Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
411.4 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):
150
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
61 710 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a developmental toxicity study in rats with the source substance (N-acetyl-L-tryptophan) (Kadota, 1980).

To take into account the interspecies difference between the rat and human the no observed adverse effect level (NOAEL) has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h) * (days of exposure per week in rats / days of exposure per week worker)

= 2500 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/0.1) * 0.67 m³ * (7/5) = 61710 mg/m³.

 

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

The inhalation absorption is assumed to be 10% based on granulometry data, which shows, D10: 14.1 µm, that a very low fraction of the particles are likely to reach the alveoli of the lungs. The D50: 94.0 µm and the D90: 292.7 µm, indicating that a fraction of the particles may be inhaled and are likely to be deposited before reaching the alveolar region. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed or coughed out.

Therefore, the corrected starting point for workers was 61710 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute (10-day) study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for the inhalation route
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACh Guidance
AF for the quality of the whole database:
2
Justification:
The DNEL is based on a study with some limitations
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41.7 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):
600
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a developmental toxicity study in rats with the source substance (N-acetyl-L-tryptophan) (Kadota, 1980).

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal)

= 2500 mg/kg bw/day * (1/0.1) = 25000 mg/kg bw/day.

The dermal absorption potential is assumed to be 10%, based on the prediction of low dermal absorption potential (please refer to the toxicokinetic statement).

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute (10-day) study
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
2
Justification:
The DNEL is based on a study with some limitations
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
72.5 µg/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):
300
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
21 739.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a developmental toxicity study in rats with the source substance (N-Acetyl-L-tryptophan) (Kadota, 1980).

To take into account the interspecies difference between the rat and human the no observed adverse effect level (NOAEL) has to be corrected as follows:

Corrected starting point for the inhalative route for the general population:

= NOAEL(oral) * (1/1.15 m³/kg bw/day) * (ABSoral-rat/ABSinh-human)

= 2500 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/0.1) = 21739.1 mg/m³

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

The inhalation absorption is assumed to be 10% based on granulometry data, which shows, D10: 14.1 µm, that a very low fraction of the particles are likely to reach the alveoli of the lungs. The D50: 94.0 µm and the D90: 292.7 µm, indicating that a fraction of the particles may be inhaled and are likely to be deposited before reaching the alveolar region. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed or coughed out.

The corrected starting point for workers was 21739.1 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute (10-day) study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for the inhalation route
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
2
Justification:
The DNEL is based on a study with some limitations
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
20.8 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):
1 200
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a developmental toxicity study in rats with the source substance (N-acetyl-L-tryptophan) (Kadota, 1980).

Corrected starting point for the dermal route for the general population:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal)

= 2500 mg/kg bw/day * (1/0.1) = 25000 mg/kg bw/day.

The dermal absorption potential is assumed to be 10%, based on the prediction of low dermal absorption potential (please refer to the toxicokinetik statement).

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
2
Justification:
The DNEL is based on a study with some limitations
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.08 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 200
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation necessary.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
2
Justification:
The DNEL is based on a study with some limitations
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population