Reaction mass of copper oxide and manganese dioxide

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

European Union Risk Assessment Report COPPER, COPPER II SULPHATE PENTAHYDRATE, COPPER(I)OXIDE, COPPER(II)OXIDE, DICOPPER CHLORIDE TRIHYDROXIDE CAS No: 7440-50-8, 7758-99-8, 1317-39-1, 1317–38–0, 1332-65-6 - VOLUNTARY RISK ASSESSMENT

Author:

European Copper Institute

Year:

2007

Bibliographic source:

https://echa.europa.eu/de/copper-voluntary-risk-assessment-reports

Reference 2

Reference Type:

review article or handbook

Title:

Copper and its inorganic compounds - MAK Value Documentation

Author:

Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

Year:

2014

Bibliographic source:

http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb744050e5715/pdf

Reference 3

Reference Type:

other: biocidal products assessment report

Title:

Biocidal products Assessment Report - Copper (II) oxide (Inclusion of active substances in Annex I or IA to Directive 98/8/EC)

Author:

BPC, Biocidal Products Committee (French competent authority)

Year:

2011

Bibliographic source:

ECHA, European Chemicals Agency. - http://dissemination.echa.europa.eu/Biocides/ActiveSubstances/0017-08/0017-08_Assessment_Report.pdf

Reference 4

Reference Type:

review article or handbook

Title:

Recommendation from the Scientific Committee on Occupational Exposure Limits for Copper and its inorganic compounds

Author:

SCOEL, Scientific Committee for Occupational Exposure Limits

Year:

2014

Bibliographic source:

SCOEL/SUM/171

Reference 5

Reference Type:

review article or handbook

Title:

SIDS Initial Assessment Profile for Copper and copper compounds

Author:

OECD, Organisation for Economic Co-Operation and Development

Year:

2014

Bibliographic source:

CoCAM 6, September 30-October 3, 2014; online: http://webnet.oecd.org/hpv/ui/handler.axd?id=6fd34008-70ec-4114-aaa2-df10f8f7b111

Materials and methods

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

Test material

Test material information

Constituent 1

Reference substance name:

Manganese dioxide

EC Number:

215-202-6

EC Name:

Manganese dioxide

Cas Number:

1313-13-9

Molecular formula:

MnO2

IUPAC Name:

Manganese dioxide

Constituent 2

Reference substance name:

Copper oxide

EC Number:

215-269-1

EC Name:

Copper oxide

Cas Number:

1317-38-0

Molecular formula:

CuO

IUPAC Name:

Copper (II) oxide

Test material form:

solid: particulate/powder

Details on test material:

Boundary composition

Specific details on test material used for the study:

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

Administration / exposure

Details on exposure:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Any other information on results incl. tables

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).

Applicant's summary and conclusion

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.