Christopher M. Teaf, Michele M. Garber, and J. Michael Kuperberg

For purposes of this chapter, solvent classes and individual examples are presented, as well as selected substances (e.g., vinyl chloride, polycyclic aromatic hydrocarbons (PAHs)) not typically viewed as solvents but that are addressed in conjunction with solvents or are major elements of solvent mixtures. Information is provided concerning solvent chemistry, toxicology, and potential health effects, including:

  • Exposure potential and possible health hazards associated with industrial and environmental aspects of organic solvents
  • Chemical properties of selected classes of organic solvents
  • Target organ systems of selected classes of organic solvents
  • Relationships among solvent chemical structures and potential effects
  • Toxicology of selected solvent examples, including some substances not traditionally considered to be solvents, though they are used as such
  • Important substances present as components of commercial solvents


Solvents are defined as chemicals capable of dissolving and dispersing other substances. That fundamental property explains the economic value and potential health significance in residential, commercial, and environmental circumstances for products used as cleaners, degreasers, chemical intermediates, and chemical delivery vehicles. Organic solvents are carbon-based substances representing a very large, chemically diverse group of industrially, occupationally, and ecologically important products. The first historically useful organic solvents (e.g., ethanol, other alcohols, wood resins, turpentine) were derived from vegetable sources, and development of cosmetics containing organic solvent components dates to ancient Egypt. Inorganic solvents (e.g., water, ammonia, inorganic acids) are not addressed in this chapter, but comprise a chemically and economically important group as well.

There are thousands of organic solvents and related compounds, both pure compounds and commercial mixtures (e.g., mineral spirits, naphthas). The large numbers often result in generic statements about what solvents are or what they are not, as well as generalization about toxicity. However, there are marked differences among even similarly structured solvents. For example, low-molecular-weight members within a chemical class often exert greater toxicity than higher class members, due to differences in volatility, water solubility, and ability to cross biomembranes. That diversity demands care when comparing chemical and toxicological properties.


Exposure Routes

Solvent exposure in the human environment is common, due to widespread use in occupational settings of many large industries and small commercial operations (e.g., automotive shops), and common potential for exposure via household products. Such exposure can be by oral (e.g., drinking water), dermal (e.g., bathing, industrial direct contact), or inhalation routes (e.g., airborne workplace exposure, residential vapor intrusion), or a combination, depending upon the circumstances.

This chapter addresses airborne exposure potential in detail, due to the volatile nature of many solvents. However, as noted, solvent exposure is possible by multiple routes. For example, in situations where groundwater with solvent contamination is used for household purposes, there is the possibility of ingestion from drinking the water, dermal exposure from bathing activities, and inhalation related to volatilized solvents during clothes washing, showering, cooking, and other chores. Similarly, in industrial operations that employ solvents, joint exposure may occur due to splashes onto the skin, inhalation of vapors in work areas, and hand-to-mouth transfer of the chemicals during eating, smoking, or other common activities. Recognition of these multiple potential pathways has led to workplace requirements involving respiratory protection and hygiene practices limiting exposure possibilities. Differences in absorption, and other route-specific considerations for solvents, are further addressed in Section 18.3.

Not only is it important to address potential exposures to individual solvent agents but also possible interactive effects of multiple exposures, since these are the rule, rather than the exception. Assessment of the magnitude of exposure is often complex and may require detailed evaluation of inhalation and/or dermal contact, as well as estimates of exposure frequency and duration. Some common volatile organic chemical (VOC) solvents that may be encountered indoors and outdoors include benzene, toluene, xylenes, alcohols, trichloroethylene (trichloroethene, TCE), and formaldehyde. Exposure to organic solvents and their constituents can occur for individuals who live near industrial facilities that presently use or have used these solvents, as well as in the home. Many solvents are found in groundwater, soils, air, and other environmental media near National Priorities List (NPL) sites that are managed under Superfund (Comprehensive Environmental Response, Compensation, and Liability Act, aka CERCLA). Much of this is related to past storage, handling, and disposal practices at numerous industrial facilities. As of September 2014, there were over 1300 listed NPL sites and another 51 proposed sites in the United States, many of which are significant for the presence of variable solvent contamination profiles in soils and groundwater.

Industrial Exposures

There have been extensive advances in worker protection standards in the United States; however, industrial solvent exposures remain of global health interest for workers, many of whom are unfamiliar with potential hazards associated with exposures. The Occupational Safety and Health Administration (OSHA) has concluded that millions of U.S. workers are exposed to solvents in varying degrees on a daily basis. In some professions (e.g., painters), nearly all workers may have some degree of exposure, though education and protective measures (e.g., ventilation, spraybooths, respirators), coupled with introduction of water-based paints and adhesives, have reduced such exposure. Japan reports that smaller industries use nearly five times as much solvent volume compared to large enterprises, and they have experienced shifts in solvent use from aromatics to alcohols.

Exposures to organic solvents in an occupational setting also may occur in research laboratories, hospitals, and dry cleaners. In histology labs, formaldehyde (preservative) and xylenes (clearing agents) are the most common chemicals used and historically have been associated with pulmonary damage. Recently, housekeeping practices in the healthcare industry, which employ solvent-based cleaning products, have been identified as an occupational risk due to the asthma-like symptoms and dermatitis reported by some workers.

A limited epidemiologic database suggests that exposure to solvents and volatile chemicals in service station workers may be associated with restrictive airway disease, but demonstration of persistent lung complications has been inconsistent. A relationship also has been postulated for exposure to some chlorinated solvents during automotive degreasing work and an increase in risk of non-Hodgkin’s lymphoma (NHL); however, that literature also is inconsistent. Ubiquity of solvents in industry, and potential for concurrent or sequential exposure to multiple chemicals, complicates the distinction between chemical causation of adverse effects and simple association of adverse effects with exposure in time and place. Relationships between simple association and chemical causation are discussed elsewhere in this book (see Chapter 21).

Industrial practices that result in the evaporative loss of volatile solvents (e.g., metal degreasing, application of surface coatings, chemical separations) are of particular interest in an exposure context. Protective equipment, engineering controls, and work practices can be effective in limiting exposures, but careless or inexperienced handling of solvents may still occur in small facilities (e.g., automobile service and repair, metal fabricators) and during activities in large and otherwise well-run factories and service industries. Methods used for worker exposure characterization and quantification are discussed elsewhere in this book (see Chapter 22). Solvent exposure potential varies among individuals, as well as over time for a specific individual, based on job type, workplace duties, and schedule. Within possible occupational exposure groups, it is important to consider sensitive individuals and populations when evaluating exposure and risk, including those with preexisting health conditions such as weakness of the immune system.

Occupational airborne guidelines that are designed to control exposures to solvents and other materials in the workplace may be expressed in units of volume/volume (e.g., parts per million (ppm)), as well as units of mass/volume (e.g., mg per cubic meter (mg/m3)). For vapors and gases, these data if expressed in either form may be interconverted according to the following expressions:



X ppm (or ppb) = concentration in units of volume/volume
Y mg/m3 (or µg/m3) = concentration in units of mass/volume
MW = molecular weight of the chemical
24.45 = molar volume of an ideal gas at standard temperature and pressure

Rearranging this expression provides an opportunity to convert airborne concentrations that are expressed with different units in the other direction as well, as follows:


For dose estimates, units of mg/m3 are useful in conjunction with inhalation rates (units of m3/h or m3/day) to determine chemical intake in risk calculations. These unit conversion relationships do not apply for dusts, aerosols, and other nongaseous forms.

Household and Other Exposures

As noted, in addition to what are considered conventional industrial exposures, potential exposures to household products containing solvents and nonoccupational handling of petroleum products remain significant sources of exposure to hydrocarbon solvents. Residential exposure by all routes can occur when practicing hobbies (e.g., paints, thinners, adhesives), conducting home repairs (e.g., paints varnishes, thinners), using household cleaning products (alcohols, ethers, floor strippers, tub/tile cleaners), using fuels in lawn equipment (gasoline, diesel), and during recreational abuse of volatile inhalants, known as “huffing,” in which a variety of solvents and pressurizing agents are used to attain intoxication-related euphoria, delusions, sedation, and hallucinations. Chronic inhalant abuse may lead to adverse neurologic conditions.


Structural variability and the range of physical/chemical properties exhibited by organic solvents limit the number of generalizations that can be made regarding physiological effects and exposure hazards. However, because of their common industrial, commercial, and household use, often in large quantities, it is useful to discuss some fundamental characteristics that are common to the principal classes of organic solvents. Table 18.1 summarizes selected important physical/chemical properties for solvents discussed in subsequent chapter sections. Of particular interest are vapor pressure (i.e., volatility) and water solubility, since these properties greatly influence environmental behavior and exposure potential. Many organic solvents are flammable/explosive, depending on their volatility, and have lower densities than water, except for some halogenated solvents. Solvent toxicity is greatly influenced by the number of carbon atoms, whether as a saturated or unsaturated molecule, as well as the chemical configuration (e.g., straight chain, branched, cyclic).

Table 18.1 Physical/Chemical Properties of Representative Solvents and Related Materials

Chemical CAS # Molecular Formula Molecular Weight (g/mole) Freezing or Melting Point (°F) Boiling Point (°F) Vapor Pressure (20 °C) (mm Hg) Water Solubility (20 °C) mg/l Specific Gravity (unitless)

Carbon tetrachloride 56-23-5 CCl4 153.8 −9 170 91 500 1.59
Chloroform 67-66-3 CHCl3 119.4 −82 143 160 5,000 (25 °C) 1.48
Methylene chloride 75-09-2 CH2Cl2 84.9 −139 104 350 20,000 1.33
Tetrachloroethene 127-18-4 C2Cl4 165.8 −2 250 14 200 1.62
Trichloroethylene 79-01-6 C2HCl3 131.4 −99 189 58 1,000 1.46
Vinyl chloride 75-01-4 C2H3Cl 62.5 −256 7 2508 1,000 (25 °C) 2.21

Acetaldehyde 75-07-0 C2H4O 44.1 −190 69 740 Miscible 0.79
Acetone 67-64-1 C3H6O 58.1 −140 133 180 Miscible 0.79
Acrolein 107-02-8 C3H4O 56.1 −126 127 210 400,000 0.84
Aniline 62-53-3 C6H7N 93.1 21 363 0.6 40,000 1.02
Benzene 71-43-2 C6H6 78.1 42 176 75 700 0.88
Benzidine 92-87-5 C12H12N2 184.3 239 752 low 400 (12 °C) 1.25
Carbon disulfide 75-15-0 CS2 76.1 −169 116 297 3,000 1.26
N,N-Dimethylaniline 121-69-7 C8H11N 121.2 36 378 1 20,000 0.96
1,4-Dioxane 123-91-1 C4H8O2 88.1 53 214 29 Miscible 1.03
Ethanol 64-17-5 C2H5OH 46.1 −173 173 44 Miscible 0.79
Ethyl acetate 141-78-6 C4H8O2 88.1 −117 171 73 100,000 (25 °C) 0.9
Ethyl ether 60-29-7 C4H10O 74.1 −177 94 440 80,000 0.71
Ethylene glycol 107-21-1 C2H6O2 62.1 9 388 0.06 Miscible 1.11
Formaldehyde 50-00-0 CH2O 30.0 −134 −6 >760 Miscible 1.04
n-Hexane 110-54-3 C6H14 86.2 −219 156 124 20 0.66
Hydrazine 302-01-2 N2H4 32.1 36 236 10 Miscible 1.01
Isopropanol 67-63-0 C3H8O 60.1 −127 181 33 Miscible 0.79
Isopropyl ether 108-20-3 C6H14O 102.2 −76 154 119 2,000 0.73
Methanol 67-56-1 CH4O 32.1 −144 147 96 Miscible 0.79
Methyl ethyl ketone 78-93-3 C4H8O 72.1 −123 175 78 280,000 0.81
Naphthalene 91-20-3 C10H8 128.2 176 424 0.08 30 1.15
Nitrobenzene 98-95-3 C6H5NO2 123.1 42 411 0.3 (25 °C) 2,000 1.2
Nitromethane 75-52-5 CH3NO2 61.0 −20 214 28 100,000 1.14
Phenol 108-95-2 C6H6O 94.1 109 359 0.4 90,000 (25 °C) 1.06
Pyridine 110-86-1 C5H5N 79.1 −44 240 16 Miscible 0.98
Styrene 100-42-5 C8H8 104.2 −23 293 5 300 0.91
Tetrahydrofuran 109-99-9 C4H8O 72.1 −163 151 132 Miscible 0.89
Toluene 108-88-3 C7H8 92.1 −139 232 21 700 (23.3 °C) 0.87

Table 18.2 presents occupational guidelines and standards for selected solvents and solvent constituents. These values include the health-based guidelines of the American Conference of Governmental Industrial Hygienists (ACGIH), termed threshold limit values (TLVs), as well as legally enforceable standards developed by the OSHA, termed permissible exposure limits (PELs). These guidelines and standards may be viewed as long-term protective levels, represented by a time-weighted average (TWA), as well as a protective value for a shorter time frame, termed a short-term exposure limit (STEL) or a ceiling (C) concentration. To the extent that they are available, carcinogen classifications from the United States Environmental Protection Agency (U.S. EPA), ACGIH, and National Toxicology Program (NTP) are included as well. Nearly half of the listed chemicals on Table 18.2 have no U.S. EPA carcinogenic classification, due to limitations to what the agency considers acceptable data.

Table 18.2 Occupational Exposure Limits for Selected Solvents and Related Materials

Source: Compiled from ACGIH (2014).

ACGIH TLV (ppm) OSHA PEL (ppm) U.S. EPA Oral Carcinogen Classification
Compound CAS # TWA STEL/Ceiling TWA STEL/Ceiling RfD (mg/kg-day) ACGIH U.S. EPA NTP
Acetaldehyde 75-07-0 NE 25 200 NE NE A2 B2 R
Acetone 67-64-1 250 (NIC) 500 (NIC) 1000 NE 0.9 A4 I NE
Acrolein 107-02-8 NE 0.1 0.1 NE 0.0005 A4 I NE
Aniline 62-53-3 2 NE 5 NE NE A3 B2 NE
Benzene 71-43-2 0.5 2.5 1 5 0.004 A1 A K
Benzidine 92-87-5 NE NE NE NE 0.003 A1 A K
Carbon disulfide 75-15-0 1 NE 20 30 0.1 A4 NE NE
Carbon tetrachloride 56-23-5 5 10 10 25 0.004 A2 L R
Chloroform 67-66-3 10 NE NE 50 0.01 A3 B2;L (acute); NL (low dose) R
N,N-Dimethylaniline 121-69-7 5 10 5 NE 0.002 A4 NE NE
1,4-Dioxane 123-91-1 20 NE 100 NE 0.03 A3 L R
Ethanol 64-17-5 NE 1000 1000 NE NE A3 NE K
Ethyl acetate 141-78-6 400 NE 400 NE 0.9 NE NE NE
Ethyl ether 60-29-7 400 500 400 NE NE NE NE NE
Ethylene glycol 107-21-1 10 (NIC) 100 (NIC) NE NE 2 A4 NE NE
Formaldehyde 50-00-0 NE 0.3 0.75 2 0.2 A2 B1 K
n-Hexane 110-54-3 50 NE 500 NE 0.7 NE II NE
Hydrazine 302-01-2 0.01 NE 1 NE NE A3 B2 R
Isopropanol 67-63-0 200 400 400 NE NE A4 NE NE
Isopropyl ether 108-20-3 250 310 500 NE NE NE NE NE
Methanol 67-56-1 200 250 200 NE 2 NE NE NE
Methylene chloride 75-09-2 50 NE 25 125 0.006 A3 L R
Methyl ethyl ketone 78-93-3 200 300 200 NE 0.6 NE I NE
Naphthalene 91-20-3 10 NE 10 NE 0.02 A3 CBD R
Nitrobenzene 98-95-3 1 NE 1 NE 0.002 A3 L R
Nitromethane 75-52-5 20 NE 100 NE NE A3 NE R
Phenol 108-95-2 5 NE 5 NE NE A4 I;D NE
Pyridine 110-86-1 1 NE 5 NE 0.001 A3 NE NE
Styrene 100-42-5 20 40 100 200 0.2 A4 NE R
Tetrachloroethylene 127-18-4 25 100 100 200 0.006 A3 L R
Tetrahydrofuran 109-99-9 50 100 200 NE 0.9 A3 S NE
Toluene 108-88-3 20 NE 200 300 NE A4 II NE
Trichloroethylene 79-01-6 10 25 100 200 0.0005 A2 CaH R
Vinyl chloride 75-01-4 1 NE 1 5 0.003 A1 A K

K, known to be a human carcinogen; NE, not established; NIC, Notice of Intended Changes; PEL, permissible exposure limit; R, reasonably anticipated to be human carcinogens; RfD, reference dose; STEL/ceiling, short-term exposure limit or ceiling; TLV, threshold limit value; TWA, time-weighted average; see Table 18.4 for additional abbreviations.

In addition to the occupational air guidelines and standards, the ACGIH has published a series of biological exposure index (BEI) values for substances of specific industrial interest to guide the monitoring and control of health hazards. The BEIs are measures of a specific chemical or its metabolites in biological media (e.g., urine, blood, expired air). In principle, the BEI value is that which would be expected if airborne exposure regularly occurs at the TLV. The BEI is complementary to workplace air monitoring and can be a useful adjunct in situations where information is variable or contradictory. For example, in a situation where the BEI is exceeded but where workplace air levels are low, it would be prudent to investigate potential unrecognized peaks in air levels or to investigate the potential for unrecognized dermal exposure and absorption. Table 18.3 presents BEI values for selected solvents and related materials.

Table 18.3 ACGIH Biological Exposure Index (BEI) for Selected Solvents and Related Materials.

Source: Compiled from ACGIH (2001) or updates as released.

Compound CAS # Recommended BEI Sampling Medium Sampling Time ACGIH Notation
Acetone 67-64-1 50 mg/l Urine End of shift Ns
Aniline 62-53-3 1 mg/l (tentative) Urine End of shift Nq

Nonquantitative Released from hemoglobin End of shift Nq

50 mg/l p-Aminophenola in urine End of shift Ns, Sq, B
Benzene 71-43-2 25 µg/g creatinine S-Phenylmercapturic acid in urine End of shift B

500 µg/g creatinine t,t-Muconic acid in urine End of shift B
2-Butoxyethanol 111-76-2 200 mg/g creatinine Butoxyacetic acid (BAA) in urine End of shift
Carbon disulfide 75-15-0 0.5 mg/g creatinine 2-Thioxothiazolidine-4-carboxylic acid (TTCA) in urine End of shift Ns, B
Chlorobenzene 108-90-7 100 mg/g creatinine Total 4-chlorocatechol in urineb End of shift at end of workweek Ns

20 mg/g creatinine Total p-chlorophenol in urineb End of shift at end of workweek Ns
2-Ethoxyethanol 110-80-5 100 mg/g creatinine 2-Ethoxyacetic acid in urine End of shift at end of workweek
n-Hexane 110-54-3 0.4 mg/l 2,5-Hexanedionec in urine End of shift at end of workweek
Methanol 67-56-1 15 mg/l Urine End of shift B, Ns
2-Methoxyethanol 109-86-4 Nonquantitative 2-Methoxyacetic acid in urine End of shift at end of workweek Nq
Methylene chloride 75-09-2 0.3 mg/l Urine End of shift Sq
Methyl ethyl ketone 78-93-3 2 mg/l Urine End of shift Ns
Methyl n-butyl ketone 591-78-6 0.4 mg/l 2,5-Hexanedionec in urine End of shift at end of workweek
Methyl isobutyl ketone 108-10-1 1 mg/l Urine End of shift
Nitrobenzene 98-95-3 5 mg/g creatinine Total p-nitrophenol in urine End of shift at end of workweek Ns

1.5% hemoglobin Methemoglobin in blood End of shift B, Ns, Sq
Phenol 108-95-2 250 mg/g creatinine Urine End of shift B, Ns
2-Propanol 67-63-0 40 mg/l Acetone in urine End of shift at end of workweek Ns, B
Styrene 100-42-5 400 mg/g creatinine Mandelic acid plus phenylglyoxylic acid in urine End of shift Ns

0.2 mg/l Venous blood End of shift Sq
Tetrachloroethylene 127-18-4 3 ppm End-exhaled air Prior to shift

0.5 mg/l Blood Prior to shift
Toluene 108-88-3 0.02 mg/l Blood Prior to last shift of workweek

0.03 mg/l Urine End of shift

0.3 mg/g creatinine o-Cresol in urinea End of shift B
1,1,1-Trichloroethane 71-55-6 40 ppm End-exhaled air Prior to last shift of workweek

10 mg/l Trichloroacetic acid in urine End of workweek Ns, Sq

30 mg/l Total trichloroethanol in urine End of shift at end of workweek Ns, Sq

1 mg/l Total trichloroethanol in blood End of shift at end of workweek Ns
Trichloroethylene 79-01-6 15 mg/l Trichloroacetic acid in urine End of shift at end of workweek Ns

0.5 mg/l Trichloroethanold in blood End of shift at end of workweek Ns

Screening only Blood End of shift at end of workweek Sq

Screening only End-exhaled air End of shift at end of workweek Sq
Xylenes 1330-20-7 1.5 g/g creatinine Methylhippuric acids in urine End of shift

B, background; Ns, nonspecific; Nq, nonquantitative; Sq, semiquantitative.

a With hydrolysis.

b After hydrolysis.

c Without hydrolysis; metabolite is specific to n-hexane and methyl n-butyl ketone.

d Without hydrolysis.

Table 18.4 provides definitions and differences among the most common occupational guidelines described in Table 18.2, as well as carcinogen classifications used by the U.S. EPA and ACGIH. As noted, the PEL is the legally enforceable standard for workplace air exposure and governs employers with regard to engineering practices, ventilation, and personnel protective equipment. It considers cost and technical feasibility in its development, as well as health considerations. The TLV is a guideline criterion that is based on health considerations only, derived from available animal and human toxicology information. In that respect, the TLV is analogous to the NIOSH recommended exposure limit (REL). TLVs and RELs often are used for occupational screening purposes. The U.S. EPA has established regulatory benchmark values for many of the substances discussed in this chapter [e.g., reference dose (RfD), cancer slope factor (CSF), and reference concentration (RfC) for air]. The RfD is defined as “An estimate of a daily oral exposure for a given duration to the human population (including susceptible subgroups) that is likely to be without an appreciable risk of adverse health effects over a lifetime. It is derived from a BMDL, a NOAEL, a LOAEL, or another suitable point of departure, with uncertainty/variability factors applied to reflect limitations of the data used.” The oral CSF is defined as “An upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime oral exposure to an agent. This estimate, usually expressed in units of proportion (of a population) affected per mg/kg-day, is generally reserved for use in the low-dose region of the dose–response relationship, that is, for exposures corresponding to risks less than 1 in 100.” The RfC is “an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.” Inhalation CSF values are available for some substances. These toxicological benchmarks often are used in calculating risk-based exposure targets and regional screening levels (RSLs) for solvents to be used in evaluation of risks posed by contaminated sites. They change periodically based on new information and can be acquired directly from online databases such as the U.S. EPA Integrated Risk Information System (IRIS).

Table 18.4 Occupational Exposure Guideline Definitions

ACGIH—American Conference of Governmental Industrial Hygienists (ACGIH, 2011)
TLV–TWA Threshold limit value–time-weighted average. Time-weighted average concentration for a normal 8 h workday and a 40 h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effects
STEL Short-term exposure limit. Defined as 15 min TWA exposure not to be exceeded during a workday. Concentration to which workers can be exposed continuously for a short period without suffering irritation, chronic/irreversible tissue damage, or narcosis to increase likelihood of injury, impair self-rescue, or materially reduce work efficiency
Categories for Carcinogenic Potential
A1 Confirmed human carcinogen
A2 Suspected human carcinogen
A3 Animal carcinogen
A4 Not classifiable as a human carcinogen
A5 Not suspected as a human carcinogen
OSHA—Occupational Safety and Health Administration (ACGIH, 2011)
PEL–TWA Permissible exposure limit–time-weighted average. Concentration not to be exceeded during any 8 h work shift of a 40 h workweek
C Ceiling concentration not to be exceeded any part of workday; if instantaneous monitoring not feasible, ceiling assessed as 15 min TWA
U.S. EPA—United States Environmental Protection Agency
Cancer Classification (1986–1996)
A Known human carcinogen
B1 Probable human carcinogen. Based on human data
B2 Probable human carcinogen. Based on animal data
C Possible human carcinogen
D Not classifiable as to human carcinogenicity
Guidelines for Carcinogen Risk Assessment (Final in 2005)
CaH Carcinogenic to humans
L Likely to be carcinogenic to humans
S Suggestive evidence of carcinogenic potential
I or II Inadequate information to assess carcinogenic
NL Not likely to be carcinogenic to humans

As a point of comparison, Table 18.5 presents common ranges of concentrations encountered in environmental media and in occupational airborne circumstances.

Table 18.5 Concentration Ranges for Selected Solvents and Related Substances in Environmental and Occupational Circumstances

Chemical Class Compound CAS # Common Occupational Exposure Range Common Environmental Exposure Range: Air Common Environmental Exposure Range: Water
Alkanes n-Hexane 110-54-3 3–200 ppm <50 ppb outdoor Low; BDL, 10 µg/l

<10 ppb indoor
Aromatic hydrocarbons—monocyclic Benzene 71-43-2 0.05–83 ppb 0.02–34 ppb Moderate; BDL, 100 µg/l
Styrene 100-42-5 6.9–51 ppm 0.07–11.5 ppb indoor air Low; BDL, 20 µg/l

0.06–4.6 ppb outdoor air
Toluene 108-88-3 5–50 ppm 8 ppb indoor air High; BDL, 1000 µg/l
Xylenes 1330-20-7 0.5–1300 ppb 1–30 ppb outdoor air High; BDL, 1000 µg/l

1–10 ppb indoor air
Aromatic hydrocarbons—polycyclic Naphthalene
1.9–3.7 ppb 0.2 ppb or less outdoor air Moderate; BDL, 200 µg/l

<1 ppb indoor air
Aliphatics—halogenated Methylene chloride 75-09-2 1–1000 ppm <1–11 ppb outdoor Moderate; BDL, 200 µg/l
Tetrachloroethylene 127-18-4 16.9–48.4 ppm <10 ppb outdoor air Moderate; BDL, 200 µg/l

<15 ppb indoor air

74–428 ppb indoor air, newly dry-cleaned clothes
1,1,1-Trichloroethane 71-55-6 Up to 1300 ppm 0.1–1 ppb outdoor air Low; BDL, 200 µg/l

0.3–4.4 ppb indoor air
Trichloroethylene 79-01-6 50–100 ppm 0.08–12 ppb outdoor air High; BDL, 1000 µg/l

<5 ppb indoor air
Aromatics—halogenated Chlorobenzene 108-90-7 Up to 4 ppm <1 ppb outdoor air Moderate; BDL, 100 µg/l
Alcohols Phenol 108-95-2 0.03–3.2 ppm 0.5–44 ppb outdoor air Low; BDL, 1–20 µg/l
Aldehydes, ketones Acetone 67-64-1 1.5–166 ppm 7 ppb outdoor air Moderate; BDL, 100 µg/l
8 ppb indoor air
Methyl ethyl ketone 78-93-3 0.3–11 ppm <10 ppb outdoor air Low; BDL, 20 µg/l
Esters, ethers, epoxides 2-Butoxyethanol 111-76-2 0.1–169 ppm <10 ppb outdoor air Low; BDL, 10 µg/l
Amines—aromatic Aniline 62-53-3 <2 ppm 1–5 ppb indoor air Low; BDL, 10 µg/l
Nitro compounds Nitrobenzene 98-95-3 1 ppm 0.01–5.7 ppb outdoor air Low; BDL, 20 µg/l
Sulfur-containing compounds Carbon disulfide 75-15-0 1–47 ppm <10 ppb outdoor air Low; BDL, 20 µg/l

Absorption, Distribution, Metabolism, and Excretion

As noted, solvent exposure may occur via oral, dermal, and inhalation routes, as well as a combination of these. Absorption can occur from direct liquid contact, and abraded or cut skin may enhance dermal absorption. While dermal penetration of solvents typically is negligible at low air concentrations, the ACGIH and OSHA note that this route for some substances may be significant at high air concentrations, hence an occupational “skin” designation, applicable in confined spaces or areas where respiratory protection (e.g., use of air-purifying or air-supplied respirators) limits potential for inhalation. For example, exposure to 2-butoxyethanol vapor may cause dermal uptake that exceeds inhalation. Solvent absorption by the lungs is dependent on several factors, including air concentration, as well as ventilation rate, depth of respiration, and pulmonary circulation, all of which are influenced by workload.

Once absorbed, solvents may be transported to other areas of the body, including organs where biotransformation may occur, resulting in formation of metabolites. Significant route-specific differences exist between uptake and the potential for adverse effects from solvents. Intake via the oral and dermal routes causes absorption into the venous circulation, which allows what is known as “first-pass” degradation or clearance by enzymatic process of the liver. Inhalation intake results in absorption via the alveoli into the arterial circulation, which distributes absorbed solvents to various locations prior to hepatic metabolism. For this reason, as well as the fact that airborne concentrations may be quite high in some cases, the inhalation route often is of greater toxicological concern on a strict numerical dose comparison.

Many volatile solvents can be eliminated either as the parent compound or in metabolized form in exhaled breath, varying with workload. This can be independent of exposure route and is the basis for sampling expired air as a measure of occupational exposure (see Table 18.3). Less water-soluble substances (e.g., chlorinated solvents) may penetrate more deeply into the lungs.

Given heterogeneity among solvents, numerous potential metabolic pathways exist, as described elsewhere in this book. The P450 enzyme system and the glutathione pathways often are involved, catalyzing oxidative reactions and conjugation to form water-soluble substances excretable in urine or bile. Several pathways may exist for the biotransformation of a specific solvent, depending on exposure route and concentration. Excretion of metabolites (e.g., s-phenylmercapturic acid from benzene, trichloroacetic acid from TCE, mandelic acid from styrene) forms the basis for biological monitoring programs in exposure characterization. Although the liver is the primary site of metabolism, other organs (e.g., kidney, lung) exhibit biotransformation capacity as well. Formation and accumulation of metabolites can occur if initial steps of biotransformation are present, but not later steps. For example, aldehydes may be metabolized readily in the liver, while the same aldehyde may accumulate in the lung and cause pulmonary damage due to limited aldehyde dehydrogenase. Beyond generally beneficial aspects of biotransformation (i.e., detoxification) and excretion, solvent metabolism occasionally may generate products that are more toxic than the parent compound. Such metabolic “activation,” also termed “bioactivation,” and resultant reactive intermediates (e.g., epoxides and radicals) are considered responsible for some toxic effects of solvents, especially with chronic exposure. This is illustrated by TCE, which exhibits variable metabolism in some rodents with dose, and that metabolism may produce novel toxicity elsewhere.

Metabolic enzymes may be increased in activity (“induced”) by previous or concomitant chemical exposures, such as therapeutic drugs, foods, alcohol, cigarette smoke, and industrial exposures. Competitive interactions, which may affect enzyme activity for solvents in industrial scenarios, also may influence toxicity, such that exposure to multiple chemicals is not always worse than individual exposures (e.g., toluene inhibits benzene metabolism and toxicity). Saturation of normal metabolic degradation pathways may cause qualitative shifts in metabolism to other pathways. While a normal pathway may cause detoxification, saturation or overwhelming of the pathway may cause “shunting” to activation pathways (e.g., 1,1,1-trichloroethane, n-hexane, perchloroethylene (PERC), and 1,1-dichloroethene).

Partition coefficients (Kp) for air–blood, fat–blood, and brain–blood can be calculated and used to describe differential solvent behavior in various tissues. Such values are useful to understand the preferential uptake and storage of solvents and to explain greater sensitivity of some organs to adverse effects.

Acute versus Chronic Effects

As discussed subsequently in greater detail by chemical class, solvents can have both acute, short-term effects based upon one or a few high-level exposures (e.g., irritation, neurological effects) and chronic effects that may be expressed in delayed fashion following prolonged exposures at lower levels (e.g., kidney disease, liver injury, cancer). Acute effects typically result from the rapid overwhelming of existing detoxification and excretion mechanisms, and they may be transient/reversible. Chronic effects often are related to repetitive, unrepaired, low-level damage that is accumulative over lengthy periods of exposure, and these effects are less likely to be reversible. The intermediate case, where more frequent or regular high-level exposures may occur, is difficult to predict, given individual sensitivities and resilience.

For some solvents (e.g., aldehydes, ketones), the ability to detect odor or irritation at low air concentrations is a useful characteristic that can act as an “early warning” tool against acute and chronic exposure potential. However, for most industrially and environmentally important solvents (e.g., benzene, chlorohydrocarbons), odor does not serve as a sufficient warning property, and significant exposures can occur before they are detectable by smell. Avoidance of such exposure circumstances is a foundation of occupational and environmental monitoring programs.

Central Nervous System Effects

A common physiological effect associated with short- or long-term, high-level exposure to some organic solvents is depression of central nervous system (CNS) activity, causing general anesthesia, decreased brain/spinal cord activity, and lowered sensitivity to external stimuli, with unconsciousness or death as the severest consequence. Many solvents are lipophilic (“fat loving”), a feature typically coupled with a low affinity for water (hydrophobic). Those compounds tend to accumulate in lipid-rich areas, including blood, brain, and depot (storage) fats. Accumulation in or direct damage to nerve cells can disrupt normal nerve excitability and adversely affect nerve impulse conduction. While organic solvents with few or no functional groups generally are lipophilic and exhibit some limited degree of CNS-depressant activity, this property generally increases with carbon chain length. Changes in toxicity are most evident when larger functional groups are added to small organic compounds, since the increase in molecular size generally decreases water solubility and increases lipophilicity. In practical terms, this applies only to chemicals up to carbon chain length of about six. As molecular size increases beyond this point for a functional class (e.g., amines, alcohols, ethers), vapor pressure decreases and exposure issues (e.g., inhalation) decrease dramatically.

Unsaturated chemicals (i.e., where hydrogens have been lost, forming double or triple bonds between carbon atoms) typically are more potent CNS-depressant chemicals than their saturated (i.e., single bond) counterparts. Similarly, CNS-depressant properties of organic solvents generally are enhanced by an increasing extent of halogenation (e.g., chlorine, bromine) and, to a lesser extent, by addition of alcohol (OH) groups. For example, while methane and ethane are gases, are not anesthetics, and act as simple asphyxiants at high concentrations, both of the corresponding alcohol analogs (i.e., methanol and ethanol) are liquids and are potent CNS depressants. Methylene chloride has anesthetic properties, but chloroform (CHCL3) is more potent than methylene chloride, and carbon tetrachloride (CCL4) is the most potent anesthetic of the group.

Toluene encephalopathy has been reported in high-level inhalant abuse, characterized by severe neurotoxicity. Evidence is limited that such a syndrome occurs at low-level exposures and there is considerable doubt as to whether “solvent-induced chronic encephalopathy” exists in reasonable exposure circumstances. That syndrome, described in the late 1970s, was explored more fully in the 1980s, though recent reviews do not conclude that chronic low-level solvent exposure typically results in CNS or peripheral nervous system (PNS) injury.

To illustrate the nonspecificity of solvent neurotoxic effects, and related problems that may be faced by a health specialist in trying to diagnose poorly characterized exposure situations, the following constellations of symptoms are described for a few common agents. It should be noted that, in contrast to these acute effects, effects of chronic exposure to these agents may differ dramatically, as discussed elsewhere in the chapter:

  • Benzene: euphoria, excitement, headache, vertigo, dizziness, nausea, vomiting, irritability, narcosis, coma, and death
  • Carbon tetrachloride: conjunctivitis, headache, dizziness, nausea, vomiting, abdominal cramps, nervousness, narcosis, coma, and death
  • Methanol: euphoria, conjunctivitis, decreased vision, headache, dizziness, nausea, vomiting, abdominal cramps, sweating, weakness, delirium, coma, and death

PNS Effects

The literature is clear that select organic solvents (e.g., n-hexane, methyl n-butyl ketone, carbon disulfide) can cause “distal axonal peripheral neuropathy,” also often termed “dying-back axonopathy” as defined by degradation of the axon or nerve cell body. It typically affects the feet and lower legs before the hands and may be partially reversible if identified sufficiently early in the process. The condition is associated with weakness, alteration or loss of sensation, impairment of reflexes, and eventual generalized muscle wasting. Occupational development of the condition has been reported in painters, automotive technicians, and workers in the shoe and furniture manufacturing sectors. Development of the condition is slow, though it may be accelerated in cases of inhalant abuse, and deterioration arguably may progress beyond the time at which exposure ceases, though the mechanism for such progression is not described. It is necessary to diagnose these disorders carefully while keeping in mind the possibility of other potential etiologies for the peripheral neurological observations (e.g., trauma, lead exposure, inflammation, diabetes, autoimmunity, heredity).

Renal and Hepatic Effects

Nephrotoxic effects have been associated with both acute and chronic exposures to halogenated hydrocarbons (e.g., chloroform, tetrachloroethylene). The primary target of chloroform is the proximal kidney tubule where metabolism via renal cellular P450 produces reactive intermediates that cause damage followed by protein and glucose leakage to the urine, as well as increased blood urea nitrogen (BUN) levels. PERC is one of a group of chemicals that cause serious sex-specific and species-specific α2-microglobulin nephropathy in animals. However, humans are not at risk of this particular nephropathy because we do not synthesize the α2-microglobulin protein. As described in subsequent sections, organic solvents known to damage the liver include ethanol and chlorinated hydrocarbons. Enzymes (e.g., P450) and other factors that affect solvent transformation play a role in determining the extent of hepatotoxicity associated with these and related chemicals. Factors that activate P450 increase toxicity of many chlorinated solvents, and those that inhibit (decrease) P450 activity tend to reduce toxicity. Coexposure to some alcohols and chlorinated solvents has been associated with exacerbation of toxicity compared with that expected from either agent alone.

Irritation of Tissues and Membranes

Cell membranes are composed principally of a protein–lipid matrix, and organic solvents may act to dissolve that matrix or extract the fat (lipid) portion from the membrane, causing membrane and tissue irritation. This “defatting” process, when applied to skin, causes drying, irritation, and cell damage. Injury to the lungs and eyes may be caused by similar processes. As described previously, addition of some functional groups to organic molecules predictably influences toxicological properties. For example, amines, organic acids, alcohols, aldehydes, and ketones may cause cell membrane damage by precipitation and denaturation of proteins following sufficient exposures.

As is true for CNS depression, irritation by unsaturated compounds generally is stronger than for the corresponding saturated analogs. As molecular size increases, irritant properties typically decrease, and solvent defatting action of the hydrocarbon portion is altered. Table 18.6 presents relative potency of selected functional groups regarding CNS-depressant effects and irritation. The rankings become less applicable as the larger, more complex, multisubstituted compounds are considered.

Table 18.6 Relative CNS-Depressant and Irritant Potency of Selected Organic Solvent Classes


A number of solvents are inhalation irritants, though irritation often is restricted to the upper airways due to the high degree of water solubility of the substances and the tendency to dissolve in moisture of mucous membranes.


As with toxicological evaluations of other potential solvent-related adverse effects, the complex nature of industrial exposure scenarios complicates the objective evaluation of malignancy attributed to a specific solvent. Thus, many occupational studies end up considering solvent exposure as a general “risk factor” for neoplasia but stop short of establishing “cause and effect” relationships. While in some occupational exposure circumstances it is possible to establish a causative element of human cancer risk for industrial activities (asbestos and mesothelioma in some shipyard employees; angiosarcoma in concentrated vinyl chloride exposure), such is not the case for most solvents. There is historical documentation for benzene as a human carcinogen under well-described intense exposure circumstances. Multiple factors may be responsible for the observed effects, but metabolism of benzene to one or more reactive metabolites (e.g., epoxides) is likely to be responsible for the myelotoxicity. A complementary hypothesis suggests that a depressant effect by benzene or its metabolites on cell-mediated immunity may influence the carcinogenic process. It is interesting that the substituted benzene analogs toluene and xylenes are noncarcinogenic, while styrene (or vinylbenzene) forms reactive metabolites, as does benzene, notably styrene oxide. Styrene recently was listed as reasonably anticipated to be a human carcinogen in the NTP 12th Report on Carcinogens. That listing was based on limited evidence in human studies, sufficient evidence in animals, and supporting data on carcinogenesis mechanisms.

Some chlorinated solvents, such as carbon tetrachloride, chloroform, tetrachloroethylene (PERC), TCE (trichloroethylene), and vinyl chloride, exhibit carcinogenic potential, notably hepatic tumors, in animals. Carcinogenic potential associated with TCE exposure has been of interest since the mid-1970s, when the National Cancer Institute (NCI) reported increases in liver cancer in male mice receiving TCE by gastric intubation. TCE, like some other chlorinated hydrocarbons, exhibits limited, inconsistent, and controversial mutagenic activity in bacterial test systems after microsomal activation, so the mutagenic effect is likely dependent on the products of metabolism, which has influenced recent interest in actual TCE potency. In the recent 2011 Toxicological Review, the U.S. EPA characterizes TCE as “carcinogenic to humans” based upon procedures outlined in the U.S. EPA 2005 Guidelines for Carcinogen Risk Assessment. That classification relies on evidence of a putative causal association between TCE exposure in humans and kidney cancer, in addition to carcinogenicity in the liver and lymphoid tissues. Other groups (e.g., ACGIH) continue to classify TCE as A2 (“suspected human carcinogen”), while the International Agency for Research on Cancer (IARC) considers TCE in class 2A “probably carcinogenic to humans.” PERC is considered “likely to be a human carcinogen by all routes of exposure” as published in the 2012 Toxicological Review released by the U.S. EPA.

Apart from leukemogenic effects associated with chronic benzene exposure, the literature available to document specific cancer hazards from exposure to organic solvents is inconsistent, though some epidemiological observations have been published regarding cancer and chlorinated solvent exposure. For example, Hodgkin’s lymphoma and NHL arguably have been linked to occupational exposure to some aliphatic, aromatic, and chlorinated solvents. Recently, a study of nearly 15,000 aircraft maintenance workers with exposure to TCE and other solvents reported a decrease in overall cancer mortality but a small excess in NHL, multiple myeloma, and bile duct cancer. The U.S. EPA inhalation unit risk and oral CSF for TCE were predicated partly on NHL risk.

Reproductive Effects

For most solvents, reproductive effects are not among the most sensitive measures of toxic effects. Reproductive toxicity has been reported following exposure to 2-methoxyethanol (2-ME), 2-ethoxyethanol (2EE), and n-hexane. 2-ME may damage the testes and cause infertility at extreme doses. It also has been shown to be teratogenic in animal studies, as has exposure to 2-bromopropane, carbon disulfide, and ethylene glycol monomethyl ether. Reproductive dysfunction was reported following exposure at high levels to toluene and other petrochemicals, though more sensitive measures of exposure occur at lower levels. Toluene abuse in pregnancy can lead to teratogenic effects labeled “fetal solvent syndrome.” Organic solvent exposure in pregnant women reportedly has been associated with poor cognitive development and neuromotor functioning in childhood, as well as low childhood birth weight. Retail products containing ethanol require federal warning labels directed at notification of potential birth defects and other elements of reproductive consequences.


Aliphatic Solvents

Alkanes (CnH2n + 2 )

The chemical class of the saturated aliphatic hydrocarbons (alkanes, also termed paraffins) has many members and generally ranks among the least potentially toxic solvents based on acute effects. The group is comprised of straight chain or branched hydrocarbons containing only single bonds. Vapors of these solvents are mildly irritating to mucous membranes at the high concentrations required to induce their relatively weak anesthetic properties. The four chemicals in this series with the lowest molecular weight (i.e., methane, ethane, propane, butane) are gases with negligible toxicity, and their hazardous nature is limited almost entirely to flammability, explosivity, and basic asphyxiant potential. The chemicals are found in natural gas and can be released into the environment from the exhaust of gasoline and diesel engines, from municipal waste incinerators, and from many other combustion sources.

Higher-molecular-weight class representatives are liquid at ambient temperature (i.e., 20–25 °C) and have some CNS-depressant, neurotoxic, and irritant properties, but this is primarily a concern of the lighter, more volatile compounds in the series (e.g., pentane, hexane, heptane, octane, nonane). Higher-viscosity liquid paraffins, beginning with the 10-carbon compound decane, are fat solvents and primary irritants capable of dermal irritation and dermatitis after repeated, prolonged, or intense contact. Many of these substances occur naturally in crude and refined petroleum products.

Symptoms of acute poisoning are similar to those previously described as generally present in solvent intoxication (e.g., nausea, vomiting, cough, pulmonary irritation, vertigo/dizziness, slow and shallow respiration, narcosis, coma, convulsions, and death), with severity of symptoms dependent on the magnitude and duration of exposure. Ingestion of large liquid quantities (i.e., exceeding several ounces, about 1–2 ml/kg body weight) may produce systemic toxicity. If less than 1–2 ml/kg is ingested, the therapeutic approach typically involves a cathartic used in conjunction with activated charcoal to limit GI absorption. In either situation, pulmonary aspiration of the solvent is the primary concern from a medical perspective. Low-viscosity hydrocarbons attract particular attention in this context because their low surface tension allows them to spread over a large surface area, with the potential to damage the lungs after exposure to relatively small quantities. These chemicals may sensitize the heart to epinephrine (adrenaline), but that feature is not often a practical issue given the narrow range separating cardiac sensitization from fatal narcosis.

Chronic exposure to some alkanes (e.g., hexane, heptane) may cause polyneuropathy in humans and animals, characterized by lowered nerve conduction velocity and a “dying-back” degenerative change in the distal neuron sheath. Symptoms may include muscle pain and spasms, weakness, and paresthesias, characterized by tingling or numbness in the extremities. Common metabolites have been implicated as the causative agents, with 2,5-hexanedione and 2,6-heptanedione as toxic degradation products of hexane and heptane, respectively. Since the metabolites are oxidative products, first to the alcohol and then to the diketone, there is concern that structurally similar alcohols and ketones may produce similar neuropathies compared to the parent aliphatic hydrocarbons. Alkanes generally are not considered carcinogenic.


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