Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: review
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Review of literature data

Data source

Reference
Reference Type:
review article or handbook
Title:
DRAFT TOXICOLOGICAL PROFILE FOR MANGANESE
Author:
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Year:
2008
Bibliographic source:
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Literature review
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The ATSDR document reviews and summarises the available data on the toxicokinetics of manganese compounds, including permanganate.

Potassium permanganate has been used as a surrogate for sodium permanganate where data are not available. Read-across from potassium permanganate to sodium permanganate is appropriate from the toxicological point of view as the most toxicologically relevant part of the substances is the same (permanganate). The contribution of the sodium/potassium ions to the toxicity of the respective substances is likely to be minimal. The toxicity of both substances is therefore likely to be very similar and will be dominated by local (site of contact) irritant/corrosive effects and systemic toxicity due to the absorption of manganese ions. This toxicophore similarity is adequate justification for waiving the conduct of specific studies with sodium permanganate and the dossier reflects this waiving proposal by including summaries of read-across studies where appropriate.
Radiolabelling:
no

Test animals

Species:
other: various
Details on test animals and environmental conditions:
Not provided

Administration / exposure

Route of administration:
other: various

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Manganese is required by the body and is found in virtually all diets. Adults consume between 0.7 and 10.9 mg of manganese per day in the diet, with higher intakes for vegetarians who may consume a larger proportion of manganese-rich nuts, grains, and legumes than non-vegetarians. Manganese intake from drinking water is substantially lower than intake from food. Exposure to manganese from air is considered negligible as compared to intake from diet, although persons in certain occupations may be exposed to much higher levels than the general public. Even though daily dietary intake of manganese can vary substantially, adult humans generally maintain stable tissue levels of manganese through the regulation of gastrointestinal absorption and hepatobiliary excretion. Following inhalation exposure, manganese can be transported into olfactory or trigeminal presynaptic nerve endings in the nasal mucosa with subsequent delivery to the brain, across pulmonary epithelial linings into blood or lymph fluids, or across gastrointestinal epithelial linings into blood after mucociliary elevator clearance from the respiratory tract
Details on distribution in tissues:
Manganese is found in the brain and all other mammalian tissues, with some tissues showing higher accumulations of manganese than others. For example, liver, pancreas, and kidney usually have higher manganese concentrations than other tissues.
Details on excretion:
The principal route of elimination of manganese from the body is fecal elimination via hepatobiliary excretion; contributions from pancreatic, urinary, and lactational elimination are expected to be small. Excess manganese is expected to be eliminated from the body rapidly. For example, following the intravenous bolus injection of manganese chloride in rats, manganese concentrations in plasma return to normal levels within 12 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Follwoing oral exposure, it is likely that permanganate is converted to Mn (II) in the acidic conditions of the stomach.

Any other information on results incl. tables

Absorption

Following inhalation exposure, absorption from the lung is predicted as sodium permanganate is soluble. Studies with manganese salts have shown that absorption can occur via the trigeminal and olfactory nerves. Absorption from the gastrointestinal tract is variable but low (3 -5%) and is influenced by iron status and age. One of the key determinants of absorption appears to be dietary iron intake, with low iron levels leading to increased manganese absorption. Studies of oral absorption of manganese in animals have yielded results that are generally similar to those in humans. Dermal absorption is likely to be extremely limited, excpet in cases where exposure to corrosive forms such as permanganate disrupts the integrity of the skin barrier. Therefore in accidental exposure involving skin burns, dermal absorption may be significanlt greater.

Distribution

Manganese is a normal component of human and animal tissues and fluids. In humans, most tissue concentrations range between 0.1 and 1 μg manganese/g wet weight with the highest levels in the liver, pancreas, and kidney and the lowest levels in bone and fat. Inhaled manganese may be transported directly to the brain via the trigeminal and olfactory nerves.

Metabolism

Sodium permanganate is not metabolised per se, however it is predicted that it will react to form manganese salts in a physiological environment.

Excretion

In humans, absorbed manganese is removed from the blood by the liver where it conjugates with bile and is excreted into the intestine. Biliary secretion is the main pathway by which manganese reaches the intestines where most of the element is excreted in the faeces. However, some of the manganese in the intestine is reabsorbed through enterohepatic circulation. Small amounts of manganese can also be found in urine, sweat, and milk.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The toxicokinetic properties of various forms of manganese are well characterised and are relevant to sodium permanganate.
Executive summary:

The ATSDR document reviews and summarises the available data on the toxicokinetics of manganese compounds, including permanganate. Absorption is likely to be significant from the respiratory tract, low from the gastrointestinal tract and negligible through the skin. Manganese is an essential element and is well distributed in the body, however there is evidence that inhaled forms may distribute directly to the brain via the olfactory and trigeminal nerves. Excretion is primarily in the bile.