2022/09/29 by Hartwig, Andrea, MAK Commission
#1-Oxa-4-azacyclohexan #1-Oxa-4-azacyclohexane #4-oxazin #4-oxazine #BMDL 05 #Entwicklungstoxizität #Luft #MAK value #MAK-Wert #Momentanwert #Morpholin #Morpholine #Reizwirkung #Tetrahydro-1 #air #developmental toxicity #focal necrosis turbinates #fokale Nekrose Turbinalien #irritation #maximale Arbeitsplatzkonzentration #maximum workplace concentration #momentary value #oberer Respirationstrakt #upper respiratory tract
paper · doi:10.34865/mb11091d7_3ad
The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated the maximum concentration at the workplace (MAK value) and the pregnancy risk group of morpholine [110-91-8] considering also irritating and sensitizing effects. 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/m 3 is a NOAEC. As focal necrosis of turbinates at the next higher concentration of 50 ml/m 3 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 BMDL 05 of 19.78 ml/m 3 . Based on this BMDL 05 a MAK value of 5 ml/m 3 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/m 3 is set. In 1996, no specific data on reproduction or developmental toxicity had been available. In a developmental toxicity study in rats, the NOAEL for developmental and maternal toxicity 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. I.e. 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/m 3 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.