Morpholine
MAK Value Documentation, addendum – Translation of the German version from 2022
Andrea Hartwig1 (Chair of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Deutsche Forschungsgemeinschaft)MAK Commission2
1 Institute of Applied Biosciences, Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology (KIT), Adenauerring 20a, Building 50.41, 76131 Karlsruhe, Germany
2 Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Deutsche Forschungsgemeinschaft, Kennedyallee 40, 53175 Bonn, Germany
Abstract
The German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) has re-evaluated the occupational exposure limit value (maximum concentration at the workplace, MAK value) and the pregnancy risk group of morpholine [110-91-8] considering also irritating and sensitizing effects. Relevant studies were identified from a literature search and also unpublished study reports were used. The critical effect of morpholine is the local effect on the upper respiratory tract. There are no human data to derive a MAK value. In a 2-year inhalation study with rats already reported in the evaluation 1996, the lowest concentration of 10 ml/m3 is a NOAEC. As focal necrosis of turbinates at the next higher concentration of 50 ml/m3 was not pronounced and had a low incidence, a benchmark dose (BMD) calculation based on focal necrosis of turbinates in male rats was performed, resulting in a BMDL05 of 19.78 ml/m3. Based on this BMDL05 a MAK value of 5 ml/m3 is established. Since a local effect is critical, Peak Limitation Category I is retained. As data on humans are not available and the calculated NAEC is close to the MAK value, an excursion factor of 1 and by analogy with other amines with a MAK value of 5 ml/m3, a momentary value of 10 ml morpholine/m3 is set. In 1996, no specific data on reproduction or developmental toxicity had been available. In a study conducted in the meantime, the NOAEL for developmental and maternal toxicity in rats was 52.9 mg/kg body weight and day, the LOAEL was 176 mg/kg body weight and day. In a one-generation toxicity study in rats, a NOAEL of 423 mg/kg body weight and day was obtained for perinatal toxicity whereas at this dose maternal toxicity occurred. In rabbits, the NOAEL for developmental and maternal toxicity is 49.7 mg/kg body weight and day, the LOAEL is 148 mg/kg body weight and day. The studies were conducted with the hydrochloride in order to be able to administer a maximum amount of morpholine by gavage to the animals. However, the oral hydrochloride dose does not correlate with real workplace exposure to morpholine vapours. The corresponding morpholine concentrations would lead to significant irritant effects, at least in the range of LOAECs. Therefore, such a high dose could not be tested via inhalation. After toxicokinetic scaling, the margins between the effect doses and the MAK value of 5 ml/m3 are evaluated as sufficient and morpholine is assigned to Pregnancy Risk Group C. There are no indications of a sensitizing potential of morpholine in humans or animals. Studies investigating respiratory sensitization are not available. According to skin absorption models, percutaneous absorption is not expected to contribute significantly to systemic toxicity.
