Morpholine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

36 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German occupational exposure limit (MAK)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

72 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German occupational exposure limit (MAK) - short term

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.84 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

84 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Please refer to " Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for other interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Long term, systemic DNEL – exposure via inhalation (workers)

In a two-year chronic inhalation study similar to OECD TG 452 (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. Based on this study, a systemic NOEC of 543 mg/m³(150 ppm) and a local NOEC of 36 mg/m³ for repeated dose toxicity is derived. Local effects are considered to be more critical and the derived DNEL for local effects by inhalation exposure is considered to be sufficient to protect against possible systemic effects.

Acute, systemic DNEL- exposure via inhalation (workers)

The substance is harmonized classified for acute inhalation toxicity Cat.4 (H332) according to Annex VI of Regulation (EC) No 1272/2008. Local effects after long term exposure are considered more relevant and the MAK value ensures a sufficient level of protection for the systemic effects following acute/short term inhalative exposure. Nevertheless, a qualitative approach has to be implemented to deal with the corrosive potential of the substance. Therefore, a medium hazard was identified.

Long term, local DNEL- exposure via inhalation (workers)

The health-based German occupational exposure limit (MAK-value, implemented in TRGS 900 01/2006) of 36 mg/m³ is used as worker-DNEL (inhalation, long-term/local). An Occupational Exposure Limit (OEL) of 36 mg/m³(Long-term Exposure Value, eight-hours time weighted average) was also established from the Scientific Committee for Occupational Exposure Limits (SCOEL).

Short term, local DNEL- exposure via inhalation (workers)

The substance is irritating to the upper respiratory tract and is harmonized classified for acute inhalation toxicity Cat.4 (H332) according to Annex VI of Regulation (EC) No 1272/2008. The health-based short-term German occupational exposure limit of 72 mg/m³ (MAK-value, implemented in TRGS 900 01/2006) is used as worker-DNEL(inhalation, acute/short-term/local). The short-term value concentration results from the product of the occupational exposure limit value (36 mg/m³) and the excursion factor (2). This is in line with the ECHA guidance on information requirements and chemical safety assessment, Chapter R.8 (2012). An Occupational Exposure Limit (OEL) of 72 mg/m³(Short-term Exposure Value, 15 minutes) was also established from the Scientific Committee for Occupational Exposure Limits (SCOEL).

2. Dermal

Long term, systemic DNEL- dermal exposure (workers)

The worker-DNEL for systemic effects associated with dermal long-term exposure is derived by means of route-to-route extrapolation based on the NOAEL of 60 mg/kg bw/day from the extended-one generation reproduction toxicity study (BASF SE, 2020). In this study Morpholine hydrochloride was administered to groups of 25 male and 25 female healthy young Wistar rats for test as an aqueous preparation by stomach tube at different dosages (0, 60, 200 and 600 mg/kg body weight/day [mg/kg bw/d]). F0 animals were treated at least for 10 weeks prior to mating to produce a litter (F1 generation). Pups of the F1 litter were selected (F1 rearing animals) and assigned to 2 different cohorts (1A and 1B) which were subjected to specific post-weaning examinations. Under the conditions of the extended one-generation reproduction toxicity study the NOAEL for general, systemic toxicity is 200 mg/kg bw/day, based on clinical pathological findings indicating marginal anemia, changed protein and lipid metabolism as well as metabolic acidosis at the LOAEL of 600 mg/kg bw/day. The NOAEL for fertility and reproductive performance for the parental male rats is 60 mg/kg bw/day, based on increased incidence of males showing tubular degeneration in the testis and subsequent alteration of sperm at 200 mg/kg bw/day and above. The NOAEL for fertility and reproductive performance for the parental female rats is 600 mg/kg bw/day, the highest tested dose. Neither the ability of the affected males to reproduce nor the integrity of female sexual organs was influenced by the test compound at any dose. The NOAEL for developmental toxicity in the F1 progeny is 600 mg/kg bw/day, the highest tested dose.

Step 1: PoD: NOAEL = 60 mg/kg bw/day

Step 2: Modification into a correct starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100%

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker (=1.4)

Corrected NOAEL (dermal) for workers:

= 60 mg/kg bw/day x (100/100)x 1.4

= 84 mg/kg bw/day

Step 3: Overall AF= 100

Exposure duration AF: 2 for sub-chronic to chronic (default)

Interspecies AF, allometric scaling (rat to human): 4 (default)

Interspecies AF, remaining differences: 2.5 (default)

Intraspecies AF (worker): 5 (default)

Whole database AF: 1

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic dermal DNEL, workers = 0.84 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

The substance is classified for acute dermal toxicity Cat.4 (H312) according to Regulation (EC) No 1272/2008 (CLP Regulation). Furthermore, morpholine is harmonized classified as corrosive to skin and eyes (Cat. 1B, H314) according to Annex VI of Regulation (EC) No 1272/2008. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion.

Long term & acute, local DNEL- dermal exposure (workers)

According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the eye as well as skin corrosive properties of the substance. As a result, a high hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure.

Hazard to the eye-local effects (worker)

Morpholine is harmonized classified as corrosive to skin and eyes (Cat. 1B, H314) according to Annex VI of Regulation (EC) No 1272/2008. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment.Part E: Risk Characterisation, Version 3.0, May 2016

MAK-Liste, Deutsche Forschungsgemeinschaft, Ständige Senatskommission zur Prüfung gesundheitlicher Arbeitsstoffe, Online-Ausgabe, 2018

SCOEL, Morpholine, Commission Directive 2006/15/EC of 7^th February 2006 (second list of indicative occupational exposure limit values)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Human via the environment

Although there are no consumer uses for morpholine (CAS 110-91-8), the oral systemic long-term DNEL for the general population is necessary for the assessment of indirect exposure of humans via the environment (ECHA GD R.16, 2016).

Long term, systemic DNEL- exposure by oral route (human via environment)

The NOAEL of 60 mg/kg bw/day from the extended-one generation reproduction toxicity study performed with rats was used as POD (BASF SE, 2020).

Step 1: PoD: NOAEL = 60 mg/kg bw/day

Step 2: Overall AF= 200

Exposure duration AF: 2 for sub-chronic to chronic (default)

Interspecies AF, allometric scaling (rat to human): 4 (default)

Interspecies AF, remaining differences: 2.5 (default)

Intraspecies AF (general population): 10 (default)

Dose-response relationship AF: 1

In conclusion, long term systemic oral DNEL, human via environment= 0.3 mg/kg bw/day

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016) Guidance on information requirements and Chemical Safety Assessment, Chapter R.16: Environmental exposure assessment, Version 3.0, Feb 2016