Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.97 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:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
49.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Two studies, a combined 28-day/reproduction screening by gavage and a combined 90-day/2-generation study by dietary admixture, resulted to LOAELs of 100 mg/kg bw/d resp. 1000 ppm (72 to 90 mg/kg bw/day) in F0 and F1, based on minimal to slight necrotizing granulomas in mesenteric lymph nodes observed in some animals at the lowest dose groups in these studies. Extrapolation indicates a NOEL of around 20 mg/kg bw/day (conservative; Extrapolation of the three dose-response curves results to 28 - 52 mg/kg bw as NOEL; 20 mg/kg bw/d corresponds to a factor between 3.6 to 5 from the LOAELs to NOEL), as threshold for the effects irrespective duration of the study (45 day in OECD 422 or 90 to 126-days in 2 generation study), but with increasing duration the severity of effects at higher dose levels tend to increase.

The corrected 8 hr inhalation NOEC systemic toxicity for workers is NOEL(20 mg/kg) * 1.76 mg/m3  * 7/5 (correction 5 working days/wk) = 49.4 mg/m3.

No factor 2 route extrapolation from oral to inhalation is applied: di-C16-C18 (evennumbered) alkyl tripropylenetetramine is a viscous fluid with a high boiling point (> 400 °C) and very low vapour pressure (1.3 x 10-6 Pa at 20°C). Exposure by inhalation would only be possible in the form of aerosol, consisting of larger droplets depositing in upper airways. Aerosols will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This result to no principal difference in absorption compared to oral route.

AF for dose response relationship:
1
Justification:
Effects at LOAEL are not severe. The performed extrapolation to a NOEL of 20 mg/kg bw/day from the various dose-response curves is comparable to a factor of 3.6 to 5 being applied to the LOAELs.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for sub-chronic to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
Default.
AF for intraspecies differences:
5
Justification:
Default
AF for the quality of the whole database:
1
Justification:
Available data is from studies with high reliability
AF for remaining uncertainties:
1
Justification:
Independent studies lead to comparable results.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.28 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:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
28 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Two studies, a combined 28-day/reproduction screening by gavage and a combined 90-day/2-generation study by dietary admixture, resulted to LOAELs of 100 mg/kg bw/d resp. 1000 ppm (72 to 90 mg/kg bw/day) in F0 and F1, based on minimal to slight necrotizing granulomas in mesenteric lymph nodes observed in some animals at the lowest dose groups in these studies. Extrapolation indicates a NOEL of around 20 mg/kg bw/day (conservative; Extrapolation of the three dose-response curves results to 28 - 52 mg/kg bw as NOEL; 20 mg/kg bw/d corresponds to a factor between 3.6 to 5 from the LOAELs to NOEL), as threshold for the effects irrespective duration of the study (45 day in OECD 422 or 90 to 126-days in 2 generation study), but with increasing duration the severity of effects at higher dose levels tend to increase.

The corrected 8 hr dermal NOEL systemic toxicity for workers is NOEL(20 mg/kg) * 7/5 (correction 5 working days/wk) = 28 mg/kg bw/day.

At this stage no data are available on dermal absorption. It is not expected to easily pass the skin in view of its ionised (4+) form under physiological conditions. Based on the severe irritant properties, increased dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. Although dermal absorption is not expected at any considerable rate, as conservative approach the absorption via dermal route is considered to be similar to the absorption rate via oral route.

AF for dose response relationship:
1
Justification:
Effects at LOAEL are not severe. The performed extrapolation to a NOEL of 20 mg/kg bw/day from the various dose-response curves is comparable to a factor of 3.6 to 5 being applied to the LOAELs.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for sub-chronic to chronic.
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:
Default
AF for intraspecies differences:
5
Justification:
Default
AF for the quality of the whole database:
1
Justification:
Available data is from studies with high reliability
AF for remaining uncertainties:
1
Justification:
Independent studies lead to comparable results
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
14.81 mg/m³
Explanation for the modification of the dose descriptor starting point:

Two studies, a combined 28-day/reproduction screening by gavage and a combined 90-day/2-generation study by dietary admixture, resulted to LOAELs of 100 mg/kg bw/d resp. 1000 ppm (72 to 90 mg/kg bw/day) in F0 and F1, based on minimal to slight necrotizing granulomas in mesenteric lymph nodes observed in some animals at the lowest dose groups in these studies. Extrapolation indicates a NOEL of around 20 mg/kg bw/day (conservative; Extrapolation of the three dose-response curves results to 28 - 52 mg/kg bw as NOEL; 20 mg/kg bw/d corresponds to a factor between 3.6 to 5 from the LOAELs to NOEL), as threshold for the effects irrespective duration of the study (45 day in OECD 422 or 90 to 126-days in 2 generation study), but with increasing duration the severity of effects at higher dose levels tend to increase.

The corrected 24 hr inhalation NOEC systemic toxicity for general population is NOAEL (20) * 1/1.35 mg/m3 = 14.81 mg/m3.

No factor 2 route extrapolation from oral to inhalation is applied: di-C16-C18 (evennumbered) alkyl tripropylenetetramine is a viscous fluid with a high boiling point (> 400 °C) and very low vapour pressure 1.3 x 10-6 Pa at 20°C). Due to the low vp no significant contribution to exposures can be expected via vapour. Exposure by inhalation would only be possible in the form of aerosol, consisting of larger droplets depositing in upper airways. Aerosols will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This result to no principal difference in absorption compared to oral route.

AF for dose response relationship:
1
Justification:
Effects at LOAEL are not severe. The performed extrapolation to a NOEL of 20 mg/kg bw/day from the various dose-response curves is comparable to a factor of 3.6 to 5 being applied to the LOAELs.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for sub-chronic to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
Default.
AF for intraspecies differences:
10
Justification:
Default.
AF for the quality of the whole database:
1
Justification:
Available data is from studies with high reliability
AF for remaining uncertainties:
1
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:
0.1 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):
200
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Two studies, a combined 28-day/reproduction screening by gavage and a combined 90-day/2-generation study by dietary admixture, resulted to LOAELs of 100 mg/kg bw/d resp. 1000 ppm (72 to 90 mg/kg bw/day) in F0 and F1, based on minimal to slight necrotizing granulomas in mesenteric lymph nodes observed in some animals at the lowest dose groups in these studies. Extrapolation indicates a NOEL of around 20 mg/kg bw/day (conservative; Extrapolation of the three dose-response curves results to 28 - 52 mg/kg bw as NOEL; 20 mg/kg bw/d corresponds to a factor between 3.6 to 5 from the LOAELs to NOEL), as threshold for the effects irrespective duration of the study (45 day in OECD 422 or 90 to 126-days in 2 generation study), but with increasing duration the severity of effects at higher dose levels tend to increase.

The corrected 24 hr dermal NOEL systemic toxicity for workers is NOEL(20 mg/kg) = 20 mg/kg bw/day.

At this stage no data are available on dermal absorption. It is not expected to easily pass the skin in view of its ionised (4+) form under physiological conditions. Based on the severe irritant properties, increased dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. Although dermal absorption is not expected at any considerable rate, as conservative approach the absorption via dermal route is considered to be similar to the absorption rate via oral route.

AF for dose response relationship:
1
Justification:
Effects at LOAEL are not severe. The performed extrapolation to a NOEL of 20 mg/kg bw/day from the various dose-response curves is comparable to a factor of 3.6 to 5 being applied to the LOAELs
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for sub-chronic to chronic.
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:
Default
AF for intraspecies differences:
10
Justification:
Default
AF for the quality of the whole database:
1
Justification:
Available data is from studies with high reliability.
AF for remaining uncertainties:
1
Justification:
Independent studies lead to comparable results.
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:
0.1 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):
200
Dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
20 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Two studies, a combined 28-day/reproduction screening by gavage and a combined 90-day/2-generation study by dietary admixture, resulted to LOAELs of 100 mg/kg bw/d resp. 1000 ppm (72 to 90 mg/kg bw/day) in F0 and F1, based on minimal to slight necrotizing granulomas in mesenteric lymph nodes observed in some animals at the lowest dose groups in these studies. Extrapolation indicates a NOEL of around 20 mg/kg bw/day (conservative; Extrapolation of the three dose-response curves results to 28 - 52 mg/kg bw as NOEL; 20 mg/kg bw/d corresponds to a factor between 3.6 to 5 from the LOAELs to NOEL), as threshold for the effects irrespective duration of the study (45 day in OECD 422 or 90 to 126-days in 2 generation study), but with increasing duration the severity of effects at higher dose levels tend to increase.

AF for dose response relationship:
1
Justification:
Effects at LOAEL are not severe. The performed extrapolation to a NOEL of 20 mg/kg bw/day from the various dose-response curves is comparable to a factor of 3.6 to 5 being applied to the LOAELs.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for sub-chronic to chronic.
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:
Default
AF for intraspecies differences:
10
Justification:
Default
AF for the quality of the whole database:
1
Justification:
Available data is from studies with high reliability.
AF for remaining uncertainties:
1
Justification:
Independent studies lead to comparable results.
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

Di-C16-C18 (evennumbered) alkyl tripropylenetetramine is not used in the consumer sector. Systemic long term DNELs for general public are provided to allow for possible assessment of indirect exposure.