-982) ppm, respectively. EC50 values were calculated from a graph of exposure concentration versus either probit of the number of failures (rotarod) or percent over controls in latency (pain sensitivity).

Male Wistar rats were exposed for 6 h/day, 5 days/week in whole-body chambers to 1,2,4- or 1,2,3-TMB at 25, 100, or 250 ppm for 28 days (Gralewicz et al. 1997a; Wiaderna et al. 1998) or 90 days (Korsak and Rydzyński, 1996; Korsak et al. 1997). In a follow-up study, male Wistar rats were exposed to the same isomers at 100 ppm for 28 days (Gralewicz and Wiaderna 2001). Chamber atmospheres were generated by heating the liquid solvent in washers and diluting it with air to the desired concentration. Concentrations were monitored by a gas chromatograph equipped with a flame-ionization detector. No treatment-

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

related clinical signs of toxicity were observed and all animals survived. Body weight was not affected by exposure to any TMB isomer.

In the 28-day exposure studies, a series of neurotoxicity tests was conducted (n = 10-15/group) 14-61 days after exposure ended to assess residual effects (Gralewicz et al. 1997a; Wiaderna et al. 1998; Gralewicz and Wiaderna 2001). No effects from any of the TMB isomers were noted in the radial maze or pain sensitivity assays. Passive avoidance learning was delayed and the foot-shock-induced increase in latency of the paw-lick response persisted in rats exposed to 1,2,4-TMB at 100 and 250 ppm, to 1,2,3-TMB at 25 and 100 ppm, and to 1,3,5-TMB at 100 ppm. When observed in the open field, grooming and locomotor activity were increased in rats exposed to 1,2,4- and 1,3,5- TMB at 100 ppm. Acquisition of the active avoidance response was impaired in rats exposed to the three isomers at 100 ppm. Electroencephalogram recordings were made on an additional group of rats exposed to 1,24-TMB at 0, 25, 100, or 250 ppm for 28 days (Gralewicz et al. 1997b). The spike-wave discharge activity in the control and 25-ppm groups progressively increased during a 4-month postexposure period, and decreased in the 100- and 250-ppm groups.

In the 90-day exposure studies, only rotarod performance and pain sensitivity (hot plate behavior) were evaluated (n = 6-7/group) (Korsak and Rydzyński 1996; Korsak et al. 1997). A concentration-dependent increase in the number of failures in rotarod performance was observed throughout the study with 1,2,4-TMB at 250 ppm and 1,2,3-TMB at 100 and 250 ppm. Recovery of rotarod performance was not evident in rats 2 weeks they were exposed at the highest concentration of either isomer. Similarly, a concentration-dependent reduction in pain sensitivity was observed with 1,2,4-TMB at 100 and 250 ppm and at all concentrations of 1,2,3-TMB. However, there was complete recovery of pain sensitivity 2 weeks after exposure (Korsak and Rydzyński 1996). In an additional experiment, pulmonary lavage fluid was collected and analyzed 24 h after the last exposure to 1,2,4-TMB. The total number of cells in the bronchoalveolar lavage fluid was increased in all TMB-exposed groups due to an increase in macrophages, polymorphonuclear leucocytes, and lymphocytes. Lactate dehydrogenase and acid phosphatase activities in the lavage fluid were increased in all groups (Korsak et al. 1997).

Male Mol:WIST rats (n = 5) exposed to white spirit (constituent composition not described) at 0, 400, or 800 ppm for 6 h/day, 5 days/week for 3 weeks had concentration-related increases in whole brain levels of noradrenaline, dopamine, and 5-hydroxytryptamine; brain weight, protein concentration, and acetyl- and butyryl-cholinesterase activities were unaffected (Lam et al. 1992). Clinical signs of toxicity were not described.

Groups of four male Wistar rats and eight female H strain mice were exposed by whole body for 4 or 2 h, respectively, to a range of concentrations of each TMB isomer (“analytical purity”) (Frantík et al. 1994). Details of atmosphere generation and monitoring were not included and the exact concentrations were not provided. Within 1 min of removal from the chamber, each animal was measured for inhibition of propagation and maintenance of the electrically

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

evoked seizure discharge. An electrical impulse was applied through ear electrodes and the duration of tonic extension of the hindlimbs was recorded; control values were subtracted from values recorded after exposure with inhibition considered a measure of neurotoxicity. Concentrations of 1,2,4-, 1,3,5-, and 1,2,3-TMB that resulted in 30% depression in rats were 636, 440, and 489 ppm, respectively, and in mice were 391, 611, and 416 ppm, respectively. No other information was provided.

3.4. Developmental and Reproductive Toxicity

Female Sprague-Dawley rats (n = 24) were exposed whole body to 1,3,5-TMB at 100-1,200 ppm or to 1,2,4-TMB at 100-900 ppm (purity was 99% for both isomers) for 6 h/day on gestation days 6-20 (Saillenfait et al. 2005). Test atmospheres were generated by passing air flow through the fritted disk of a heated bubbler containing the test chemical. Vaporized compound was carried into the main air inlet pipe and concentration was adjusted by varying the airflow passing through the bubbler. Atmospheres were monitored by gas a chromatograph equipped with a flame-ionization detector. Mean measured concentrations differed by less than 2% of nominal concentrations. Maternal toxicity was evident as decreased body weight gain and reduced food consumption with 1,3,5-TMB at concentrations of 300 ppm and greater and with 1,2,4-TMB at concentrations of 600 ppm and greater. All dams survived, and no clinical signs of toxicity were observed. Fetal body weight was decreased with both isomers at concentrations of 600 ppm and greater. No external, visceral, or skeletal malformations were observed with either isomer.

Groups of 30 female CD-1 mice were exposed whole body to C9 aromatic hydrocarbons at concentrations of 0, 100, 500, or 1,500 ppm for 6 h/day on gestation days 6-15 (IRDC 1988a; McKee et al. 1990). Mean analytically-determined concentrations during the study were within 2% of nominal concentrations. The composition of the test material contained 8.37% 1,3,5-TMB, 40.5% 1,2,4-TMB, and 6.18% 1,2,3-TMB. The remainder of the mixture was comprised of o-xylene, cumene, n-propyl benzene, and 4-, 3-, and 2-ethyltoluene. No treatment-related mortality, clinical signs of toxicity, or changes in food consumption were observed at 100 or 500 ppm. A total of 12 animals exposed at 1,500 ppm died between gestation days 8-16. Clinical signs of toxicity at 1,500 ppm included abnormal gait (18 animals), labored breathing, hunched posture, weakness, inadequate grooming, circling, and ataxia (7-9 animals). Most of these signs were observed after one or two days of exposure. Body weight gain by the 500- and 1,500-ppm groups was 88 and 63%, respectively, of the control group during exposure. Food consumption by the 1,500-ppm group was 65-77% of the control group. Hematologic analysis on gestation day 15 revealed significantly reduced hematocrit and mean corpuscular volume and increased mean corpuscular hemoglobin concentration in mice exposed at 1,500 ppm compared with controls. Maternal necropsy was unremarkable. At

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

cesarean section on gestation day 18, dams in the 1,500-ppm group had significantly fewer live fetuses/dam because of an increase in post-implantation loss compared with controls. Fetal body weight in the mid- and high-concentration groups was significantly reduced compared to that of controls (1.16 and 0.82 g, respectively, vs. 1.25 g for controls). Cleft palate was found in 14 fetuses from seven high-concentration litters compared with one control fetus, and reduced ossification of the skull was found in 18 fetuses from six high-concentration litters compared with none in the controls.

In a range-finding developmental toxicity study, groups of five female CD-1 mice were exposed whole body to C9 aromatic hydrocarbons at concentrations of 0, 100, 250, 500, 1,000, or 1,500 ppm for 6 h/day on gestation days 6-15 (IRDC 1988b). Composition of the test article was as described by McKee et al. (1990). Two dams in the 1,500-ppm group were sacrificed moribund on gestation day 6. All remaining animals survived. Clinical signs in high-concentration animals were similar to those described by McKee et al. (1990). During the treatment interval, body weight gain was reduced at 1,000 and greater, and food consumption was reduced at 1,500 ppm compared with controls. Fetal body weight was reduced at 500 ppm or greater. No treatment-related external fetal malformations were observed. Fetuses were not examined viscerally or skeletally.

In a three-generation reproduction study, groups of 30 or 40 male and 30 or 40 female Charles River COBS CD rats were exposed whole body to C9 aromatic hydrocarbons at concentrations of 0, 100, 500, or 1,500 ppm for 6 h/day, 5 days/week for 10 weeks prior to mating and during a 2-week mating interval. After mating, the males were killed. Females continued to be exposed for 6 h/day, 7 days/week on gestation days 0-20, and exposure was resumed on lactation days 5-21 (McKee et al. 1990). Mean analytically-determined concentrations during the study were within 2% of nominal concentrations. The composition of the test material contained 8.37% 1,3,5-TMB, 40.5% 1,2,4-TMB, and 6.18% 1,2,3-TMB. The remainder of the mixture was comprised of o-xylene, cumene, n-propyl benzene, and 4-, 3-, and 2-ethyltoluene.

All F0 and F1 parental males survived the exposure. In the 1,500-ppm groups, a total of seven of 30 F0 females, six of 30 F1 females, 36 of /40 F2 males, and 34 of 40 F2 females died or were sacrificed. Clinical signs of toxicity of ataxia and reduced motor activity were described in the F1 parental animals. During premating, males and females of all generations exposed at 500 and 1,500 ppm and the F2 animals exposed at100 ppm had reduced body weight and body weight gain. Body weight reductions were more pronounced in each successive generation. Food consumption was similar between the treated and control groups throughout the study and gross necropsy of the adults was unremarkable (McKee et al. 1990).

The precoital interval was increased at 1,500 ppm for all generations. Mating, gestation, and fertility indices were not affected in the F0 or F2 generations, although only six F3 litters were produced due to deaths of the F2 animals. At 1,500 ppm, F1 parental animals had decreased male fertility index and decreased

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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live litter size at birth. F2 offspring in the 1,500-ppm group had reduced live birth index (85.1% vs 97.5% in controls) and reduced survival to postnatal day 4 (87.4% vs 95.4% for controls). Body weight of F1, F2, and F3 pups exposed at 1,500 ppm was significantly less than that of controls beginning on lactation day 7. In addition, body weights of the F3 pups in the 1,500-ppm group were lower than that of controls at birth, and in the 500-ppm group were lower starting on lactation day 14 (McKee et al. 1990).

3.5. Genotoxicity

The three TMB isomers were evaluated for mutagenicity using Salmonella typhimurium strains TA97a, TA98, TA100, and TA102, for micronucleus formation, and for induction of sister chromatid exchange in male and female mice (Janik-Spiechowicz et al. 1998). Only 1,2,3-TMB increased both base-pair substitutions and frameshift mutations in the absence of metabolic activation. The 1,2,4- and 1,3,5-TMB isomers were negative for mutagenicity, and all three were negative for micronucleus formation. The isomers were cytotoxic at 20-40 μL/plate, and the highest doses in mice (>2,900 mg/kg) caused overt hematopoietic toxicity and death of several animals. Positive results for sister chromatid exchange induction were found with all isomers at nonlethal doses.

3.6. Subchronic Toxicity, Chronic Toxicity, and Carcinogenicity

Alderley Park rats (n = 4/sex) were exposed whole body in dynamic chambers to 1,2,4-TMB (purity not reported) for 6 h/day, for 5 days/week; exposures were either at nearly saturated vapor for a total of 12 exposures or at 1,000 ppm for a total of 15 exposures (Gage 1970). Nearly saturated atmospheres of 2,000 ppm (estimated by weighing the sample before and after the day’s exposure) were obtained by passing air through the liquid contained in a bubbler with a sintered glass air-distributor disc. The 1,000-ppm atmosphere was generated by injecting liquid at a known rate into a metered stream of air by means of a controlled fluid-feed atomizer. Rats exposed to the saturated atmosphere displayed nasal irritation, described as sneezing that progressed in severity to nasal discharge and bloody exudates; ocular irritation, described as eyes closed that progressed in severity to lachrymation; respiratory difficulty, such as rapid, shallow breathing that progressed to labored and slow breathing; lethargy, which included decreased activity; a lower response to noise; tremors; and decreased weight gain over the course of the experiment. Exposure at 1,000 ppm resulted in initial signs of slight ocular and nasal irritation. Onset and progression of clinical signs was not further described. All animals survived and no hematology changes or gross or histopathologic lesions were noted after exposure at either concentration.

Groups of male Wistar rats (n = 6) were exposed to 1,3,5-TMB at 0 or 609 ppm for 6 h/day, 6 days/week for 5 weeks; no details were provided on the pu-

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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rity of the test article, exposure apparatus, atmosphere generation, or monitoring (Wiglusz et al. 1975a,b). Blood was collected at various times after exposure for analysis of hematology and serum enzyme activity. No changes in hematology were found, but aspartate aminotransferase activity was slightly elevated on day 14 postexposure. Clinical findings and body weight were not mentioned.

Male and female Wistar rats (n = 20/sex/group) were exposed to 1,2,3-TMB (>97% pure) at 0, 25, 100, or 250 ppm for 6 h/day, 5 days/week for 3 months (Korsak et al. 2000). Chamber atmospheres were generated by heating the liquid and diluting with air to the desired concentration. Concentration was monitored by a gas chromatograph equipped with a flame-ionization detector. All animals survived to scheduled necropsy and no treatment-related clinical signs of toxicity were observed. Body weight gain and food consumption were not affected by treatment. Animals exposed at 250 ppm exhibited increased liver weight relative to body weight (males), decreased erythrocyte counts (males), increased reticulocyte counts (males), decreased neutrophil counts (both sexes), increased lymphocyte counts (both sexes), increased serum sorbitol dehydrogenase (males), and increased serum alkaline phosphatase (females). Microscopic examination of the respiratory tract revealed an increased number of goblet cells in females of the 100- and 250-ppm groups, and interstitial lymphocytic infiltration in males of the 250-ppm group.

No adverse effects were observed in rats exposed at 1,700 ppm of an isomeric mixture of TMB for 10-21 days; the isomer composition was not described (Rossi and Grandjean 1957). Decreased weight gain, lymphopenia, neutrophilia, and marked central nervous system depression were seen when animals were exposed at the same concentration for 4 months (Bättig et al. 1958). Hematotoxicity observed in these older studies may have been due to benzene in the solvents (ACGIH 1992).

3.7. Summary

Animal data are summarized in Table 8-3. Clinical signs of irritation were observed in laboratory animals at concentrations >1,000 ppm in some studies but not in others. Lethargy or narcosis in animals correlated with neurotoxicity measured in rats. Alterations in hematology observed in some studies were not confirmed in other studies. TMB is not a selective developmental toxicant. Results from a three-generation reproductive toxicity study suggest cumulative systemic toxicity in both male and female rats over successive generations.

4. SPECIAL CONSIDERATIONS

4.1. Metabolism and Disposition

TMB is readily absorbed, accumulates in adipose tissue, and metabolites are excreted in the urine in both humans and rats exposed by inhalation. 1,2,4-

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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TMB was detected in the serum of a laboratory technician 2 h after handling a liquid scintillation cocktail; it was assumed that inhalation was the main route of exposure and a duration was not specified (Kenndler et al. 1989).

TABLE 8-3 Summary of Animal Studies of Trimethylbenzenes

Species (sex) Concentration (ppm) Duration Effects Reference
Rat (M/F) 2,240 24 h 4/16 died Cameron et al. 1938
Rat (M/F) 560 24 h or 8 h/d for 14 d None
1,800-2,000 48 h or 8 h/day for 14 d None
Rat (M) 768-1,212 4 h Calculated EC50 for mild neurotoxic effects Korsak et al. 1995; Korsak and Rydzyński 1996
Rat (M/F) 1,000 6 h, 15 times Ocular and nasal irritation Gage 1970
2,000 6 h, 12 times Severe irritation, lethargy
Mouse (M) 519-578 6 min RD50 Korsak et al. 1995, 1997
Mouse (M/F) 560 24 h or 8 h/d for 14 d None Cameron et al. 1938
1,800-2,000 12 h None
Mouse 5,000-8,100 Lateral position Lazarew 1929
7,000-9,000 2 h Loss of reflexes
Rat (M) 25, 100, 250 6 h/d, 5 d/wk, 28 or 90 d Mild neurotoxicity at 100 and 250 ppm Korsak and Rydzyński 1996; Gralewicz et al. 1997a; Korsak et al. 1997; Wiaderna et al. 1998; Gralewicz and Wiaderna 2001
Rat (M/F) 25, 100, 250 6 h/d, 5 d/wk, 90 d Hematology and clinical chemistry changes at 250 ppm, lesions in respiratory tract at 100 and 250 ppm Korsak et al. 2000
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Järnberg et al. (1996, 1997a,b, 1998) studied the kinetics of inhaled 1,2,4-, 1,2,3-, or 1,3,5-TMB (purity of >99, 90-95, and 99%, respectively) in healthy male volunteers (ages 26-48 years). Subjects were exposed in a chamber to 25 ppm of each isomer or 2 ppm of 1,2,4-TMB for 2 h at a work load of 50 W. Relative respiratory uptake was 56-64% and exhalation after exposure accounted for 30-37% of the absorbed dose. Large volumes of distribution and terminal half-lives in blood of 78-120 h indicated accumulation in a deep compartment, most likely adipose tissue (Järnberg et al. 1996). Between 3-18% of the absorbed dose of each isomer was recovered in the urine as dimethylhippuric acid after 24 h and only about 3% of the absorbed dose was excreted as the unconjugated dimethylbenzoic acid (Järnberg et al. 1997a). When subjects were exposed concurrently to 1,2,4-TMB at 2 ppm and white spirit (16% aromatics) at 61 ppm, both blood concentrations of 1,2,4-TMB and excretion rates of dimethylhippuric acid were increased compared with exposure to 1,2,4-TMB alone (Järnberg et al. 1997b, 1998).

In a similar experiment, volunteers (ages 20-39 years) were exposed at rest in a chamber with each TMB isomer at 1-30 ppm for 4 or 8 h (Kostrzewski and Wiaderna-Brycht 1995; Kostrzewski et al. 1997). Retention by the lungs was 67-71% of the inhaled concentration, and elimination from the blood followed a three-compartment model. Urinary excretion of dimethylbenzoic acid was greatest 2 h before the end of exposure until 2 h after exposure ended.

Jones et al. (2006) exposed two male and two female volunteers (ages not specified) in a chamber to 1,3,5-TMB at 25 ppm for 4 h. TMB was measured in blood and breath during and after exposure and urinary dimethylbenzoic acids were measured after exposure. Blood concentrations reached steady-state after 1-2 h of exposure, with the mean concentration 0.85 μmol/L; blood concentrations remained constant through the last sampling time of 1 h postexposure. Breath concentrations of TMB peaked rapidly after initiation of exposure, and concentrations ranged from 114 to 160 nmol/L during exposure. Biphasic elimination was observed after exposure with a mean half-life of 60 min for the rapid phase and 600 min for the slow phase. 3,5-Dimethylbenzoic acid was measured in the urine, with a peak mean concentration of 40 mmol/mol creatinine at 4-8 h postexposure. Urinary elimination was biphasic with an initial mean half-life of 13 h and a secondary half-life of 60 h.

1,3,5-TMB was measured in the blood of rats after a 2 h whole-body exposure at 120-720 ppm; blood concentrations ranged from 15.7 to 143.5 μmol/L in a concentration-related manner (Römer et al. 1986; Freundt et al. 1989). Concentrations of all three isomers were measured in the whole brains of rats exposed to white spirit (Stoddard solvent) at 400 or 800 ppm for 6 h/day, 5 days/week for 3 weeks (Lam et al. 1992). 1,3,5-TMB was found at 0.10 and 0.08 mg/kg of brain (wet weight) after exposure at 400 and 800 ppm, respectively; the 1,2,4- and 1,2,3-TMB isomers were not detected in rats exposed at 400 ppm, but were measured at 0.40 and 0.07 mg/kg, respectively, in rats exposed at 800 ppm. Although the total white spirit concentration increased in the brain with

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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increasing concentration, the accumulation was mainly from the aliphatic components and not the aromatic components (Lam et al. 1992).

Zahlsen et al. (1992) measured tissue concentrations in rats exposed whole-body to 1,2,4-TMB at 100 ppm for 12 h/day for 3 days. After each day of exposure, low concentrations of the isomer were found in the blood, brain, liver, and kidneys, with little difference in concentration after successive days of exposure suggesting no accumulation. In fat, the concentration decreased with each day. Only trace amounts were detected in the tissues 12 h after the last exposure. These investigators also exposed rats to 1,2,4-TMB at 1,000 ppm for 12 h/day for up to 14 days (Zahlsen et al. 1990). With the exception of fat, steady state was established between days 3 and 7. The highest concentration of 1,2,4-TMB in the fat was measured on day 1, with a significantly lower steady state level found on days 3-14. The brain-blood and fat-blood ratios were 2.0 and 63, respectively.

Similar tissue distribution was found in rats after an oral dose of 14C-1,2,4-TMB (Huo et al. 1989). Small amounts of radioactivity were found throughout the body, with the greatest amount (up to 28% of the dose) in the adipose tissue 3 h after dosing. Tissue concentrations declined rapidly within 24 h, and more than 99% of the radioactivity recovered in the urine during this period.

Induction of microsomal enzymes follows exposure to TMB. Rats exposed to 1,2,4-TMB at 0.2 or 2 ppm for 4 h had increased cytochrome P-450 content in the liver, lungs, and kidneys (Shakirov et al. 1999). Cytochrome P-450 content was increased in the liver and decreased in the lungs of male Sprague-Dawley rats after a single intraperitoneal injection of each of the TMB isomers (Pyykkö et al. 1987). Concurrently, 7-ethoxycoumarin O-deethylase activity was increased in the liver and decreased in the lung, 7-ethoxyresorufin O-deethylase activity was increased in both tissues, and aryl hydrocarbon hydroxylase activity was increased in the liver. Cytochrome b5 content and NADPH-cytochrome c-reductase activity were unchanged in the lungs and liver (Pyykkö et al. 1987).

Urinary metabolites in rats were measured after oral administration of each TMB isomer at 1.2 g/kg (Mikulski and Wiglusz 1975). With 1,3,5-TMB, 20.7-28.2% of the dose was recovered as 3,5-dimethylhippuric acid. That metabolite was not found with either 1,2,4- or 1,2,3-TMB. Both the 1,3,5- and 1,2,4-TMB isomers were mainly excreted as glycine conjugates with smaller amounts excreted as glucuronic and sulfuric acid conjugates. In contrast, sulphate conjugates were predominate metabolites with 1,2,3-TMB. Approximately 73, 37, and 33% of the dose was excreted in urine within 48 h after administration of 1,3,5-, 1,2,4-, and 1,2,3-TMB, respectively. Pretreatment with phenobarbital increased excretion of glucuronic and sulfate conjugates and decreased excretion of glycine conjugates for all three isomers (Mikulski and Wiglusz 1975). In a similar study, approximately 30.2% of an oral dose of 1,2,4-TMB was recovered in the urine of rats as dimethylhippuric acid (Huo et al. 1989).

A similar metabolic profile was found in male rabbits. Following oral administration of 1,2,4-TMB, the major urinary metabolites were 2,4-dimethylbenzoic acid and 3,4-dimethylhippuric acid (Cerf et al. 1980). Like-

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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wise, following oral administration of 1,3,5-TMB, 9.0% of the dose was excreted in the urine as 3,5-dimethylbenzoic acid and 68.5% was recovered as the glycine conjugate 3,5-dimethylhippuric acid (Laham and Potvin 1989).

Urinary 3,4-dimethylhippuric acid concentrations have been used to determine worker or occupational exposure to 1,2,4-TMB (Ichiba et al. 1992; Fukaya et al. 1994). This metabolite correlates with workplace atmospheric concentration, and has been found at higher concentration postshift compared with preshift concentrations.

Minor metabolic pathways include production of mercapturic acid and hydroxylation. About 5% of an intraperitoneal dose of 1,2,3-TMB to rats was excreted in the urine as 2,3-dimethylbenzyl mercapturic acid (Tsujimoto et al. 1999). After an oral dose of either 1,2,4-TMB or 1,2,5-TMB at 100 mg/kg, only 0.05 and 0.4% of the dose, respectively, were recovered in the urine of rats as phenolic metabolites (Bakke and Scheline 1970).

4.2. Mechanism of Toxicity

Little is known about the mechanism of TMB toxicity. At higher concentrations, direct irritation of mucous membranes and narcosis was apparent in some of the animal studies (Lazarew 1929; Cameron et al. 1938; Gage 1970). Hematologic evaluations were highly variable among studies, and some investigators believe benzene might have contaminated some preparations and affected results (Gerarde 1960). This is particularly true of older studies.

4.3. Structure Activity Relationships

Little difference in toxicity has been observed between the TMB isomers. Calculated ED50 values for neurologic deficits in rats were similar for the three isomers. Likewise, RD50 values in mice did not differ. Since occupational exposures are likely to involve more than one isomer, regulatory standards are for the individual isomers and any mixture thereof. In the monitoring studies described in Section 2.2.3, the most abundant isomer was 1,2,4-TMB.

For derivation of AEGL values, all available data on the individual TMB isomers were considered. The most appropriate end point for each AEGL category was used as the point of departure for deriving AEGL values. Therefore, even though the point of departure might be based on data from an individual isomer, the AEGL values are considered applicable to all three TMB isomers.

4.4. Other Relevant Information

4.4.1. Species Variability

Rats appear to be slightly more sensitive than mice to the toxic effects of the TMB isomers. However, differences in results might be due to the methods of atmosphere generation and concentration measurement, not due to the animal

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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response. Mild clinical signs were reported in male and female rats exposed repeatedly to TMB at 1,000 ppm for 6 h (Gage 1970), but not in mice exposed at up to 2,000 ppm for 12 h (Cameron et al. 1938). Lethality was reported in rats exposed at 2,240 ppm for 24 h (Cameron et al. 1938), but no mortality data on mice were found. Marked central nervous system depression was noted in mice exposed to TMB at 5,000 ppm for 2 h (Lazarew 1929). Thus, differences in analytic techniques between the older and more recent literature might explain the differences in species responses.

4.4.2. Susceptible Populations

Limited data suggest that the pregnant mouse is most susceptible to alkyl benzene toxicity. Exposure of mice for 6 h/day on gestation days 8-16 to a mixture of TMB isomers and other alkyl benzenes resulted in maternal and developmental toxicity at 500 and 1,500 ppm (IRDC 1988a; McKee et al. 1990). In contrast, no adverse effects were reported in female mice exposed to 1,2,4-TMB at 2,000 ppm for 12 h (Cameron et al. 1938). However, differences in response might have been due to total absorbed dose as a consequence of repeated versus single exposure.

4.4.3. Concentration-Exposure Duration Relationship

The concentration-exposure duration relationship for substances like TMB can be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of a chemical-specific data to empirically derive an exponent, a default value of n = 1 can be used when extrapolating to longer durations and a default value of n = 3 can be used when extrapolating to shorter durations (NRC 2001).

5. DATA ANALYSIS FOR AEGL-1

5.1. Summary of Human Data Relevant to AEGL-1

No human data relevant to derivation of AEGL-1 values were found. In occupational studies, exposures were not correlated with symptoms, and exposures involved a mixture of hydrocarbon compounds. In pharmacokinetic studies with all three TMB isomers, no irritation or other adverse effects were reported in volunteers exposed at up to 25 ppm for 2 h (Järnberg et al. 1996) or at up to 30 ppm for 8 h (Kostrzewski et al. 1997).

5.2. Summary of Animal Data Relevant to AEGL-1

The most appropriate animal data for derivation of AEGL-1 values are neurotoxicity studies (Korsak et al. 1995; Korsak and Rydzyński 1996). In a

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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study of rats exposed to the three TMB for 4 h, the calculated EC50 values for rotarod performance were 954, 963, and 768 ppm, indicating little difference in the effect level between isomers.

Exposure of male and female rats to 1,2,4-TMB at 1,000 ppm for 6 h resulted in signs of slight ocular and nasal irritation (Gage et al. 1970). Although the exposures were repeated 15 times, the onset of clinical signs was not reported. All animals survived and no changes in hematology or gross lesions were noted.

Maternal toxicity was not evident in rats exposed to 1,3,5-TMB at 100 ppm or to 1,2,4-TMB at 300 ppm for 6 h/day on gestation days 6-20 (Saillenfait et al. 2005).

No adverse effects were reported in mice after exposure to 1,2,4-TMB at 1,800-2,000 ppm for 12 h (Cameron et al. 1938).

5.3. Derivation of AEGL-1 Values

Few studies were available on which to base AEGL-1 values. A concentration of 900 ppm for 4 h, calculated as the average EC50 for mild neurologic effects for the three TMB isomers, was chosen as the point of departure. The EC50 is considered a threshold consistent with the AEGL-1 definition as a no-effect level for asymptomatic nonclinical effects. A slightly higher concentration resulted in signs of irritation. A total uncertainty factor of 10 was used. A factor 3 for intraspecies variability was applied because the threshold for narcosis differs by no more than 2- or 3-fold among the general population (NRC 2001), and a factor of 3 for interspecies differences was used because the mechanism of action for narcosis is not expected to differ between rats and humans. Because the point of departure is a systemic effect, values were scaled using the equation Cn × t = k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n = 3 for extrapolating to the 30-min and 1-h durations and n = 1 for the 8-h duration. According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), 10-min values should not to be scaled from an experimental duration of 4 h or longer. Therefore, the 30-min AEGL-1 value was adopted as the 10-min value. AEGL-1 values for TMB are presented in Table 8-4.

6. DATA ANALYSIS FOR AEGL-2

6.1. Summary of Human Data Relevant to AEGL-2

No human data relevant to derivation of AEGL-2 values were found.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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TABLE 8-4 AELG-1 Values for Trimeth lbenzenes

10 min 30 min 1 h 4 h 8 h
180 ppm (890 mg/m3) 180 ppm (890 mg/m3) 140 ppm (690 mg/m3) 90 ppm (440 mg/m3) 45 ppm (220 mg/m3)

6.2. Summary of Animal Data Relevant to AEGL-2

Animal data relevant to derivation of AEGL-2 values are those of Gage (1970). Exposure of male and female rats to 1,2,4-TMB at 2,000 ppm for 6 h resulted in signs of nasal and ocular irritation, respiratory difficulty, lethargy, tremors, and reduced weight gain over the course of the experiment. Although the exposure was repeated 12 times, the onset of clinical signs was not reported. All animals survived and no hematologic changes or gross lesions were noted.

In a study evaluating neurotoxicity, rats were exposed to each TMB isomer at concentrations up to 2,000 ppm for 4 h (Korsak et al. 1995; Korsak and Rydzyński 1996). A concentration-dependent increase in the number of failures in rotarod performance and decrease in pain sensitivity (measured as latency to the paw-lick response) occurred in exposed animals. Clinical signs were not mentioned and all animals survived.

6.3. Derivation of AEGL-2 values

Rats exposed to 1,2,4-TMB at 2,000 ppm for 6 h exhibited irritation, respiratory difficulty, lethargy, and tremors; therefore, 2,000 ppm was chosen as the basis for deriving AEGL-2 values. The weight of evidence supports that point of departure, with neurologic deficits also measured at 2,000 ppm (Korsak et al. 1995; Korsak and Rydzyński 1996). Furthermore, no adverse effects were reported in rats exposed to a mixture of TMBs at 1,700 ppm for 10-21 days (Rossi and Grandjean 1957), no effects were reported in mice exposed to 1,2,4-TMB at 1,800-2,000 ppm for 12 h (Cameron et al. 1938), and cumulative effects on body weight and reproductive parameters were found over successive generations of rats exposed to a mixture TMB isomers and other alkyl benzenes at 1,500 ppm (McKee et al. 1990). The point of departure might not be a no-effect-level for AEGL-2 values, because the effects could lead to an impaired ability to escape. However, because the key study involved repeated exposures, 2,000 ppm was considered a conservative estimate of effects from a single exposure. A total uncertainty factor of 10 was used. A factor of 3 for intraspecies variability was applied because the threshold for narcosis differs by no more than 2- to 3-fold among the general population (NRC 2001), and a factor 3 for interspecies differences was used because the mechanisms for irritation and narcosis are not expected to differ between animals and humans. Values were scaled using the equation Cn × t = k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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absence of an empirically derived, chemical-specific exponent, scaling was performed using a default of n = 3 for extrapolating to the 30-min, 1-, and 4-h durations and n = 1 for the 8-h duration. According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), 10-min values should not to be scaled from an experimental exposure duration of 4 h or longer. Therefore, the 30-min AEGL-2 value was adopted as the 10-min value. AEGL-2 values are presented in Table 8-5.

7. DATA ANALYSIS FOR AEGL-3

7.1. Summary of Human Data Relevant to AEGL-3

Human data relevant to deriving AEGL-3 values for TMBs were not available.

7.2. Summary of Animal Data Relevant to AEGL-3

The only available lethality data on TMB was a study in rats that were exposed continuously to 1,3,5-TMB for 24 h, but concentration-response data were not reported (Cameron et al. 1938). In another study, white mice were exposed to 1,2,4- or 1,3,5-TMB in whole body inhalation chambers for 2 h (Lazarew 1929). The lowest concentration of either isomer that resulted in lateral position of the animals was 5,000 ppm. At slightly higher concentrations, the animals had loss of reflexes. Although the narcosis causing lateral position in mice could possibly lead to respiratory failure if the exposure duration was extended or the concentration was increased, data supporting this premise are lacking.

7.3. Derivation of AEGL-3 Values

Insufficient data were available to derive AEGL-3 values for TMB. Thus, AEGL-3 values were not recommended.

8. SUMMARY OF AEGL VALUES

8.1. AEGL Values and Toxicity End Points

AEGL values for TMB are presented in Table 8-6. AEGL-1 values were based on slight neurotoxicity in rats, and AEGL-2 values were based on irritation and neurotoxicity in rats. AEGL-3 values were not recommended.

TABLE 8-5 AEGL-2 Values for Trimethylbenzenes

10 min 30 min 1 h 4 h 8 h
460 ppm (2,300 mg/m3) 460 ppm (2,300 mg/m3) 360 ppm (1,800 mg/m3) 230 ppm (1,100 mg/m3) 150 ppm (740 mg/m3)
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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8.2. Comparison with Other Standards and Guidelines

Standards and guidance levels for workplace and community exposures are presented in Table 8-7. These standards have been established for the individual TMB isomers and any mixture thereof. The time-weighted average exposure concentration for workers is 25 ppm in the United States and Sweden. An Immediately Dangerous to Life or Health (IDLH) concentration has not been established by National Institute for Occupational Safety and Health. The occupational exposure limit from The Netherlands and Germany is 20 ppm. The short-term exposure limit in Sweden (OEL-STEL) for a 15-min exposure (35 ppm) is lower than the AEGL-1 value for 10 or 30 min (180 ppm). Information describing the basis of the OEL-STEL value was not available for comparison to the AEGL-1 derivation.

8.3. Data Adequacy and Research Needs

Few relevant human and animal data were available despite the widespread use of these TMB in common fuels and hydrocarbon solvents in commerce. Thus, a clear concentration-response was difficult to assess for both nonlethal and lethal concentrations. Some discrepancies also were noted in the available data, which might be due to differences in analytic techniques used in the older studies compared with more studies.

TABLE 8-6 AEGL Values for Trimethylbenzenes

Classification Exposure Duration
10 min 30 min 1 h 4 h 8 h
AEGL-1 (nondisabling) 180 ppm (890 mg/m3) 180 ppm (890 mg/m3) 140 ppm (690 mg/m3) 90 ppm (440 mg/m3) 45 ppm (220 mg/m3)
AEGL-2 (disabling) 460 ppm (2,300 mg/m3) 460 ppm (2,300 mg/m3) 360 ppm (1,800 mg/m3) 230 ppm (1,100 mg/m3) 150 ppm (740 mg/m3)
AEGL-3 (lethal) NR NR NR NR NR

Abbreviations: NR, not recommended.

TABLE 8-7 Extant Standard and Guidelines for Trimethylbenzenes

Guideline Exposure Duration
10 min 30 min 1 h 4 h 8 h
AEGL-1 180 ppm 180 ppm 140 ppm 90 ppm 45 ppm
AEGL-2 460 ppm 460 ppm 360 ppm 230 ppm 150 ppm
AEGL-3 NR NR NR NR NR
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×
Guideline Exposure Duration
10 min 30 min 1 h 4 h 8 h
TLV-TWA (ACGIH)a 25 ppm
REL-TWA (NIOSH)b 25 ppm
MAK (Germany)c 20 ppm (II)
MAC (The Netherlands)d 20 ppm
OEL-LLV (Sweden)e 25 ppm
OEL-STV (Sweden)f 35 ppm

aTLV-TWA (threshold limit value - time weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2005) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. TMB isomers have a sensitizer notation.
bREL-TWA (recommended exposure limit - time weighted average, National Institute for Occupational Safety and Health) (NIOSH 2011) is defined analogous to the ACGIH TLV-TWA.
cMAK (maximale arbeitsplatzkonzentration [maximum workplace concentration]) (Deutsche Forschungsgemeinschaft - German Research Association] (DFG 2005) is defined analogous to the ACGIH TLV-TWA. Category II is for substances with systemic effects: excursion factor = 2; duration = 15 min, average value; 4/shift with 1 h interval.
dMAC (maximaal aanvaarde concentratie [maximal accepted concentration]) (Dutch Expert Committee for Occupational Standards, The Netherlands (MSZW 2004) is defined analogous to the ACGIH TLV-TWA.
eOEL-LLV (occupational exposure limit - level limit value) (Swedish Work Environment Authority 2005) is an occupational exposure limit value for exposure during one working day.
fOEL-STV (occupational exposure limit - short-term value) (Swedish Work Environment Authority 2005) is an occupational exposure limit value for exposure during a reference period of 15 min.
Abbreviations: NR, not recommended.

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×

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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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APPENDIX A

DERIVATION OF AEGL VALUES FOR TRIMETHYLBENZENES

Derivation of AEGL-1 Values

Key studies: Korsak et al. 1995; Korsak and Rydzyński 1996
Toxicity end point: Average ED50 for decrements in rotarod performance in rats exposed to 1,2,4-, 1,3,5-, or 1,2,3-TMB at 900 ppm for 4 h (954 ppm + 963 ppm + 768 ppm) ÷ 3 = 900 ppm
Time scaling: Cn × t = k (ten Berge et al. 1986), default values of n = 3 for extrapolating to the 30-min and 1-h durations and n = 1 for extrapolating to the 8-h duration (900 ppm ÷ 10)3 × 4 h = 2.9 × 106 ppm-h (900 ppm ÷ 10)1 × 4 h = 360 ppm-h
Uncertainty factors: 3 for interspecies differences
3 for intraspecies variability
Total uncertainty factor of 10
Modifying factor: None
Calculations:
10-min AEGL-1: Set equal to the 30-min value of 180 ppm
30-min AEGL-1: (2.9 × 106 ppm-h ÷ 0.5 h)1/3 = 180 ppm
1-h AEGL-1: (2.9 × 106 ppm-h ÷ 1 h)1/3 = 140 ppm
4-h AEGL-1: 900 ppm ÷ 10 = 90 ppm
8-h AEGL-1: 360 ppm-h ÷ 8 h = 45 ppm
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

Derivation of AEGL-2 Values

Key study: Gage 1970
Toxicity end point: Nasal and ocular irritation, respiratory difficulty, lethargy, tremors, and decreased weight gain over the course of the experiment in rats exposed 12 times to 1,2,4-TMB at 2,000 ppm for 6 h.
Time scaling: Cn × t = k (ten Berge et al. 1986), default values of n = 3 for extrapolating to the 30-min and 1- and 4-h durations and n = 1 for extrapolating to the 8-h duration (2,000 ppm ÷ 10)3 × 6 h = 4.8 × 107 ppm-h (2,000 ppm ÷ 10)1 × 6 h = 1,200 ppm-h
Uncertainty factors: 3 for interspecies differences
3 for intraspecies variability
Total uncertainty factor of 10
Modifying factor: None
Calculations:
10-min AEGL-2: Set equal to the 30-min value of 460 ppm
30-min AEGL-2: (4.8 × 107 ppm-h ÷ 0.5 h)1/3 = 460 ppm
1-h AEGL-2: (4.8 × 107 ppm-h ÷ 1 h)1/3 = 360 ppm
4-h AEGL-2: (4.8 × 107 ppm-h ÷ 4 h)1/3 = 230 ppm
8-h AEGL-2: 1,200 ppm-h ÷ 8 h = 150 ppm

Derivation of AEGL-3 Values

Insufficient data were available to derive AEGL-3 values for TMBs. Thus, AEGL-3 values were not recommended.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

APPENDIX B

ACUTE EXPOSURE GUIDELINE LEVELS FOR TRIMETHYLBENZENES

Derivation Summary for Trimethylbenzenes

AEGL-1 VALUES

10 min 30 min 1 h 4 h 8 h
180 ppm 180 ppm 140 ppm 90 ppm 45 ppm
Key references: Korsak, Z., R. öwiercz, and K. Rydzyński. 1995. Toxic effects of acute inhalation exposure to 1,2,4-trimethylbenzene (pseudocumene) in experimental animals. Int. J. Occup. Med. Environ. Health 8(4):331-337.
Korsak, Z., and K. Rydzyński. 1996. Neurotoxic effects of acute and subchronic inhalation exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimellitene) in rats. Int. J. Occup. Med. Environ. Health 9(4):341-349.
Test species/Strain/Number: Rat, Wistar, 10 males
Exposure route/Concentrations/Durations: Inhalation, 250-2,000 ppm of each isomer, 4 h.
Effects:
Calculated ED50 for decrements in rotarod performance:
   1,2,4-TMB: 954 ppm
   1,3,5-TMB: 963 ppm
   1,2,3-TMB: 768 ppm
End point/Concentration/Rationale: Average of EC50 values = 900 ppm.
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3, because the mechanism of action for narcosis is not expected to differ between rats and humans.
Intraspecies: 3, because the threshold for narcosis differs by no more than 2- to 3- fold among the general population (NRC 2001).
Modifying factor: None
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Cn × t = k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n = 3 for extrapolating to the 30-min and 1-h durations and n = 1 for the 8-h duration. According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), 10-min values are not to be scaled from an experimental exposure duration of 4 h or more. Therefore, the 30-min AEGL-1 value was adopted as the 10-min value.
Data adequacy: Limited data which meet the definition of AEGL-1.
Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

AEGL-2 VALUES

10 min 30 min 1 h 4 h 8 h
460 ppm 460 ppm 360 ppm 230 ppm 150 ppm
Key Reference: Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18.
Test species/Strain/Number: Rat, Alderley Park, 4 per sex
Exposure route/Concentrations/Durations: Inhalation, 1,2,4-TMB at 1,000 or 2,000 ppm for 6 h repeated 15 or 12 times, respectively.
Effects:
1,000 ppm: slight ocular and nasal irritation.
2,000 ppm: nasal and ocular irritation, respiratory difficulty, lethargy, tremors, and decreased weight gain over the course of the experiment.
End point/Concentration/Rationale: Severe irritation and narcosis in rats exposed at 2,000 ppm.
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3, because the mechanisms of action for irritation and narcosis are not expected to differ between humans and rats.
Intraspecies: 3, because the threshold for narcosis differs by no more than 2- to 3-fold among the general population (NRC 2001).
Modifying factor: None
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Cn × t = k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n = 3 for extrapolating to the 30-min, 1-, and 4-h durations and n = 1 for the 8-h duration. According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), 10-min values should not to be scaled from an experimental exposure duration of 4 h or more. Therefore, the 30-min AEGL-2 value was adopted as the 10-min value.
Data adequacy: Limited data which meet the definition of AEGL-2.

AEGL-3 VALUES

Insufficient data were available to derive AEGL-3 values for TMBs. Thus, AEGL-3 values were not recommended.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
×

APPENDIX C

CATEGORY PLOT FOR TRIMETHYLBENZENES

image

FIGURE C-1 Category plot of toxicity data and AEGL values for trimethylbenzenes.

Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Suggested Citation:"8 Trimethylbenzenes." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13. Washington, DC: The National Academies Press. doi: 10.17226/15852.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13 Get This Book
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At the request of the Department of Defense and the Environmental Protection Agency, the National Research Council has reviewed the relevant scientific literature compiled by an expert panel and established Acute Exposure Guideline Levels (AEGLs) for several chemicals. AEGLs represent exposure levels below which adverse health effects are not likely to occur and are useful in responding to emergencies, such as accidental or intentional chemical releases in community, workplace, transportation, and military settings, and for the remediation of contaminated sites.

Three AEGLs are approved for each chemical, representing exposure levels that result in: 1) notable but reversible discomfort; 2) long-lasting health effects; and 3) life-threatening health impacts. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 13 includes AEGLs for boron trifluoride, bromoacetone, chloroacetone, hexafluoroacetone, perchloryl fluoride, piperidine, propargyl alcohol, trimethoxysilane and tetramethoxysilane, and trimethylbenzenes.

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