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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
OCR for page 266
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.
OCR for page 267
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.
OCR for page 268
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.
OCR for page 269
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.
