Resin acids and Rosin acids, manganese salts

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: Well performed and described study, but due to the space limitations in publications, no individual animal data is given.

Justification for type of information:

No data on toxicokinetics is available for Resin acids and rosin acids, manganese salts. After being systemically absorbed, Resin acids and rosin acids, manganese salts would most likely dissociate into free Mn and resin acids and rosin acids. Therefore, available supportive data on the toxicokinetics of manganese salts is provided to supplement information available on the toxicokinetics of resin acids and rosin acids already included in the category endpoint summary for the Category 'Rosins and their salts.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference Type:

publication

Title:

Influence of Particle Solubility on the Delivery of Inhaled Manganese to the Rat Brain: Manganese Sulfate and Manganese Tetroxide Pharmacokinetics Following Repeated (14-Day) Exposure

Author:

Dorman DC, Struve M, Arden J, Marshall MW, Parkinson CU and Wong Ba

Year:

2001

Bibliographic source:

Toxicology and Applied Pharmacology 170, 79–87 (2001)

Materials and methods

Objective of study:

absorption

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

14-day inhalation exposure, followed by investigation of distribution and elimination kinetics

GLP compliance:

no

Test material

Test material information

Constituent 1

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): Manganese(II)sulfate monohydrate
- Physical state: solid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling): 0.1mCi/mg (applied as MnCl2 tracer)
- Locations of the label (if radiolabelling): Mn
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: stable
- Storage condition of test material: in 0.5M hydrochloric acid, to prevent air oxidation to Mn3+
- Other: [54Mn]-MnCl2 was supplied from NEN Life Science Products (Boston, MA, USA)

Specific details on test material used for the study:

- Name of test material (as cited in study report): Manganese(II)sulfate monohydrate
- Physical state: solid- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling): 0.1mCi/mg (applied as MnCl2 tracer)
- Locations of the label (if radiolabelling): Mn
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: stable
- Storage condition of test material: in 0.5M hydrochloric acid, to prevent air oxidation to Mn3+
- Other: [54Mn]-MnCl2 was supplied from NEN Life Science Products (Boston, MA, USA)

Radiolabelling:

yes

Remarks:

54Mn

Test animals

Species:

rat

Strain:

other: Crl:CD (DS)Br

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc (Raleigh, NC, USA)
- Age at study initiation: 8 weeks
- Weight at study initiation: no data
- Fasting period before study: none
- Housing: individual cages
- Individual metabolism cages: yes/no
- Diet: ad libitum (endogenous Mn content: 100-150 ppm)
- Water: ad libitum (reverse osmosis purified)
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.5 - 21.5°C
- Humidity (%):40-60%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body
GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Rats were exposed in stainless-steel wire cage units contained within eight Hazelton 1-m3 stainless-steel and glass inhalation exposure chambers (Lab Products, Maywood, NJ). Each 1-m3 exposure chamber was contained within an 8-m3 Hinners-style stainless-steel and glass inhalation exposure chamber. Prior to animals being placed in the 1-m3 chambers, each chamber was checked for uniformity of distribution of the test compound aerosols by measuring its concentration at nine positions within the chamber. Animal positions within the 1-m3 exposure chambers were rotated once during the experiment to minimize experimental error due to any undetected differences in the environment or the manganese aerosol concentration
- Method of holding animals in test chamber:
- Source and rate of air: HEPA-filtered air, 200–250 L/min to provide 12–15 air changes per hour
- Method of conditioning air:
- System of generating particulates/aerosols: Wright Dust Feeder with an air delivery pressure of 25 psi. A Trost Airjet Mill (Garlock Corp., Newton, PA) was also required to generate the MnSO4 aerosol).
- Method of particle size determination: The particle size distribution was measured with a time-of-flight aerosol spectrometer (TSI APS Model 3320) and a microorifice uniform deposit cascade impactor (MOUDI, MSP Corp., Minneapolis, MN).


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: no data
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.5–2 mm with a geometric standard deviation of less than 2

Duration and frequency of treatment / exposure:

6h daily for 2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0.092, 0.92, and 9.2 mg MnSO4/m3 (corresponding to 0.03, 0.3, and 3 mg Mn/m3)

No. of animals per sex per dose / concentration:

12

Control animals:

yes

Details on dosing and sampling:

One-half of the rats from each exposure group (6 rats/concentration/chemical) were used to determine tissue manganese concentrations.
Bile was collected perimortem immediately after the last inhalation exposure and following an overnight fast.

Manganese concentrations in serum, bile, left olfactory bulb, left striatum, left cerebellum, left lung, left median lobe of the liver, proximal portion of the left femur, and left testis were determined by neutron activation analysis at the North Carolina State University Nuclear Energy Services.

Immediately after the last inhalation exposure, the remaining rats from each exposure group (6 rats/concentration/chemical) were anesthetized with air containing 5% CO2 and given 0.5 mCi of 54MnCl2 (in sterile saline) by tail-vein injection (0.4 ml injection volume). Whole-body gamma spectrometry was performed immediately after injection and at 1, 2, 4, 6, 9, and 12 weeks after 54Mn tracer administration. An integrated spectrometry system consisting of a multichannel analyzer with two perpendicular 10.2-cm diameter sodium iodide scintillation detectors, preamplifier, amplifier, and high-voltage power supply (Nuclear Data, Inc., Schaumburg, IL) was used to determine total radioactivity (54Mn) in the animal’s body. The animals were placed in plastic restraint tubes during whole-body gamma spectrometry (live time ,2 min).

Statistics:

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, and Dunnett’s multiple comparison procedure for significant ANOVA. A Tukey’s honestly significant difference test was used to perform pairwise multiple comparisons. Statistical analyses were performed using SAS Statistical Software. A probability value of 0.01 was used for Levene’s test, while < 0.05 was used as the critical level of significance for all other statistical tests. Unless otherwise noted, data presented are mean values 6 ± SEM.

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

Initial phase elimination half life: 3.8 ± 0.32 days (control), 2.8 ± 0.71 days (0.03 mgMn/m3), 3.8 ±0.46 days (0.3 mg Mn/m3) and 2.4 ±0.24 days (3 mg Mn/m3)

Main ADME results 2

Type:

excretion

Results:

Final phase elimination half life: 31.8 ±3.3 days (control), 25.3 ± 2.9 days (0.03 mgMn/m3), 32.3 ± 3.9 days (0.3 mg Mn/m3) and 27.1 ± 1.4 days (3 mg Mn/m3)

Main ADME results 3

Type:

distribution

Results:

At 3 mg Mn/m3 air after 14 days, Mn concentration was increased threefold in femur and bile and less than threefold in testes and liver. Increase in lung was 16fold.

Main ADME results 4

Type:

distribution

Results:

Striatal Mn concentration was increased ca 6 fold at 3 mg/m3 air, it was not increased at the lower concentrations.

Main ADME results 5

Type:

distribution

Results:

Olfactory bulb concentrations were increased ca 2 fold at 0.3 mg/m3 air and ca 5fold at 3 mg/m3 air. Relative regional concentrations were olfactory bulb > striatum> cerebellum.