N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.45 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):

75

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 234 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) *(7 days exposure rat/5 days exposure worker)

= 500 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(1/1)*0.67*1.4 = 1234 mg/m³.

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group “Toxicology”, 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group “Toxicology”, 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

For N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine several toxicological hazards were identified. In an acute inhalation toxicity study systemic effects (mortality) were observed leading to Acute Tox Cat 4 classification. These effects were supposed to be secondary to local respiratory irritation, as the clinical signs of respiratory irritation precede mortality and pathology revealed effects on the lung. The respiratory effects were concentration dependent.

In addition local effects such as eye corrosion and skin sensitisation (Cat 1A) were observed or presumed based on structure and data from structural analogues.

No hazard leading to classification was observed for long-term systemic toxicity. For the safety assessment of long-term systemic toxicity of the registered substance an available screening study according to OECD TG 422 and the corresponding range-finding test on the source substance N-(3-(trimethoxysilyl)propyl)ethylenediamine was used. A NOAEL of 500 mg/kg bw/day (highest dose tested) was derived in the main study. The doses were chosen based on the range-finding test, were mortality was observed (1/3 males, 1/3 females) between day 4-6 at 1000 mg/kg bw/day.

The DNEL for systemic effects after repeated inhalation exposure was calculated based on the NOAEL of 500 mg/kg bw/day of the oral screening study . Standard ECHA REACH Guidance assessment factors were applied after route-to-route extrapolation.

Based on the local effects observed such as eye corrosion and skin sensitisation (Cat 1A) no DNEL was calculated for the dermal route, neither for local nor for systemic effects. To ensure safe handling a qualitative assessment was carried out with respect to the local properties; assigning the substance into the high hazard class according to ECHA CSA Guidance Part E Table E 3-1 (see CSR section 9/10). 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.9 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):

150

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed from a combined repeated dose oral study with the reproduction/developmental toxicity screening test (OECD 422) with the structural analogue substance CAS 1760 -24 -3 in rats.

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAELoral * (1/1.15 m³/kg bw/day (24h)) * (ABSoral-rat / ABSinh-human)

= 500 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 434.8 mg/m³

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group “Toxicology”, 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group “Toxicology”, 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for general population was 434.8 mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.83 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):

600

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was a rat.

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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)