Dipotassium hexacyanocobalt(II)-ferrate(II)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: A paper-based toxicokinetics assessment by a qualified toxicologist based on summaries of studies on the substance and literature.

Adequacy of study:

key study

Study period:

26.08.2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment has been conducted by a qualified toxicologist based on summaries of studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance is provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, November 2014).

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, November 2014). In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment has been conducted for the substance by a qualified toxicologist.

GLP compliance:

no

Toxicokinetic behaviour

The substance is a black/brown granular solid and the molecular weight is 349 g/mol. The substance has low solubility in water. The substance has a low vapour pressure value (calculated as <1.2x 10^-9 Pa at 25°C), is not highly flammable and does not have explosive or oxidising properties. It is therefore considered to be of low volatility. The percentage of the test item having an inhalable particle size of less than 100 μm was determined to be 1.05%. The test item has been considered to be essentially non-inhalable.

The available repeated dose reproductive OECD 422 screening study (oral route) showed toxicologically significant treatment-related effects. The oral administration of the substance to rats by gavage, at dose levels of 30, 100 and 300 mg/kg bw/day resulted in the premature termination or early death of all females around the time of parturition at 300 mg/kg bw/day. One female given 100 mg/kg bw/day was also found dead shortly after completing parturition. These deaths were considered to be treatment related with histopathological changes in the gastrointestinal tract considered to the be primary cause along with secondary changes to the liver, adrenals and lympho-reticular system at the point of parturition when the intrinsic stress on these females was notably increased. The surviving animals of either sex treated with 100 mg/kg bw/day and males given 300 mg/kg bw/day showed adverse changes in hematology profile which were associated with toxicologically significant alterations in the spleen and sternal bone marrow.

The OECD 422 study therefore showed evidence of absorption of the substance. The acute toxicity studies via oral and dermal routes showed no signs of systemic toxicity. The substance is not classified as a skin sensitiser, skin irritant or eye irritant. The substance gave negative results in three appropriate in vitro genotoxicity studies in either the presence or absence of an auxiliary metabolising system.

Absorption

Results of the repeated dose reproductive OECD 422 screening study (oral route) showed evidence to support the gastric absorption of the test item. The molecular size of the substance may also allow absorption through passive diffusion. This would suggest the gastro-intestinal tract may provide a route of absorption, following oral administration, before entering the circulatory system via the blood.

An acute dermal toxicity study showed no signs of systemic toxicity, so did not show evidence to support significant dermal absorption. As the substance is not a skin corrosive or irritant, potential dermal absorption will not be increased by damage to the skin at point of contact.

Inhalation is not considered to be a significant route of exposure based on the low volatility of the substance and particle size.

Distribution

Systemic distribution of the substance is evident from the repeated dose reproductive OECD 422 screening study due to the changes seen in histopathology, organs and hematology.

The substance is of low water soluble so is unlikely to be absorbed unchanged. The substance is not a skin sensitiser (based on results of a LLNA study). This suggests that the substance does not bind to carrier proteins in the circulatory system.

Metabolism

The results of the repeated dose reproduction OECD 422 screening study showed some effects in the liver of rats (e.g. organ weight, hepatocellular atrophy),which can be associated with enhanced metabolism. However, review of the study suggests the hepatic changes observed are not conclusively indicative of hepatic induction but may be associated with other detoxification processes. The effects observed in the liver therefore may suggest there is potential for enhanced metabolism but does not provide strong evidence to support enhanced metabolism.

The results of the genotoxicity assays showed that genotoxicity is neither enhanced or diminished in the presence of the S9 metabolising system.

Excretion

Poorly-water soluble substances are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this substance.

There is no strong evidence to support enhanced hepatic metabolism, but there may be some potential for this. Therefore, urinary excretion is not expected to be a major route of excretion but cannot be ruled out completely.

Any substance that is not adsorbed from the gut will be excreted in the faeces.

Conclusions:

The available information suggests that absorption of the test substance from the gastrointestinal tract can take place. Dermal absorption is considered unlikely. Based on available evidence once absorbed, the substance would be distributed systemically. Biliary excretion is likely to be the significant route of excretion. Experimental toxicokinetic studies were not available.

Executive summary:

In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment was conducted by a qualified toxicologist based on summaries of studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. Experimental toxicokinetic studies were not available.

The available information suggests that the substance is available for absorption via the oral route but unlikely to be available for absorption via the dermal route. This is supported by the physico-chemical properties of the substance and by available toxicological data. Once absorbed, the substance is likely to be distributed systemically. Biliary excretion is considered to be the significant route of excretion for the substance.

Description of key information

Experimental toxicokinetic studies are not available. A paper-based toxicokinetics assessment concludes the following: absorption of the test substance from the gastrointestinal tract can take place. Dermal absorption is considered unlikely. Any substance that is absorbed would be distributed systemically. Biliary excretion is likely to be the significant route of excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

A paper-based toxicokinetics assessment was conducted based on available studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. Experimental toxicokinetic studies were not available.

Toxicokinetic behaviour

The substance is a black/brown granular solid and the molecular weight is 349 g/mol. The substance has low solubility in water. The substance has a low vapour pressure value (calculated as <1.2x 10^-9 Pa at 25°C), is not highly flammable and does not have explosive or oxidising properties. It is therefore considered to be of low volatility. The percentage of the test item having an inhalable particle size of less than 100 μm was determined to be 1.05%. The test item has been considered to be essentially non-inhalable.

The available repeated dose reproductive OECD 422 screening study (oral route) showed toxicologically significant treatment-related effects. The oral administration of the substance to rats by gavage, at dose levels of 30, 100 and 300 mg/kg bw/day resulted in the premature termination or early death of all females around the time of parturition at 300 mg/kg bw/day. One female given 100 mg/kg bw/day was also found dead shortly after completing parturition. These deaths were considered to be treatment related with histopathological changes in the gastrointestinal tract considered to the be primary cause along with secondary changes to the liver, adrenals and lympho-reticular system at the point of parturition when the intrinsic stress on these females was notably increased. The surviving animals of either sex treated with 100 mg/kg bw/day and males given 300 mg/kg bw/day showed adverse changes in hematology profile which were associated with toxicologically significant alterations in the spleen and sternal bone marrow.

The OECD 422 study therefore showed evidence of absorption of the substance. The acute toxicity studies via oral and dermal routes showed no signs of systemic toxicity. The substance is not classified as a skin sensitiser, skin irritant or eye irritant. The substance gave negative results in three appropriate in vitro genotoxicity studies in either the presence or absence of an auxiliary metabolising system.

Absorption

Results of the repeated dose reproductive OECD 422 screening study (oral route) showed evidence to support the gastric absorption of the test item. The molecular size of the substance may also allow absorption through passive diffusion. This would suggest the gastro-intestinal tract may provide a route of absorption, following oral administration, before entering the circulatory system via the blood.

An acute dermal toxicity study showed no signs of systemic toxicity, so did not show evidence to support significant dermal absorption. As the substance is not a skin corrosive or irritant, potential dermal absorption will not be increased by damage to the skin at point of contact. Inhalation is not considered to be a significant route of exposure based on the low volatility of the substance and particle size.

Distribution

Systemic distribution of the substance is evident from the repeated dose reproductive OECD 422 screening study due to the changes seen in histopathology, organs and hematology. The substance is of low water soluble so is unlikely to be absorbed unchanged. The substance is not a skin sensitiser (based on results of a LLNA study). This suggests that the substance does not bind to carrier proteins in the circulatory system.

Metabolism

The results of the repeated dose reproduction OECD 422 screening study showed some effects in the liver of rats (e.g. organ weight, hepatocellular atrophy),which can be associated with enhanced metabolism. However, review of the study suggests the hepatic changes observed are not conclusively indicative of hepatic induction but may be associated with other detoxification processes. The effects observed in the liver therefore may suggest there is potential for enhanced metabolism but does not provide strong evidence to support enhanced metabolism. The results of the genotoxicity assays showed that genotoxicity is neither enhanced or diminished in the presence of the S9 metabolising system.

Excretion

Poorly-water soluble substances are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this substance. There is no strong evidence to support enhanced hepatic metabolism, but there may be some potential for this. Therefore, urinary excretion is not expected to be a major route of excretion but cannot be ruled out completely. Any substance that is not adsorbed from the gut will be excreted in the faeces.

Bioaccumulation potential

The substance can be considered to have no bioaccumulation potential as it has a very low solubility in water and negligible lipophilicity. Due to the low solubility, the substance will be released to solution (e.g. bowel contents) only very slowly. As it has a low likelihood of passing through biological membranes, systemic exposure to the substance will also be very slow and very limited. There is no reason for the elimination of the substance to be slower than its access to the body, meaning that no bioaccumulation of the substance is expected.

Absorption rates

The oral absorption rate for the substance has been estimated as 50 %, due to the fact that the substance is highly insoluble in water and has a large particle size (1.05% of particles <100 µm), with a molecular weight of 349. The oral LD50 for the substance is >2000 mg/kg and there were no acute systemic effects after oral exposure. However, systemic toxic effects in the OECD 422 study suggest some systemic bioavailability, although the contribution of local effects in the gastrointestinal tract cannot be excluded. For precautionary reasons, an absorption rate of 50 % has been assumed.

The dermal absorption rate for the substance has been estimated as 10 %, due to the fact that the substance is highly insoluble in water and has a large particle size (1.05% of particles <100 µm), with a molecular weight of 349. The dermal LD50 for the substance is >2000 mg/kg and there were no acute systemic effects after dermal exposure. Results for skin corrosion, irritation and sensitization were negative.

The inhalatory absorption rate for the substance has been estimated as 10 %, due to the fact that the substance has a very low vapour pressure (< 1.2 x 10^-9 Pa) and a large particle size (1.05% of particles <100 µm). It is highly insoluble in water with a molecular weight of 349.