Potassium permanganate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Assessment from available information

Adequacy of study:

key study

Study period:

October 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific method and is described in sufficient detail.

Data source

Reference

Reference Type:

other: Final Report

Title:

Unnamed

Year:

2009

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

Potassium permanganate

EC Number:

231-760-3

EC Name:

Potassium permanganate

Cas Number:

7722-64-7

Molecular formula:

HMnO4.K

IUPAC Name:

potassium manganesoylolate

Details on test material:

- Name of test material (as cited in study report): Potassium permanganate
- Molecular formula (if other than submission substance): KMnO4
- Molecular weight (if other than submission substance): 158.03
- Batch No.: 69
- Substance type: technical product
- Physical state: solid crystals
- Analytical purity: 99.42 % wt.
- Impurities (identity and concentrations): Manganese dioxide ca 0.1 % wt.
- Appearance: dark violet-purple crystalline powder with bronze lustre
- pH: 1% solution-6.1

Results and discussion

Preliminary studies:

Based on avalable literature, there is no toxicokinetic data on the regitered substance, probably because of its corrosivity. However, data on its disintergration products report that in humans and animals, manganese is an essential nutrient that plays a role in bone mineralization, protein and energy metabolism, metabolic regulation, cellular protection from damaging free radical species, and formation of glycosaminoglycans. Manganese acts as both a constituent of metalloenzymes and an enzyme activator. Enzymes that contain manganese include arginase, pyruvate carboxylase, and manganese-superoxide dismutase (MnSOD). Manganese, in its activating capacity, can bind either to a substrate (such as adenosine triphosphate, ATP), or to a protein directly, thereby causing conformational changes. Manganese has been shown to activate numerous enzymes involved with either a catalytic or regulatory function (e.g., transferases, decarboxylases, hydrolases) (ATSDR, 2012).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption
Potassium permanganate, manganese dichloride and manganese sulphate are soluble in water. Water solubility of 799 g/L of solution at 20.0 °C is reported (O'Connor and Butler, 2009) for MnCl2. MnSO4 has a water solubility value in the range of 42.5 to 45.0 % w/w of solution at 20.0 °C (O'Connor and Woolley, 2009) and KMnO4 has a water solubility of 64 g/L at 20°C (CRC Handbook 86th Ed 2005-2006). As such, all three substances would be expected to be bioavailable after oral administration. The oral absorption of soluble manganese substances has been measured at 3-5% in humans (IEH, 2004). Gwaizda et al (2007) confirmed this after reviewing more than 100 publications on Mn and its inorganic compounds and concluded that while systemic bioavailability of inhaled Mn is essentially equivalent to that of intravenous injection (100%), systemic uptake of ingested inorganic Mn (e.g. chlorides and oxides) was not more than 3%. EFSA, (2013) also reported that after ingestion, the amount of manganese absorbed is variable, but is generally considered less than 10% (and typically between 3-5% in humans) in adults. The reduced bioavailability from ingested inorganic manganese has been attributed to regulation of intestinal uptake and hepatic elimination (IEH, 2004; SCOEL, 2011). Several factors influence the oral uptake of soluble manganese substances, primarily the body’s natural homeostatic regulation of manganese which balances iron status, dietary matrix, fasted status and existing body burden of manganese.

Details on distribution in tissues:

The majority (~95 %) of any soluble manganese salts that are ingested orally are likely to pass through the GI tract unchanged and be excreted in the faeces. When adult male rats were exposed to 0.5 % manganese as MnCl2 in their drinking water for 1, 4, or 6 weeks, the manganese concentrations in the blood, brain, liver and kidney, were highest after one week of exposure (Hietanen et al., 1981). The authors concluded that the results suggested an adaptation to manganese absorption during continuous exposure. The distribution of manganese in rats following repeated oral dosing of MnCl2 (75 mg Mn/kg/day) showed the highest accumulation of manganese in the femur and the brain (Missy et al., 2000), not surprising as manganese is essential for skeletal formation and brain function.


A 14-day (6 hours/day) repeat dose inhalation study of MnSO4 (MMAD 2.1 μm) at 3 mg Mn/m3 in rats lead to significant increases in manganese levels in many tissues including the femur, liver, bile, lung, testes, olfactory bulb and striatum (Dorman et al., 2001). In this study, the distribution of manganese following the inhalation of either MnSO4 or a less-soluble manganese substance, Mn3O4 was compared. Inhalation exposure to soluble forms of manganese resulted in higher brain manganese concentrations than those achieved following exposure to an insoluble form of manganese (this clearly supports the lack of need to further examine MnO2 exposure/toxicity and increases the read-across hypothesis that the MnCl2 reproductive studies/evaluation via inhalation is a worse-case analysis). Following a sub-chronic inhalation study with MnSO4 (MMAD 2.1 μm) in Rhesus monkeys, it was found that the tissue manganese concentrations depended upon the aerosol concentration, exposure duration, and tissues (Dorman et al., 2006). Monkeys exposed to MnSO4 at ≥0.06 mg Mn/m3 for 65 exposure days or to MnSO4 at 1.5 mg Mn/m3 for ≥15 exposure days developed increased manganese concentrations in the olfactory epithelium, olfactory bulb, olfactory cortex, globus pallidus, putamen, and cerebellum. The olfactory epithelium, olfactory bulb, globus pallidus, caudate, putamen, pituitary gland, and bile developed the greatest relative increase in manganese concentration following MnSO4 exposure. Tissue manganese concentrations returned to levels observed in the air-exposed animals by 90 days after the end of the sub-chronic MnSO4 exposure – an indication of reversibility upon lack of exposure.
It can be concluded from the toxicokinetic profile that MnCl2 has a potential for absorption by oral ingestion, as does MnSO4; MnSO4 has a low potential for toxicity via the oral route. The toxicokinectic profile for KMnO4 via this route is complicated to assess due to its corrosive nature. Hence to analyse via worse-case for oral toxicity, MnCl2 will produce worse-case results compared to MnSO4, meanwhile KMnO4 will produce mainly local effects.
Fine particle aerosols (MMAD ~2 μm) of MnCl2 and MnSO4 that are inhaled have the potential to be absorbed and widely distributed throughout the body, including the brain, where there has been considerable scientific focus investigating the potential of the neurotoxicity of manganese. Inhalation exposure of MnCl2 and MnSO4 is considered a worse-case exposure because of the absence of homeostatic control – systemic availability occurs rapidly. Meanwhile, the corrosivity effects of KMnO4 make this route of exposure difficult to examine/investigate.
Manganese crosses the placental barrier in man and in animals, accumulates in the foetus and crosses the blood-brain barrier four times as readily in newborn babies as in adults. It is secreted in the milk. The gastrointestinal absorption of manganese is significantly more effective in infant/children than in adults (up to 40%), it is not effectively eliminated from the body and even less effectively from the brain (MAK, 2012; ANSES, 2018). Thus, foetus/infant/children are expected to be particularly sensitive to manganese exposure. However, it is also essential in the skeletal development of the foetus hence its presence in breast will with or without external exposure.
Therefore, regarding reproductive and developmental toxicity, read-across from available MnCl2, studies to the other category members – MnSO4 and KMnO4, is justified based on the high-water solubility, 100% bioavailability via inhalation/greater absorption and the ultimate identical physiological fate all three category members share. The lack of evidence of effects in the reproductive and developmental studies discussed above coupled with the considerable conclusive evidence from studies in humans that inhalation to high levels of manganese compounds can lead to subclinical neurological effects, the Repro. 2 classification as agreed by the RAC, 2016 is plausible. The view on the quality of the human studies and the weight of evidence approach/conclusion will also align with the ATSDR, 2012 and the German MAK Commission 2012.

Transfer into organs

Transfer into organs 1

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Transfer into organs 2

Transfer type:

blood/placenta barrier

Observation:

slight transfer

Details on excretion:

In humans, absorbed manganese is removed from the blood by the liver where it is secreted in the bile and is excreted into the intestine and then in the faeces. The enterohepatic circulation plays an important role in the maintenance of the steady-state manganese concentrations in the body (ATSDR, 2012; MAK, 2012). Very little (round 1 % of dietary intake) is excreted in the urine (EFSA, 2013). Elimination of manganese from the body is reported to vary, with a half-life between 13 and 37 days (ATSDR, 2012).

A 14-day (6 hours/day) repeat dose inhalation study of MnSO4 (MMAD 2.1 μm) at 3 mg Mn/m3 in rats lead to significant increases in manganese levels in many tissues including the femur, liver, bile, lung, testes, olfactory bulb and striatum (Dorman et al., 2001). In this study, the distribution of manganese following the inhalation of either MnSO4 or a less-soluble manganese substance, Mn3O4 was compared. Inhalation exposure to soluble forms of manganese resulted in higher brain manganese concentrations than those achieved following exposure to an insoluble form of manganese (this clearly supports the lack of need to further examine MnO2 exposure/toxicity and increases the read-across hypothesis that the MnCl2 reproductive studies/evaluation via inhalation is a worse-case analysis). Following a sub-chronic inhalation study with MnSO4 (MMAD 2.1 μm) in Rhesus monkeys, it was found that the tissue manganese concentrations depended upon the aerosol concentration, exposure duration, and tissues (Dorman et al., 2006). Monkeys exposed to MnSO4 at ≥0.06 mg Mn/m3 for 65 exposure days or to MnSO4 at 1.5 mg Mn/m3 for ≥15 exposure days developed increased manganese concentrations in the olfactory epithelium, olfactory bulb, olfactory cortex, globus pallidus, putamen, and cerebellum. The olfactory epithelium, olfactory bulb, globus pallidus, caudate, putamen, pituitary gland, and bile developed the greatest relative increase in manganese concentration following MnSO4 exposure. Tissue manganese concentrations returned to levels observed in the air-exposed animals by 90 days after the end of the sub-chronic MnSO4 exposure – an indication of reversibility upon lack of exposure.
It can be concluded from the toxicokinetic profile that MnCl2 has a potential for absorption by oral ingestion, as does MnSO4; MnSO4 has a low potential for toxicity via the oral route. The toxicokinectic profile for KMnO4 via this route is complicated to assess due to its corrosive nature. Hence to analyse via worse-case for oral toxicity, MnCl2 will produce worse-case results compared to MnSO4, meanwhile KMnO4 will produce mainly local effects.

Fine particle aerosols (MMAD ~2 μm) of MnCl2 and MnSO4 that are inhaled have the potential to be absorbed and widely distributed throughout the body, including the brain, where there has been considerable scientific focus investigating the potential of the neurotoxicity of manganese. Inhalation exposure of MnCl2 and MnSO4 is considered a worse-case exposure because of the absence of homeostatic control – systemic availability occurs rapidly. Meanwhile, the corrosivity effects of KMnO4 make this route of exposure difficult to examine/investigate.

Manganese crosses the placental barrier in man and in animals, accumulates in the foetus and crosses the blood-brain barrier four times as readily in newborn babies as in adults. It is secreted in the milk. The gastrointestinal absorption of manganese is significantly more effective in infant/children than in adults (up to 40%), it is not effectively eliminated from the body and even less effectively from the brain (MAK, 2012; ANSES, 2018). Thus, foetus/infant/children are expected to be particularly sensitive to manganese exposure. However, it is also essential in the skeletal development of the foetus hence its presence in breast will with or without external exposure.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

well established from published lietrature:

K+
Mn4+
Mn7+
Mn2+

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

well established from literature - 100% bioaccessibility of Mn salts via inhalation and 3-5% via oral exposure with less than 1% via dermal exposure

Any other information on results incl. tables

TOXICOKINETIC EVALUATION

According to the experimental data

    The test substance, Potassium permanganate, was applied to laboratory animals (rat, rabbit, guinea-pig) during studies with different way of entry into organism (e.g. skin, stomach).

Acute toxicity studies

Result: The test substance in dose level 2000 mg/kg administered orally caused death of 2 animals from five.

-          LD50 of the test substance Potassium permanganate for female rats is higher than 2000 mg/kg of body weight

-          clinical signs of intoxication were observed in all six animal

 

Result: Nontoxic for rats after single dermal application of the test substance at the dose level 2000 mg/kg.

-          Potassium permanganate applied on the skin of rats at the dose level of 2000 mg/kg caused no death of animals

-          no clinical signs of intoxication were observed in animals

 

Result: Corrosive on the skin of rabbit.

-          full thickness destruction of skin tissue was observed after application of 0.5 g of the test substance

 

Result: the test substance is not a contact allergen.

Induction - intradermal injections:   1 % test substance in water for injections

Induction - topical application:        10 % test substance in vaseline

Challenge- topical application:       0.1 % test substance in vaseline

the test substance applied in doses mentioned above caused:

-          no allergic skin reactions

-          no other negative clinical symptoms throughout the experiment

 

 

Result:Non- mutagenic for rat, after administration to animals by stomach tube in single dose levels 300, 800 and 1500 mg/kg of body weight.

-          negative result in micronucleus test

-          no other negative clinical symptoms were observed throughout the experiment

 

 

Conclussion:The test substance, Potassium permanganate – CAS No.: 7722-64-7, was applied to laboratory animals (rat, rabbit, guinea pig) during acute studies with different way of entry into organism (oral – by stomach, dermal, skin).

    Single oral application of the test substance at the dose level 2000 mg/kg caused death of 2 rats (from 6 animals). The test substance applied to the stomach of the rat elicited clinical signs of intoxication (erected hair, anaemic cutis and anaemic mucous membrane, hunched posture, gasping, no feed consuming) that disappeared till the end of study. The substance applied on the skin of rabbit elicited corrosive effects at the site of application. The test substance did not cause a significant increase of count of immature erythrocytes with micronuclei in bone marrow after single oral administration.

 

Long-term toxicity study

Result:Potassium permanganate after 28-day oral application of the dose levels 40, 100 and 250 mg/kg/day caused:

-          decrease of growth increments, food consumption and food conversion

-          negative effect on red blood component: increased values of total erythrocytes, concentration of haemoglobin and haematocrit

-          negative effect on urinary tract: increased specific weight and pH of urine, decreased values of total protein and albumin in blood

-       Significant local effects on the gut

    

Result:The dermal administration of the test substance Potassium permanganate for a period of 28-day consecutive days at dose level 150 mg/kg/day produced:

-          no toxicologically significant changes

-          no major functional changes in any organ systems or severe organ dysfunction

-          no pathological changes

Potassium permanganate at dose level 300 and 600 mg/kg/day produced:

-          reversible changes of application area with histopathological findings (focal inflammation, erythrocytosis and hyperplasia of regional lymph nodes)

-          changes in differential leucocyte count

-          changes in biochemical parameters: changes of ions concentration(increased sodium concentration)

-          changed urinary parameters: decreased urine volume and increased pH of urine

 

 

Conclussion:The results of the 28-day subacute toxicity study with oral administration to the rats showed decrease of growth increments, food consumption and food conversion and showed the negative effect on haematological parameters and negative effect on urinary tract with severe local effects.

The results of the 28-day subacute toxicity study with dermal administration to the rats showed changes in differential leucocyte count, changes in biochemical parameters: changes of ions concentration(increased sodium concentration) and changed urinary parameters: decreased urine volume and increased pH of urine.

 

    

 

Reproduction and developmental toxicity study

Result:Administration of the test substance Potassium permanganate at the dose levels 20, 100 and 500 mg/kg/day in treated maternal animals caused in Prenatal Developmental Toxicity Study caused

-          decreased body weight of maternal animals

-          clinical changes (cachexia, anemia, cough or hoarse breath, secretion from nostrils and eyes, piloerrection, apathy)

-          pathologic changes in stomach and uterus

-          lower relative weight of pregnant uterus

-          reproductive parameters – increased number of aborted females, increase postimplantation losses

-          development of organism in uterus – markedly decreased average body weight of foetuses

-          increased incidence of skeletal variations (incomplete ossification of sternum or cervical vertebrae) in foetuses

 

Result:Administration of the test substance Potassium permanganateat in One-Generation Reproduction Toxicity Test mainly at the dose level 320 mg/kg of body weight (highest dose level) affected reproductive male organs and development of pups.

-          reproductive system of parental males: high incidence of affected males: damage of spermatogenesis, decreased weight of prostate gland, changes in testicular function

-          observation of pups: presence of macroscopic abnormalities – oedematous appearance of brain; significant increased absolute and relative weight of brain; the high incidence of vacuolisation of cell nuclei in cortex and hippocampus

-          observance of development: late opening of eyes

-          pathological changes of stomach and genital organs in pups: missing or reduced testis and epididymis, congested stomach mucosa and chyme with blood

-          reproduction parameters: lowered number of pregnant females, fertility index and conception index  decreased ability of the animals to achieve a pregnancy

 

Conclussion:

The test substance, Potassium permanganate – CAS No.: 7722-64-7 administered into the stomach to pregnant females - daily from the 5th to the 19th day of pregnancy in Prenatal Developmental Toxicity Study had negative influence on clinical status of maternal animals (hoarse breath or dyspnoe, cough, gibbous pose, anemia and atathy). Negative effect of the test substance on relative weight of pregnant uterus and increased number of aborted females was recorded. Average body weight of foetuses was markedly decreased and skeletal variations – incomplete ossification of sternum or cervical vertebrae were recorded.

The test substance, Potassium permanganate in One-Generation Reproduction Toxicity Test, showed the negative effect on reproductive male organs and development of pups. The test substance negative affected reproductive system of parental males - when it is applied orally. The test substance influenced spermatogenesis and testicular function. In pups, the test substance caused pathological changes of genital organs – missing or reduced testis and epididymis were recorded. In parental females lowered number of pregnant females were recorded. Lowered fertility index and conception index are indicative of decreased ability of the animals to achieve a pregnancy.

 

           According to results of development studies, the test substance Potassium permanganate had negative effect on development of foetuses. The test substance has negative effect on reproductive parameters of treated animals - the test substance influenced spermatogenesis and testicular function and caused increased number of aborts. Skeletal variations (incomplete ossification of sternum or cervical vertebrae) and pathological changes of genital organs in pups (missing or reduced testis and epididymis) were observed.

  However, all available reproductive and developmental studies on the registered substance are considered to be of low quality - reliability with significant restirction.

According to the results of literature data

No relevant toxicokinetic references.

 

According to the databases data

           

Result: After repeated oral administration, reproductive system is affected  

 

Conclusion: Potassium permanganate is powerful oxidizing agent and corrosive. Analysis its "real" absorption is impossible as it damanges, the skin, the gut and the lungs via local effects. Its toxicokinetic potential is better analysed via its metabolites/disnitergration products.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: See Conclusions
Systemic effects were described after single oral administration of the dose level 2000 mg/kg of body weight of Potassium permanganate (CAS No. 7722-64-7) to rats. Clinical signs of intoxication (erected hair, anaemic cutis and anaemic mucous membrane, hunched posture, gasping, no feed consuming) in all six animals and macroscopic changes (stomach – hyperaemia, acute catarrhal inflammation, small intestine - acute catarrhal inflammation, liver – dystrophia) were observed. So, results of acute oral toxicity studies showed, that the test substance penetrates from digestive system into the organism.
After single application to skin, negative effect of the test substance was also detected – the test substance caused full thickness destruction of skin tissue. So, the test substance is corrosive on the skin of rabbit.
After repeated application of the test substance, negative effect on blood parameters (increased values of total erythrocytes, concentration of haemoglobin and haematocrit) and on urine excretion system (decreased urine volume and increased pH of urine) in 28-day study confirmed that the test substance at the dose levels 40, 100 and 250 mg/kg/day is absorbed from digestive tract, enters the blood circulation and probably is eliminated by kidneys.


Results of reproduction toxicity study showed that the test substance when it is applied orally in the dose levels 20, 80 and 320 mg/kg of body weight enters the reproductive system of males and females.
The test substance caused damage of spermatogenesis, decreased weight of prostate gland and changes in testicular function of treated males. In pregnant females treated by the test substance, decreased ability to achieve a pregnancy was recorded.
The test substance probably penetrates through the blood into the uterus and there affects the development of pups - missing or reduced testis and epididymis and increased incidence of skeletal variations (incomplete ossification of sternum or cervical vertebrae) in foetuses were recorded.