Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
293.5 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
2 935 mg/m³
AF for dose response relationship:
1
Justification:
No adverse effects were observed during the test. The NOAEL is based on max. tested concentration.
AF for differences in duration of exposure:
2
Justification:
NOAEL from 90d study: subchronic to chronic extrapolation, REACH guidance AF value.
AF for interspecies differences (allometric scaling):
1
Justification:
Only differences not related to calorimetric differences are to be taken into account. Calorimetric differences are taken into account during route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
See discussion section below.
AF for intraspecies differences:
5
Justification:
REACH Guidance AF value.
AF for the quality of the whole database:
1
Justification:
REACH Guidance AF value.
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 (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
833 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
33 300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
No adverse effects were observed during the test. The NOAEL is based on max. tested concentration.
AF for differences in duration of exposure:
2
Justification:
NOAEL from 90d study: subchronic to chronic extrapolation, REACH guidance AF value.
AF for interspecies differences (allometric scaling):
4
Justification:
REACH Guidance AF value for calorimetric differences between rat and human.
AF for other interspecies differences:
1
Justification:
See discussion section below.
AF for intraspecies differences:
5
Justification:
REACH Guidance AF value.
AF for the quality of the whole database:
1
Justification:
REACH Guidance AF value.
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The additional assessment factor 2.5 for "remaining interspecies differences" was not used for the following reasons:

"The factor of 2.5 accounts for other interspecies differences in toxicokinetics (not related to metabolic rate) and toxicodynamics. Absorption, Distribution, Metabolism as well as Excretion of proteinogenic amino acids are very similar between animals (mammals) and humans: These amino acids are taken up via the oral route by animals as well as humans by generally the same mechanisms (or/and are build endogenously).Regardless of whether they enter the intestinal cells as peptides or amino acids they enter the hepatic portal circulation as single amino acids. Absorbed amino acids leave the hepatic portal system and enter the peripheral blood. These amino acids are taken up by tissues for synthesis of cellular proteins and other physiologically active compounds in animals and humans. Degradation involves removal of the amino group, which in mammals is converted to urea and excreted in the urine. After removal of the amino group the rest of the acid is utilised as energy or used to synthesize other endogenous substances. Also with regard to toxicodynamics (however real toxic effects of amino acids in humans as well as in animals are hardly detectable even at high doses) there is no obvious difference between mammals and humans."

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
72.4 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):
20
Modified dose descriptor starting point:
NOAEC
Value:
1 448 mg/m³
AF for dose response relationship:
1
Justification:
No adverse effects were observed during the test. The NOAEL is based on max. tested concentration.
AF for differences in duration of exposure:
2
Justification:
NOAEL from 90d study: subchronic to chronic extrapolation, REACH guidance AF value.
AF for interspecies differences (allometric scaling):
1
Justification:
Only differences not related to calorimetric differences are to be taken into account. Calorimetric differences are taken into account during route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
See discussion section below.
AF for intraspecies differences:
10
Justification:
REACH Guidance AF value.
AF for the quality of the whole database:
1
Justification:
REACH Guidance AF value.
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 (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
416 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
33 300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
No adverse effects were observed during the test. The NOAEL is based on max. tested concentration.
AF for differences in duration of exposure:
2
Justification:
NOAEL from 90d study: subchronic to chronic extrapolation, REACH guidance AF value.
AF for interspecies differences (allometric scaling):
4
Justification:
REACH Guidance AF value for calorimetric differences between rat and human.
AF for other interspecies differences:
1
Justification:
See discussion section below.
AF for intraspecies differences:
10
Justification:
REACH Guidance AF.
AF for the quality of the whole database:
1
Justification:
REACH Guidance AF.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41.6 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
3 330 mg/kg bw/day
AF for dose response relationship:
1
Justification:
No adverse effects were observed during the test. The NOAEL is based on max. tested concentration.
AF for differences in duration of exposure:
2
Justification:
NOAEL from 90d study: subchronic to chronic extrapolation, REACH guidance AF value.
AF for interspecies differences (allometric scaling):
4
Justification:
REACH Guidance AF value for calorimetric differences between rat and human.
AF for other interspecies differences:
1
Justification:
See discussion section below.
AF for intraspecies differences:
10
Justification:
REACH Guidance AF.
AF for the quality of the whole database:
1
Justification:
REACH Guidance AF.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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

The additional assessment factor 2.5 for "remaining interspecies differences" was not used for the following reasons:

"The factor of 2.5 accounts for other interspecies differences in toxicokinetics (not related to metabolic rate) and toxicodynamics. Absorption, Distribution, Metabolism as well as Excretion of proteinogenic amino acids are very similar between animals (mammals) and humans: These amino acids are taken up via the oral route by animals as well as humans by generally the same mechanisms (or/and are build endogenously).Regardless of whether they enter the intestinal cells as peptides or amino acids they enter the hepatic portal circulation as single amino acids. Absorbed amino acids leave the hepatic portal system and enter the peripheral blood. These amino acids are taken up by tissues for synthesis of cellular proteins and other physiologically active compounds in animals and humans. Degradation involves removal of the amino group, which in mammals is converted to urea and excreted in the urine. After removal of the amino group the rest of the acid is utilised as energy or used to synthesize other endogenous substances. Also with regard to toxicodynamics (however real toxic effects of amino acids in humans as well as in animals are hardly detectable even at high doses) there is no obvious difference between mammals and humans."