Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
304 mg/m³
Explanation for the modification of the dose descriptor starting point:
oral study available - systemic effects
AF for dose response relationship:
1
Justification:
dose-response study available
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
already taken into account for inhalation exposure
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
5
Justification:
standard factor for workers
AF for the quality of the whole database:
1
Justification:
several studies available on chelates
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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:
25 000 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 500 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral study available - systemic effects
AF for dose response relationship:
1
Justification:
dose-response study available
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
standard factor
AF for other interspecies differences:
2.5
Justification:
remaining differences (but low absorption and not metabolized)
AF for intraspecies differences:
5
Justification:
standard for worker
AF for the quality of the whole database:
1
Justification:
several studies available for chelates
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

According to SCOEL (2009), "the most sensitive endpoint for manganese exposure is neurological (i.e. systemic rather than at the principal point of entry, the lungs) and, for manganese, the respirable fraction is considered to be the best indicator of systemic availability. However, it is also appropriate to consider that every inhaled fraction reaching the respiratory tract contributes to workers' exposure, being via rapid and complete absorption in the alveoli, dissolution in the airway mucus, some olfactory uptake in the upper airways or limited gastro-intestinal uptake

after mucociliary clearance and deglutition. A large proportion of the inhaled fraction will, however, ultimately enter the gastrointestinal tract, yet gastrointestinal absorption is fairly low, even for soluble forms of manganese (~5%), and there is little evidence for manganese toxicity following dietary exposure".

Although no inhalation studies are available for EDTA-Mn(NH4)2, the following comments can be made:

- Most probably the neurotoxicity of manganese is due to uptake of particles of inorganic, insoluble manganese compounds, especially in metallurgic industries. Most manganese compounds are insoluble (manganese dioxide, manganese oxide, manganese sulphide, manganese carbonate). Metallic manganese particles decompose in water. Manganese compounds that are water soluble are manganese sulphate, manganese dichloride tetrahydrate, and manganese nitrate hydrate. EDTA-Mn(NH4)2 is also well soluble in water (> 713 g/L). There is experimental evidence of olfactory uptake of manganese particles to the brain. Because, by definition, this route is applicable to insoluble particles only, it is not expected that soluble manganese fractions will be directly transported to the brain. Instead, the soluble fractions will be taken up by the blood and become systematically available or they will pass to the gut where they can be absorbed (although absorption from the gut is low, viz. ca. ~5%), which is similar to that of EDTA (EDTA-H4/EDTA-Na4; RAR, 2004).

- SCOEL (2009) indicated that there is little evidence for manganese toxicity following oral exposure which may be (partly) due to the low absorption, and as such exposure via inhalation may be more toxic; however, the manganese compounds that were studied in their evaluation were inorganic, mostly insoluble substances. In contrast, the acute oral and inhalation studies with EDTA-MnNa2 did not show any difference with regard to acute toxicity. Both studies did not show mortality at the limit dose/concentration tested. This will not be different for EDTA-Mn(NH4)2.

- Finally, according to SCOEL (2009) most manganese compounds are classified as harmful by inhalation and if swallowed. Several of these manganese compounds (also) show skin and eye irritating properties, and possible risk of irreversible effects. These hazards are not applicable to EDTA-Mn(NH4)2. In addition, an acute ip study showed that EDTA-MnNa2 on a molar basis was 7.5 times less toxic than the metal salt MnSO4.H2O.

As such, in order to be able to compare EDTA-MnNa2 toxicity with that of EDTA (EDTA-H4/EDTA-Na4), it was decided to carry out the extended OECD 422 test via oral exposure. Concordingly, all DNELs for repeated exposure to EDTA-Mn(NH4)2 are therefore based on the results of this extended OECD 422 study (using a 10 -week pre-mating period) with EDTA-MnNa2.

General Population - 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:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
150 mg/m³
Explanation for the modification of the dose descriptor starting point:
oral study available - systemic effects
AF for dose response relationship:
1
Justification:
dose-response study available
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not needed for inhalation exposure
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
standard factor
AF for the quality of the whole database:
1
Justification:
several studies available on chelates
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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:
12 500 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
DNEL value:
2 500 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral route available - systemic effects
AF for dose response relationship:
1
Justification:
dose-response study available
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
standard factor
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
standard factor
AF for the quality of the whole database:
1
Justification:
several studies available on chelates
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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:
2.5 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not applicable (oral study available)
AF for dose response relationship:
1
Justification:
dose response study available
AF for differences in duration of exposure:
2
Justification:
subchornic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
standard factor
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
standard factor
AF for the quality of the whole database:
1
Justification:
several studies on chelates available
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

See above at worker exposure.