Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted to sound scientific principles with a suficient level of detail to assess the reliability of the relevant results. There was a sufficient number of plasma time-points to enable TK calculations to be made. The study was conducted with manganese chloride, which represents a more available form of manganese, rather than with the registered substance itself, the study was assigned a reliability score of 2.
Justification for type of information:
See the read-across report attached in Section 13.

Data source

Reference
Reference Type:
publication
Title:
Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats.
Author:
Zheng W, Kim H and Zhao Q
Year:
2000
Bibliographic source:
Toxicol Sci 54:295-301

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
The toxicokinetics of manganese (Mn) was investigated in male rats either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg). The plasma concentrations of manganese were quantified by atomic absorption spectrophotometry (AAS).
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
manganese chloride
IUPAC Name:
manganese chloride
Details on test material:
- Molecular formula: MnCl2
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Halran Inc., Indianapolis, IN, USA
- Age at study initiation: 2 months
- Weight at study initiation: 210 - 230 g
- Fasting period before study: animals were fasted for 12 hours prior to administration (oral dosing)
- Housing: animals were housed in a temperature controlled room
- Diet:Teklad 4% Mouse-Rat Diet (Teklad, Madison, WI, USA), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
other: oral and intravenous
Vehicle:
other: sterile saline
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
MnCl2 was dissolved in sterile saline for both iv and oral administration; the test material was dosed at 6.0 mg Mn/kg (1.0 mL/kg) via both routes of administration.
Duration and frequency of treatment / exposure:
Single administration of test material
Doses / concentrations
Remarks:
Doses / Concentrations:
6.0 mg Mn/kg (1.0 mL/kg)
No. of animals per sex per dose / concentration:
not reported
Control animals:
not specified
Details on study design:
- Dose selection rationale: The dose regimen was chosen because it was known to be associated with a significant reduction of succinic dehydrogenase and aconitase in rat brain.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Blood (0.3 - 0.5 mL)
- Time and frequency of sampling: 0, 0.05, 0.17, 0.33, 0.5, 1, 2, 4, 8, and 12 h
The blood was centrifuged at 5000 x g for 5 minutes, and the plasma was separated and stored at -20°C prior to analysis.
Statistics:
Statistical analysis for comparison of two means was performed usinf one-way ANOVA. In all cases, a probility level of p < 0.05 was considered as the criterion of significance.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
Tmax: Oral dose MnCl2: 0.25±0.21 h
Toxicokinetic parameters:
Cmax: Oral dose MnCl2: 0.30±0.11µg/mL
Toxicokinetic parameters:
AUC: Oral dose: MnCl2 1.95±0.51 mM·h
Toxicokinetic parameters:
AUC: iv dose MnCl2: 14.8±3.60 mM·h

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Intravenous (iv) Dosing

After an iv-bolus injection of MnCl2, the concentration-time profile of manganese in plasma followed a multi-exponential equation:

C(t) = 41.94e-4.2t + 2.08e-0.44t

In general, the two-compartment model with first-order elimination from the central compartment provided a good fit to the observed data. Manganese was rapidly eliminated from the plasma with an initial faster phase between 0 and 3 hours and a slower terminal phase between 3 and 12 hours. Accordingly, the first-order initial disposition t1/2α and the terminal elimination t1/2ß were estimated to be 0.19h and 1.38h, respectively. By 12 hours, manganese concentrations in plasma were restored to normal levels in all tested animals. Although the total volume distribution (Vß) of manganese was about 1.16 L/kg, the central volume distribution (Vc) was only 0.14 L/kg, suggesting an extensive distribution of manganese to the peripheral compartment following iv injection of MnCl2.

 

Oral (op) Dosing

Single oral gavage of MnCl2 resulted in a rapid appearance of manganese in plasma. The Cmax (0.296 µg/mL) was achieved within 0.5 hours of the oral dose. Thereafter, manganese concentrations declined and the terminal phase followed the first-order kinetics. The absolute bioavailability (F) of manganese following oral MnCl2was 13.2% at a dose of 6 mg/kg. Similar to iv injection, plasma manganese returned to normal levels 12 hours after dosing. Oral dosing of MnCl2 resulted in a significant increase in terminal t½ compared to rats receiving iv injection.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Upon iv administration of MnCl2, manganese rapidly disappeared from blood with a terminal elimination t½ of 1.83 hours and CLs of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.94e-4.2t + 2.08e-0.44t
Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax = 0.25 h). The absolute oral bioavailability was about 13%.
Executive summary:

The toxicokinetics of manganese (Mn) was investigated in male rats either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg). The plasma concentrations of manganese were quantified by atomic absorption spectrophotometry (AAS).

Upon iv administration of MnCl2, manganese rapidly disappeared from blood with a terminal elimination t½ of 1.83 hours and CLs of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.94e-4.2t + 2.08e-0.44t

Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax= 0.25 h). The absolute oral bioavailability was about 13%.