Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.004 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):
250
Dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
0.88 mg/m³
Explanation for the modification of the dose descriptor starting point:

A 90-day oral gavage study on Etherdiamine C13i/acetate resulted to an overall LOAEL of 0.5 mg/kg/day based on leukocytosis, inflammatory responses in mesenteric lymph nodes and lungs, and inflammatory effects in the hindlegs and/or tail of a few animals. Related to the low vp (< 0.005 Pa), significant exposures will be as aerosol. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route, and therefore no additional factor 2 is considered necessary.  The corrected 8 hr inhalation LOAEC for workers is LOAEL(0.5 mg/kg) * 1.76 mg/m3 = 0.88 mg/m3.

The calculation follows an additional conservative approach, as correction in the default calculations for 5 day/week occupational exposures vs 7 day/week dosing in the studies has not been applied.

AF for dose response relationship:
10
Justification:
Extrapolation of a LOAEC to a NOAEC: factor 10 in view of serious effects.
AF for differences in duration of exposure:
2
Justification:
Default from sub-chronic (90-day) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in LOAEC/NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
ECHA default. ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5 . As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling could be considered to already represent a worst case.
AF for intraspecies differences:
5
Justification:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intra-species differences for workers is 3 and not 5. As the effects for which the risk assessment is made is based on a local response following an non-specific mechanism with expected inherently relative low variation between individuals, no additional factor is needed to accommodate for possible high uncertainty between individuals on the basis of possible specific sensitivities.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
Data is based on high quality studies.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.001 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):
1 000
Dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A 90-day oral gavage study on Etherdiamine C13i/acetate resulted to an overall LOAEL of 0.5 mg/kg/day based on leukocytosis, inflammatory responses in mesenteric lymph nodes and lungs, and inflammatory effects in the hindlegs and/or tail of a few animals.   At this stage no data are available on dermal absorption. Etherdiamine C13i/acetate is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

The calculation follows an additional conservative approach, as correction in the default calculations for 5 day/week occupational exposures vs 7 day/week dosing in the studies has not been applied.

AF for dose response relationship:
10
Justification:
Extrapolation of a LOAEC to a NOAEC: factor 10 in view of serious effects.
AF for differences in duration of exposure:
2
Justification:
Default from sub-chronic (90-day) 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:
ECHA default. ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5. As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling could be considered to already represent a worst case.
AF for intraspecies differences:
5
Justification:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intra-species differences for workers is 3 and not 5. As the effects for which the risk assessment is made is based on a local response following an non-specific mechanism with expected inherently relative low variation between individuals, no additional factor is needed to accommodate for possible high uncertainty between individuals on the basis of possible specific sensitivities.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results
AF for remaining uncertainties:
1
Justification:
Data is based on high quality studies.
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium 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:
0.001 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):
500
Dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
0.43 mg/m³
Explanation for the modification of the dose descriptor starting point:

A 90-day oral gavage study on Etherdiamine C13i/acetate resulted to an overall LOAEL of 0.5 mg/kg/day based on leukocytosis, inflammatory responses in mesenteric lymph nodes and lungs, and inflammatory effects in the hindlegs and/or tail of a few animals.  Related to the low vp (< 0.005 Pa), significant exposure is only possible as aerosol. The use does not include (high pressure) spraying. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route, and therefore no additional factor 2 is considered necessary. Besides, absorption is considered to be 100% both via oral and inhalation route. The corrected 24 hr inhalation LOAEC for general population is LOAEL(0.5 mg/kg) * 1/1.15 mg/m3 = 0.43 mg/m3.

AF for dose response relationship:
10
Justification:
Extrapolation of a LOAEC to a NOAEC: default factor 3. Effects at LOAEL are not severe and probably only of local nature.
AF for differences in duration of exposure:
2
Justification:
Default from sub-acute (28-day) to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in LOAEC/NOAEC calculation
AF for other interspecies differences:
2.5
Justification:
ECHA default. ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5. As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling already represents a worst case.
AF for intraspecies differences:
10
Justification:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for general public is 5 and not 10.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
Data is based on high quality studies.
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 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):
2 000
Dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A 90-day oral gavage study on Etherdiamine C13i/acetate resulted to an overall LOAEL of 0.5 mg/kg/day based on leukocytosis, inflammatory responses in mesenteric lymph nodes and lungs, and inflammatory effects in the hindlegs and/or tail of a few animals.   At this stage no data are available on dermal absorption. Etherdiamine C13i/acetate is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

AF for dose response relationship:
10
Justification:
Extrapolation of a LOAEC to a NOAEC: factor 10 in view of serious effects.
AF for differences in duration of exposure:
2
Justification:
Default from sub-chronic (90-day) 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:
ECHA default. ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5. As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling already represents a worst case.
AF for intraspecies differences:
10
Justification:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for general public is 5 and not 10.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
Data is based on high quality studies.
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 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):
2 000
Dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
0.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A 90-day oral gavage study on Etherdiamine C13i/acetate resulted to an overall LOAEL of 0.5 mg/kg/day based on leukocytosis, inflammatory responses in mesenteric lymph nodes and lungs, and inflammatory effects in the hindlegs and/or tail of a few animals. No route-to-route extrapolation is needed.

AF for dose response relationship:
10
Justification:
Extrapolation of a LOAEC to a NOAEC: factor 10 in view of serious effects.
AF for differences in duration of exposure:
2
Justification:
Default from sub-chronic (90-day) 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:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for general public is 5 and not 10.
AF for intraspecies differences:
10
Justification:
ECHA default. ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for general public is 5 and not 10.
AF for the quality of the whole database:
1
Justification:
Available data derived from valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
Data is based on high quality studies.
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

Etherdiamine C13i/acetate is only used in industrially settings. 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.