Risk Assessment of Morpholine (Tetrahydro-2H-1, 4-Oxazine): A Time for Reevaluation of Current Occupational Exposure Standards?

Abstract

Morpholine (tetrahydro-2H-1, 4-oxazine; Chemical Abstract Society No. 110-91-8), a cyclic secondary amine, is a high volume production chemical with annual worldwide production exceeding 10,000 tonnes per year. It is an important intermediate for rubber-processing chemicals, and is used as a component of laundry detergents and in the textile industry. The compound is also used to control corrosion in steam condensate systems. In both experimental animals and humans the primary acute and chronic effects are irritation of mucous membranes at high levels of exposure, consistent with the strong alkaline properties of morpholine. Available data do not provide enough evidence for the carcinogenicity of morpholine in exposed workers or in studies in experimental animals. It was found that exposure of workers to morpholine vapors may cause a transient edema of the cornea of the eye, leading to the so-called glaucopsia in workers exposed for several hours. Unfortunately, there are no data available on the concentrations of morpholine vapors and the duration of exposure leading to these effects; thus, it is not possible to establish the relationship between the exposure and adverse health effects in humans. There are, however, some studies that demonstrate a relationship between exposure and adverse health effects in animals. The studies of Harbison et al. (Fund. Appl. Toxicol. 12:491–507; 1989) are critical for risk evaluation and recommendations for occupational exposure limits. In these studies Sprague-Dawley rats were exposed to 0, 10, 50, or 150 ppm (0, 36, 180, or 540 mg/m³) of morpholine for 6 hours/day, 5 days/week, for 104 weeks. Since the adverse ocular effects which occurred at the lower doses tested (i.e., 10 and 50 ppm) were equivocal as compared with the control animals, a no observed adverse effect level of 10 ppm (36 mg/m³) and a lowest observed adverse effect level of 50 ppm (180 mg/m³) are proposed based on the adverse nasal irritation effects and used as a basis for risk evaluation. For the occupational exposure, the recommended hygienic standard for workplace air of 3 mg/m³ was derived. Therefore, taking into consideration existing data on morpholine and, as discussed in this article, its possible nitrosation to carcinogenic N-nitrosomorpholine, current occupational exposure standards should be reevaluated and reduced.