Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
198.4 mg/m³
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: sub-chronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
The default value for 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 dermal repeated dose 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:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
562.5 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: sub-chronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default value for allometric scaling is used.
AF for other interspecies differences:
2.5
Justification:
The default value for 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 dermal repeated dose 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:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
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:
1
Justification:
According ECHA REACH Guidance no time extrapolation factor is needed.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.
AF for other interspecies differences:
2.5
Justification:
The default value for 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 dermal repeated dose 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:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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).

1.    Inhalation

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

No sub-chronic or chronic studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it is necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

In a sub-chronic dermal toxicity study (similar to OECD guideline 411) performed with MDEA, rats were exposed to 100, 250 and 750 mg/kg bw/day. The observed local effects were dose-related irritation in the mid and high dose groups; major histopathological features were acanthosis, hyperkeratosis, parakeratosis, dermatitis, dermal fibrosis, eschar, and ulceration. No systemic effects were observed up to the highest dose tested. Local and systemic NOAELs of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) and 750 mg/kg bw/day were established upon dermal exposure, respectively.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The systemic NOAEL of 750 mg/kg bw/day derived from a study similar to OECD TG 411 study was used as the PoD.

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 750 mg/kg bw/day

Dermal absorption of the rat / inhalation absorption of humans (ABS dermal-rat / ABS inh-human): 20/100

A dermal absorption of 20% is assumed for MDEA from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after inhalatory exposure is assumed in absence of any experimental data as recommended in TGD R8.

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between experimental and human exposure conditions: 6 h/5days per week vs. 8 h / 5 day

Corrected NOAEC (inhalation) for workers:

= 750 mg/kg bw/day× 0.2 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 0.75

= 198.4 mg/m³

Step 3: Overall AF= 25

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (dermal)-to route (inhalation) is applied.

Interspecies AF, remaining differences: no evidence for species differences in the general mode of

Action

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

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

Whole database AF: 1

The repeated dose dermal 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 inhalation DNEL, workers = 7.9 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified". In inhalation risk tests performed with the substance no mortality was observed after 6 and 8 hours exposure to a saturated MDEA vapour atmosphere. Therefore, a DNEL is not required.

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

The substance is in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 classified as eye irritant (Cat. 2). 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. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent eye and mucous membrane exposure.

2.    Dermal

In a sub-chronic dermal toxicity study (similar to OECD guideline 411) performed with MDEA, rats were exposed to 100, 250 and 750 mg/kg bw/day. The observed local effects were dose-related irritation in the mid and high dose groups; major histopathological features were acanthosis, hyperkeratosis, parakeratosis, dermatitis, dermal fibrosis, eschar, and ulceration. No systemic effects were observed up to the highest does tested. Local and systemic NOAELs of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) and 750 mg/kg bw/day were established upon dermal exposure, respectively.

Long term, systemic DNEL- exposure via dermal route (workers)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The NOAEL of 750 mg/kg bw/day derived from a study similar to OECD TG 411.

Correction for difference between experimental and human exposure conditions: 6 h/5days per week vs. 8 h / 5 day

NOAEL corr = 750 mg/kg bw/day x 0.75

= 562.5 mg/kg bw/day

Step 2: Overall AF= 100

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

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

In conclusion, long term systemic dermal DNEL, workers = 5.63 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Long term local DNEL- dermal exposure (workers)

MDEA is not classified for skin irritation. However, after repeated dermal exposure local dermal effects were reported.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The local NOAEL of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) derived from a study similar to OECD TG 411.

Correction for difference between experimental and human exposure conditions: 6 h/5days per week vs. 8 h / 5 day

Step 2: Modification into a correct starting point: NOAEL corr = 100 mg/kg bw/day x 0.75

= 75 mg/kg bw/day

Step 3: Overall AF= 12.5

Interspecies AF, allometric scaling: 1

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term local dermal DNEL, workers = 6 mg/kg bw/day (=0.05 mg/cm2/day)

Short term local DNEL- dermal exposure (workers)

A qualitative approach has to be implemented to deal with the eye irritating properties of MDEA. As a result, a low hazard is derived. Eyes and mucous membranes with potential exposure should be protected.

Hazard to the eye-local effects (workers)

The test item is classified for eye irritation (Cat. 2, H 319) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (low hazard).

 

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
19.9 mg/m³
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):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
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 relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The dermal repeated dose 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:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
134.25 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: sub-chronic (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 relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The dermal repeated dose 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:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
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:
1
Justification:
According ECHA REACH Guidance no time extrapolation factor is needed.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.
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 relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The dermal repeated dose 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:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
26.8 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: sub-chronic (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 relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The dermal repeated dose 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:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

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).

1.    Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

No sub/chronic studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it is necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

In a sub-chronic dermal toxicity study (similar to OECD guideline 411) performed with MDEA, rats were exposed to 100, 250 and 750 mg/kg bw/day. The observed local effects were dose-related irritation in the mid and high dose groups; major histopathological features were acanthosis, hyperkeratosis, parakeratosis, dermatitis, dermal fibrosis, eschar, and ulceration. No systemic effects were observed up to the highest does tested. Local and systemic NOAELs of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) and 750 mg/kg bw/day were established upon dermal exposure, respectively.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The systemic NOAEL of 750 mg/kg bw/day derived from a study similar to OECD TG 411 was used as the PoD.

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 750 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m3/kg bw

Dermal absorption of the rat / inhalation absorption of humans (ABS dermal-rat / ABS inh-human): 20/100

A dermal absorption of 20% is assumed for MDEA from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after inhalatory exposure is assumed in absence of any experimental data as recommended in TGD R8.

Differences experimental/human exposure conditions: 6h/24h x 5d/7d (=0.179)

Corrected NOAEC (inhalation) for general population:

= 750 mg/kg bw/day x 0.2 x (1 / 1.35 m3/kg bw/24h) x 0.179

= 19.9 mg/m3

Step 3: Overall AF=50

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF for allometric scaling is needed when route (oral)-to route (inhalation) extrapolation is applied.

Intraspecies AF (general population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

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

In conclusion, long term systemic inhalation DNEL, general population= 0.4 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified". In inhalation risk tests performed with the substance no mortality was observed after 6 and 8 hours exposure to a saturated MDEA vapour atmosphere.

Long & Short term, local DNEL- exposure via inhalation (general population)

The substance is in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 classified as eye irritant (Cat. 2). 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. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent eye and mucous membrane exposure.

2.    Dermal

No sub/chronic studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it is necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

In a sub-chronic dermal toxicity study (similar to OECD guideline 411) performed with MDEA, rats were exposed to 100, 250 and 750 mg/kg bw/day. The observed local effects were dose-related irritation in the mid and high dose groups; major histopathological features were acanthosis, hyperkeratosis, parakeratosis, dermatitis, dermal fibrosis, eschar, and ulceration. No systemic effects were observed up to the highest does tested. Local and systemic NOAELs of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) and 750 mg/kg bw/day were established upon dermal exposure, respectively.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The systemic NOAEL of 750 mg/kg bw/day derived from a study similar to OECD TG 411 was used as the PoD.

Relevant dose descriptor (NOAEL): 750 mg/kg bw/day

Correction for difference between experimental and human exposure conditions: 6h/24h x 5d/7d (=0.179)

Corrected NOAEL (dermal) for general population:

= 750 mg/kg bw/day x 0.179

= 134.25 mg/kg bw/day

Step 2: Overall AF= 200

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 10

Dose-response relationship AF: 1

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

In conclusion, long term systemic dermal DNEL, general population = 0.67 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, a DNEL is not required.

Long term local DNEL- dermal exposure (general population)

MDEA is not classified for skin irritation. However, after repeated dermal exposure local dermal effects were reported.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

The local NOAEL of 100 mg/kg bw/day (corresponding to 0.8 mg/cm2) derived from a study similar to OECD TG 411.

Correction for difference between experimental and human exposure conditions: 6h/24h x 5d/7d (=0.179)

Step 2: Modification into a correct starting point: NOAEL corr = 100 mg/kg bw/day x 0.179

= 17.9 mg/kg bw/day

Step 3: Overall AF= 25

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term local dermal DNEL, general population = 0.71 mg/kg bw/day (=0.03 mg/cm2/day)

 

Acute local DNEL- dermal exposure (general population)

A qualitative approach has to be implemented to deal with the irritating properties of MDEA. As a result, a low hazard is derived. Eyes and mucous membranes with potential exposure should be protected.

3.    Oral

Long term, systemic DNEL – exposure by oral route (general population)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (dermal)

Step 2: Relevant dose descriptor (NOAEL): 750 mg/kg bw/day

Correction for difference between experimental and human exposure conditions: 6h/24h x5d/7d

Dermal absorption of the rat / oral absorption of humans (ABS dermal-rat / ABS oral-human): 20/100

A dermal absorption of 20% is assumed for MDEA from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after oral exposure is assumed in absence of any experimental data as recommended in TGD R8.

Corrected NOAEL (oral) for general population:

= 750 mg/kg bw/day x 0.179 x 0.2

= 26.8 mg/kg bw/day

Step 3: Overall AF= 200

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

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric

scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

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

In conclusion, long term systemic oral DNEL, general population= 0.134 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute oral toxicity with the LD50 >2000 mg/kg bw. Therefore, a DNEL is not required.

Hazard to the eye-local effects (general population)

The test item is classified for eye irritation (Cat. 2, H 319) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (low hazard).

 

References

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

Characterization 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 Characterization, Version 3.0, May 2016