Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
Acute/short term exposure
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
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Long-term – inhalation, local/systemic effects (based on the 28 days inhalation study in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 10 mg/m3

The exposure of rats to MEA caused concentration-related lesions in larynx, trachea and lung. No histopathological effects were seen in any other organ outside the respiratory tract. The NOAEC for local effect was the lowest tested concentration of 10 mg/m3under the current test conditions. The NOAEC for systemic toxicity is the highest concentration of 150 mg/m3.

Step 2) Modification of starting point

1

 

 

 

 

 

According to the REACH guidance, time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration;

 

Correction for activity is not neccesary becaues the effect is mainly driven by a local mechanism and the corrosive properties of the substance on the larynx and on the trachea. Due to the fact that the rat is an obligatory nose breather the teat-species is in this case over-predictive.No modification of the starting point is applied.

Modified dose-descriptor

10 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No factor for allometric scaling is needed in case of inhalation exposure.Furthermore, the factor for remaining uncertainties is not needed as the rat is a more sensitive species for inhalation exposure and an obligatory nose breather.

Intraspecies

 

 

3

 

Using a reduced factor of 3 is justified because the critical effect is a local effect that is hardly, if at all, determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.

Local effects are largely concentration-dependent whereas exposure time and enzyme polymorphisms are of minor importance in such cases.

Due to the fact that the local effects are driven by local exposure peaks and are not supposed to worsen with time and considering the rat is over-predictive in this case, a joint assessment factor of 3 is applied for intraspecies differences and exposure duration correction.

Exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

10 / (1 x 3 x 1 x 1) = 3.3 mg/m3

 

Long-term – dermal, systemic effects(based on the 28 days inhalation study in rats)

 

As no systemic effects were observed after inhalation exposure up to the highest concentration tested, 150 mg/m3, for 28 days, derivation of a dermal long-term DNEL for systemic effects based on the inhalation study is a conservative approach. As MEA is classified as corrosive to skin and eyes (C, R34), local dermal effects are considered more critical compared to systemic effects after dermal exposure.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 ‘adequate control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion. Using these risk management measures the remaining dermal exposure will be rather low and therefore the risks for systemic effects will also be adequately controlled.

 

According to the Guidance on the Application of Regulation (EC) No 1272/2008, when a substance is present in concentrations of less than 5% the preparation is not considered corrosive to skin. In case concentrations are between 1% and 5% classification for skin irritation is applicable.

Current information indicates that exposure scenarios exist in which exposure to MEA concentrations of less than 5% occurs. For these situations MEA is not corrosive to skin and therefore dermal exposure needs to be assessed. For the risk characterisation for these situations a long-term dermal DNEL (systemic) is needed. Using the inhalation study as starting point, the following DNEL is derived:

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 150 mg/m3

No systemic effects were observed after inhalation exposure up to 150 mg/m3for 28 days.

Step 2) Modification of starting point

0.29

 

 

 

100/37.5

A 6 h respiratory volume of 0.29 m3/kg bw for rats was used for conversion into NAEL upon dermal exposure.

 

Correction for absorption: 100% absorption upon inhalation exposure; 37.5% absorption is assumed for dermal exposure.

Modified dose-descriptor

150 x 0.29 x (100/37.5) = 116 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4 x 1

Assessment factor for allometric scaling. As no effects were observed up to the highest concentration tested, the factor for remaining uncertainties is not applied.

Intraspecies

5

Default assessment factor

Exposure duration

6

The key study is a 28 days inhalation study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

116 / (4 x 1 x 5 x 6 x 1 x 1) =1 mg/kg bw/day

 

(Taking the dermal NOAEL for maternal toxicity (systemic effects) from the developmental toxicity study with rats (Liberacki et al, 1996) as starting point, i.e., 75 mg/kg bw/day, a DNEL of 1.5 mg/kg bw/day (75 / (4 x 2.5 x 5 x 1 x 1) = 1.5 mg/kg bw/day) is calculated)

 

It has to be noted that this is a conservative approach. Nevertheless, it is expected that safe use will be easily shown as for this situation the percentage of the substance in the product is only 5% or lower and as concentrations of the substance between 1% and 5% are irritating to the skin which requires wearing gloves.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.24 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term – oral, systemic effects (based on the oral two-generation study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 300 mg/kg bw/day

Reduced food consumption and/or body weight gain, as well as organ weight changes unaccompanied by histopathological findings

Step 2) Modification of starting point

-

 

Step 3) Assessment factors

 

Interspecies

4

Assessment factor for allometric scaling. As no effects were observed up to the highest dose tested, the factor for remaining uncertainties is not applied.

Intraspecies

10

Default assessment factor

Exposure duration

2

The key study concernssemichronic duration (> 75 days).

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

300 / (4 x 2.5 x 10 x 2 x 1 x 1) = 3.75 mg/kg bw/day

 

 

Long-term – inhalation, local/systemic effects (based on the 28 days inhalation study in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 10 mg/m3

The exposure of rats to MEA caused concentration-related lesions in larynx, trachea and lung. No histopathological effects were seen in any other organ outside the respiratory tract. The NOAEC for local effect was the lowest tested concentration of 10 mg/m3under the current test conditions. The NOAEC for systemic toxicity is the highest concentration of 150 mg/m3.

Step 2) Modification of starting point

-

 

 

According to the REACH guidance, time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration.

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of local effects. Furthermore, the factor for remaining uncertainties is not needed as the rat is a more than sensitive species for inhalation exposure and an obligatory nose breather.

Intraspecies

5

 

Using a reduced factor of 5 is justified because the critical effect is a local effect that is hardly, if at all, determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.

Local effects are largely concentration-dependent whereas exposure time and enzyme polymorphisms are of minor importance in such cases.

Due to the fact that the local effects are driven by local exposure peaks and are not supposed to worsen with time and considering the rat is over-predictive in this case, a joint assessment factor of 5 is applied for intraspecies differences and exposure duration correction.

Exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

10 / (1 x 5 x 1 x 1) =2 mg/m3

 

 

Long-term – dermal, systemic effects (based on the 28 days inhalation study in rats)

 

As no systemic effects were observed after inhalation exposure up to the highest concentration tested, 150 mg/m3, for 28 days, derivation of a dermal long-term DNEL for systemic effects based on the inhalation study is a conservative approach. As MEA is classified as corrosive to skin and eyes (C, R34), local dermal effects are considered more critical compared to systemic effects after dermal exposure.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. Using these risk management measures the remaining dermal exposure will be rather low and therefore the risks for systemic effects will also be adequately controlled.

 

According to the Guidance on the Application of Regulation (EC) No 1272/2008, when a substance is present in concentrations of less than 5% the preparation is not considered corrosive to skin. In case concentrations are between 1% and 5% classification for skin irritation is applicable.

Current information indicates that exposure scenarios exist in which exposure to MEA concentrations of less than 5% occurs. For these situations MEA is not corrosive to skin and therefore dermal exposure needs to be assessed. For the risk characterisation for these situations a long-term dermal DNEL (systemic) is needed. Using the inhalation study as starting point, the following DNEL is derived:  

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 150 mg/m3

No systemic effects were observed after inhalation exposure up to 150 mg/m3for 28 days.

Step 2) Modification of starting point

0.29

 

 

 

100/75

A 6 h respiratory volume of 0.29 m3/kg bw for rats was used for conversion into NAEL upon dermal exposure.

 

Correction for absorption: 100% absorption upon inhalation exposure; 75% absorption is assumed for dermal exposure

Modified dose-descriptor

150 x 0.29 x (100/75) = 58 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4 x 1

Assessment factor for allometric scaling. As no effects were observed up to the highest concentration tested, the factor for remaining uncertainties is not applied.

Intraspecies

10

Default assessment factor

Exposure duration

6

The key study is a 28 days inhalation study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

58 / (4 x 1 x 10 x 6 x 1 x 1) =0.24 mg/kg bw/day

 

(Taking the dermal NOAEL for maternal toxicity (systemic effects) from the developmental toxicity study (Liberacki et al, 1996) as starting point, i.e., 75 mg/kg bw/day, a DNEL of 1.5 mg/kg bw/day (75 / (4 x 2.5 x 10 x 1 x 1) = 0.75 mg/kg bw/day) is calculated)

 

It has to be noted that this is a conservative approach. Nevertheless, it is expected that safe use will be easily shown as for this situation the percentage of the substance in the product is only 5% or lower and as concentrations of the substance between 1% and 5% are irritating to the skin which requires wearing gloves.