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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 Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This 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 neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 242
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Trimethylbenzenes 243 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding 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 iso- mers. Because occupational exposures are likely to involve more than one iso- mer, 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 result- ing AEGL values are considered applicable to all three TMB isomers. Human data were not available for derivation of AGEL values. No symp- toms 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-
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244 Acute Exposure Guideline Levels 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 em- pirically 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 ex- posed to 1,2,4-TMB at 2,000 ppm for 6 h exhibited irritation, respiratory diffi- culty, 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 sup- ported by the weight of evidence on neurologic deficits measured at this concen- tration (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 compo- nent 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).
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Trimethylbenzenes 245 TABLE 8-1 AEGL Values for Trimethylbenzenes End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 180 ppm 180 ppm 140 ppm 90 ppm 45 ppm Average ED50 (nondisabling) (890 (890 (690 (440 (220 for rotarod mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) performance after 4 h (Korsak et al. 1995; Korsak and Rydzyński 1996). AEGL-2 460 ppm 460 ppm 360 ppm 230 ppm 150 ppm Ocular and (disabling) (2,300 (2,300 (1,800 (1,100 (740 nasal irritation mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) and lethargy in rats exposed at 2,000 ppm for 6 h (Gage 1970). AEGL-3 NR NR NR NR NR (lethal) 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.
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246 TABLE 8-2 Chemical and Physical Properties of Trimethylbenzenes 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
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Trimethylbenzenes 247 2.2.3. Epidemiologic Studies and Occupational Exposures No epidemiologic data specifically on TMB exposure were found. Occu- pational exposures usually involve a complex mixture of hydrocarbons includ- ing 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 corre- late 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 as- phalt 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 hyper- chromic 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).
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248 Acute Exposure Guideline Levels 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 devel- opmental 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. Envi- ronmental Protection Agency or the International Agency for Research on Can- cer. 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 re- ported from exposure to TMB. Occupational studies involved exposure to mix- tures 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)
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Trimethylbenzenes 249 (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 ami- notransferase, alanine amino transferase, or glutamate dehydrogenase. However, a concentration-related slight increase in the percentage of segmented neutro- phils 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 atmos- pheres were described as being accurate during a continuous run. No adverse clinical signs, deaths, or necropsy findings occurred in animals (n = 4-8) ex- posed 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 respira- tory 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, respec- tively (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. Cham- ber 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.
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250 Acute Exposure Guideline Levels Male and female mice (strain and number per sex not specified) were ex- posed 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 con- tinuous 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 speci- fied) 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 chro- matograph equipped with a flame-ionization detector. Immediately after expo- sure 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 con- centration-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 calcu- lated 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 sen- sitivity 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 dilut- ing it with air to the desired concentration. Concentrations were monitored by a gas chromatograph equipped with a flame-ionization detector. No treatment-
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Trimethylbenzenes 251 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 con- ducted (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 ex- posed 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 lo- comotor 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 ex- posed 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 post- exposure period, and decreased in the 100- and 250-ppm groups. In the 90-day exposure studies, only rotarod performance and pain sensi- tivity (hot plate behavior) were evaluated (n = 6-7/group) (Korsak and Rydzyń- ski 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 per- formance was not evident in rats 2 weeks they were exposed at the highest con- centration 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 addi- tional 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 dehy- drogenase 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 composi- tion 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, do- pamine, and 5-hydroxytryptamine; brain weight, protein concentration, and ace- tyl- 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 ex- posed 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 atmos- phere 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
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252 Acute Exposure Guideline Levels evoked seizure discharge. An electrical impulse was applied through ear elec- trodes and the duration of tonic extension of the hindlimbs was recorded; control values were subtracted from values recorded after exposure with inhibition con- sidered 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, re- spectively, and in mice were 391, 611, and 416 ppm, respectively. No other in- formation 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 air- flow passing through the bubbler. Atmospheres were monitored by gas a chro- matograph equipped with a flame-ionization detector. Mean measured concen- trations 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 mal- formations 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 ges- tation days 6-15 (IRDC 1988a; McKee et al. 1990). Mean analytically- determined concentrations during the study were within 2% of nominal concen- trations. 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 ani- mals). 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%, respec- tively, 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
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264 Acute Exposure Guideline Levels 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 indi- vidual TMB isomers and any mixture thereof. The time-weighted average expo- sure 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 occu- pational 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 wide- spread use of these TMB in common fuels and hydrocarbon solvents in com- merce. 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 Exposure Duration Classification 10 min 30 min 1h 4h 8h AEGL-1 180 ppm 180 ppm 140 ppm 90 ppm 45 ppm (nondisabling) (890 (890 (690 (440 (220 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-2 460 ppm 460 ppm 360 ppm 230 ppm 150 ppm (disabling) (2,300 (2,300 (1,800 (1,100 (740 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 NR NR NR NR NR (lethal) Abbreviations: NR, not recommended. TABLE 8-7 Extant Standard and Guidelines for Trimethylbenzenes Exposure Duration Guideline 10 min 30 min 1h 4h 8h 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 (Continued)
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Trimethylbenzenes 265 TABLE 8-7 Continued Exposure Duration Guideline 10 min 30 min 1h 4h 8h TLV-TWA 25 ppm (ACGIH)a REL-TWA 25 ppm (NIOSH)b MAK 20 ppm (II) (Germany)c MAC 20 ppm (The Netherlands)d OEL-LLV 25 ppm (Sweden)e OEL-STV 35 ppm (Sweden)f a TLV-TWA (threshold limit value - time weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2005) is the time-weighted average con- centration 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. b REL-TWA (recommended exposure limit - time weighted average, National Institute for Occupational Safety and Health) (NIOSH 2011) is defined analogous to the ACGIH TLV-TWA. c MAK (maximale arbeitsplatzkonzentration [maximum workplace concentration]) (Deutsche Forschungsgemeinschaft - German Research Association] (DFG 2005) is de- fined 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. d MAC (maximaal aanvaarde concentratie [maximal accepted concentration]) (Dutch Expert Committee for Occupational Standards, The Netherlands (MSZW 2004) is de- fined analogous to the ACGIH TLV-TWA. e OEL-LLV (occupational exposure limit - level limit value) (Swedish Work Environment Authority 2005) is an occupational exposure limit value for exposure during one working day. f OEL-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. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1992. Trimethyl Benzene Isomers. Pp. 1648-1649 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Government and Industrial Hygienists). 2005. P. 57 in TLVs® and BEIs® Based on the Documentation of the Threshold Limit Values for
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266 Acute Exposure Guideline Levels Chemical Substances and Physical Agents and Biological Exposure Indices. Ameri- can Conference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 1995. P. 79 in Odor Thresholds for Chemicals with Established Occupational Health Standards. American Industrial Hygiene Association, Fairfax, VA. Bakke, O.V., and R.R. Scheline. 1970. Hydroxylation of aromatic hydrocarbons in the rat. Toxicol. Appl. Pharmacol. 16(3):691-700. Bättig, K., E. Grandjean, and V. Turrian. 1956. Damage to health after long-term exposure to trimethylbenzene in a paint shop [in German]. Z. Prav. Med. 1:389- 403. Bättig, K., E. Grandjean, L. Rossi, and J. Rickenbacher. 1958. Toxicological studies on trimethylbenzene [in German]. Arch. Gewerbepathol. Gewerbehyg. 16(5):555- 566. Cameron, G.R., J.L.H. Paterson, G.S.W. de Saram, and J.C. Thomas. 1938. The toxicity of some methyl derivatives of benzene with special reference to pseudocumene and heavy coal tar naphtha. J. Pathol. Bacteriol. 46(1):95-107. Cerf, J., M. Potvin, and S. Laham. 1980. Acidic metabolites of pseudocumene in rabbit urine. Arch. Toxicol. 45(2):93-100. Delic, J., R. Gardner, J. Cocker, E.M. Widdowson, and R. Brown. 1992. Trimethylben- zenes: Criteria Document for an Occupational Exposure Limit. London: HM Sta- tionery Office. 34 pp. DFG (Deutsche Forschungsgemeinschaft). 2005. List of MAK and BAT Values 2005. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 41. Weinheim, Federal Republic of Germany: Wiley VCH. EPA (U.S. Environmental Protection Agency). 1987. Health Effects Assessment for Trimethylbenzenes. EPA/600/8-86/060. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH. Earhart, H.W., and A.P. Komin. 2000. Polymethylbenzenes. Kirk-Othmer Encyclopedia of Chemical Technology. John Wiley & Sons, Inc. [online]. Available: http://onli nelibrary.wiley.com/doi/10.1002/0471238961.1615122505011808.a01/abstract [accessed Nov. 2, 2012]. Frantík, E., M. Hornychová, and M. Horváth. 1994. Relative acute neurotoxicity of sol- vents: Isoeffective air concentration of 45 compounds evaluated in rats and mice. Environ. Res. 66(2):173-185. Freundt, K.J., K.G. Römer, and R.J. Federsel. 1989. Decrease of inhaled toluene, ethyl benzene, m-xylene, or mesitylene in rat blood after combined exposure to ethyl acetate. Bull. Environ. Contam. Toxicol. 42(4):495-498. Fukaya, Y., I. Saito, T. Matsumoto, Y. Takeuchi, and S. Tokudome. 1994. Determination of 3, 4-dimethylhippuric acid as a biological monitoring index for trimethylben- zene exposure in transfer printing workers. Int. Arch. Occup. Environ. Health 65(5):295-297. Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18. Gerarde, H.W. 1960. Toxicology and Biochemistry of Aromatic Hydrocarbons. Amster- dam: Elsevier. Gralewicz, S., and D. Wiaderna. 2001. Behavioral effects following subacute inhalation exposure to m-xylene or trimethylbenzene in the rat: A comparative study. Neuro- toxicology 22(1):79-89.
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Trimethylbenzenes 267 Gralewicz, S., D. Wiaderna, T. Tomas, and K. Rydzyński. 1997a. Behavioral changes following 4-week inhalation exposure to pseudocumene (1, 2, 4-trimethylbenzene) in the rat. Neurotoxicol. Teratol. 19(4):327-333. Gralewicz, S., D. Wiaderna, and T. Tomas. 1997b. Retardation of the age-related increase in spontaneous cortical spike-wave discharges (SWD) in rats after a 28-day inhala- tion exposure to an industrial solvent, pseudocumene (1, 2, 4-trimethylbenzene). Int. J. Occup. Med. Environ. Health 10(2):213-222. Henderson, R.F. 2001. Aromatic hydrocarbons: Benzene and other alkylbenzenes. Pp. 231-301 in Patty’s Toxicology, Vol. 4, 5th Ed., E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: John Wiley & Sons. Huo, J.Z., S. Aldous, K. Campbell, and N. Davies. 1989. Distribution and metabolism of 1, 2, 4- trimethylbenzene (pseudocumene) in the rat. Xenobiotica 19(2):161-170. Ichiba, M., H. Hama, S. Yukitake, M. Kubota, S. Kawasaki, and K. Tomokuni. 1992. Urinary excretion of 3, 4-dimethylhippuric acid in workers exposed to 1,2,4- trimethylbenzene. Int. Arch. Occup. Environ. Health 64(5):325-327. IRDC (International Research and Development Corporation). 1988a. Inhalation Devel- opmental Toxicity Study in Mice with C9 Aromatic Hydrocarbons (Final Report) with Cover Letter Dated 042688. FYI-AX-0588-0605. American Petroleum Insti- tute, Washington, DC. 97 pp. IRDC (International Research and Development Corporation). 1988b. Range-Finding Inhalation Developmental Toxicity Study in Mice with C9 Aromatic Hydrocar- bons, April 4, 1988. Submitted by Shell Oil Company with Cover Letter Dated April 10, 1989. EPA Document No. 86-890000223. Microfiche No. OTS0516758 57 pp. Janik-Spiechowicz, E., K. Wyszyńska, and E. Dziubałtowska. 1998. Genotoxicity evalua- tion of trimethylbenzenes. Mutat. Res. 412(3):299-305. Järnberg, J., G. Johanson, and A. Löf. 1996. Toxicokinetics of inhaled trimethylbenzenes in man. Toxicol. Appl. Pharmacol. 140(2):281-288. Järnberg, J., B. Ståhlbom, G. Johanson, and A. Löf. 1997a. Urinary excretion of di- methylhippuric acids in humans after exposure to trimethylbenzenes. Int. Arch. Occup. Environ. Health 69(6):491-497. Järnberg, J., G. Johanson, A. Löf, and B. Ståhlbom. 1997b. Inhalation toxicokinetics of 1,2,4- trimethylbenzene in volunteers: Comparison between exposure to white spirit and 1,2,4- trimethylbenzene alone. Sci. Total Environ. 199(1-2):65-71. Järnberg, J., G. Johanson, A. Löf, and B. Ståhlbom. 1998. Toxicokinetics of 1,2,4- trimethylbenzene in humans exposed to vapours of white spirit: Comparison with exposure to 1,2,4-trimethylbenzene alone. Arch. Toxicol. 72(8):483-491. Jones, K., M. Meldrum, E. Baird, S. Cottrell, P. Kaur, N. Plant, S. Dyne, and J. Cocker. 2006. Biological monitoring for trimethylbenzene exposure: A human volunteer study and a practical example in the workplace. Ann. Occup. Hyg. 50(6):593-598. Kenndler, E., C. Schwer, and J.F. Huber. 1989. Determination of 1,2,4-trimethylbenzene (pseudocumene) in serum of a person exposed to liquid scintillation counting solu- tions by GC/MS. J. Anal. Toxicol. 13(4):211-213. Korsak, Z., and K. Rydzyński. 1996. Neurotoxic effects of acute and subchronic inhala- tion exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimel- litene) in rats. Int. J. Occup. Med. Environ. Health 9(4):341-349. Korsak, Z., R. Świercz, and K. Rydzyński. 1995. Toxic effects of acute inhalation expo- sure to 1,2,4-trimethylbenzene (pseudocumene) in experimental animals. Int. J. Occup. Med. Environ. Health 8(4):331-337.
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268 Acute Exposure Guideline Levels Korsak, Z., K. Rydzyński, and J. Jajte. 1997. Respiratory irritative effects of trimethyl- benzenes: An experimental animal study. Int. J. Occup. Med. Environ. Health 10(3):303-311. Korsak, Z., J. Stetkiewicz, W. Majcherek, I. Stetkiewicz, J. Jajte, and K. Rydzyński. 2000. Subchronic inhalation toxicity of 1,2,3-trimethylbenzene (hemimellitene) in rats. Int. J. Occup. Med. Environ. Health 13(3):223-232. Kostrzewski, P., and A. Wiaderna-Brycht. 1995. Kinetics of elimination of mesitylene and 3,5-dimethylbenzoic acid after experimental human exposure. Toxicol. Lett. 77(1-3):259-264. Kostrzewski, P., A. Wiaderna-Brycht, and B. Czerski. 1997. Biological monitoring of ex- perimental human exposure to trimethylbenzene. Sci. Total Environ. 199(1-2):73-81. Laham, S., and M. Potvin. 1989. Identification and determination of mesitylene acidic metabolites in rabbit urine. Toxicol. Environ. Chem. 24(1-2):57-69. Lam, H.R., A. Löf, and O. Ladefoged. 1992. Brain concentrations of white spirit compo- nents and neurotransmitters following a three week inhalation exposure of rats. Pharmacol. Toxicol. 70(5):394-396. Lazarew, N.W. 1929. On the toxicity of various hydrocarbon vapors [in German]. Arch. Exp. Pathol. Pharmacol. 143:223-233. McKee, R.H., Z.A. Wong, S. Schmitt, P. Beatty, M. Swanson, C.A. Schreiner, and J.L. Schardein. 1990. The reproductive and developmental toxicity of high flash aro- matic naphtha. Toxicol. Ind. Health 6(3-4):441-460. Mikulski, P.I., and R. Wiglusz. 1975. The comparative metabolism of mesitylene, pseu- documene, and hemimellitene in rats. Toxicol. Appl. Pharmacol. 31(1):21-31. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: 1,2,3-Trimethylbenzeen, 1,2,4-Trimethylbenzeen, 1,3,5-Trimethylbenzeen. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/ maclijst2004.htm [accessed Nov. 6, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: 1,2,4-Trimethylbenzene. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Insti- tute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http:// www.cdc.gov/niosh/npg/npgd0638.html [accessed Nov.6, 2012]. Norseth, T., J. Waage, and I. Dale. 1991. Acute effects and exposure to organic compounds in road maintenance workers exposed to asphalt. Am. J. Ind. Med. 20(6):737-744. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. O’Neil, M.J., A. Smith, and P.E. Heckelman, eds. 2001. Pp. 1055-1056 and 1416 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Pyykkö, K., S. Paavilainen, T. Metsä-Ketelä, and K. Laustiola. 1987. The increasing and decreasing effects of aromatic hydrocarbon solvents on pulmonary and hepatic cy- tochrome P-450 in the rat. Pharmacol. Toxicol. 60(4):288-293. Römer, K.G., R.J. Federsel, and K.J. Freundt. 1986. Rise of inhaled toluene, ethyl ben- zene, m-xylene, or mesitylene in rat blood after treatment with ethanol. Bull. Envi- ron. Contam. Toxicol. 37(6):874-876.
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Trimethylbenzenes 269 Rossi, L., and E. Grandjean. 1957. The urinary excretion of phenol in animals exposed to trimethyl benzene [in Italian]. Med. Lavoro 48:523-532 (as cited in ACGIH 1992). Saillenfait, A.M., F. Gallissot, J.P. Sabate, and G. Morel. 2005. Developmental toxicity of two trimethylbenzene isomers, mesitylene and pseudocumene, in rats following inhalation exposure. Food Chem. Toxicol. 43(7):1055-1063. Shakirov, D.F., R.R. Farhutdinov, and T.R. Zulkarnaev. 1999. State of energy metabo- lism and microsomal monoxygenases in animals exposed to inhaled 1,2,4- trimethylbenzene [in Russian]. Gig. Sanit. 4:44-49. Swedish Work Environment Authority. 2005. Trimethylbenzene. P. 52 in Occupational Exposure Limit Values and Measures against Air Contaminants. AFS 2005:17 [online]. Available: http://www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed Nov. 7, 2012]. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Tsujimoto, Y., T. Noda, M. Shimizu, H. Moriwaki, and M. Tanaka. 1999. Identification of the dimethylbenzyl mercapturic acid in urine of rats treated with 1,2,3- trimethylbenzene. Chemosphere 39(5):725-730. van der Wal, J.F., and A. Moerkerken. 1984. The performance of passive diffusion moni- tors for organic vapours for personal sampling of painters. Ann. Occup. Hyg. 28(1):39-47. Wadden, R.A., P.A. Scheff, J.E. Franke, L.M. Conroy, M. Javor, C.B. Keil, and S.A. Milz. 1995. VOC emission rates and emission factors for a sheetfed offset printing shop. Am. Ind. Hyg. Assoc. J. 56(4):368-376. Wiaderna, D., S. Gralewicz, and T. Tomas. 1998. Behavioral changes following a four- week inhalation exposure to hemimellitene (1,2,3-trimethylbenzene) in rats. Int. J. Occup. Med. Environ. Health 11(4):319-334. Wiglusz, R., G. Delag, and P. Mikulski. 1975a. Serum enzymes activity of mesitylene vapour treated rats. Bull. Inst. Marit. Trop. Med. Gdynia 26(-4):303-313. Wiglusz, R., M. Kienitz, G. Delag, E. Galuszko, and P. Mikulski. 1975b. Peripheral blood of mesitylene vapour treated rats. Bull. Inst. Marit. Trop. Med. Gdynia. 26(3-4):315-321. Zahlsen, K., A.M. Nilsen, I. Eide, and O.G. Nilsen. 1990. Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4-trimethylbenzene) and naphthenic (1,2,4- trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation. Pharma- col. Toxicol. 67(5):436-440. Zahlsen, K., I. Eide, A.M. Nilsen, and O.G. Nilsen. 1992. Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic hydrocarbons in the rat after repeated expo- sures. Pharmacol. Toxicol. 71(2):144-149.
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270 Acute Exposure Guideline Levels 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
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Trimethylbenzenes 271 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.
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272 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR TRIMETHYLBENZENES Derivation Summary for Trimethylbenzenes AEGL-1 VALUES 10 min 30 min 1h 4h 8h 180 ppm 180 ppm 140 ppm 90 ppm 45 ppm Key references: Korsak, Z., R. Świercz, 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.
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Trimethylbenzenes 273 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 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.
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274 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR TRIMETHYLBENZENES Chemical Toxicity - TSD Animal Data Trimethylbenzene 10000 No Effect 1000 Discomfort Disabling ppm AEGL-2 Some Lethality 100 AEGL-1 Lethal AEGL 10 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of toxicity data and AEGL values for trimethylbenzenes.