Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.53 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:
No long-term study on inhalation is available, route-to-route extrapolation has been performed.
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
Difference in duration sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Covered by calculation for route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
1 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal long-term study is available, route to route extrapolation has been performed assuming absorption via dermal route does not exceed oral absorption.
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
Difference in duration sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

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

- No acute data were available for the inhalation route of exposure. In accordance with REACH Annex VIII, this study does not need to be conducted as inhalation is a less likely route of exposure than the dermal route. Therefore the second route of exposure for acute toxicity has been covered by the dermal exposure route.

- An acute dermal toxicity test has been performed in rabbits. The LD50 is greater than 8.000 mg/kg bw. The test solution used was a 50% aqueous solution of NMMO. The LD50 of the pure NMMO is therefore considered to be > 4.000 mg/kg. Therefore, a DNEL for acute dermal toxicity would not be quantifiable.

- According to the criteria of the CLP Regulation, NMMO is not classified as irritating to the skin nor to the eyes.

 

Long-term exposure (systemic effects)

- Dermal: No long-term dermal toxicity studies are available for NMMO. However, data from an oral 90 d study could be used after extrapolation to the dermal route. The test solution was administered daily, by gavage, on a 7-day week basis. Han Wistar rats (10 per sex and per dose) were treated at dose levels of 0, 30, 100, and 300 mg/kg/day (dosed as a 50% aqueous solution). The No Observed Adverse Effect Level (NOAEL) was determined at 100 mg/kg/day (expressed as pure NMMO).

There were no unscheduled deaths or treatment-related clinical observations noted. There was a slight effect on body weights in females receiving 100 mg/kg/day and in males (15.5%) and females (8.3%) receiving 300 mg/kg/day of Methylmorpholine oxide such that lower weight gains over the dosing period were observed when compared to concurrent controls. However, there were no changes in food consumption, ophthalmology, detailed functional observations and functional tests, clinical pathology parameters, gross necropsy findings, organ weights, organ weights relative to body weight or histopathology considered to be related to treatment. There were some dose-related effects on a few clinical chemistry parameters (e.g. decreased triglycerides and globulin levels in females dosed at 100 or 300 mg/kg/day and in males dosed at 300 mg/kg/day), but as there were no correlating histopathological changes observed in the liver of any treated animals, the toxicological significance of these changes is unclear. The study director concluded an NOAEL of 300 mg/kg/d. However, based on the decresae in body weight (> 15%) in male rats at 300 mg/kg/d, this dose was considered the LOAEL by the registrant.

Therefore, the dose-descriptor starting point for DNEL calculations is 100 mg/kg bw/day (NOAEL). For route-to-route extrapolation (oral to dermal), no default factor (i.e. factor 1) should be applied as part of the overall assessment factor, as it is assumed that dermal absorption will not be higher than oral absorption. The long-term dermal, systemic DNEL is derived with an overall assessment factor of 100: 10 (interspecies differences) x 2 (difference in duration sub-chronic to chronic) x 5 (intraspecies differences). A long-term, systemic DNEL of 100 mg/kg/day/100 = 1 mg/kg/day is derived.

 

- Inhalation: The NOAEL observed in the 90d repeated dose toxicity study 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 = 100 mg/kg bw/day x 1/(0.38 m³/kg/day) x 6.7m³/10m³ x 0.5 = 88.16 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 of workers). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric 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). In addition, the NOAEL was divided by 2 as the bioavailability via the inhalation route is considered as 100%, while for oral exposure this is only 50% (by default). With an overall assessment factor of 25: 2 (difference in duration sub-chronic to chronic) x 5 (intraspecies differences) x 2.5 (interspecies - remaining differences), the long-term DNEL, inhalation for systemic effects of 88.16 mg/m³/25 = 3.53 mg/m³ is derived.

 

Long-term exposure (local effects)

- No repeated dose toxicity study was available for this substance via the (local) dermal and inhalation route of exposure. Therefore, a DNEL long-term exposure, local effects cannot be derived. However, due to a lack of significant local effects on the skin and eyes, it can be concluded that local effects are not driver for human health risk assessment.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:
As no long-term study on inhalation is available, route-to-route extrapolation has been performed.
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
Difference in duration sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Covered by calculation for route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default for the general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
DNEL (Derived No Effect Level)
Value:
0.5 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal long-term study is available, route to route extrapolation has been performed assuming absorption via dermal route does not exceed oral absorption.
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
Difference in duration sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
Difference in duration sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default for the general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

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

- No acute data were available for the inhalation route of exposure. In accordance with REACH Annex VIII, this study does not need to be conducted as inhalation exposure is a less likely route of exposure than the dermal route. Therefore the second route of acute toxicity has been covered by the dermal exposure route.

- An acute dermal toxicity test has been performed in rabbits. The LD50 is greater than 8000 mg/kg bw. The test solution used was a 50% aqueous solution of NMMO. The LD50 of the pure NMMO is therefore considered to be > 4000 mg/kg.

Therefore, a DNEL for acute dermal toxicity would not be quantifiable.

- An acute oral toxicity test has been performed in rats. The LD50 is 9200 mg/kg bw. Therefore, a DNEL for acute oral toxicity would not be quantifiable. The test solution used was a 50% aqueous solution of NMMO. The LD50 of the pure NMMO is therefore considered to be > 4600 mg/kg.

- According to the criteria of the DSD and CLP Regulation, NMMO is not classified as irritating to the skin nor to the eyes.

 

Long-term exposure (systemic effects):

- Oral:

An oral 90d repeated dose toxicity study has been performed. The test solution was administered daily, by gavage, on a 7-day/week basis. Han Wistar rats (10 per sex and per dose) were treated at dose levels of 0, 30, 100, and 300 mg/kg/day (dosed as a 50% aqueous solution). The No Observed Adverse Effect Level (NOAEL) was determined at 300 mg/kg/day (expressed as pure NMMO).

There were no unscheduled deaths or treatment-related clinical observations noted. There was an effect on body weights in females receiving 100 mg/kg/day and in males (15.3%) and females (8.3%) receiving 300 mg/kg/day of Methylmorpholine oxide such that lower weight gains over the dosing period were observed when compared to concurrent controls. However, there were no changes in food consumption, ophthalmology, detailed functional observations and functional tests, clinical pathology parameters, gross necropsy findings, organ weights, organ weights relative to body weight or histopathology considered to be related to treatment. There were some dose-related effects on a few clinical chemistry parameters (e.g. decreased triglycerides and globulin levels in females dosed at 100 or 300 mg/kg/day and in males dosed at 300 mg/kg/day), but as there were no correlating histopathological changes observed in the liver of any treated animals, the toxicological significance of these changes is unclear. The study director concluded an NOAEL of 300 mg/kg/d. However, based on the decresae in body weight (> 15%) in male rats at 300 mg/kg/d, this dose was considered the LOAEL by the registrant. The long-term oral, systemic DNEL is derived with an overall assessment factor of 200: 10 (interspecies differences) x 2 (difference in duration sub-chronic to chronic) x 10 (intraspecies differences). A long-term, systemic DNEL of 100 mg/kg/day/200 = 0.5 mg/kg/day is derived. -

- Dermal:

No long-term dermal toxicity studies are available for NMMO. However, data from an 90d oral repeated dose toxicity study was used after extrapolation to the dermal route. For route-to-route extrapolation (oral to dermal), no default factor (i.e. factor 1) was be applied as part of the overall assessment factor, as it is assumed that dermal absorption will not be higher than oral absorption. The long-term dermal, systemic DNEL is derived with an overall assessment factor of 200: 10 (interspecies differences) x 2 (difference in duration sub-chronic to chronic) x 10 (intraspecies differences). A long-term, systemic DNEL of 100 mg/kg/day/200 = 0.5 mg/kg/day.

- Inhalation:

The NOAEL observed in the 90d oral repeated dose toxicity study 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 = 100 mg/kg bw/day x 1/(1.15 m³/kg/day) x 0.5 = 43.5 mg/m³. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 hours exposure). In addition, the NOAEL was divided by 2 as the default bioavailability via the inhalation route is considered as 100%, while for oral exposure this is only 50%. With an overall assessment factor of 50: 2 (difference in duration sub-chronic to chronic) x 10 (intraspecies differences) x 2.5 (interspecies - remaining differences), the long-term DNEL inhalation for systemic effects of 43.5 mg/m³/50 = 0.87 mg/m³ is derived.

 

Long-term exposure (local effects):

- No repeated dose toxicity study was available for this substance via the (local) dermal and inhalation route of exposure. Therefore, a DNEL long-term exposure, local effects cannot be derived. However, due to a lack of significant local effects on the skin and eyes, it can be concluded that local effects are not driver for human health risk assessment.