Manganese sulphide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

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 materials and methods only give details of male rats, yet results are quoted for female rats for MMT.

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)

Deviations:

yes

Remarks:

One dose level used rather than the recommended two. For MnCl2, only male rats are used.

Principles of method if other than guideline:

The toxicokinetics of manganese (Mn) was investigated in male and female rats either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg), or following a single oral dose of methylcyclopentadienyl manganese tricarbonyl (MMT) (20 mg MMT/kg or 5.6 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 dichloride

EC Number:

231-869-6

EC Name:

Manganese dichloride

Cas Number:

7773-01-5

Molecular formula:

Cl2Mn

IUPAC Name:

manganese(2+) dichloride

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Inc Indianapolis IN.
- Age at study initiation: 2 months
- Weight at study initiation: 210-230g
- Fasting period before study: 12 hours before oral study
- Diet: Ad libitum, Teklad 4% Mouse-Rat Diet
- Water: Ad libitum, Tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature controlled (no temperature stated)
- Photoperiod (hrs dark / hrs light): 12:12h light/dark

Administration / exposure

Route of administration:

other: oral and iv for MnCl2 and oral only for MMT

Vehicle:

other: Sterile saline for MnCl2 and corn oil for MMT

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: MnCl2 dissolved in sterile saline for both iv and oral administration both dosed at 6.0mg Mn/kg (1.0mL/kg). MMT was dissolved in corn oil and dosed at 20mg/kg (3.3mL/kg in volume) equivalent to 5.6mg Mn/kg.

Duration and frequency of treatment / exposure:

Single dose for each test.

Doses / concentrations

Remarks:

Doses / Concentrations:
MnCl2 dissolved in sterile saline for both iv and oral administration both dosed at 6.0mg Mn/kg (1.0mL/kg). MMT was dissolved in corn oil and dosed at 20mg/kg (3.3mL/kg in volume) equivalent to 5.6mg Mn/kg.


For the iv dosing study, MnCl2 was injected via the tail vein at a dose of 6.0 mg Mn/kg (1.0 mL/kg) over approximately 5 seconds. For the oral dosing study, MnCl2 was administered by a single gavage at the same dose level. MMT was also dosed by a single oral gavage to rats.

Control animals:

not specified

Details on study design:

For the oral dose MnCl2 was administered by a single gavage at 6.0mg Mn/kg as it was known to be associated with a significant reduction of succinic dehydrogenase and aconitase in rat brain.

Details on dosing and sampling:

MnCl2

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Blood plasma (0.3-0.5mL)
- Time and frequency of sampling: 0, 0.05, 0.17, 0.33, 0.5, 1, 2, 4, 8, and 12 h

MMT

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Blood plasma (0.3-0.5mL)
- Time and frequency of sampling: 0, 0.17, 0.5, 1, 2, 4, 8, 12, 24, 48, 120, 168, 288, 384, and 456 h

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: MMT male: 5.50±4.43h

Toxicokinetic parameters 2

Toxicokinetic parameters:

Tmax: MMT female: 10.0±2.31h

Toxicokinetic parameters 3

Toxicokinetic parameters:

Tmax: MMT combined: 7.75±4.06h

Toxicokinetic parameters 4

Toxicokinetic parameters:

Cmax: MMT male: 0.79±0.36µg/mL

Toxicokinetic parameters 5

Toxicokinetic parameters:

Cmax: MMT female: 1.07±0.46µg/mL

Toxicokinetic parameters 6

Toxicokinetic parameters:

Cmax: MMT combined: 0.93±0.41µg/mL

Toxicokinetic parameters 7

Toxicokinetic parameters:

AUC: MMT male: 51.8±10.9mM·h

Toxicokinetic parameters 8

Toxicokinetic parameters:

AUC: MMT female: 93.1±30.7mM·h

Toxicokinetic parameters 9

Toxicokinetic parameters:

AUC: MMT combined: 72.5±30.7mM·h

Toxicokinetic parameters 10

Toxicokinetic parameters:

Tmax: Oral dose MnCl2: 0.25±0.21 h

Toxicokinetic parameters 11

Toxicokinetic parameters:

Cmax: Oral dose MnCl2: 0.30±0.11µg/mL

Toxicokinetic parameters 12

Toxicokinetic parameters:

AUC: Oral dose: MnCl2 1.95±0.51 mM·h

Toxicokinetic parameters 13

Toxicokinetic parameters:

AUC: iv dose MnCl2: 14.8±3.60 mM·h

Any other information on results incl. tables

Upon iv administration of MnCl2, manganese rapidly disappeared from blood with a terminal elimination t1/2 of 1.83 h and CL8 of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.9e(-424t) + 2.1e(-0.44t). Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax = 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT resulted in a delayed Tmax (7.6 h), elevated Cmax (0.93 microg/mL), and prolonged terminal t1/2 (55.1 h). The rats receiving MMT had an apparent clearance (CL/F = 0.09 L/h x kg) about 37-fold less than did those who were dosed with MnCl2. Accordingly, the area under the plasma concentration-time curves (AUC) of manganese in MMT-treated rats was about 37-fold greater than that in MnCl2-treated rats. A gender-dependent difference in toxicokinetic profiles of plasma manganese was also observed. Female rats displayed a greater AUC than that of male rats. Although the apparent volume of distribution of manganese was similar in both sexes, the apparent clearance in males was about twice that observed in females.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results
The results indicated that after oral administration, the MMT-derived manganese displayed higher and more prolonged plasma concentration-time profiles than MnCl2-derived manganese. Thus, MMT-derived manganese appeared likely to accumulate in the body following repeated exposure.