Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.492 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):
25
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
12.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

An OECD 408 compliant 90-day study in rat via oral route with AAI-DETA resulted to an overall NOAEL of 10 mg/kg/day. The corrected 8 hr inhalation NOAEC for workers is NOAEL (10) * 1.76 *0.5 *1.4 mg/m3 = 12.32 mg/m3.

- 0.5 or ½: factor 2 for route extrapolation from oral to inhalation is applied However, it is worthy to note that due to very low vp (1.7 x 10-7 Pa at 25°C), exposure is only possible as aerosol. If any exposure via inhalation does occur, this can only be in the form of larger droplets, as the use does not include fine spraying or mists. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal differences in absorption compared to oral route. Thus, apply a factor 2 is a very conservatism approach.

- 1.4 : correction for differences between human and experimental exposure condition (workers)

- 1.76 : correction for differences in respiratory volume (workers)

AF for dose response relationship:
1
Justification:
No specific concerns. Effects at LOAEL are of local nature.
AF for differences in duration of exposure:
2
Justification:
The guidance indicates that for subchronic to chronic a factor 2 should be applied. In addition, a lower factor could be considered on the basis of the understanding that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
Reach guidance recommendations
AF for intraspecies differences:
5
Justification:
Assessment factor of 5 for workers recommended by Reach guidance.
AF for the quality of the whole database:
1
Justification:
Available data are derived from recent, high quality and valid studies showing consistent results within category.
AF for remaining uncertainties:
1
Justification:
NOAEL of 10 mg/kg for systemic toxicity is conservative, considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
0.1 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):
100
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An OECD 408 compliant 90-day study in rat via oral route with AAI-DETA resulted to an overall NOAEL of 10 mg/kg/day. Extrapolation from oral NOAEL represents a worst case situation, as dermal absorption is considered to be lower compared to oral absorption.

AF for dose response relationship:
1
Justification:
No specific concerns. Effects at LOAEL are of local nature.
AF for differences in duration of exposure:
2
Justification:
The guidance indicates that for subchronic to chronic a factor 2 should be applied. A lower factor could be considered on the basis of the understanding that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for workers
AF for the quality of the whole database:
1
Justification:
Available data are derived from recent, high quality and valid studies showing consistent results within category.
AF for remaining uncertainties:
1
Justification:
NOAEL of 10 mg/kg for systemic toxicity is conservative, considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
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

Workers - Inhalation route:

Use of the substance is limited to industrial and professional users. The likelihood of exposure via inhalation is low considering its high boiling point (> 300 °C) and very low vapour pressure (1.7 x 10-7 Pa at 25°C) and use applications that do not involve the forming of aerosols, particles or droplets of an inhalable size.

 

Workers - Dermal route:

No threshold effect: Substance is corrosive and sensitising. Effects following dermal exposures will be characterized by local corrosive and possible sensitising effects that are related to duration, quantity and concentration of the substance, rather than by systemic toxicity due to dermal uptake. Specifically as acute oral toxicity is low.

For corrosive and sensitising substances, the use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. As a result, direct dermal contact occurs only occasionally. Therefore, repeated substantial daily dermal exposure is unlikely. (For properly labelled corrosives, the emphasis in the CSR and ES should be on the presentation of adequate risk management measures, rather than on the assessment of the risks from dermal exposure.)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.09 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):
50
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

An OECD 408 compliant 90-day study in rat via oral route with AAI-DETA resulted to an overall NOAEL of 10 mg/kg/day. The corrected 8 hr inhalation NOAEC for general population is NOAEL (10) * 1/1.15 *1/2 mg/m3 = 4.34 mg/m3.

- 0.5 or½: factor 2 for route extrapolation from oral to inhalation is applied However, it is worthy to note that due to very low vp (1.7 x 10-7 Pa at 25°C), exposure is only possible as aerosol. If any exposure via inhalation does occur, this can only be in the form of larger droplets, as the use does not include fine spraying or mists. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal differences in absorption compared to oral route. Thus, apply a factor 2 is a very conservatism approach.

- 1/1.15: correction for differences in respiratory volume (general population)

AF for dose response relationship:
1
Justification:
No specific concerns. Effects at LOAEL are of local nature.
AF for differences in duration of exposure:
2
Justification:
The guidance indicates that for subchronic to chronic a factor 2 should be applied. A lower factor could be considered on the basis of the understanding that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for general population.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results within category.
AF for remaining uncertainties:
1
Justification:
NOAEL of 10 mg/kg for systemic toxicity is conservative, considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se.
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:
0.05 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):
200
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An OECD 408 compliant 90-day study in rat via oral route with AAI-DETA resulted to an overall NOAEL of 10 mg/kg/day. Extrapolation from oral NOAEL represents a worst case situation, as dermal absorption is considered to be lower compared to oral absorption.

AF for dose response relationship:
1
Justification:
No specific concerns. Effects at LOAEL are of local nature.
AF for differences in duration of exposure:
2
Justification:
The guidance indicates that for subchronic to chronic a factor 2 should be applied. A lower factor could be considered on the basis of the understanding that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for general population.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results within category.
AF for remaining uncertainties:
1
Justification:
NOAEL of 10 mg/kg for systemic toxicity is conservative, considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se.
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:
0.05 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):
200
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An OECD 408 compliant 90-day study in rat via oral route with AAI-DETA resulted to an overall NOAEL of 10 mg/kg/day.  As study is based on oral dosing, no route-to-route extrapolation is needed.

AF for dose response relationship:
1
Justification:
No specific concerns. Effects at LOAEL are of local nature.
AF for differences in duration of exposure:
2
Justification:
The guidance indicates that for subchronic to chronic a factor 2 should be applied. A lower factor could be considered on the basis of the understanding that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for general population.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results within category.
AF for remaining uncertainties:
1
Justification:
NOAEL of 10 mg/kg is conservative. Considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se, the level of 100 mg/kgbw/day could also be argued to represent a NOAEL for systemic effects.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population: These substances are only applied in professional or industrial setting in oilfield and mining applications applying adequate PPE. Use results to the inclusion into or onto a matrix. Consequently, consumers/general population will not be exposed.

However, in order to be able to evaluate possible secondary exposures via environment, additionally long-term systemic DNELs for general population have been derived.