Manganese

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:

Restrictions - no claims that the study had been conducted and reported according to international accepted guidelines or in compliance with the principles of GLP. However, the study has been recently conducted and appears to contain a significant level of detail.

Data source

Reference

Reference Type:

publication

Title:

Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese.

Author:

Normandin L, Ann Beaupre L, Salehi F, St -Pierre A, Kennedy G, Mergler D, Butterworth RF, Philippe S and Zayed J

Year:

2004

Bibliographic source:

Neurotoxicology 25:433-441

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The purpose of this study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb, frontal parietal cortex, globus
pallidus, striatum and cerebellum) and other tissues (lung, liver, kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn species.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Manganese

EC Number:

231-105-1

EC Name:

Manganese

Cas Number:

7439-96-5

Molecular formula:

Mn

IUPAC Name:

manganese

Details on test material:

- Name of test material: Metallic manganese (Mn)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Sprague–Dawley CD (Crl:CD[SD] IGS BR)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (St. Constant, Quebec, Canada)
- Age at study initiation: aged between 34 and 38 days
- Weight at study initiation: weighing 125–150 g
- Housing: Rats were individually housed in a polycarbonate cage with stainless steel wire lids under constant conditions of temperature, humidity
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: Acclimatized for a week prior to initiation of the study


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

Administration / exposure

Route of administration:

inhalation: dust

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body


GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Inhalation exposure was conducted in two rectangular stainless steel chambers (131 cm long, 65 cm wide and 125 cm deep) with a total volume of 1 m3 each (Hazelton Systems Company Inc., Kalamazoo, Michigan).
- Method of holding animals in test chamber: Rats were housed individually in 15 cm (long) x 15 cm (wide) x 20 cm (deep) stainless steel wire mesh cages.
- Source and rate of air: Mn aerosol particles were supplied to the inhalation chamber using a Fluidized Bed Aerosol Generator (Model 3400 TSI Inc., St.-Paul, MN).
- Method of conditioning air: Air entering the chamber was filtered through a high efficiency particulate air (HEPA) filter. Before entering the chamber, Mn aerosol particles were delivered through a stainless steel AS ME pressure tank (Model 73, Mc Master-Carr, NJ) that allowed settling of larger Mn aerosol particles
- Method of particle size determination: Once every 2 weeks, air samples were collected using a six-stage Marple Personal cascade Impactor in order to establish the particle size.

Duration and frequency of treatment / exposure:

Rats were placed in the inhalation chamber 6 h per day, 5 days per week during 13 consecutive weeks.

Doses / concentrations

Remarks:

Doses / Concentrations:
A group was exposed to a target level of approximately 4000 mg/m3 of metallic Mn. A control group was used. Rodent pellet chow and tap water were available ad libitum except when the animals were in the exposure chambers. Manganese concentration in this diet was approximately 95 ppm while Mn concentration in drinking water was approximately 0.001 ppm.

No. of animals per sex per dose / concentration:

Animals were randomly divided into four groups of 15

Control animals:

yes, concurrent no treatment

Details on dosing and sampling:

PHARMACOKINETIC STUDY

- Tissues and body fluids sampled : All brains were removed and were hemisected in the sagittal plane. The right brain hemisphere, to be used for Mn analysis, was dissected into five regions: olfactory bulb, frontal parietal cortex, cerebellum, globus pallidus and striatum. During striatum and globus pallidus dissection, care was taken to avoid the white matter fibers of the internal capsule being blended into the sample. Also the lung, liver, testis, and kidney were also dissected for Mn analysis.

Body weights measured weekly.

Statistics:

All statistical analyses were performed using SPSS Statistical Software (Version 10.0.5). Various statistical tests, such as one-way ANOVA post hoc multiple comparison (Tukey; Bonferroni, Dunnett T3-Test and Tamhane T2) intra and inter categories, were used to compare data for locomotor activity and Mn concentration in all the organs and tissues. Homogeneity of variances for the exposed groups was tested with Levene’s test, and all statistical analyses were performed on untransformed data. A probability value of less than 0.05 (i.e. P < 0.05) was used as the critical level of significance within each statistical test.

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Mn Concentrations in the Inhalation Chamber   The Mn concentrations (mean ±S:D) in the air of the inhalation chamber for metallic Mn and the control group were 3750±846 and 0.30±0.02 mg/m^3respectively. Ninety percent of the metallic Mn particles in the inhalation chamber were smaller than 1.55mm.     Mn Tissue Concentrations   Exposure led to an increase in brain Mn concentrations (mean±S:D). With the exception of the frontal parietal cortex and the cerebellum of rats in metallic Mn exposure group, brain Mn concentrations were significantly higher compared to controls. Increased lung Mn concentrations were observed following inhalation exposure to metallic Mn. No increase in liver Mn concentrations were observed. The concentrations in the five brain regions were higher in the exposed rats.     In the table below the percentage increase of Mn in brain regions and tissues is detailed relative to the control group following 13 weeks of exposure   Region of Brain or Tissue Percentage Increase Metallic Mn Olfactory bulb NM Frontal parietal cortex 21 Globus pallidus 52 Striatum 76 Cerebellum 13 Lung 61 Liver 4 Kidney 2 Testis -3   NM: Not measured

Applicant's summary and conclusion

Conclusions:

Interpretation of results: Bioaccumulation potential cannot be judged based on study results
The results show that Mn metal can be distributed in the brain and other tissues in rat, as a result of inhalation of respirable particles.