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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is conducted according to an appropriate method, no mention of compliance with GLP.

Data source

Reference Type:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
An inhalation study was performed in rats over a period of 13-weeks. The aim of this investigation was to look at the the deposition of Mn in the brains of rats exposed.
Male rats were exposed by whole-body inhalation to doses of 0.01, 0.1 and 0.5 mg Mn/m3 for manganese sulphate and 0.1 mg Mn/m3 for Mn phosphate for 6 h/day, 5 days/week for 13 weeks. Nasal pathology, brain glial fibrillary acidic protein (GFAP) levels and brain Mn concentrations were assessed at the end of the exposure period and 45 days post-exposure.
GLP compliance:
not specified

Test material

Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): hureaulite
- Molecular formula (if other than submission substance): (Mn5(PO4)2[(PO3)(OH)]2•4H2O)
- Appearance: reddish-white fine crystalline powder
- Analytical purity: 37.7% manganese by weight
- Other: relatively insoluble in aqueous solutions

- Name of test material (as cited in study report): Manganese (II) sulfate monohydrate
- Molecular formula (if other than submission substance): (MnSO4.H2O)
- Appearance: pale pink, crystalline powder
- Analytical purity: 32% manganese by weight
- Other: relatively water-soluble

Test animals

other: Crl:CD(SD) BR
Details on test animals and environmental conditions:
This study was conducted under federal guidelines for the care and use of laboratory animals (National Research Council, 1996) and was approved by the CIIT Institutional Animal Care and Use Committee. Juvenile (6-wk-old) male Crl:CD(SD) BR rats were purchased from Charles River Laboratories, Inc. (Raleigh, NC). Pretest health screens performed on three rats confirmed the absence of selected mycoplasmal, bacterial, and viral pathogens, enteric parasites, and Syphacia sp. ova, or preexisting organ pathology. Assignment of animals to treatment groups was based on a weight randomization procedure. Animals were acclimated for approximately 30 days prior to the start of the inhalation exposure.

Animal Husbandry
Animal rooms and exposure chambers were maintained at daily temperatures of 22 ± 4◦C, relative humidity of 30–70%, and an airflow rate sufficient to provide 10–15 air changes per hour. Fluorescent lighting was controlled by automatic controls (lights on approximately 0700–1900). All animals were housed in CIIT’s animal facility, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International. Rats were individually housed in stainless steel cages with wire mesh floors or exposure cage rack units.
A pelleted, semipurified AIN-93G certified diet from Bio-Serv (Frenchtown, NJ) formulated to contain approximately 10 ppm manganese and 35 ppm iron was given throughout the study. Food was available to all animals ad libitum except during inhalation exposures. Reverse-osmosis-purified water was also available ad libitum. Detailed individual animal clinical examinations were conducted and recorded at least once weekly throughout the course of the study beginning at the start of the inhalation exposures. Body weights were measured and recorded within approximately 3 days of arrival, at least weekly throughout the study, and on the day of necropsy.

Administration / exposure

Route of administration:
unchanged (no vehicle)
Details on exposure:
Previouswork in our laboratory has shown that particle solubility is an important physicochemical property that influences manganese dosimetry, with greater brain delivery of manganese occurring following inhalation of MnSO4 when compared to the less soluble hureaulite form (Dorman et al., 2001). The present study therefore focused on MnSO4, with nominal MnSO4 exposure concentrations of 0.01, 0.1, and 0.5 mg Mn/m3 being used in this study. A single nominal hureaulite exposure concentration of 0.1 mg Mn/m3 was also used in order to confirm our previous results. Control groups were exposed to HEPA-filtered air only. Exposures were conducted for 6 h/day, 5 days/wk, for up to 13 wk (at least 65 exposure days). Rats were exposed
whole-body in stainless-steel wire cage units contained within five 8-m3 Hinners-style stainless steel and glass inhalation exposure chambers (Lab Products, Maywood, NJ). Prior to animals being placed in the 8-m3 chambers, each chamber was checked for uniformity of distribution of the manganese aerosols by measuring their concentrations at 9 positions within the chamber. Animal positions within the exposure chambers were rotated weekly during the experiment to minimize experimental error due to any undetected differences in the environment or the manganese aerosol concentration.
Exposure atmospheres were generated by aerosolizing MnSO4 or hureaulite using a dry powder generator (Wright dust feeder, model WDF-II, BGI, Inc., Waltham, MA). Separate generation systems were used for each target exposure concentration. The MnSO4 and hureaulite were packed in separate dry powder generator cups under a pressure of 1500–3000 or 200 psi, respectively. The hureaulite particles were carried from the dry powder generator through a single, 38-L mixing/ settling chamber. The MnSO4 particles were carried from the dry powder generator through two 38-L mixing/settling chambers. A 85Kr discharging unit was suspended in the primary mixing/settling chambers. Exposure atmosphere concentrations in each chamber were monitored continuously with calibrated optical particle sensors (real-time aerosol sensors, model RAM-S, MIE, Inc., Billerica, MA). The concentration in each 8-m3 chamber was recorded every 30 min during the exposure by a building automation system (Infinity, Andover Controls, Andover, MA). Weekly gravimetric filter samples were used to verify the optical particle sensor readings. Particle size distribution was measured weekly with an optical particle sizing spectrometer (aerodynamic particle sizer, model 3320, TSI, Inc., St. Paul, MN). Chamber oxygen content was monitored with an MDA oxygen sensor (model 3300, MDA Scientific, Lincolnshire, IL).
Duration and frequency of treatment / exposure:
Exposures were conducted for 6 h/day, 5 days/wk, for up to 13 wk (at least 65 exposure days).
Doses / concentrations
Doses / Concentrations:
Nominal MnSO4 exposure concentrations of 0.01, 0.1, and 0.5 mg Mn/m3
A single nominal hureaulite exposure concentration of 0.1 mg Mn/m3 was also used in order to confirm our previous results.
Control animals:
The data for quantitative, continuous variables were compared for the exposure and control groups by tests for homogeneity of variance (Levene’s test), analysis of variance (ANOVA), and Dunnett’s multiple comparison procedure for significant ANOVA. Nasal pathology data were analyzed using a Pearson chi-square test. Statistical analyses were performed using SAS statistical software. A probability value of .01 was used for Levene’s test, while <.05 was used as the critical level of significance for all other statistical tests. Data presented are mean values ± standard error of the mean (SEM).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO4 exposure to > or = 0.01, > or = 0.1, and 0.5 mg Mn/m3, respectively. Exposure to MnSO4 or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations.

Any other information on results incl. tables

Exposure to MnSO4 (0.5 mg Mn/m3) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation.

Applicant's summary and conclusion

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, it could not be confirmed that manganese inhalation would result in altered brain GFAP concentrations.