Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 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):
60
DNEL value:
177.6 mg/m³
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose inhalative toxicity study (6 weeks) is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point)
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applicable for inhalation
AF for other interspecies differences:
1
Justification:
There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
2
Justification:
An additional factor of 2 was used to cover every uncertainty of the read across approach. Therefore, the DNEL derivation is most conservative.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.26 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):
40
DNEL value:
10.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available (in mice; complete life span).
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
No default extrapolation factor for exposure duration is required as the DNEL derivation is based on a long-term dermal chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
2
Justification:
An additional factor of 2 was used to cover every uncertainty of the read across approach. Therefore, the DNEL derivation is most conservative.
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Trimethylenediamine is of high acute toxicity by the dermal route of exposure (LD50 = 178 mg/kg bw). After oral uptake or inhalation the toxicity is less pronounced: LD50 = 311 mg/kg bw and no mortality after inahalation of a saturated vapour. Trimethylenediamine has been reported to be corrosive to the skin and eyes and is considered to be a skin and respiratory sensitizer, since the structurally very similyr ethylenediamine is reported to be a respiratory sensitizer (difference: chain length / one CH2-group).

The available valid in vitro (Ames, HPRT, CA) genetic toxicity data with trimethylenediamine do not suggest a mutagenic potential. Moreover, the read across substance ethylenediamine was not carcinogenic when given as the corresponding hydrochloride to rats in their diets for two years up to doses of 350 mg/kg bw/day (corresponding to 195 mg/kg bw trimethylenediamine).

In a two-generation reproductive toxicity study, rats were dosed via feed to 0, 50, 150, and 500 mg/kg/day ethylenediamine hydrochloride. The NOAEL for reproductive effects was 500 mg/kg/day.

No developmental toxicity was observed when pregnant rats or rabbits were dosed with ethylenediamine hydrochloride up to 1000 mg/kg/day (for more detailed toxicodynamic overviews see also chapter toxicokinetics, metabolism, and distribution).

For worker exposure, respiratory sensitization has been identified as the key toxicological concern for trimethylenediamine. Human evidence has implicated trimethylenediamine as a dermal and respiratory sensitizer capable of causing early and late asthma. Based on the available data without reliable quantitative dose-response information, it is not possible to derive long or short term DNELs for the most sensitive endpoint respiratory sensitization with respect to a threshold for induction or elicitation. Therefore, a qualitative assessment for local respiratory sensitization has been carried out specifically for the production and uses of trimethylenediamine. In general, exposure should be minimized as low as reasonably achievable. Nevertheless, worker DNELs for other systemic effects were also derived.

Long-term exposure – systemic effects

 

Inhalation exposure:

In order to derive the worker DNEL (long-term inhalation exposure), the NOAEC assessed in a read across approach from a subchronic repeated dose inhalation toxicity study (Yang, 1983), recalculated for trimethylenediamine (resulting in a NOAEC of 177.6 mg/m³) was identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

  

- Calculation of the worker DNEL

Inhalatory NOAEC for workers: 177.6 mg/m³

Assessment factor for exposure duration (subchronic to chronic): 6

Assessment factor for intraspecies differences (worker): 5

Assessment factor for remaining uncertainty: 2 

Worker DNEL (long-term inhalation exposure)

= 177.6 mg/m³ / (6 x 5 x 2)

= 2.96 mg/m³

Dermal exposure:

In order to derive the worker DNEL (long-term dermal exposure), the NOAEL assessed in a read across approach from a chronic repeated dose dermal toxicity study (DePass, 1984) was identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

 

Relevant dose descriptor (NOAEL): 10.2 mg/kg bw/day

Exposure duration factor (subchronic-to-chronic): 1

Allometric scaling factor (rat-to-human): 4

Assessment factor for intraspecies differences (worker): 5

Assessment factor for remaining uncertainty: 2

 

Worker DNEL (long-term dermal exposure)

= 10.2 mg/kg bw/day / (4 x 5 x 2)

= 0.26 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic 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:
hazard unknown but no further hazard information necessary as no exposure expected
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:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

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

General Population - Hazard via oral route

Systemic 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:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Since no exposure of the general population is intended, no DNEL is derived.