Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
Value:
276 mg/m³
AF for dose response relationship:
1
Justification:
Not needed
AF for differences in duration of exposure:
6
Justification:
Default AF
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.5 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.7 mg/m³
DNEL related information
DNEL derivation method:
other: the DNEL of 3.7 mg/m3 (0.9 ppm) derived for the long-term exposure systemic effects is assumed to be protective for the local effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.5 mg/m³
DNEL related information
DNEL derivation method:
other: the DNEL of 7.5 mg/m3 (1.8 ppm) derived for the long-term exposure local effects is assumed to be protective for the local effects.
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
33.8 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Not needed
AF for differences in duration of exposure:
1
Justification:
Not needed (chronic study)
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
high hazard (no threshold derived)

Additional information - workers

DNEL long-term inhalation exposure - systemic effects (other derivation method)

According to the REACH guidance R.8, it may be possible to set a DNEL based on read-across from chemically related substances. The DNEL for long-term inhalation exposure systemic effects could also be derived by route-to-route extrapolation from the no observed effect level obtained in an oral repeated dose toxicity study with the analogue substance dihydrochloride salt of diethylenetriamine (CAS no. 3488-90-2) (Leung and van Miller, 1997). Fischer 344 rats were fed a diet containing the dihydrochloride salt of diethylenetriamine (DETA.2HCl) at concentrations of 1000, 7500 or 15,000 ppm for 90 consecutive days. Based on food consumption and body weight, the mean corresponding dosages were 70, 530 and 1060 mg DETA.2HCl /kg/day for the males and 80, 620 and 1210 mg DETA.2HCl /kg/day for the females. Decreases in food consumption were observed intermittently throughout the dosing period in both sexes at 15,000 ppm. Dose-related decreases in body weight or weight gain were observed for both sexes at 7500 and 15,000 ppm. Changes in clinical pathology measurements observed at 7500 and 15,000 ppm included increases in mean corpuscular volume and mean corpuscular haemoglobin in males, and increases in mean corpuscular volume, total leucocytes and urinary pH, and a decrease in serum glucose concentration in females. The relative kidney, brain and testes weights were increased in the 15,000 ppm males. In the females, the relative kidney, brain and liver weights were increased at 7500 and 15,000 ppm, and the relative heart and adrenal weights were elevated at 15,000 ppm. There were no treatment-related clinicat signs, gross autopsy or histopathological findings for either sex at any dose level. Animals improved only slightly from the effects of treatment following a 4-wk recovery period. A no-observed-effect level of 1000 ppm (corresponding to 41 mg DETA/kg/day in male rats and 47 mg DETA/kg/day in female rats) was established in this study. Since workers are exposed for 5 days a week, this NOAEL from a continuous study (i.e., 7 days/week) is adjusted by multiplying it with a factor of 7/5 resulting in a no-adverse effect level (NAEL) of 57 mg/kg. Therefore, the NAEC (8h) derived for workers is 101 mg DETA/m3 (57 mg/kg / 0.38 m3/kg x 6.7 m3/10 m3) after correction for difference in exposure conditions and between respiratory rates under standard conditions and under conditions of light activity. Application of assessment factors of: 2.5 for interspecies differences (for inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements), 5 for intraspecies differences, 2 for exposure duration, for extrapolation from subchronic to chronic, leads to a DNEL of 4.0 mg DETA/m3 (0.9 ppm) for long-term inhalation exposure - systemic effects.  This value supports the DNEL derived from the Gage’s study.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.65 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
NOAEC
Value:
98 mg/m³
AF for dose response relationship:
1
Justification:
Not needed
AF for differences in duration of exposure:
6
Justification:
Default AF
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.65 mg/m³
DNEL related information
DNEL derivation method:
other: the DNEL of 0.65 mg/m3 derived for the long-term exposure systemic effects is assumed to be protective for the local effects.
Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 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
Modified dose descriptor starting point:
NOAEL
Value:
41 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Not needed
AF for differences in duration of exposure:
2
Justification:
Default AF
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Inhalation Systemic effects - Long-term

As for workers, a DNEL for inhalation long-term exposure systemic effects could also be derived by route-to-route extrapolation from the no observed effect level obtained in an oral repeated dose toxicity study with the analogue substance dihydrochloride salt of diethylenetriamine (CAS no. 3488-90-2) (Leung and van Miller, 1997). A no-observed-effect level of 1000 ppm (corresponding to 41 mg DETA/kg/day in male rats and 47 mg DETA/kg/day in female rats) was established in this study. This NOAEL from a continuous feed study (i. e., 7 days/week) is used to derive the NAEC (24h) for the general population. The NAEC is 35 mg DETA/m3 (41 mg/kg / 1.15 m3/kg). Application of assessment factors of: 2.5 for interspecies differences (for inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements), 10 for intraspecies differences, 2 for extrapolation from subchronic to chronic, leads to a DNEL of 0.71 mg DETA/m3 for long-term inhalation exposure - systemic effects. This value supports the DNEL derived from the Gage’s study.

DNEL long-term oral exposure - systemic effects

According to the REACH guidance R.8, it may be possible to set a DNEL based on read-across from chemically related substances.The DNEL for long-term oral exposure systemic effects could be derived from the NOAEL obtained in an oral repeated dose toxicity study with the analogue substance dihydrochloride salt of diethylenetriamine (DETA 2 HCl, CAS no. 3488-90-2) (Leung and van Miller, 1997). Fischer 344 rats were fed a diet containing DETA.2HCl at concentrations of 1000, 7500 or 15,000 ppm for 90 consecutive days. Based on food consumption and body weight, the mean corresponding dosages were 70, 530 and 1060 mg DETA.2HCl /kg/day for the males and 80, 620 and 1210 mg DETA.2HCl /kg/day for the females. Decreases in food consumption were observed intermittently throughout the dosing period in both sexes at 15,000 ppm. Dose-related decreases in body weight or weight gain were observed for both sexes at 7500 and 15,000 ppm. Changes in clinical pathology measurements observed at 7500 and 15,000 ppm included increases in mean corpuscular volume and mean corpuscular haemoglobin in males, and increases in mean corpuscular volume, total leucocytes and urinary pH, and a decrease in serum glucose concentration in females. The relative kidney, brain and testes weights were increased in the 15,000 ppm males. In the females, the relative kidney, brain and liver weights were increased at 7500 and 15,000 ppm, and the relative heart and adrenal weights were elevated at 15,000 ppm. There were no treatment-related clinicat signs, gross autopsy or histopathological findings for either sex at any dose level. Animals improved only slightly from the effects of treatment following a 4-wk recovery period. A NOAEL of 1000 ppm (corresponding to 41 mg DETA/kg/day in male rats and 47 mg DETA/kg/day in female rats) was established in this study for a continuous exposure (i.e., 7 days/week). Therefore, the NAEC derived for the general population is also 41 mg DETA/kg bw/d. Application of assessment factors of: 4 x 2.5 for interspecies differences, 10 for intraspecies differences, 2 for exposure duration, for extrapolation from subchronic to chronic, leads to a DNEL of 0.2 mg DETA/kg bw/d for long-term oral exposure - systemic effects.