Potassium methanolate

Endpoint summary

Description of key information

Potassium methanolate is classified as corrosive to the skin according to Annex VI of the CLP regulation (EC 1272/2008). No systemic effects are expected at non-irritant concentrations / dose levels after repeated exposure to potassium methanolate via any route. It is unlikely that exposure to potassium methanolate at non-irritant concentrations / dose levels would result in exposure to toxic doses of the hydrolysis/dissociation products, particularly methanol.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data are available on the repeated dose toxicity of potassium methanolate. Potassium methanolate is classified as corrosive to the skin according to Annex VI of the CLP regulation (EC 1272/2008). The abiotic hydrolysis of potassium methanolate with tissue water results in the formation of methanol and potassium hydroxide. The latter dissociate into the corresponding cations (K⁺) and anions (OH^-). For hazard assessment of potassium methanolate at potentially non-irritating concentrations / dose levels, information on the hydrolysis / dissociation products was taken into account.

The major health hazard (and the mode of action) of potassium hydroxide (CAS No. 1310-58-3) is local irritation and/or corrosion as potassium hydroxide is also classified as corrosive to the skin according to Annex VI of the CLP regulation (EC 1272/2008). At concentrations between 0.5 and 2%, it is classified as skin and eye irritant. As outlined below, repeated exposure to K⁺and OH^-ions at non-irritant concentrations is unlikely to produce systemic toxic effects by any route and under normal handling and use conditions (OECD, 2006). Therefore, hazard assessment mainly focused on the repeated dose toxicity of methanol (CAS No. 67-56-1).

 

Oral

Potassium hydroxide

Potassium hydroxide in aqueous solution is completely dissociated into the corresponding ions (K⁺and OH^-). Due to the neutralization of OH^-by gastric hydrochloric acid (HCl) and the quick and efficient blood pH regulation mechanisms (buffer capacity of extra cellular body fluids, respiratory and renal compensation mechanisms), alkalosis due to the OH^-ions after potassium methanolate oral dosage in non-irritating conditions is prevented (OECD, 2006). Therefore, any expected systemic toxicity of potassium hydroxide would be related to the K⁺ion and studies with potassium salts in which the anion does not contribute significantly to toxicity could be used for the assessment of potassium hydroxide as well.

From a two year dietary study in rats with potassium chloride, a NOAEL of > 955 mg K⁺/kg bw/day was derived (OECD, 2006; secondary source, therefore not included in Iuclid). This NOAEL corresponds to a potassium methanolate dose of 1709 mg/kg bw/day.

For potassium ions, NOAELs in humans of 46 and 56.6 mg/kg bw/day have been suggested from human studies with potassium chloride based on lowering effects on the systolic and diastolic blood pressure (OECD, 2006; secondary source, therefore not included in Iuclid). The human NOAEL would correspond to 82 and 101 mg potassium methanolate/kg bw/day. Given the corrosive properties of the substance, it is unlikely that humans would be exposed to such dose levels under normal use conditions. Consequently, under the same conditions, it is unlikely that repeated oral exposure to non-irritating concentrations of potassium methanolate results in systemic toxic effects.

 

Methanol

There are several reliable studies in different species available for the hydrolysis product methanol (please refer to the endpoint summary of methanol for details). For the lowest NOAEL of 500 mg/kg bw/day, the corresponding approximate dose of potassium methanolate is 1000 mg/kg bw/day, which is already in the acutely toxic dose range. Due to the corrosive nature of potassium methanolate, it is unlikely that oral exposure to potassium methanolate could result in an uptake of toxic doses of methanol. Consequently, it is unlikely that repeated oral exposure to non-irritating concentrations of potassium methanolate results in systemic toxic effects related to methanol.

 

Dermal

Exposure to non-irritant levels of potassium methanolate via the dermal route is not expected to lead to relevant uptake of the ionic degradation products potassium ions or hydroxide ions in amounts that would exceed the normal physiological levels (OECD, 2006).

When humans are dermally exposed to non-irritating concentrations of potassium hydroxide, the dermal uptake of potassium hydroxide is expected to be low under normal use and handling conditions due to the low absorption of water-soluble ions (ECHA: Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance, June 2017). Under these conditions, the uptake of OH^-via exposure to potassium hydroxide, is not expected to change the pH in the blood. Furthermore, the dermal uptake of potassium via exposure to the corresponding hydroxide is much less than the uptake of potassium via food (natural or as food additive) under these conditions (OECD, 2002 and 2006). Taken all these considerations into account, it is unlikely that repeated dermal exposure to non-irritating concentrations of potassium methanolate results in systemic toxic effects referring to the dermal uptake of potassium or hydroxide ions.

 

Methanol

There are no data available on the repeated dose toxicity of methanol by the dermal route. However, as described in the OECD SIDS of methanol (OECD, 2004), methanol is readily absorbed by inhalation, ingestion and dermal contact, and partitions rapidly and equally throughout the organism in relation to the water content of organs and tissues, regardless of its exposure route. The effects of methanol on the CNS and retina in humans only occur at doses at which formate accumulates due to a rate-limiting conversion to carbon dioxide. In primates, formate accumulation was observed at methanol doses greater than 500 mg/kg bw/day (OECD, 2004; Tephly and McMartin, 1984, as cited in NTP, 2003). This value corresponds to a potassium methanolate dose of more than 1000 mg/kg bw/day, which is already in the acutely toxic dose range. The methanol dose that saturates the folate pathway in humans is estimated to be 210 mg/kg bw/day (Kavet and Nauss, 1990, as cited in OECD, 2004), which corresponds to potassium methanolate doses of ca. 460 mg/kg bw/day. Repeated dermal exposure to such high potassium methanolate dose levels, is highly unlikely under normal handling and use conditions due to the corrosive properties of potassium methanolate. Consequently, it is unlikely that repeated dermal exposure to non-irritating concentrations of potassium methanolate results in systemic toxic effects related to methanol.

 

Inhalation

Exposure to non-irritant levels of potassium methanolate via the inhalation route is not expected to lead to relevant uptake of the ionic degradation products potassium ions or hydroxide ions in amounts that would exceed the normal physiological levels (OECD, 2006). As already mentioned, the health hazard of potassium methanolate is mainly restricted to local (irritating/corrosive) effects at the portal of entry. Potassium methanolate is not expected to be systemically available under normal handling and use conditions, and therefore systemic effects of potassium or hydroxide ions after repeated inhalation exposure to non-irritating concentrations are not expected to occur.

Regarding local effects after inhalation exposure supporting information are available for sodium hydroxide (CAS No. 1310-73-2), which is the hydrolysis product of the structurally related sodium methanolate (CAS No. 124-41-4). Like potassium methanolate, sodium methanolate reacts violently with tissue water. This results in the formation of similar hydrolysis products, methanol and sodium hydroxide. The latter dissociates into the corresponding cations (Na⁺) and anions (OH^-). Due to the structural similarities of potassium and sodium methanolate, they both were assessed together by OECD (2006). A sodium hydroxide concentration of 1.0 mg/m³ was considered a NOAEC for local effects on the respiratory tract (Fritschi et al., 2001). 1 mg/m³ sodium hydroxide corresponds to an approximate potassium methanolate concentration of 1.25 mg/m³.

 

Methanol

Also for the inhalation route there are several reliable studies in different species available for the hydrolysis product methanol (please refer to the endpoint summary of methanol for details). The results of the studies in different species (rodents, monkeys) demonstrated a 100-fold greater susceptibility for methanol-related effects due to differences in metabolism of methanol. In rodents methanol is metabolised to carbon dioxide to a great extent, whereas in primates formate accumulation is responsible for the observed effects. Formate accumulation in primates has been observed at methanol doses greater than 500 mg/kg bw/day (OECD, 2004; Tephly and McMartin, 1984, as cited in NTP, 2003). The corresponding dose level for potassium methanolate that would lead to accumulation of formate in primates would be ca. 1000 mg/kg bw/day. Such dose levels are already in the acutely toxic dose range. Due to the corrosive nature of potassium methanolate it is unlikely that repeated inhalation exposure to potassium methanolate could result in an uptake of toxic doses of methanol.

 

Human data

Methanol

Please refer to the endpoint summary of methanol for details on human data.

In the European Union, the occupational exposure limit for methanol is 260 mg/m³ (200 ppm) as an 8 hour TWA. In the US, the limit is 200 ppm as an 8 hour TWA and 250 ppm as a STEL. It has been assumed that an inhalation exposure to methanol of 260 mg/m³ for 8 hours does not lead to any adverse effects (IPCS/WHO, 1997; Kavet and Nauss, 1990; NTP, 2003; OECD, 2004). This exposure level corresponds to a systemic dose of 2600 mg methanol/day (assuming an inhalation volume of 10 m³ during an 8-hour working day) or 37 mg/kg bw day (for a 70 kg human). It would require doses of ca. 81 mg/kg bw/day of potassium methanolate to achieve a systemic dose of 2600 mg methanol/day. Conversely, this would require an 8-hour exposure to approximately 570 mg/m³ of potassium methanolate. Given the corrosive properties of potassium methanolate, inhalation exposure to such concentration levels is highly unlikely. Thus, it is unlikely that repeated inhalation exposure to non-irritating concentrations of potassium methanolate results in methanol-related systemic toxic effects.

 

Conclusion:

Potassium methanolate is classified as corrosive to the skin according to Annex VI of the CLP regulation (EC 1272/2008). No systemic effects are expected at non-irritant concentrations / dose levels after repeated exposure to potassium methanolate via any route. It is unlikely that exposure to potassium methanolate at non-irritant concentrations / dose levels would result in exposure to toxic doses of the hydrolysis / dissociation products, in particularly methanol.

 

References not included in IUCLID:

OECD SIDS Initial Assessment Report for SIAM 22 (2006): Category of Methanolates: Sodium Methanolate, Potassium Methanolate (CAS No: Sodium Methanolate: 124-41-4; Potassium Methanolate: 865-33-8).

OECD SIDS Initial Assessment Report for SIAM 13 (2002): Potassium Hydroxide (CAS No: 1310-58-3).

OECD SIDS Initial Assessment Report for SIAM 19 (2004): Methanol (CAS No: 67-56-1).

Justification for classification or non-classification

The health hazard of potassium methanolate is dominated by its corrosive properties.The abiotic hydrolysis of potassium methanolate with tissue water results in the formation of potasium ions, hydroxide ions and methanol. At non-irritant concentrations, repeated exposure to potassium methanolate via any route will not result in exposure to toxic doses of any of its hydrolysis/dissociation products, in particular methanol. Therefore, the available information on the repeated dose toxicicty of potassium methanolate is conclusive but not sufficient for classification according to CLP (1272/2008/EC) / UN-GHS.