Dimanganese trioxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016-09-29 to 2017-01-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

bioaccessibility (or bioavailability)

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The study estimated the metal bio-accessibility of the test item in different artificial media: gastric juice, lysosomal, alveolar and perspiration fluids; representing ingestion, inhalation and dermic contact routes of exposure in humans.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimanganese trioxide

EC Number:

215-264-4

EC Name:

Dimanganese trioxide

Cas Number:

1317-34-6

Molecular formula:

Mn2O3

IUPAC Name:

dimangantrioxide

Specific details on test material used for the study:

- Source: Ramboll Environ, Germany
- Composition: 69.6% Mn (% w/w)

Radiolabelling:

no

Test animals

Species:

other: not applicable

Strain:

other: not applicable

Details on species / strain selection:

not applicable

Sex:

not specified

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Route of administration:

other: in vitro study

Vehicle:

other: not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.2 other: g / L

Remarks:

Loading (Gastric bio-elution test)

Doses / concentrations 2

Dose / conc.:

2 other: g / L

Remarks:

Loading (Sweat bio-elution test)

Doses / concentrations 3

Dose / conc.:

2 other: g / L

Remarks:

Loading (Alveolar bio-elution test)

Doses / concentrations 4

Dose / conc.:

2 other: g / L

Remarks:

Loading (Lysosomal bio-elution test)

No. of animals per sex per dose / concentration:

not applicable

Control animals:

other: not applicable

Positive control reference chemical:

not applicable

Details on study design:

Please see box "Any other information on materials and method incl. tables"

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Not applicable

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

The results of the bio-elution tests (see tables 1-5 in box "Any other information on results incl. tables) showed a consistent solubility pattern, where higher solubility was attained in acidic pH media, like artificial gastric juice (pH 1.5) and lysosomal fluids (pH 4.5), than in the more alkaline media of perspiration (pH 6.5) and alveolar fluids (pH 7.4). Even more, complete dissolution was observed in artificial lysosomal fluid.

Any other information on results incl. tables

Table 1: Summary of results

Metal release in gastric test (µg / L)						% Solubility (0.2 g / L loading)
Sample	Metal	2 h			CV, %	2 h	CV, %
Mn2O3	Mn	11698			1	8.40	1
Metal release in lysosomal fluid (µg / L)						% Solubility (2 g / L loading)
Sample	Metal	24 h	CV, %	72 h	CV, %	72 h	CV, %
Mn2O3	Mn	1392980	3	1380723	3	99.2	3
Metal release in alveolar fluid (µg / L)						% Solubility (2 g / L loading)
Sample	Metal	24 h	CV, %	72 h	CV, %	72 h	CV, %
Mn2O3	Mn	14.8	12	19.0	3	0.001	3
Metal release in perspiration fluid (µg / L)						% Solubility (2 g / L loading)
Sample	Metal	24 h	CV, %	72 h	CV, %	72 h	CV, %
Mn2O3	Mn	12913.4	3	39826.0	2	2.86	2

Table 2: Dimanganese trioxide 2 hours bio-elution test in gastric mimetic fluid

Gastric test parameters				Manganese, µg / L			Manganese, µg / g
Blank	Time, h	Temp, °C	pH	Mean; µg / L	S.D.	CV, %	Mean, µg / g	CV, %
	Before	37	1.50	0.05	0.02	45	0.25	45
	2	37	1.50	0.06	0.01	21	0.30	21
Mn2O3	Before	37	1.50	0.06	0.01	24	0.30	24
	2	37	1.50	11698	154	1	58490	1

Table 3: Dimanganese trioxide 72 hours bio-elution test in lysosomal mimetic fluid

Lysosomal test parameters				Manganese, µg / L			Manganese, µg / g
Blank	Time, h	Temp, °C	pH	Mean; µg / L	S.D.	CV, %	Mean, µg / g	CV, %
	Before	37	4.50	-	-	-	-	-
	2	37	4.48	-	-	-	-	-
	24	37	4.47	-	-	-	-	-
	72	37	4.45	-	-	-	-	-
Mn2O3	Before	37	4.50	-	-	-	-	-
	2	37	4.83	1328353	128705	10	664177	10
		37	4.93	1392980	38582	3	696490	3
		37	5.01	1380723	40077	3	690362	3

Table 4: Dimanganese trioxide 72 hours bio-elution test in alveolar mimetic fluid

Alveolar test parameters				Manganese, µg / L			Manganese, µg / g
Blank	Time, h	Temp, °C	pH	Mean; µg / L	S.D.	CV, %	Mean, µg / g	CV, %
	Before	37	7.41	-	-	-	-	-
	2	37	7.27	-	-	-	-	-
	24	37	7.29	-	-	-	-	-
	72	37	7.40	-	-	-	-	-
Mn2O3	Before	37	7.41	-	-	-	-	-
	2	37	7.45	13.4	1.5	11	6.7	11
		37	7.43	14.8	1.7	12	7.4	12
		37	7.45	19.0	0.6	3	9.5	3

Table 5:Dimanganese trioxide 168 hours bio-elution test in perspiration mimetic fluid

Perspiration test parameters				Manganese, µg / L			Manganese, µg / g
Blank	Time, h	Temp, °C	pH	Mean; µg / L	S.D.	CV, %	Mean, µg / g	CV, %
	Before	30	6.45	-	-	-	-	-
	24	30	6.30	0.2	0.01	4	0.1	4
	168	30	5.97	0.2	0.07	29	0.1	29
Mn2O3	Before	30	6.45	-	-	-	-	-
	24	30	6.41	12913.4	358.3	3	6456.7	3
	168	30	6.22	39826.0	839.2	2	19913.0	2

CV corresponds to the coefficient of variation between vessels

Applicant's summary and conclusion

Conclusions:

In this study, the test item showed a consistent solubility pattern, where higher solubility was attained in acidic pH media, like artificial gastric juice (pH 1.5) and lysosomal fluids (pH 4.5), than in the more alkaline media of perspiration (pH 6.5) and alveolar fluids (pH 7.4). Even more, complete dissolution was observed in artificial lysosomal fluid.

Executive summary:

A study to estimate the bioaccessibility of the test item in different artificial media: gastric juice, lysosomal, alveolar and perspiration fluids; representing ingestion, inhalation and dermal contact routes of exposure in humans, was performed. The rate and extend of the metal released in these in vitro simulations of biological compartments can be used for human health hazard classification of this substance. The results showed a consistent solubility pattern, where higher solubility was attained in acidic pH media, like artificial gastric juice (pH 1.5) and lysosomal fluids (pH 4.5), than in the more alkaline media of perspiration (pH 6.5) and alveolar fluids (pH 7.4). Even more, complete dissolution was observed in artificial lysosomal fluid.

Simulated Body Fluid	pH	Extraction time (h)	µg Mn/L sample	St. Dev.
Gastric fluid	1.50	2	11698	154
Lysosomal fluid	4.93	24	1392980	38582
	5.01	72	1380723	40077
Alveolar fluid	7.43	24	14.8	1.5
	7.45	72	19.0	0.6
Perspiration fluid	6.41	24	12913.4	358.3
	6.22	168	39826.0	839.2