1,4-Dioxane Chemistry, Uses, and Occurrence - Environmental Investigation and Remediation - page 100

to 1,4-dioxane that equates to not more than 800 ng per person per day (FDA, 2006). This exposure
level is about 1000 times lower than the suggested oral slope factor for cancer risk for 1,4-dioxane.

2.6 1,4-DIOXANE USE IN THE PHARMACEUTICAL INDUSTRY
The pharmaceutical industry fabricates, processes, and formulates medicinal chemicals and phar-
maceutical products and grinds, grades, and mills botanical products. Pharmaceutical products may
include agents of natural origin, hormonal products, basic vitamins, and isolated alkaloids from
botanical drugs and herbs (USEPA, 1997c). The majority of pharmaceutical production facilities in
the United States are located in California, New Jersey, New York, and Puerto Rico. Formulated
pharmaceutical products are manufactured by chemical synthesis, fermentation, or isolation and
recovery from natural sources, or a combination of these processes. Fermentation is economically
the most important process; however, by tons produced, chemical synthesis dominates. Fermentation
processes are used to produce antibiotics such as penicillin and tetracycline. Chemical synthesis
processes are used to manufacture psychotropic and antihistamine drugs. Extracts from animal
products provide hormone-based drugs, biological processes are used to produce vaccines and
serums, and vegetable extraction processes yield steroids and alkaloids (Chenier, 2002). Production
of some pharmaceutical products incorporates the use of various solvents, including 1,4-dioxane.
Solvents are used primarily as a vehicle or reagent and to clean residues from equipment between
production runs of different drugs. Solvent wastes, primarily as vapors, may be generated at most
steps in the production of pharmaceuticals, including

• Cleaning reaction vessels and condensers

• Separation by extracting, decanting, centrifugation, i ltration, or crystallization

• Purii cation by recrystallization, centrifugation, or i ltration

• Product drying

Solvent-laden wastewater may be generated in the reaction, separation, extraction, and purii cation
steps. Devices to control air emissions and equipment for wastewater treatment are designed to remove
residual solvent and comply with air quality and discharge elimination regulations (USEPA, 1997c).
Many bulk pharmaceutical reactions require organic solvents to dissolve chemical intermediates
and reagents. To prevent reaction with reagents and intermediates, nonreactive solvents are preferred.
Dichloromethane is often the optimum choice for pharmaceutical reactions. The most commonly
used solvents in the pharmaceutical industry include methanol, ethanol, acetone, isopropanol, and
other oxygenated organic solvents (USEPA, 1997c). 1,4-Dioxane is used in some processes but has
not been a major solvent used in production pharmaceuticals. In addition to 1,4-dioxane, other com-
pounds used in the pharmaceutical industry that also serve as solvent stabilizers include acetonitrile,
n -butyl alcohols, cyclohexane, pyridine, and tetrahydrofuran. Specii c uses for 1,4-dioxane include
chemical synthesis and biological and natural product extraction (USEPA, 1997c). 1,4-Dioxane, tolu-
ene, xylene, and pyridine are routinely monitored by the pharmaceutical industry (Kauffman, 2003).
In 1995, TRI participation involved 200 out of the 916 pharmaceutical production facilities listed
in the 1992 census of manufacturers. Of those 200 facilities, two reported releases of 1,4-dioxane
(USEPA, 1997c). This low percentage may be because very few facilities used 1,4-dioxane, but it is
more likely the result of a tendency for TRI responses to exclude chemicals used in only minor
quantities. The two facilities that did report 1,4-dioxane releases in 1995 summarized the quantities
released, in pounds per year, as follows:

Fugitive Air
Emissions

Point Air
Emissions

Water
Discharges

Total
Releases

Average Releases
per Facility

270 260 0 530 265