Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
668.2 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
DNEL value:
6 682 mg/m³
Explanation for the modification of the dose descriptor starting point:

only study for oral route available

AF for dose response relationship:
1
Justification:
starting point NOAEC
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a 90-day study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
1
Justification:
AF not used, remaining differences in toxicolocial effects are not expected
AF for intraspecies differences:
5
Justification:
AF for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
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:
947.5 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
DNEL value:
37 900 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

only study for oral route available

AF for dose response relationship:
1
Justification:
starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a 90-day study
AF for interspecies differences (allometric scaling):
4
Justification:
test animal: rat
AF for other interspecies differences:
1
Justification:
AF not used, remaining differences in toxicolocial effects are not expected
AF for intraspecies differences:
5
Justification:
AF for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Since only oral repeated dose studies are available, route-to-route extrapolation might be considered necessary for the long-term systemic dermal and inhalation DNELs.

For both oral and inhalation absorption 100% absorption is assumed and for dermal absorption 10% absorption is assumed, based on a toxicokinetic assessment.

The DNELs for human exposure are derived according to the ECHA Guidance on information requirements and chemical safety assessment (Chapter R.8: Characterisation of dose-/concentration-response for human health, Version: 2, 2010).

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 generallythe 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 synthetise 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."

An oral NOAEL of 3709 mg/kg bw /day was used for L-arginine-HCl.

 

Acute DNELs for local and systemic effects

Due to its very low systemic toxicity and the fact that L-arginine HCl (with high water solubility and a log P value well below 0) may be too hydrophilic to cross the lipid rich environment of the stratum corneum it is highly improbable that an acute dermal toxicity study would result in any toxicity. In absence of further information concerning route specific effects through dermal exposure, no acute dermal DNELs are considered applicable.

The substance is not classified for local effects and therefore DNELs for local effects were not derived.

 

Long-term DNELs for local effects

The substance is not classified for local effects and therefore DNELs for local effects were not derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
164.8 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
DNEL value:
3 296 mg/m³
Explanation for the modification of the dose descriptor starting point:

only study for oral route available

AF for dose response relationship:
1
Justification:
starting point NOAEC
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a 90-day study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
1
Justification:
AF not used, remaining differences in toxicolocial effects are not expected
AF for intraspecies differences:
10
Justification:
AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
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:
473.8 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):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
37 900 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

only study for oral route available

AF for dose response relationship:
1
Justification:
starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a 90-day study
AF for interspecies differences (allometric scaling):
4
Justification:
test animal: rat
AF for other interspecies differences:
1
Justification:
AF not used, remaining differences in toxicolocial effects are not expected
AF for intraspecies differences:
10
Justification:
AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
47.4 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
DNEL value:
3 790 mg/kg bw/day
AF for dose response relationship:
1
Justification:
starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a 90-day study
AF for interspecies differences (allometric scaling):
4
Justification:
test animal: rat
AF for other interspecies differences:
1
Justification:
AF not used, remaining differences in toxicolocial effects are not expected
AF for intraspecies differences:
10
Justification:
AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Since only oral repeated dose studies are available, route-to-route extrapolation might be considered necessary for the long-term systemic dermal and inhalation DNELs.

For both oral and inhalation absorption 100% absorption is assumed and for dermal absorption 10% absorption is assumed, based on a toxicokinetic assessment.

The DNELs for human exposure are derived according to the ECHA Guidance on information requirements and chemical safety assessment (Chapter R.8: Characterisation of dose-/concentration-response for human health, Version: 2, 2010).

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 generallythe 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 synthetise 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."

An oral NOAEL of 3790 mg/kg bw /day was used for L-arginine-HCl.

The long-term oral DNEL for systemic effects on general population is significantly lower than the mean human daily intake of L-arginine HCl from food (see summary section 7.5). The above mentioned approach of deriving that DNEL is extremely conservative. The highest median human daily intake of approximately 7.1 g/day much more reflects the actual level of no effects for long term oral intake.

Acute DNELs for local and systemic effects

Due to its very low systemic toxicity and the fact that L-arginine HCl (with high water solubility and a log P value well below 0) may be too hydrophilic to cross the lipid rich environment of the stratum corneum it is highly improbable that an acute dermal toxicity study would result in any toxicity. In absence of further information concerning route specific effects through dermal exposure, no acute dermal DNELs are considered applicable.

The substance is not classified for local effects and therefore DNELs for local effects were not derived.

 

Long-term DNELs for local effects

The substance is not classified for local effects and therefore DNELs for local effects were not derived.