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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC
Value:
324 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
2
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability of 2 likely, hence the AF of 5 by ECETOC (2010) is considered to be too conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
321 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
2
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
2
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability of 2 likely, hence the AF of 5 by ECETOC (2010) is considered to be too conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
AF for extrapolation from sub-chronic to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.
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

For workers the inhalative and dermal routes are the most likely for exposure. On account of the corrosivity of MADAME and of the highly accepted use of suitable protective equipment it can be assumed that, as a rule, daily repeated immediate skin or eye contact is avoided to a large extent by using suitable personal protective equipment. Therefore, the DNELs derived for local and systemic effects from long-term exposure by inhalation are considered sufficient to ensure the safety of human workers. However, considering the low vapour pressure of MADAME of about 0.58 hPa, a dermal DNEL for systemic effects after long-term exposure has been taken into account for the toxicological assessment of this substance.

Long-term exposure - local & systemic effects:

1) Inhalation DNEL:

The NOAEL value from a subacute repeated dose inhalation study with rats (Gage et al., 1970) was identified to be the most appropriate starting point for DNEL derivation for long-term exposure following inhalation. The respective NOAEC for local and systemic effects was 100 ppm, based on nose and eye irritation, rapid breathing and a low and irregular weight gain at the next dose level of 250 ppm. No change of haematological and clinical parameters in blood and urine as well as no pathological (macroscopical and microscopical) effects on organs were observed.

The starting point was modified to get the correct starting point for DNEL derivation (correction of exposure duration in study (6 h/day to default worker exposure (8 h/day); correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³)), resulting in a value of 50 ppm. A total assessment factor of 40 was used to calculate the DNEL value of 5 mg/kg bw/day..

Discussion of the applied assessment factors (AF):

- Interspecies factor: 1

Concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and human have to be taken into account.

- Intraspecies factor: 2

Systemic effects in the repeated dose study with rats were minimal and restricted to slow body weight gain probably due to local irritation of nose and eyes. Especially for irritation of the respiratory epithelium rodents like the rat are more sensitive than humans.

Furthermore, based on the results from the repeated dose inhalation study and from other toxicity studies the test substance is considered to be a local irritant without much specific systemic toxicity, and not much variation of the irritant effect in human workers is expected. Therefore, an assessment factor of 2 for intraspecies variations is considered to be sufficient.

- Exposure duration: 6 (default)

From subacute to chronic an assessment factor of 6 was taken by default.

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 2 x 6 = 12

Calculation: 100 * 6/8 * 6.7/10 / 12 = 4.2 ppm (27 mg/m³)

2) Dermal DNEL:

The toxicity of Dimethylaminoethyl methacrylate was investigated in Sprague Dawley rats after daily oral administration at dose levels of 100, 200 and 500 mg/kg/day for 13 weeks and recovery from any treatment-related effects during a recovery period of 4 weeks (RTC, 2014). In conclusion, the systemic No Observed Adverse Effect Level (NOAEL) for this study was 500 mg/kg/day.

On the assumption that, in general, dermal absorption will be less than oral absorption, the starting point was modified to get the correct starting point for dermal DNEL derivation. This assumption is supported by the fact that a dermal LD50 value of > 2000 mg/kg was established in rabbits (Atochem, 1992) which is suggestive of a limited dermal absorption of the test substance.

Therefore, for route-to-route extrapolation, oral and dermal absorption of MADAME were considered to be 100% and 50%, respectively, resulting in the corrected starting point for dermal DNEL derivation of 1000 mg/kg bw. A total assessment factor of 24 was used to calculate the dermal DNEL value for systemic effects after long-term exposure of 41.7 mg/kg bw/day.

Discussion of the applied assessment factors (AF):

- Interspecies factor: 4

The established dermal LD50 value of > 2000 mg/kg in rabbits (Atochem, 1992) is suggestive of a limited dermal absorption of the test substance. Therefore, the interspecies factor of 2.5 for remaining differences was not applied.

- Intraspecies factor: 3 (default)

An intraspecies factor of 3 for workers was taken by default (ECETOC).

- Exposure duration: 2 (default)

From sub-chronic to chronic an assessment factor of 2 was taken by default.

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 4 x 3 x 2 = 24

Calculation: 500 * 100/50 / 24 = 41.7 mg / kg bw / d

Short-term exposure - local effects:

1) Inhalation DNEL:

The NOAEL value from a subacute repeated dose inhalation study with rats (Gage et al., 1970) was identified to be the most appropriate starting point for DNEL derivation for short-term exposure following inhalation. The respective NOAEC for local effects was 100 ppm, based on nose and eye irritation, rapid breathing and a low and irregular weight gain at the next dose level of 250 ppm.

Discussion of the applied assessment factors (AF):

- Interspecies factor: 1

Concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and human have to be taken into account.

- Intraspecies factor: 2

Systemic effects in the repeated dose study with rats were minimal and restricted to slow body weight gain probably due to local irritation of nose and eyes. Especially for irritation of the respiratory epithelium rodents like the rat are more sensitive than humans.

Furthermore, based on the results from the repeated dose inhalation study and from other toxicity studies the test substance is considered to be a local irritant without much specific systemic toxicity, and not much variation of the irritant effect in human workers is expected. Therefore, an assessment factor of 2 for intraspecies variations is considered to be sufficient.

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 2

Calculation: 100 / 2 = 50 ppm (321 mg/m³)

2) Dermal DNEL:

Skin contact to the substance has to be minimized by adequate risk management measures as the substance is corrosive and a skin sensitizer. Due to the mandatory implementation of these risk management measures for long-term exposure, derivation of a quantitative short-term DNEL for dermal exposure is not necessary. Instead, a quantitative moderate hazard was assessed according to ECHA's Guidance Part E (2016).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
120 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
AF for extrapolation from sub-chronic to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.
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:
DNEL (Derived No Effect Level)
Value:
128.5 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
5
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern 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:
No remaining uncertainties.

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

For consumers the inhalative and dermal routes are the most likely for exposure. Therefore, the DNELs derived for local and systemic effects from long-term exposure by inhalation and the DNEL derived for systemic effects after long-term exposure by dermal contact are considered sufficient to ensure the safety of the general population. However, on account of the corrosivity of MADAME dermal contact by the general population should be limited.

Long-term exposure - local & systemic effects

1) Inhalation DNEL:

The NOAEL value from a subacute repeated dose inhalation study with rats (Gage et al., 1970) was identified to be the most appropriate starting point for DNEL derivation for long-term exposure following inhalation. The respective NOAEL for local and systemic effects was 100 ppm (643 mg/m³), based on nose and eye irritation, rapid breathing and a low and irregular weight gain at the next dose level of 250 ppm. No change of haematological and clinical parameters in blood and urine as well as no pathological (macroscopical and microscopical) effects on organs were observed.

The starting point was modified to get the correct starting point for DNEL derivation (correction of exposure duration in study (6 h/day, 5 days/week) to default general population exposure (24 h/day, 7 days/week)), resulting in a value of 18 ppm. A total assessment factor of 30 was used to calculate the DNEL value of 0.6 ppm (~ 4 mg/m³).

Discussion of the applied assessment factors (AF):

- Interspecies factor: 1

Concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and human are to be taken into account.

- Intraspecies factor: 5 (default)

The intraspecies variations were recognised by an assessment factor of 5 by default (ECETOC).

- Exposure duration: 6 (default)

From subacute to chronic an assessment factor of 6 was taken by default.

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 5 x 6 = 30

Calculation: 100 * 6/24 * 5/7 / 30 = 0.6 ppm (4 mg/m³)

2) Dermal DNEL:

MADAME is corrosive. However, there are no dose-response data available for this effect, and a quantitative DNEL for local effects after dermal contact has therefore not been derived.

The toxicity of Dimethylaminoethyl methacrylate was investigated in Sprague Dawley rats after daily oral administration at dose levels of 100, 200 and 500 mg/kg/day for 13 weeks and recovery from any treatment-related effects during a recovery period of 4 weeks (RTC, 2014). In conclusion, the systemic No Observed Adverse Effect Level (NOAEL) for this study was 500 mg/kg/day.

On the assumption that, in general, dermal absorption will be less than oral absorption, the starting point was modified to get the correct starting point for dermal DNEL derivation. This assumption is supported by the fact that a dermal LD50 value of > 2000 mg/kg was established in rabbits (Atochem, 1992) which is suggestive of a limited dermal absorption of the test substance.

Therefore, for route-to-route extrapolation, oral and dermal absorption of MADAME were considered to be 100% and 50%, respectively, resulting in the corrected starting point for dermal DNEL derivation of 1000 mg/kg bw. A total assessment factor of 40 was used to calculate the dermal DNEL value for systemic effects after long-term exposure of 25 mg/kg bw/day.

Discussion of the applied assessment factors (AF):

- Interspecies factor: 4

The established dermal LD50 value of > 2000 mg/kg in rabbits (Atochem, 1992) is suggestive of a limited dermal absorption of the test substance. Therefore, the interspecies factor of 2.5 for remaining differences was not applied.

- Intraspecies factor: 5 (default)

An intraspecies factor of 5 for the general population was taken by default (ECETOC).

- Exposure duration: 2 (default)

From sub-chronic to chronic an assessment factor of 2 was taken by default.

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 4 x 5 x 2 = 40

Calculation: 500 * 100/50 / 40 = 25 mg / kg bw / d

Short-term exposure - local effects:

1) Inhalation DNEL:

The NOAEL value from a subacute repeated dose inhalation study with rats (Gage et al., 1970) was identified to be the most appropriate starting point for DNEL derivation for short-term exposure following inhalation. The respective NOAEC for local effects was 100 ppm, based on nose and eye irritation, rapid breathing and a low and irregular weight gain at the next dose level of 250 ppm.

Discussion of the applied assessment factors (AF):

- Interspecies factor: 1

Concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and human have to be taken into account.

- Intraspecies factor: 5

The intraspecies variations were recognised by an assessment factor of 5 by default (ECETOC).

- Dose-response: 1 (default)

- Quality of whole database: 1 (default)

Total AF = 5

Calculation: 100 / 5 = 20 ppm (128.5 mg/m³)

2) Dermal DNEL:

Skin contact to the substance has to be minimized by adequate risk management measures as the substance is corrosive and a skin sensitizer. Due to the mandatory implementation of these risk management measures for long-term exposure, derivation of a quaitative short-term DNEL for dermal exposure is not necessary. Instead, a quantitative moderate hazard was assessed according to ECHA's Guidance Part E (2016).