Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

In a key combined chronic/carcinogenicity study (Harbison et al., 1989), male and female Sprague Dawley rats were inhalation exposed to 0, 36, 181 or 543 mg/m³ morpholine (99.2 %) for 6 hours a day, 5 days per week for 52 (interim sacrifice) or 104 weeks (terminal sacrifice). Findings in this study were limited to local effects of irritation (ocular and nasal cavity effects) noted during clinical observation and ophthalmoscopic examination, and were confirmed histopathologically. There was no evidence of increased incidence of carcinogenesis due to morpholine inhalation at doses up to and including 543 mg/m³.
In a supporting carcinogenicity study (Kitano et al., 1997), morpholine (>97 %) was administered in the diet to male Fischer rats at approximately 220 mg/kg bw for a period of 23 weeks in combination with (i) a preceding 4-week initiation phase characterised by a treatment with 6 known carcinogens and/or (ii) sodium nitrite concurrently given in the drinking water for 23 weeks. Morpholine alone was not tested; however, morpholine plus initiation treatment (without sodium nitrite treatment) as well as morpholine plus sodium nitrite treatment (without initiation treatment) did not induce tumour promotion.

Key value for chemical safety assessment

Additional information

In a key combined chronic/carcinogenicity study (Harbison et al., 1989), morpholine (99.2 %) was administered by whole body inhalation exposure to Sprague-Dawley rats at mean concentrations of 0, 36, 181 or 543 mg/m³ (6 h/day, 5 days/week) for 52 weeks (10 animals/sex/group) or for 104 weeks (60 animals/sex/group). No treatment-related changes in mortality, body weights, organ weights, or clinical pathology parameters were observed. Ophthalmoscopic examinations at week 103 revealed signs of eye irritation. Histological findings were limited to ocular and anterior nasal cavity effects, consistent with the known irritating properties of morpholine. At the doses tested, there was no evidence of increased incidence of carcinogenesis due to chronic morpholine inhalation. Since only local effects were noted, under the conditions of this study, the NOAEC was >543 mg/m³ for both carcinogenicity and toxicity.

In a supporting carcinogenicity study (Kitano et al., 1997), the effects of dietary morpholine administration at a dose level of 0.5 % (approx. 220 mg/kg bw) to male Fischer 344 rats (10 or 20 animals/group) were investigated for a period of 23 weeks (i) in combination with sodium nitrite given in the drinking water following an initiation phase, (ii) without sodium nitrite following an initiation phase and (iii) in combination with sodium nitrite without initiation phase. In an additional experiment, male Fischer 344 rats (14 or 5 animals/group) received a dietary treatment with morpholine (2.0 %) for 1 hour with subsequent administration of sodium nitrite for determination of N-nitroso compounds in the stomach and to detect DNA adduct generation. Both experiments were run with concurrent control groups. Morpholine alone was not tested. The initiation treatment decreased the body weight of rats compared to non-initiated groups. The group that was initiated and received sodium nitrite in the drinking water and morpholine in the diet was significantly lower in body weight than the group that was only initiated. However, the liver and kidneys weights were increased. The combination of initiation followed by sodium nitrite and morpholine caused an increase in the number and area of GST-P positive liver foci as compared to the group that was only initiated, indicating that morpholine plus sodium nitrite, but not morpholine alone, has a tumour promoting effect. Treatment with morpholine or morpholine plus sodium nitrite did not clearly lead to an increased tumour incidence. No tumours were induced by morpholine plus sodium nitrite in the absence of initiation. The mean N-nitrosomorpholine yield in the group given morpholine plus sodium nitrite was 6720 µg. No DNA adducts related to morpholine treatment were detected immunohistochemically.

Overall, there was no evidence of carcinogenic activity of morpholine.

Justification for classification or non-classification

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

Since there is no evidence for a carcinogenic potential, morpholine is not subject to classification as being carcinogenic according to Regulation 1272/2008/EC.