4-ethylmorpholine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.35 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

176.31 mg/m³

Explanation for the modification of the dose descriptor starting point:

Relevant inhalation study is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

covered in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

no need for a further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for a further assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.667 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

relevant study via dermal application is not available

AF for dose response relationship:

1

Justification:

adequate data available

AF for differences in duration of exposure:

6

Justification:

subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

no need for a further assessment factor

AF for remaining uncertainties:

1

Justification:

no need for a further assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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

Acute/short term exposure (systemic and local effects):

- No data are available for acute toxicity via the inhalation route. A key study is available for the oral route of exposure and for the dermal route of exposure. According to the REACH Regulation, only one additional route of exposure other than the oral route of exposure should be tested for acute toxicity (column 2, annex VIII, section 8.5). Therefore, it is not necessary to perform an acute toxicity study via the inhalation route of exposure.

- An acute dermal toxicity study has been performed with NEM in male and female rabbits. The estimated dermal LD50 for NEM was determined to be 1980 mg/kg. Therefore, the test substance is considered to be classified category 4 according to CLP regulation. As no peak exposure is anticipated for this substance, it is considered that the long-term DNEL is sufficiently protective for acute exposure.

- According to the criteria of the CLP Regulation, the substance is classified as corrosive to skin and eye (category 1). According to ECHA's Guidance on Information Requirements and Chemical safety Assessment, part E, Table E.3 -1 the substance should be considered to cause medium hazard.

Long-term exposure (systemic effects):

-Inhalation: the NOAEL observed in the repeated dose toxicity study with the substance was used to derive a DNEL long-term, systemic effects via the inhalation route. For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 200 mg/kg/day x 1/(0.38 m3/kg/day) x 6.7m3/10m3 x 0.5 = 176.31 mg/m3. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m3/kg for 8 hours exposure for workers). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and calorix demand under light activity. This correction factor is derived from the inhaled volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity). The bioavailability via the inhalation route is considered to be 100%, while bioavailability after oral exposure is considered to be 50%, hence a correction factor of 0.5 is applied. With the overall assessment factor of 75 = 6 (difference in duration subacute to chronic) x 5 (intraspecies difference) x 2.5 (interspecies - remaining differences), the long-term DNEL, inhalation for systemic effects of 176.31 mg/m3/75 = 2.35 mg/m3.

-Dermal: No long-term dermal toxicity studies are available for the substance. A repeated dose toxicity study with the NEM after oral exposure could be used after extrapolation to the dermal route. Exposures were daily via oral gavage during 28 days. Rats were treated at dose levels of 50, 200 and 800 mg/kg/day (test item). A control group of 10 males and 10 females received concurrent vehicle treatment. The NOAEL was considered 200 mg/kg/day. For route-to-route extrapolation (oral to dermal) no factor needs to be applied as it is assumed that oral and dermal absorption will be similar (assumed to be 50%). The dose descriptor starting point is 200 mg/kg/day. The long-term dermal systemic DNEL is derived with an overall assessment factor of 300 = 4 (allometric scaling) x 2.5 (interspecies differences) x 6 (difference in duration subacute to chronic) x 5 (intraspecies differences). A long-term systemic DNEL of 200 mg/kg/day /300 = 0.667 mg/kg/day is derived

Long-term exposure (local effects):

- No reliable repeated dose toxicity study was available for NEM via the dermal route of exposure. No DNEL for long-term exposure local effects will be derived for the dermal route.

- No reliable repeated dose toxicity study was available for NEM via inhalation. No DNEL for long term exposure local effects will be derived for the inhalatory route.

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:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

No effect levels derived for general population, as no consumer use is expected.