N-(2-aminoethyl)-1,3-propanediamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.62 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):

60

Modified dose descriptor starting point:

NOAEC

Value:

37 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study by inhalation is available. Therefore an oral-to-inhalation extrapolation is done. The default factor of 2 was included.

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for time extrapolation from subacute to chronic study

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:

1

Justification:

Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for other interspecies differences is set to 1.

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:

GLP Guideline study / The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

2

Justification:

Adequate AF for uncertainties from read-across approach.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.18 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):

240

Modified dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study with dermal application is available. Therefore an oral-to-dermal extrapolation is done.

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for time extrapolation from subacute to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default value for correction for differences in metabolic rate (rat to humans)

AF for other interspecies differences:

1

Justification:

Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for other interspecies differences is set to 1.

AF for intraspecies differences:

5

Justification:

default value (worker)

AF for the quality of the whole database:

1

Justification:

GLP Guideline study / The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

2

Justification:

Adequate AF for uncertainties from read-across approach.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

 

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA (2012).

 

The primary route of anticipated industrial exposure to the test substance is via skin contact. Given its low vapor pressure at room temperature, inhalation of N3-amine is not likely to be high. However, exposition to aerosols or droplets of an inhalable size cannot be ruled out.

 

The test substance is considered harmful after single ingestion (BASF, 1977), toxic after single skin contact (BASF, 1977), corrosive after single skin (BASF, 1977) and causes serious eye damage after contact (BASF, 1977). Furthermore, it is highly sensitizing after skin contact (read across, BASF, 2008) and affects certain organs after repeated exposure (read across, BASF SE, 2013). It is not possible to derive a local DNEL based on the available data. Because of its sensitizing potential however, N3-amine should be attributed to a high hazard class according to the ECHA Guidance on information requirement and chemical safety assessment, Part E: Risk Characterization. Appropriate qualitative risk management measures and operational conditions should therefore be implemented when developing exposure scenarios.

It is concluded that the test substance (N3-amine) did not show any adverse effects regarding mutagenicity.

 

 

Acute, systemic DNEL

The test substance is classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

Furthermore, the test substance was concluded to be a skin sensitizer in a GPMT (read aceross). The substance is therefore classified as skin sensitizer, cat. 1A according to Regulation (EC) No 1272/2008 (CLP) and associated to the high Hazard Band. A qualitative risk assessment is conducted for acute dermal toxicity in order to ensure an appropriate level of protection regarding sensitization.

Acute/ long term, local effects

Respiratory irritation: Due to the corrosive/irritating effects on skin and mucous membranes local effects on the respiratory system of the test substance cannot be excluded. Therefore, a qualitative risk assessment is conducted for acute local toxicity in order to ensure an appropriate level of protection.

Skin irritation/corrosion: The test substance has skin corrosion potential and is classified as corrosive, cat. 1A according to Regulation (EC) No 1272/2008 (CLP) and associated to the high Hazard Band. A qualitative risk assessment is conducted for acute/long-term local toxicity in order to ensure an appropriate level of protection regarding skin irritation (and skin sensitization).

Eye irritation: The test substance is corrosive to skin and causes serious eye damage. Therefore, a qualitative assessment is conducted is conducted for acute local toxicity in order to ensure an appropriate level of protection regarding eye irritation.

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

 

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) with the source substance (N4 Amine) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the target test substance (N3 Amine) was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

Thus, the NOAEL of 30 mg/kg bw/day, assessed in the key combined 28-day oral repeated dose toxicity study (BASF, 2012) with a structural analogue (N4 Amine) of the target substance is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification into a correct starting point (presented in detail):

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

So this point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 20 f." The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors and by adjusting the time of exposure (rats were exposed 7 days/week and worker is exposed 5 days per week) (x 1/0.38 m³/kg/d x 6.7 m³/10 m³ x 7/5). Furthermore, it is proposed, thus, in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 37.0 mg/m³.

 

Relevant dose descriptor (NOAEL): 30 mg/kg bw/day

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

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

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

 

Corrected inhalatory NOAEC for workers

= 30 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × (7 days/5 days)

= 37 mg/m³

 

Step 3: Use of assessment factors: 60

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Intraspecies AF (worker): 5

Exposure duration AF: 6 (subacute to chronic study)

Remaining uncertainties AF (read-across): 2

 

In conclusion, long-term systemic inhalation DNEL, workers = 0.62 mg/m³

 

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) with the source substance (N4 Amine) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The NOAEL for general, systemic toxicity of the target test substance (N3 Amine) was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

Thus, the NOAEL of 30 mg/kg bw/day, assessed in the key combined 28-day oral repeated dose toxicity study with a structural analogue (N4 Amine) of the target substance is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point:

This point of departure was modified to get the corrected starting point for DNEL derivation based on a route-to-route (oral -> dermal) extrapolation with the assumption that the dermal absorption will not be higher than oral absorption (factor of 1). The starting point was further corrected by a factor of 1.4 since rats were exposed 7 days per week and the worker is exposed 5 days per week (7/5). This results in a corrected starting point of 42 mg/kg bw/day.

 

Step 3: Use of assessment factors: 240

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

Intraspecies AF (worker): 5

Exposure duration AF: 6 (sub-acute to chronic study)

Remaining uncertainties AF (read-across): 2

 

In conclusion, long term systemic dermal DNEL, workers = 0.18 mg/kg bw/day

 

 

Acute, systemic DNEL (dermal)

The test substance is classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

Furthermore, the test substance was shown to be a skin sensitizer in a GPMT (read across). The substance is therefore classified as skin sensitizer, cat. 1A according to Regulation (EC) No 1272/2008 (CLP) and associated to the high Hazard Band. Thus, a qualitative risk assessment is conducted for acute dermal toxicity in order to ensure an appropriate level of protection regarding sensitization.

 

 

 

References

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version: 2.1, ECHA-2012 -G-19 -EN.

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation.Version: 2.0, ECHA-2012 -G-16 -EN.

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008

 

- ECHA (2012). Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.094 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):

120

Modified dose descriptor starting point:

NOAEC

Value:

11.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study by inhalation is available. Therefore a oral-to-inhalation extrapolation is done. The default factor of 2 was included.

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for time extrapolation from subacute to chronic study

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:

1

Justification:

Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for other interspecies differences is set to 1.

AF for intraspecies differences:

10

Justification:

default value (consumer)

AF for the quality of the whole database:

1

Justification:

GLP Guideline study / The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

2

Justification:

Adequate AF for uncertainties from read-across approach.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.063 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):

480

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study with dermal application is available. Therefore a oral-to-dermal extrapolation is done.

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for time extrapolation from subacute to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default value for correction for differences in metabolic rate (rat to humans)

AF for other interspecies differences:

1

Justification:

Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for other interspecies differences is set to 1.

AF for intraspecies differences:

10

Justification:

default value (consumer)

AF for the quality of the whole database:

1

Justification:

GLP Guideline study / The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

2

Justification:

Adequate AF for uncertainties from read-across approach.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.063 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):

480

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for time extrapolation from subacute to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default value for correction for differences in metabolic rate (rat to humans)

AF for other interspecies differences:

1

Justification:

Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for other interspecies differences is set to 1.

AF for intraspecies differences:

10

Justification:

default value (consumer)

AF for the quality of the whole database:

1

Justification:

GLP Guideline study / The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

2

Justification:

Adequate AF for uncertainties from read-across approach.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Currently, a consumer use of N3-amine is not foreseen. However, DNEL derivation was performed completely for workers as well as the general population. Since no consumer use is planned, a derivation of the DNELs for general population does not affect risk characterization at all.

DNEL Derivation - General Population

 

General

 

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA (2012).

Acute, systemic DNEL (inhalation)

The test substance is classified and labelled for acute dermal and oral systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus no DNELs for acute systemic toxicity for the inhalation route are required.

The test substance was regarded to be a skin sensitizer (read across). The substance was therefore classified as skin sensitizer, cat. 1A according to Regulation (EC) No 1272/2008 (CLP) and associated to the high hazard band. A qualitative risk assessment is conducted for dermal toxicity in order to ensure an appropriate level of protection regarding sensitization.

 

Acute, systemic DNEL (dermal, oral)

The DNEL for long-term exposure is considered to ensure a sufficient level of protection for potential systemic effects following acute/short term exposure. Nevertheless, a qualitative approach has to be implemented to deal with the corrosivity and sensitising potential of N3-amine.

Acute/long term DNEL for local effects

Skin irritation/corrosion: 

The test substance is classified for skin corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, a qualitative assessment is conducted.

Eye irritation:

The substance is classified as eye damaging, cat. 1 according to Regulation (EC) No 1272/2008 (CLP) and associated to the medium hazard band. A qualitative risk assessment is conducted for the eye in order to ensure an appropriate level of protection.

 

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure (if aerosol formation occurs). Therefore corresponding long-term DNELs are calculated for consumers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Inhalation long-term exposure – systemic effects:

 

Exposure by inhalation

Calculation based on a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats:

 

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted with the source substance N4 Amine according to OECD TG 422 (BASF, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance (N3-amine) was defined as 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived. This general population DNEL is considered to ensure an appropriate level of protection with regard to inhalation exposure for single as well as repeated exposure.

Relevant dose descriptor (NOAEL): 30 mg/kg bw/day

In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For general population a NOEC long-term, inhalation was calculated assuming 60 kg per person, 24h activity (20 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.

NOEC (general population) inhalation = 30 mg/kg bw/day * 1/4 *60 kg * 1/20 m³/day * 50%Abs, (oral) / 100 % Abs, (inhal) = 11.3 mg/m³

 

Step 3: Use of assessment factors: 120

Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute to chronic study)

Remaining uncertainties AF (read-across): 2

 

In conclusion, long term systemic inhalation DNEL, general population = 0.094 mg/m3

 

 

Dermal long-term exposure – systemic effects:

 

Exposure by dermal contact

Calculation based on a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats:

 

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted with the source substance (N4 Amine) according to OECD TG 422 (BASF, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The NOAEL for general, systemic toxicity of the test substance (N3 Amine) was defined as 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Using a conservative approach, a general population DNEL (long-term dermal exposure) is derived. No dermal penetration study is available for the test substance. Thus, the point of departure was not modified to get the corrected starting point for DNEL derivation because it isassumed that the dermal absorption will not be higher than oral absorption (factor of 1). This results in a corrected starting point of 30 mg/kg bw/day.

 

Step 3: Use of assessment factors: 480

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

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute to chronic study)

Remaining uncertainties AF (read-across): 2

 

In conclusion, long term systemic dermal DNEL, general population = 0.063 mg/kg bw/day

 

 

Oral long-term exposure – systemic effects:

 

In addition, the DNEL for oral long-term exposure was derived from the no observed adverse effect level obtained in a gavage study conducted with the source substance (N4 Amine) in rats according to OECD TG 422 (BASF, 2013). The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

 

Step 2: Modification of the starting point:Not necessary since an oral study is available.

 

Step 3: Use of assessment factors: 480

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

Intraspecies AF (general population): 10

Exposure duration AF: 6 (sub-acute to chronic study)

Remaining uncertainties AF (read-across): 2

 

In conclusion, long term systemic dermal DNEL, general population = 0.063 mg/kg bw/day

 

 

 

References

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version: 2.1, ECHA-2012 -G-19 -EN.

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation.Version: 2.0, ECHA-2012 -G-16 -EN.

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008

 

- ECHA (2012). Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.