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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:
29.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
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:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
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:
medium hazard (no threshold derived)

Additional information - workers

Eye irritation

Ethylenediamine, +4PO is classified for eye irritation. The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

 

Ethylenediamine, +4PO is not classified for skin sensitisation. Therefore, no DNEL has to be derived.

 

 

Repeated dose toxicity

 

a.      General

 

The most relevant endpoint is a combined repeated dose toxicity study with a reproduction / developmental toxicity screening test (OECD 422). All rats of the highest dose group (1000 mg/kg bw/day) developed vacuolisation in the epithelial cells of the choroid plexus of the lateral ventricles in the brain. Neither abnormalities in behavior nor pecularities in motor activity were recorded. In conclusion, the observed vacuolisation of the choroid plexus did not cause neuronal impairment within the timeframe of the study. Although the adversity of the vacuolisation was not finally clarified, the NOAEL was set to 300 mg/kg bw/day.

 

b.     Worker-DNEL long-term dermal, systemic

 

To obtain a starting point, route-to-route extrapolation is applied for the oral NOAEL derived from rat. On the assumption that, in general, dermal absorption will not be higher than oral absorption (default factor = 1) no modification of the dose descriptor is necessary to set the correct starting point when performing oral-to-dermal extrapolation

 

Oral NOAEL (rat) = dermal NOAEL(rat) = 300 mg/kg bw/day

 

The DNEL long-term dermal, systemic is calculated by applying assessment factors to the corrected NOAEL.Taking into account the following considerations, an overall assessment factor of 72 is calculated:

·        Inter-species differences = 4

As proposed in the R.8 TGD; 2008

·        Remaining differences = 1

Significant metabolism of Ethylenediamine, +4PO is not expected (Dunphy, 1991). After i.v. injection of ethylenediamine, +4PO, metabolites could not be detected in the blood of the rats. 92 – 96 % of the test substance are rapidly excreted via the renal route. Therefore, remaining species differences concerning metabolism seem to be unlikely.

·       Intra-species differences = 3

As described above, significant metabolism is not expected. In conclusion, there is a reduced risk of intra-species variability as different metabolic kinetics do not play a role. Therefore, the assessment factor of 5 recommended by the R.8 TGD was reduced to 3.

·       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

As proposed by the R.8 TGD

·        Dose-response = 1

The R.8 TGD proposes an assessment factor of 1, if the starting point for DNEL derivation is a reliable NOAEL like in the present case.

·        Quality of whole database = 1

Taking into account the completeness, the consistency and the standard information requirements, the available data is of high quality. Here, the R.8 TGD proposes an assessment factor of 1.

 

Worker-DNEL long-term, dermal, systemic = 300 mg/kg bw/day /72 = 4.2 mg/kg bw/day

 

c.       Worker-DNEL long-term, inhalation systemic

   

The NOAEL of 300 mg/kg bw/day from the combined repeated dose study with a reproduction / developmental screening test (OECD 422) was taken as the most relevant dose descriptor. The NOAEC worker (8h) was calculated as described in the R.8 TGD:

 

Corrected inhalatory NOAEC = rat oral NOAEL x (1/sRVrat) x (ABSoral rat/human inhal) x (sRVhuman/wRV)

 

N  = [300 mg/ kg /d] x (1/ [0.38 m3/kg /d) x 1 x (6.7 m3/10 m3)

    =300 x 2.63 x 0.67 mg/m3= 528.9 mg/m³.

 

The DNEL long-term inhalation, systemic is calculated by applying assessment factors to the corrected NOAEC. Taking into account the following considerations, an overall assessment factor of 18 was calculated:

·        Inter-species differences = 1

The calculation to correct the starting point already sufficiently considers inter-species differences.

·        Remaining differences = 1

See section “Worker-DNEL long-term dermal, systemic”.

·       Intra-species differences = 3

See section “Worker-DNEL long-term dermal, systemic”.

·       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

As proposed by the R.8 TGD

·        Dose-response = 1

The R.8 TGD proposes an assessment factor of 1, if the starting point for DNEL derivation is a NOAEL/NOAEC like in the present case.

·        Quality of whole database = 1

Taking into account the completeness, the consistency and the standard information requirements, the available data is of high quality. Here, the R.8 TGD proposes an assessment factor of 1.

 

Worker-DNEL long-term inhalation, systemic = 528,9 mg/m³/18 = 29.4 mg/m³

 

 

Mutagenicity and carcinogenicity

 

Ethylenediamine, +4PO is not considered to be mutagenic. Based on the toxicological profile of the substance, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for toxicity to reproduction was concluded to be 1000 mg/kg bw/day (highest dose tested in OECD 422 study). As no adverse effects to reproduction and development were observed at the highest dose level tested, a DNEL for toxicity to reproduction is not quantifiable. Emanated from the fact, that the DNELs for systemic, long-term toxicity are derived from a starting point of 300 mg/kg bw (NOAEL general systemic toxicity; OECD 422) any toxic effects on reproduction and development are sufficiently covered.

 

Reference

 

R.8 TGD (ECHA, 2008).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
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:
2.5 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
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:
2.5 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
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Eye irritation

Ethylenediamine, +4PO is classified for eye irritation. The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

 

Ethylenediamine, +4PO is not classified for skin sensitisation. Therefore, no DNEL has to be derived.

 

 

Repeated dose toxicity

 

a.      General

 

The most relevant endpoint is a combined repeated dose toxicity study with a reproduction / developmental toxicity screening test (OECD 422). All rats of the highest dose group (1000 mg/kg bw/day) developed vacuolisation in the epithelial cells of the choroid plexus of the lateral ventricles in the brain. Neither abnormalities in behavior nor pecularities in motor activity were recorded. In conclusion, the observed vacuolisation of the choroid plexus did not cause neuronal impairment within the timeframe of the study. Although the adversity of the vacuolisation was not finally clarified, the NOAEL was set to 300 mg/kg bw/day.

 

b.     General population-DNEL long-term, oral, systemic

 

The NOAEL of 300 mg/kg bw/day is chosen as starting point to derive the general population DNEL long-term, oral, systemic. Taking into account the following considerations, an overall assessment factor of 120 is calculated:

·        Inter-species differences = 4

As proposed in the R.8 TGD; 2008

·        Remaining differences = 1

Significant metabolism of Ethylenediamine, +4PO is not expected (Dunphy, 1991). After i.v. injection of ethylenediamine, +4PO, metabolites could not be detected in the blood of the rats. 92 – 96 % of the test substance are rapidly excreted via the renal route. Therefore, remaining species differences concerning metabolism seem to be unlikely.

·       Intra-species differences = 5

As described above, significant metabolism is not expected. In conclusion, there is a reduced risk of intra-species variability as different metbolic kinetics do not play a role. Therefore, the assessment factor of 10 recommended by the R.8 TGD was reduced to 5.

·       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

As proposed by the R.8 TGD

·        Dose-response = 1

The R.8 TGD proposes an assessment factor of 1, if the starting point for DNEL derivation is a reliable NOAEL like in the present case.

·        Quality of whole database = 1

Taking into account the completeness, the consistency and the standard information requirements, the available data is of high quality. Here, the R.8 TGD proposes an assessment factor of 1.

 

General population-DNEL long-term, oral, systemic = 300 mg/kg bw/day /120 = 2.5 mg/kg bw/day

 

 

c.      General population DNEL long-term, dermal, systemic

 

To obtain a starting point for calculating the general population DNEL long-term, dermal, systemic, route-to-route extrapolation is applied for the oral NOAEL derived from rat. On the assumption that, in general, dermal absorption will not be higher than oral absorption (default factor = 1) no modification of the dose descriptor is necessary to set the correct starting point when performing oral-to-dermal extrapolation

 

Oral NOAEL (rat) = dermal NOAEL(rat) = 300 mg/kg bw/day

 

The general population DNEL long-term, dermal, systemic is calculated by applying an overall assessment factor of 120 to the NOAEL. The considerations leading to the individual assessment factors are described in section b.

 

General population-DNEL long-term, dermal, systemic = 300 mg/kg bw/day /120 = 2.5 mg/kg bw/day

 

 

d.     General population-DNEL long-term, inhalation, systemic

 

The NOAEL of 300 mg/kg bw/day from the combined repeated dose study with a reproduction / developmental screening test (OECD 422) was taken as the most relevant dose descriptor. The NOAEC general population (8h) was calculated as described in the R.8 TGD:

 

Corrected inhalatory NOAEC = rat oral NOAEL x (1/sRVrat) x (ABS oral rat/ABS inhal human)

 

N = [300 mg /kg /d] x (1/ [1.15 m3/ kg /d]) = 260.9 mg/m³.

 

The DNEL long-term inhalation, systemic is calculated by applying assessment factors to the corrected NOAEC. Taking into account the following considerations, an overall assessment factor of 30 is calculated:

·        Inter-species differences = 1

The calculation to correct the starting point already sufficiently considers inter-species differences.

·        Remaining differences = 1

See section “General population DNEL long-term oral, systemic”.

·       Intra-species differences = 5

See section “General population DNEL long-term oral, systemic”.

·       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

As proposed by the R.8 TGD

·        Dose-response = 1

The R.8 TGD proposes an assessment factor of 1, if the starting point for DNEL derivation is a NOAEL/NOAEC like in the present case.

·        Quality of whole database = 1

Taking into account the completeness, the consistency and the standard information requirements, the available data is of high quality. Here, the R.8 TGD proposes an assessment factor of 1. 

 

General population-DNEL long-term inhalation, systemic = 260.9 mg/m³ /30 = 8.7 mg/m³

 

 

Mutagenicity and carcinogenicity

 

Ethylenediamine, +4PO is not considered to be mutagenic. Based on the toxicological profile of the substance, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for toxicity to reproduction was concluded to be 1000 mg/kg bw/day (highest dose tested in OECD 422 study). As no adverse effects to reproduction and development were observed at the highest dose level tested, a DNEL for toxicity to reproduction is not quantifiable. Emanated from the fact, that the DNELs for systemic, long-term toxicity were derived from a starting point of 300 mg/kg bw/ day (NOAEL general systemic toxicity; OECD 422) any toxic effects on reproduction and development are sufficiently covered.

 

Reference

 

R.8 TGD (ECHA, 2008).