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Description of key information

In a feeding study, classified as key study, morpholine was applied to rats for eight weeks (Sander & Bürkle, 1969). A LOAEL of 500 mg/kg bw/d is derived based on the study results. No specific target organ was identified in this study. Other studies pointed towards the liver and the kidneys as possible target organs (Shea, 1939; Shibata,1987). With respect to dermal studies on rabbits, repeated application of 900 mg/kg bw morpholine resulted in death of all animals; necrosis of the skin, inflammation and congestion of the underlying organs were observed (Shea, 1939). In a Two-Year Chronic inhalation study (HAZLETON INC, 1983), rats exposed by inhalation to morpholine at concentrations of 0, 36, 181 or 543 mg/m³, 6 hours/day, 5 days/week for 104 weeks showed normal growth, survival and haematology and clinical chemistry parameters. A systemic intoxication was not observed. At the highest dose, chronic nasal irritation and some ocular injury was observed. Owing to its corrosivity, morpholine exposure resulted in irritation and inflammation of the upper digestive tract on oral intake, irritation of the respiratory tract and eyes following inhalation and, in high concentrations, irritation on contact with the skin.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
500 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
36 mg/m³

Additional information

Repeated dose toxicity: oral:

In a repeated dose toxicity study on Sprague-Dawley rats, Morpholine was added to feed for eight weeks (Sander & Bürkle, 1969). Seven rats took in a daily average of 500 m/kg bw. This dosage did not kill the animals. After 270 days had elapsed, the only symptom noted was moderate adiposis of the liver. The oral toxicity of Morpholine was evaluated before (Shea, 1939). In a subacute study on rats damage to liver, kidneys and stomach mucosa first appeared after intake of approx. 160 mg/kg bw. Intake of 800 mg/kg bw caused the death of 10 out of 20 rats within 20 days. At the end of 30 days, only 1 rat was still alive. Eventual effects caused by subchronic oral intake of Morpholine depended markedly on the individual dose and route of administration.

In a subchronic study Morpholine oleic acid salt (MOAS) was applied to mice for 13 weeks (Shibata, 1987). The dose levels of MOAS used were 0, 0.15, 0.3, 0.6, 1.25, and 2.5 % in drinking water (approximately 0, 70, 140, 200, 400 and 700 mg/kg bw/d). It seems that a dose equivalent to approx. 200 mg/kg bw/day impaired renal activity, as evidenced by the rise in the blood urea and the specific gravity of the urine. Approximately 700 mg/kg bw/day caused swelling of the proximal renal tubules (no further treatment-related histopathological alterations were observed in organs of either sex). Due to the given data, a LOAEL of 500 mg/kg bw/day is derived for oral repeated toxicity.

 

Repeated dose toxicity: dermal

Shea (1939) assessed the dermal toxicity and skin absorption of Morpholine in one investigation using rabbits. Unneutralized, diluted Morpholine (1 part Morpholine, 2 parts water) was applied at a daily dose of 900 mg/kg bw to the clipped skin. All rabbits (7/7) died before the eleventh dose. Necrosis of the treated skin, and inflammation and congestion of the underlying organs were evident upon gross examination. Microscopic lesions of the liver and effects on kidneys and spleen were observed.

 

Repeated dose toxicity: inhalation

Rats were exposed by inhalation to 18,000 ppm Morpholine. Exposures were nominal 8 hours a day for five days. Irritation of the eyes, nose and thoracic walls were registered. Some animals died during the study period. In animals that died after 5 days repeated exposure to ca. 65 g/m³ Morpholine, lung haemorrhage, severe damage to the secreting tubules of the kidney, and fatty degeneration of the liver were noted (Shea1939).

 

Twenty male Wistar rats were exposed intermittently to 300 ppm (12.5 µM/L) Morpholine vapour 5 days a week for 6 h daily during 4-15 weeks. The animals were killed after 4, 8, 12 or 15 weeks, and brain and perirenal fat samples taken. The specimens were analyzed for Morpholine content by gas chromatography. All exposed rats appeared similar to controls; weight gain of treated animals was similar to that of nontreated controls. Concentrations of Morpholine in the brain increased towards the end of the exposure period. Fat morpholine concentrations were a fraction of those detected in brain; a decreasing trend was discernible after 8 exposure weeks. Axonal succinate dehydrogenase activity of the test group was below the control group after 15 weeks. The muscle acetylcholine esterase activities were above the control level in the test group after 8 weeks and decreased to the level of the control group after 15 weeks. With regard to the concentrations in the brain, the authors (Savolainen & Rosenberg, 1983) postulated that the “metabolic clearance is saturated” in case of Morpholine.

 

The induction of lysosomal enzymes by Morpholine were examined in rabbits. Two acid hydrolases, alpha-mannosidase and acid phosphatase, were induced in the lung alveolar macrophages during the course of inhalation exposure (905 mg/m³, 250 ppm, 6 h/day, 5 days/week for a total of 33 exposures). The induction was also observed when macrophages were cultured in the presence of Morpholine (Tombropoulos, 1983).

 

Grodeckaja and Karamzina (1973) evaluated thyroid function as an indicator of Morpholine toxicity. In an inhalation study male rats were exposed to 0.08 g Morpholine/m³, 4 hours/day for 2, 4, or 8 days. Then iodine-131 was administered and thyroid gland uptake of iodine-131 was measured over 48 hours. Treated rats accumulated a larger amount of iodine-131 compared to control animals after 4 days exposure, indicating increased thyroid gland activity. Microscopic examination of the thyroid gland indicated hypersecretion by thyroid cells. As a main result increased thyroid activity was observed in rats.

 

In a two-year chronic inhalation study (Huntsman, 1983), male and female rats that inhaled Morpholine at concentrations of 0, 10, 50, or 150 ppm (0, 36, 181 or 543 mg/m³), 6 hours/day, 5 days/week for 104 weeks showed normal growth, survival, hematology, and clinical chemistries.The incidence of neoplasia in morpholine-exposed rats was not altered significantly compared to the concurrent controls. Rats exposed at the 150 ppm concentration developed focal erosion and focal squamous metaplasia of the epithelium of the anterior nasal cavity. Obvious evidence of chronic nasal irritation and inflammation with neutrophilic infiltration was documented in these same tissues. Ocular injury, including retinal degeneration, corneal irritation, uveitis, and corneal damage, were demonstrated only in rats exposed at 150 ppm. The distribution of ocular changes recorded in the groups exposed at 10 or 50 ppm Morpholine was similar to that seen in the controls. Chronic exposure of rats to morpholine for 2 years at concentrations of 150 ppm or less revealed no carcinogenic potential or chronic systemic toxicity. Consistent with its known irritating properties, Morpholine produced only local irritation, which was limited almost exclusively to high-dose animals.

In a previous subchronic inhalation study (Conaway, 1984), rats inhaled Morpholine at concentrations of 0, 25, 100, and 250 ppm. None of the animals died or were sacrificed in extremis during the study. No treatment-related trends or findings were apparent in either sex for haematology, clinical chemistry and gross pathology. Exposure to Morpholine at 250 ppm for 13 weeks confirmed the result, seen at week 7, of focal erosion of the maxillary turbinates accompanied by the presence of necrotic cell debris and focal squamous metaplasia. Lesions were then noted involving the nasal septum and anterior nasal cavities. Lesions of chronic murine pneumonia were also increased in severity in rats of the high-level group. A maximum tolerated dose (MTD) of 150 ppm was established on the basis of the nasal irritation. The subchronic study of Conaway (1984) is based on a range-finding study, Rats inhaling morpholine at 3.62 or 18.1 g/m³ for 9 days, 6 h per day, died within the exposure period (Huntsman, 1981d). At lower concentrations (1.81 g/m³), weight loss and irritation to nose and eyes, as well as two deaths, were reported. It was concluded that the maximal tolerated dose for rats is about or just below 0.3 g/m³.

This author demonstrated also in a subchronic inhalation study with rats that none of the animals died or were sacrificed in extremis during the study and no treatment-related findings were apparent in either sex for haematology, clinical chemistry and gross pathology. Thus, a maximum tolerated dose (MTD) of 150 ppm was established on the basis of nasal irritation (Huntsman, 1981c).

 

The 2-year chronic inhalation study of Huntsman (1983) is considered to be the best available base for setting of relevant toxicological parameters.Based on this study, a systemic NOEC of 181 mg/m³ (50 ppm) and a local NOEC of 36 mg/m³ for repeated dose toxicity is derived.

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

Based on the results of the chronic dose toxicity study with special regard to specific target organ toxicity after repeated inhalation exposure, morpholine is not subject to classification and labelling according to Regulation 1272/2008/EC.