Manganese oxide

Basic toxicokinetics

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

Test material information

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 parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Tmax: Oral dose MnCl2: 0.25±0.21 h

Toxicokinetic parameters 2

Toxicokinetic parameters:

Cmax: Oral dose MnCl2: 0.30±0.11µg/mL

Toxicokinetic parameters 3

Toxicokinetic parameters:

AUC: Oral dose: MnCl2 1.95±0.51 mM·h

Toxicokinetic parameters 4

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 t_1/2α and the terminal elimination t_1/2ß 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 (V_ß) of manganese was about 1.16 L/kg, the central volume distribution (V_c) 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 C_max (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 t_½ 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 t_½ of 1.83 hours and CL_s 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 (T_max= 0.25 h). The absolute oral bioavailability was about 13%.