Manganese sulphide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

See the read-across report attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Toxicokinetic parameters:

Tmax: MMT male: 5.50±4.43 h

Toxicokinetic parameters:

Tmax: MMT female: 10.0±2.31 h

Toxicokinetic parameters:

Tmax: MMT combined: 7.75±4.06 h

Toxicokinetic parameters:

Cmax: MMT male: 0.79±0.36 µg/mL

Toxicokinetic parameters:

Cmax: MMT female: 1.07±0.46 µg/mL

Toxicokinetic parameters:

Cmax: MMT combined: 0.93±0.41 µg/mL

Toxicokinetic parameters:

AUC: MMT male: 51.8±10.9 mM/h

Toxicokinetic parameters:

AUC: MMT female: 93.1±30.7 mM/h

Toxicokinetic parameters:

AUC: MMT combined: 72.5±30.7 mM/h

Toxicokinetic parameters:

Tmax: Oral dose MnCl2: 0.25±0.21 h

Toxicokinetic parameters:

Cmax: Oral dose MnCL2: 0.30±0.11 µg/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

Reference 2

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.

Objective of study:

toxicokinetics

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

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

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.

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.

Toxicokinetic parameters:

Tmax: MMT male: 5.50±4.43h

Toxicokinetic parameters:

Tmax: MMT female: 10.0±2.31h

Toxicokinetic parameters:

Tmax: MMT combined: 7.75±4.06h

Toxicokinetic parameters:

Cmax: MMT male: 0.79±0.36µg/mL

Toxicokinetic parameters:

Cmax: MMT female: 1.07±0.46µg/mL

Toxicokinetic parameters:

Cmax: MMT combined: 0.93±0.41µg/mL

Toxicokinetic parameters:

AUC: MMT male: 51.8±10.9mM·h

Toxicokinetic parameters:

AUC: MMT female: 93.1±30.7mM·h

Toxicokinetic parameters:

AUC: MMT combined: 72.5±30.7mM·h

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

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.

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.

Additional information

 

 

 

TOXICOKINETIC ASSESSMENT

 

TOXICOKINETIC ASSESSMENT 

  

TEST MATERIAL: Manganese Sulphide (MnS); (EC Number 242-599-3, CAS Number 18820-29-6)

 

The test material, manganese sulphide, is a dark green powder commonly used as a machinability enhancing additive in powder metallurgy applications. Particle size analysis of the test material has shown that it has a relatively small particle size, with 95 % of the particles smaller than 11.36 µm diameter. 

 

   

Absorption 

 

The test material, manganese sulphide, has a low water solubility 3.89 x 10^-3 g/L of manganese in solution at 20.0 ^oC, which is equivalent to 6.16 x 10^-3 g/L of the test material in solution at 20.0 ^oC based on the manganese content of the test material (O'Connor and Woolley 2009). However, it has considerable solubility (55±3.3 %) in artificial gastric juice, a very similar level to manganese metal powder (Anderson 2009). As the oral absorption of even soluble manganese salts is still relatively low, typically less than 5 %, this means that manganese sulphide also has a relatively low potential for substantial oral absorption. Several factors influence the oral uptake of soluble manganese substances, primarily the body’s natural homeostatic regulation of manganese which includes iron status, dietary matrix, fasted status and existing body burden of manganese. The acute oral median lethal dose (LD50) of manganese sulphide in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Pooles 2009).

 

Manganese sulphide also has a low solubility (0.011 %) in artificial alveolar fluid based upon the extractable manganese (Anderson 2009). Since the test material particles were smaller than 100 µm diameter, the test material was subjected to an acute inhalation toxicity (nose only) study in the rat (Griffiths 2010). In order to facilitate aerosolisation and reduce particle size, the test material was ground using a centrifugal ball mill prior to use. A group of 10 rats were exposed to a mean atmosphere concentration of 5.34 mg/L test material with a mean mass median aerodynamic diameter of 2.49 µm and a prediction of 72 % of particles being less than 4 µm. The results concluded that the acute inhalation median lethal concentration (4 hr LC50) of manganese sulphide was greater than 5.34 mg/L in the rat. As such, although manganese sulphide has the potential to be inhaled due to its particle size distribution; it doesn’t exhibit acute inhalation toxicity at a high dose in the rat. Since the test material has a low solubility (0.011 %) in artificial alveolar fluid it is likely that most of the inhaled test material was not absorbed but instead was cleared from the lungs by the mucocilliary elevator into the gastrointestinal (GI) tract.

 

Results from in vitro tests indicate that the test material is considered to be an irritant to the reconstituted human epidermis model EPISKIN™ and also to the reconstituted human corneal epithelial model, SkinEthic. However, as the test material has a low solubility in water coupled with its physical inorganic nature (crystalline powder) means that in practice it is very unlikely to be absorbed through the skin.

 

In conclusion, due to a low water solubility, the test material is expected to have a low potential for any significant absorption by oral ingestion, inhalation or dermal absorption. With respect to absorption values to be used in risk and exposure assessments, those for the soluble manganese salt, manganese chloride, are adopted as a worst case, although the figure for inhalation absorption is adjusted downwards (absence of solubility in Anderson, 2009) to match oral absorption as a worst case (inhalation 5 %, oral 5 %, dermal 1 %).

 

 

Metabolism, Distribution and Excretion 

 

Since the test material has a low potential for absorption by any route it means that the test material will not be readily bioavailable. Repeat dose toxicity studies with manganese dichloride and manganese sulphate show that following absorption the test material is distributed throughout the body (Grieve, 2017; Dorman et al., 2006; Ali et al., 1983). The majority of any test material that is ingested orally is likely to pass through the gastrointestinal (GI) tract unchanged and be excreted in the faeces. Any small amount of manganese from the test material that is absorbed by the gut will enter the essential manganese pool along with that which is absorbed from the daily nutritional requirement of manganese. The circulating amount of manganese will be controlled by the normal homeostatic mechanism provided by the liver that controls the manganese balance. Any test material that is inhaled is likely to be cleared from the lungs by the mucocilliary elevator into the GI tract and again excreted unchanged in the faeces.

 

 

References 

 

Ali, M.M., Murthy, R.C., Saxena, D.K., Srivastava, R.S. and Chandra, S.V. (1983). Effect of low protein diet on manganese neurotoxicity: I. Developmental and biochemical changes. Neurobehavioural toxicology and teratology, 5: 377-383.

Anderson, K. A. (2009). Bioaccessibility of manganese from manganese Materials in Gastric and Lung (Alveolar) Biofluids, Oregon State University.

Dorman, D.C., Struve, M.F., Marshall, M.W., Parkinson, C.U., Arden James, R. and Wong, B.A. (2006). Tissue manganese concentrations in young male Rhesus monkeys following subchronic manganese sulphate inhalation. Toxicological Sciences. 92(1); 201-210.

Griffiths, D. R. (2010). MnS: Acute Inhalation Toxicity (Nose Only) Study in the Rat. H. L. Ltd, Harlan Laboratories Ltd.

Grieve, L. (2017) Two generation reproduction inhalation toxicity study of manganese dichloride in rats. Charles River Laboratories, Tranent, Edinburgh, EH33 2NE, UK.

O'Connor, B. and S. M. Woolley (2009). MnS (Hoganas): Determination of Water Solubility. H. L. Ltd., Harlan Laboratories Ltd.

Pooles, A. (2009). MnS: Acute Oral Toxicity in the Rat - Fixed Dose Method, Harlan Laboratories Ltd.