Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
neurotoxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Most sensitive endpoint:
neurotoxicity
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Additional information - workers

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.

Toxicokinetics

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 (ATSDR, 2008).

Acute toxicity

The acute dermal LD50 of the read-across substance potassium permanganate is reported to be >2000 mg/kg bw (Dvorakova, 2006). Waiving of study requirements are proposed for acute oral and inhalation toxicity for sdium permanganate, as the substance is considered likely to be corrosive, based on read-across from study data presented for potassium permanganate. The acute effects of exposure to the substance are likely to be dominated by local effects; additional testing is therefore not appropriate on scientific grounds and for reasons of animal welfare. No classification is proposed for acute toxicity.

Irritation

Classification as corrosive (R34) is considered to be appropriate, based on the results of a study with the closely-related read-across substance potassium permanganate. No study of eye irritation is available and none has been performed as the substance is considered to be corrosive.

Sensitisation

No study of skin sensitisation is available. Based on read-across from the closely-related substance potassium permanganate, the substance is considered to be corrosive. Testing for skin sensitisation is not justified on scientific grounds or for reasons of animal welfare. The local effects of dermal exposure to the substance will be dominated by irritation/corrosion and sensitisation is considered to be unlikely. In addition, it is noted that potassium permangante in dilute solution is used for the treatment and prevention of skin infections and no reports of sensitisation have been identified. There is no evidence that permanganate can cause occupational asthma. No classification is therefore proposed for sensitisation.

Repeated dose toxicity

In a 28 -day study (Plodikova, 2006), groups of rats were gavaged with potassium permanganate at dose levels of 0, 40, 100 or 250 mg/kg bw/d for 28 days. There were no deaths and no signs of toxicity. FOB revealed mminor behavioural changes at teh top dose level. Bodyweight, weight gain, food consumption, food conversion and water conumption were reduced at 250 mg/kg bw/d. Haematology revealed effects on white blood cell counts at 250 mg/kg bw/d; clinical chemistry parameters and urinalysis were also affected in this group. Organ weight changes were noted in all treated groups but are not considered to be clearly related to treatment as they may be secondary to bodyweight effects and were without andy pathological correlates. Pathology showed that effects were limited to the stomach, with local irrittation at 250 mg/kg bw/d and to a lesser extent at 100 mg/kg bw/d. No additional target organs were identified. A NOAEL of 40 mg/kg bw/d can be identified for this study, however it is noted that the effects at this dose level (gastric irritation) are not of relevance to the human risk assessment.

The substance is considered to be corrosive, therefore inhalation exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the inhalation route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Genetic toxicity

No evidence of mutagenicity was seen in a guideline-compliant Ames test with the read-across substance potassium permanagate (Taublova, 2006). No evidence of clastogenicity was seen in a guideline-compliant rat bone marrow micronucleus assay with potassium permangate (Plodikova, 2006).

Carcinogenicity

High quality NTP studies are available for the read-across substance, manganese (II) sulphate. The substance, sodium permanganate is a strong oxidising agent and will react with organic molecules and in the conditions of the stomach and following contact with skin to produce Mn (II). Read-across is therefore appropriate and justified.

There was no evidence of carcinogenic activity (according to the NTP Levels of Evidence of Carcinogenic Activity) of manganese (II) sulfate monohydrate in male or female rats.

There was equivocal evidence of carcinogenic activity (according to the NTP Levels of Evidence of Carcinogenic Activity) of manganese (II) sulfate monohydrate in male and female mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia.

Reproductive and developmental toxicity

Effects on fertility were seen at the highest dose level of 320 mg/kg bw/d in a one-generation reproductive toxicity study with potassium permanganate (Plodikova, 2008). A reduction in litter number was associated with parental toxicity, including histopathological effects on the reproductive organs of both sexes. Litter size and pup survival was unaffected by treatment, however eye opening was delayed at 320 mg/kg bw/d and histopathology revealed effects on the brain in pups of all treated groups.

Neurotoxicity

There is a substantial literature on the effects of manganese on the human nervous system. High exposures can result in severe neurotoxic signs and symptoms, some of which resembie those of idiopathic Parkinson's disease. This syndrome, which may also include psychiatric manifestations, has become known as 'manganism'. Manganese mainly induces damage to the globus pallidus (particularly the internal segment) with changes to the substantia nigra pars compacta and the absence of Lewy bodies. This contrasts with what is seen in Parkinson's disease, in which there is preferential degeneration of dopamine neurons in the substantia nigra pars compacta coupled with Lewy bodies and preservation of the pallidum. Overt manganism has been described in a number of early papers that reported studies on neurological signs and symptoms in workers with relatively high and long-term occupational exposures. More recently, several studies on lower occupational exposures to manganese have reported less severe, subtle, non-clinical neurofunctional effects. These subtle effects usually consist of deterioration in motor function and co-ordination and, as such, may constitute manganese-induced changes in the same area of the brain as manganism, that is the basal ganglia and, in particular, the globus pallidus.

A review of the neurological effects of inorganic manganese is beyond the scope of this IUCLID dossier. Nevertheless, it is considered likely that the substance sodium permanganate may cause similar neurotoxicity to other manganese compounds and this is therefore considered in the DNEL derivation.

DNEL derivation

The critical local (dermal, respiratory tract) effects of exposure to sodium permanganate will be irritation / corrosion at the site of contact due to the corrosive nature of the substance. These effects must be managed by the use of PPE and / or engineering controls to eliminate the potential for dermal exposure to high concentrations of the substance. Local irritation may not occur following dermal or inhalation exposure to low concentrations of the substance, however this cannot be quantified and therefore DNEL values for local effects are not proposed.

The critical effect of exposure to the substance, based on extensive data from other manganese compounds, is assumed to be neurotoxicity. Neurotoxicity has not been specifically investigated for the substance, however it is assumed that will occur by analogy with other inorganic manganese compounds. While the majority of effects in the studies with the substance are consistent with local irritation, findings from the reproduction range-finding study indicate neurological effects in offspring. It is therefore concluded that neurotoxicity is the critical effect relevant to the derivation of systemic DNEL values.

The SCOEL (SCOEL/SUM/127 December 2009) has recently published a consultation on the derivation of IOEL values for manganese and inorganic manganese compounds. This consideration is based on a comprehensive review of the extensive database for this group of substances which is beyond the scope of this IUCLID dossier.

The SCOEL conclude that, although manganism has long been recognised as being associated with high occupational manganese exposures, recent attention has focused on more subtle neurofunctional effects that may occur at lower levels of exposure. A recent review of the evidence, supported by additional studies published subsequently led to the conciusion that, in humans, the critical effects associated with contemporary (low) occupational exposure to manganese are neurological. These subtle neurological effects, that is, principally small sub-clinical neuromotor effects, are considered to be of sufficient concern to warrant the establishment of an

appropriate occupational exposure standard. A limited number of longitudinal investigations on these more subtle effects indicate a stability (lack of progression) of adverse effects when exposure is reduced, but also indicate that such effects, once established, may not be reversible. Furthermore, most of the neurofunctional effects observed reflect changes in neuromotor function, as is the case with overt manganism. There are a sufficient number of well-conducted studies on workers exposed to known or reasonably well-estimated amounts of manganese to use human data for the derivation of a health-based Indicative Occupational Exposure Limit Value (IOELV). SCOEL highlighted that it was not possible to identify a single critical study as the best basis for DNEL derivation, but used a global approach based on the entire dataset.

A respirable IOELV of 0.05 mg/m3 was recommended, and a reasonable inhalable IOELV of 0.2 mg/m3 was also recommended. While recommending these values, SCOEL recognised that the overall systemic absorption of coarser particles (> respirable) is probably substantially lower than for the respirable fraction. Thus, SCOEL recommended both a respirable and an inhalable IOELV which would need to be observed conjointly. It was recommended that workplaces should, as a default procedure, measure both respirable and inhalable manganese to ensure compliance with both limits. This will protect workers exposed to respirable manganese, such as welders, and also workers exposed to inhalable manganese in workplaces with low fractions of respirable manganese, likley the case for sodium permanganate. In each specific working circumstance, professional judgement should however, be applied to select the most appropriate fraction to be measured. It was considered that a STEL was not required. Dermal absorption of manganese is likely to be negligible (and exposure limited due to corrosivity), therefore systemic dermal DNEL values are not proposed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.025 mg/m³
Most sensitive endpoint:
neurotoxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.025 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Most sensitive endpoint:
neurotoxicity
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
Most sensitive endpoint:
neurotoxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
DNEL related information
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

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.

Inhalation DNEL values for the general population are proposed at the same level as for workers (corrected for 24 hour exposure and breathing rate). Oral DNEL value is proposed for the general population assuming 10% oral absorption of manganese and 60 kg bodyweight (0.05 mg/m3 is equivalent to 0.5 mg; 0.08 mg/kg bw/d).

DNEL values for local effects are not proposed as the critical local effects (irritation / corrosion) cannot be quantified. A dermal systemic DNEL value is not proposed as dermal absorption is likely to be negligible.