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6 Final Report on the Safety Assessment of Morpholine

Morpholine is metabolized in guinea pigs but was not significantly metabolized in rats, dogs, or rabbits. Dermal LD₅₀s in rabbits ranged between 0.3 and 1.2 g/kg. The oral LD₅₀s in rats were between 1.1 and 1.6 g/kg; in guinea pigs the oral LD₅₀ was 0.9 g/kg.

In studies of acute and short-term dermal toxicity Morpholine as an undiluted and unneutralized solution or as a diluted and unneutralized solution applied daily to the skin of guinea pigs and rabbits, respectively, caused the deaths of the test animals within 2 weeks. In both cases, the skin was necrotic.

Unneutralized solutions of Morpholine caused severe corneal necrosis, but upon neutralization Morpholine was not injurious to rabbit eyes.

In short-term inhalation studies (in rats) with varying concentrations of Morpholine, the effects observed included irritation of the mucous membranes and an increased respiratory rate. Chronic inhalation studies of Morpholine in rats and guinea pigs reported changes in the nervous system activity and arterial and peripheral blood pressure. At high concentrations Morpholine produced swelling of the alveolar cells and atrophy of lymphoid elements in the spleen. At lower concentrations a decrease in the size of the lymph nodules in the spleen was noted.

Morpholine was a weak positive mutagen in L5178 mouse lymphoma assay, in BALB/3T3 malignant cell transformation and fibroblast transformation assays, and in sister chromatid exchange assays, but was negative in the Ames test with and without metabolic activation. At nontoxic doses Morpholine did not increase the rate of DNA repair in rat hepatocytes. Results of other mutagenic assays varied according to the system used.

Nitrosation of Morpholine produces N-nitrosomorpholine, which has been mutagenic in a variety of test systems. Simultaneous exposure of laboratory animals to Morpholine and nitrites has caused a number of different cancers. A carcinogenic response was produced in rats in a long-term feeding study of Morpholine in which nitrites were present in the diet.

In humans, Morpholine is absorbed and is considered to be a skin and eye irritant, as well as a skin sensitizer. A formulation containing 1% Morpholine indicated that the ingredient was neither an irritant nor sensitizer.

Morpholine is not considered to be an animal carcinogen. It reacts easily with nitrosating agents, resulting in the formation of N-nitrosomorpholine. Under conditions of use, it is highly unlikely that Morpholine is totally free of carcinogenic nitrosoamines. Without quantitative data regarding the formation of N-nitrosomorpholine under conditions of use, it cannot be concluded that Morpholine is safe for use in cosmetic products.

International Journal of Toxicology, Vol. 8, No. 4, 707-748 (1989)
DOI: 10.3109/10915818909010528


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