Reaction mass of copper oxide and manganese dioxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not applicable as this is a summary of various reviews containing information from different studies

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

not applicable as this is a summary of various reviews containing information from different studies

GLP compliance:

not specified

Specific details on test material used for the study:

not applicable as this is a summary of various reviews containing information from different studies

Details on exposure:

not applicable

Details on absorption:

% of biavailable substance after different exposure routes - specifications used for hazard assessment:
- inhalation: 100%
- dermal: 5%
- oral: 25% oral absorption rats (humans should be calculated on a case by case basis as absorption is dose-dependent, however a value of 36% can be used for a first assumption)

Details on excretion:

Hepatobiliary excretion is the main excretion pathway.

1            Background

“Copper is an essential nutrient for humans and non-human organisms and, therefore, low concentrations may lead to deficiency while high concentrations of copper ions may lead to copper toxicity. …copper ions have more than one oxidation state. The principal ionic forms are cuprous (Cu(I), Cu+) and cupric (Cu(II), Cu2+). ... Cu+ is unstable in aqueous media and Cu1+-ions readily trans-form into Cu2+-ions. Depending on the chemistry of the receiving environment, soluble and/or insoluble copper compounds are formed. Hence Cu1+-ions are, due to their instability, considered as a source of Cu2+ ions for environmental and systemic toxicity”(OECD, 2014).

Most of the data on toxicokinetics comes from studies in which copper was administered as copper sulphate, one of the most soluble forms of the copper salts. It is assumed that orally-administered copper will occur in the GIT, at least in part, in the ionic form and therefore be available for absorption. Data on bioavailability which are currently available do not allow reliable conclusions to be reached regarding different rates of absorption based on the solubility of each copper substance. Consequently, it is considered appropriate to adopt a conservative approach and read-across from copper sulphate to other less soluble substances, recognising that this may result in over-estimation of effects for poorly soluble substances (ECI, 2008).

Comparative acute toxicity values for various copper compounds (table as provided by BPC, 2011)

Copper salt	Solubility	Acute oral  toxicity (LD50)	Acute dermal toxicity (LD50)
CuSo4	317 g/L	482 mg/kg	> 1000 mg/kg
CuCO3	1.5 mg/L	1400 mg/kg	> 2000 mg/kg
CuO	0.3 mg/L	> 2000 mg/kg	> 2000 mg/kg
Cu(OH)2	6.6 µg/L	763 mg/kg	> 2000 mg/kg

1.1.2            Absorption

·        Inhalation

In absence of relevant data, fractional and regional deposition was modelled by other experts and provided in their assessments (e.g. ECI, 2008). Copper deposited in the upper respiratory tract (extrathoracic and traceobronchial fractions) is assumed to be translocated to the gut and subject to intake-dependent absorption along with dietary copper. The default absorption factor of 100% is applied to the pulmonary fraction (ECI, 2008).

·        

Absorption rate for subjects with adequate diet for copper is 36 %. Based on these studies, an oral absorption factor of 36 % is used in risk characterisation as a realistic case value of copper oral absorption for humans and 25 % for animals (BPC, 2011).

·        

A fewin vitrostudies are available which have reported on the dermal absorption of copper in human skin. 

In the biocidal products assessment report (BPC, 2011) the study from Pirot et al. 1996 which investigated the soluble copper sulfate pentahydrate foundhuman percutaneous copper absorption in the range 0.66 to 5.04% of the applied dose. For the purpose of risk assessment, a percutaneous absorption level of copper of 5% was chosen here as well as by other regulators.

1.1.3            Distribution, accumulation and metabolism

Once absorbed by oral route, copper is bound to albumin and transcuprein and then rapidly transported to the liver where it is incorporated to ceruloplasmin, a transport protein that circulates in the organism and deliver the copper to other organs. The liver is the main organ involved in copper distribution and plays a crucial role in copper homeostasis by regulating its release. It should be however noted that a minor fraction of the absorbed dose can directly be distributed to peripheral organs. In both humans and animals, copper is tightly regulated at a cellular level, involving metallothionein and metallochaperones. These regulating molecules prevent from the accumulation of potentially toxic, free copper ions within the cell. In addition to the liver, the brain is another organ which contains relatively high concentrations of copper (BPC, 2011).

1.1.4            Excretion

Biliary excretion, with subsequent elimination in the faeces, represents the main route of excretion for copper in animals (rats) and humans, with an excretion rate approximately of 1.7 mg Cu/day in humans. Available data show that copper is excreted in the bile in a relatively inabsorbable form.

Consequently, little enterohepatic absorption takes place. Biliary excretion of copper and elimination in the faeces is recognised to be essential to the homeostatic regulation of copper in animals and humans.

A small amount of copper is also excreted in urine and sweat (BPC, 2011).

Conclusions:

Copper is an essential nutrient and exists in various oxidation states, with divalent Cu being the most important for humans.
Solubility of the different Cu compunds will impact the absorption and thus also the resulting systemic toxicity (more soluble forms revealing e.g. higher acute systemic toxicity). Most data investigating toxicokinetic processes are using highly soluble Cu forms, the resulting data thus represents a worst
case assumption for the assessment of CuO. The specifications used for hazard assessment in trems of % of biavailable substance after different exposure routes are a) inhalation: 100%; b) dermal: 5%, and c) oral: 25% oral absorption in rats.
High levels of copper are found in the liver (as this is the organ playing a crucial role in copper homeostasis, regulating the release) and also to some extent in the brain.
Hepatobiliary excretion is the main excretion pathway.

Reference 2

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not applicable as this is a summary of various reviews containing information from different studies

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

not applicable as this is a summary of varioues reviews containing information from different studies

GLP compliance:

not specified

Specific details on test material used for the study:

not applicable as this is a summary of various reviews containing information from different studies

Duration and frequency of treatment / exposure:

not applicable

Details on absorption:

% of biavailable substance after different exposure routes - specifications used for hazard assessment:
- inhalation: 100 %
- dermal: 0.5 % (assumption based on data of solubility study, dermal absorption might even be lower as not all bioaccessible Mn will be absorbed into the skin and become bioavailable)
- oral: 5 % (assumption based on data of limited absorption after oral administration of manganese in various forms)

Details on distribution in tissues:

manganese can cross the placenta and the blood-brain barrier

Details on excretion:

hepatobiliary excretion is the main excretion pathway

1.            Background

Manganese exists in seven oxidation states. The most important and stable oxidation state is divalent manganese, Mn(II). MnO2 however is a quaternary compound.

Manganese is a reducing agent or an oxidizing agent, dependent on its oxidation state. Manganese(II) can capture superoxide radicals and so is a powerful antioxidant. In the higher oxidation states (III, IV) the manganese ion is an effective oxidizing agent (Greim, 1994).

Most of the divalent salts are readily soluble in water (~400 – 2000 g/L; Hartwig, 2011). In contrast, the oxides like MnO2 are poorly soluble in water. Most of the experimental results investigating toxicokinetic processes are performed using highly soluble manganese compounds like manganese dichloride (MnCl2) or manganese sulphate (MnSO4), sometimes manganese dioxide (MnO2) is used for comparison as solubility impacts greatly the absorption rate of each compound. Thus using the data obtained for soluble manganese compounds represents a conservative approach as most probably less manganese will become bioavailable from MnO2 (ATSDR, 2012; Hartwig, 2011;OECD, 2007; 2012).

Manganese is an essential trace element. It is a component of various metalloproteins and a normal constituent of almost all tissues. Manganese is a cofactor essential for the activity of a variety of enzymes, e.g. pyruvate carboxylase, arginase, phosphatase, superoxide dismutase, glutamine synthetase and manganese-dependent ATPase (Note – most enzymes require the divalent form; Greim, 1994).

Manganese is found in virtually all diets.In Europe average daily intake might be up to 10 mg Mn/day (Hartwig, 2011).Manganese intake from drinking water is substantially lower than intake from food. Exposure to manganese from air for the general population is considered negligible as compared to intake from diet (low ambient air concentration around 0.01-0.02 µg Mn/m³; ATSDR, 2012).As high manganese concentrations can be toxic, body burden is tightly controlled via dose-dependent biological processes like intestinal absorption and biliary excretion.

2            Absorption

·        Inhalation

There are no quantitative data available for systemic availability after inhalation exposure of humans and animals. The particle size of inhaled manganese forms will greatly impact the extent and location of particle deposition in the respiratory tract, and thus amount of absorption. In general, smaller particles reach the lower airways and are mainly absorbed into blood and lymph fluids. For larger manganese particles or nanosized particles, which are deposited in the nasal mucosa direct transport to the brain via olfactory or trigeminal nerves was observed (mainly to bulbus olfactorius, saturable process). However, direct transport from nasal mucous into the brain as observed in several studies using rodents might be less relevant for humans as there are considerable species differences. Clearance of a significant fraction of manganese-containing particles initially deposited in the lung (upper or lower respiratory tract) will be through mucociliary transport to the throat, where they are swallowed and enter the stomach. Absorption of manganese dust thus occurs in the nasal mucosa, in the lung, and in the gastrointestinal tract. Yet, the relative amounts absorbed from each site are not accurately known.

Absorption of more soluble forms of manganese (e.g. manganese dichloride) compared to less soluble forms (e.g. manganese dioxide) is expected to be higher. Several animal studies support this notion, e.g. after intratracheal instillation of manganese dichloride peak blood peak concentrations were earlier reached after 30 minutes instead of 168 hours after administration of manganese dioxide and were four times higher for the more soluble form (ATSDR,2012), thus water solubility of manganese compounds appears to affect the time course of respiratory tract absorption.

Also iron status affects manganese uptake after inhalation. There is enhanced nasal absorption of manganese under iron-deficient conditions and diminished absorption under iron-excess conditions, respectively (ATSDR, 2012).

·        Oral

Recommended daily intake is around 2 to 5 mg Mn/day for adults. In Europe average daily intake might be up to 10 mg Mn/day (Hartwig, 2011). US agencies recommend a daily intake of 1.8 and 2.3 mg Mn/d for females and males, respectively. The tolerable upper intake level for adults is given as 11 mg Mn/day (ATSDR, 2012).

Manganese is an essential element and thus homeostasis is tightly regulated via control of absorption from gastro-intestinal tract and mostly biliary excretion. Manganese absorption through the gut may occur through a nonsaturable simple diffusion process through the mucosal layer of brush border membranes or via an active-transport mechanism that is high-affinity, low-capacity, and rapidly saturable. Iron content of the organism greatly impacts manganese absorption. In case of iron deficiencies manganese is absorbed increasingly via active transport mechanisms, when organism iron concentrations are high manganese absorption is only via diffusion and thus considerably lower (both elements use the same transport system). Resorption of manganese from the gastro-intestinal tracts is usually 3 to 5% in humans (ATSDR, 2012).

In one study with rats oral absorption of up to 13.9% was determined when using the more soluble from manganese dichloride. In another study with rats either manganese dichloride or manganese dioxide (at 24.3 mg manganese/kg) were administered orally via gavage. Whereas the maximal level in blood (7.05 μg/100 mL) was reached within the first 30 minutes post-dosing (first time point measured), manganese from manganese dioxide did not reach a maximal level in blood until 144 hours (6 days) post-dosing and also maximal manganese level in blood was around 8 times lower (900 ng/100 mL). Thus based on these results it can be stated that the gastrointestinal absorption of manganese is rapid and expected to be higher for soluble forms of manganese compared with relatively insoluble forms of manganese (ATSDR, 2012).

·        Dermal

There are no data on dermal absorption of manganese dioxide or other forms of manganese. In the acute dermal toxicity study in which manganese dioxide was administered at the limit dose of 2000 mg/kg no substance-related systemic effects were observed, thus no further conclusions on bioavailability can be drawn. Based on the low water solubility and the knowledge of limited absorption within the gastro-intestinal tract we assume a very low dermal absorption as well (ATSDR, 2012; Hartwig, 2011).

3            Distribution, accumulation and metabolism

As manganese is an essential element it is available in every tissue in the body (up to about 20 mg for adults) and highest levels are usually observed in liver, pancreas, kidneys and the brain (typical tissue concentration 0.1-1 µg Mn/g wet weight; Hartwig, 2011).

Manganese (II) will bind to either albumin or globulin and when oxidized, manganese (III) will also bind to transferrin (low affinity bindings; Hartwig, 2011).

Manganese is able to cross the placenta and the blood-brain barrier (Hartwig, 2011; ATSDR, 2012; OECD, 2012).

In rats administered manganese dichloride (four weekly gavage doses at 24.3 mg manganese/kg per dose), a significant increase in manganese concentration was observed in blood and the cerebral cortex, but not cerebellum or striatum, as compared to controls. When manganese dioxide was administered, manganese levels were significantly increased only in blood. The lack of significant increase in manganese levels in any brain region following administration of the dioxide is likely due to the delayed uptake of manganese in the blood (ATSDR, 2012).

In studies with rodents it was shown that biliary excretion of manganese is not well developed in neonates, thus leading possibly to age-differences in retention of manganese.

4            Excretion

As noted earlier, some of the particles that are deposited in the lung are transported to the gastrointestinal tract (mucociliary clearance). The rate of particle transport from the lungs has not been quantified in humans, but half-times of elimination in animals range from 3 hours to 1 day.

In humans, absorbed manganese is removed from the blood by the liver where it conjugates with bile and is excreted into the intestine. Some of the manganese in the intestine is reabsorbed through enterohepatic circulation (note: biliary bound manganese is better absorbed than free manganese (II)). However, hepatobiliary excretion is the main excretion pathway. E.g. in one study it was determined that 60 % of the material originally deposited in the lung was excreted in the feces within 4 days (humans were exposed to manganese dichloride). Humans ingesting manganese (usually as manganese dichloride) excreted the manganese with whole-body retention half-times of 13–37 days.

Small amounts of manganese can also be found in urine, sweat, and milk. Urinary excretion of manganese by healthy humans was in the range of around 10 nmole/day. While in some studies occupationally exposed men showed significantly increased levels of urinary manganese, other studies could not find the same effects. The differences in urinary excretion may be due to differences in duration or extent of exposure (ATSDR, 2012).

Elimination from the brain is much slower than compared to the rest of the body (SIDS, 2012).

Conclusions:

Manganese exists in various oxidation states, with Mn (II) and Mn (III) being the most important for humans.
Solubility of the different Mn compunds will greatly impact the absorption rate and also overall amount (the higher the solubility the faster and higher the absorption will occur). Most data investigating toxicokinetic processes are using highly soluble Mn forms, the resulting data thus represents a worst case assumption for the assessment of MnO2. The specifications used for hazard assessment in trems of % of biavailable substance after different exposure routes are a) inhalation: 100 %, b) dermal: 0.5 % (assumption based on data of solubility study; highest solubility rate observed at any concentration, see IUCLID section 4.8), dermal absorption might even be lower as not all bioaccessible Mn will be absorbed into the skin and become bioavailable) and c) oral: 5 % (assumption based on data of limited absorption after oral administration of manganese in various forms).
Manganese is a reducing agent or an oxidizing agent, dependent on its oxidation state.
Within the body Mn can cross the placenta and the blood-brain barrier.
Hepatobiliary excretion is the main excretion pathway.

Description of key information

No data are available for the registration substance. However the two constituents of the registration substance, i.e. copper oxide and manganese dioxide are well understood in terms of toxicokinetic behaviours. General information of each of these constituents and respective other copper or manganese compounds are provided in the respective endpoint study records. The relevant key values for each constituent are then used to adjust the results from the studies with the respective constituent as well.