isliFe

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement based on available physical/chemical and toxicological data.

GLP compliance:

no

Radiolabelling:

not specified

Details on test animals or test system and environmental conditions:

Not applicable

Details on exposure:

Not applicable

Duration and frequency of treatment / exposure:

Not applicable

Remarks:

Doses / Concentrations:
Not applicable

No. of animals per sex per dose / concentration:

Not applicable

Positive control reference chemical:

Not applicable

Details on study design:

Not applicable

Details on dosing and sampling:

Not applicable

Statistics:

Not applicable

Preliminary studies:

Not applicable

Details on absorption:

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the low log Kow value Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe) is expected to be too hydrophilic to be readily absorbed via the GI tract, but may be taken up by passive diffusion. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. As the substances molecular weight of the main constituent of this UCVCB (C10H11NO4Fe(OH)(H2O) is higher than 200, MEAHA-Fe is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Administered in an acute study MEAHA-Fe caused no mortalities up to the limit dose of 2000 mg/kg bw. Therefore, it can be assumed that only limited direct absorption across the gastrointestinal tract epithelium will occur when applied orally.
Based on the low vapour pressure of < 0.0015 Pa at 20°C, inhalation exposure is not likely. Only 10 % of the particle showed a diameter lower than 100 µm and no particles were found less than 10 µm. Thus, it is very unlikely, that big amounts of the substance reach the lung. Nevertheless, if the substance reaches the lung, it is not very likely that the substance is taken up rapidly because of its physical and chemical parameters (high water solubility and low log Kow). A structural analogue substance (FeNa-EDDHA) showed no toxicity after inhalation administration, in an acute inhalation toxicity study when applied at a dose of 4200 mg/m3. Together, this indicates low systemic availability after inhalation and if bioavailable, no toxicity effects via this route of administration.
Similarly, based on physical – chemical properties of MEAHA-Fe, the substance is not likely to penetrate skin to a large extent as the very low log Kow value of <–1.5 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. Very high water solubilities above 10 g/l together with the log Kow value below 0 further indicate that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Therefore, dermal uptake for these substances will be low. Furthermore, an in vitro skin irritation study with MEAHA-Fe did not identify irritation or corrosion effects. An acute dermal toxicity study with a structural analogue substance (FeNa-EDDHA) did also not observe effects up to the highest dose tested of 2000 mg/kg bw. In a repeated dose toxicity study (28 day) with FeNa-EDDHA, beside local effects, only slight systemic effects on body and adrenal weight were observed at the limit dose of 1000 mg/kg bw/day, supporting the limited bioavailability via this route compared with the toxic effects noted after oral application. No sensitising effects were observed in an in vivo LLNA study with MEAHA-Fe, again supporting the limited availability of this substance via dermal exposure.

Details on distribution in tissues:

When reaching the body MEAHA-Fe will be distributed in body liquids due to its high water solubility (≥50 g/L) and very low log Kow (<-1.5). Based on this low Kow value MEAHA-Fe is very unlikely to bioaccumulate in the human body.

Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist on phase-II metabolising steps, leading to an even better water solubility for excretion. This is in compliance with the results obtained in the genotoxic tests showing no differences with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely.

Details on excretion:

Based on the high water solubility (≥50 g/L) and very low log Kow (<-1.5), excretion via the urine is likely. As the substance has a molecular weight of 300 g/mol the excretion of a considerable amount via the bile is also possible, especially if phase-II conjugation takes place e.g. with formation of glucoronid derivates.

Metabolites identified:

not measured

Details on metabolites:

NA

no remarks

Conclusions:

Based on physical-chemical characteristics, particularly the high water solubility (≥50 g/L), low octanol-water partition coefficient (log Kow <-1.5) and low vapour pressure (<0.0015 Pa at 20°C), no or only limited absorption by the dermal and inhalation routes is expected. For the oral route uptake is more likely compared to the other routes. Bioaccumulation is not likely to occur based on the physical-chemical properties. Excretion is expected to occur rapidly via the urine and the faeces. No sex differences with regard to toxicity are expected based on data from repeated dose toxicity tests with structural analogue test substances.

Executive summary:

Toxicokinetic analysis of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe)

MEAHA-Fe is a fine grained, homogeneous solid at room temperature. The molecular weight of the main constituent (C10H11NO4Fe(OH)(H2O)) is 300.094 g/mol. The substance is highly soluble in water (≥50 g/L). The log Kow of MEAHA-Fe was estimated from its solubilities in water and n-octanol to be < -1.5. Based on this log Kow, it is predicted that MEAHA-Fe has low potential for bioaccumulation. MEAHA-Fe has a low vapour pressure of < 0.0015 Pa at 20°C. MEAHA-Fe is not readily (bio)degradable.

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the low log Kow value, Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe) is expected to be too hydrophilic to be readily absorbed via the GI tract, but may be taken up by passive diffusion. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. As the substances molecular weight of the main constituent of this UCVCB (C10H11NO4Fe(OH)(H2O)) is higher than 200, MEAHA-Fe is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Administered in an acute study MEAHA-Fe caused no mortalities up to the limit dose of 2000 mg/kg bw. Therefore, it can be assumed that only limited direct absorption across the gastrointestinal tract epithelium will occur when applied orally.

Based on the low vapour pressure of < 0.0015 Pa at 20°C, inhalation exposure is not likely. Only 10 % of the particle showed a diameter lower than 100 µm and no particles were found less than 10 µm. Thus, it is very unlikely, that big amounts of the substance reach the lung. Nevertheless, if the substance reaches the lung, it is not very likely that the substance is taken up rapidly because of its physical and chemical parameters (high water solubility and low log Kow). A structural analogue substance (FeNa-EDDHA) showed no toxicity after inhalation administration, in an acute inhalation toxicity study when applied at a dose of 4200 mg/m3. Together, this indicates low systemic availability after inhalation and if bioavailable, no toxicity effects via this route of administration.

Similarly, based on physical – chemical properties of MEAHA-Fe, the substance is not likely to penetrate skin to a large extent as the very low log Kow value of <–1.5 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. Very high water solubilities above 10 g/l together with the log Kow value below 0 further indicate that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Therefore, dermal uptake for these substances will be low. Furthermore, an in vitro skin irritation study with MEAHA-Fe did not identify irritation or corrosion effects. An acute dermal toxicity study with a structural analogue substance (FeNa-EDDHA) did also not observe effects up to the highest dose tested of 2000 mg/kg bw. In a repeated dose toxicity study (28 day) with FeNa-EDDHA, beside local effects, only slight systemic effects on body and adrenal weight were observed at the limit dose of 1000 mg/kg bw/day, supporting the limited bioavailability via this route compared with the toxic effects noted after oral application. No sensitising effects were observed in an in vivo LLNA study with MEAHA-Fe, again supporting the limited availability of this substance via dermal exposure.

When reaching the body MEAHA-Fe will be distributed in body liquids due to its high water solubility (≥50 g/L) and very low log Kow (<-1.5). Based on this low Kow value MEAHA-Fe is very unlikely to bioaccumulate in the human body. Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist on phase-II metabolising steps, leading to an even better water solubility for excretion. This is in compliance with the results obtained in the genotoxic tests showing no differences with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely.

Based on the high water solubility and very low log Kow, excretion via the urine is likely. As the substance has a molecular weight of 300 g/mol the excretion of a considerable amount via the bile is also possible, especially if phase-II conjugation takes place e.g. with formation of glucoronid derivates.

Summary

Based on physical-chemical characteristics, particularly the high water solubility (≥50 g/L), low octanol-water partition coefficient (log Kow <-1.5) and low vapour pressure (<0.0015 Pa at 20°C), no or only limited absorption by the dermal and inhalation routes is expected. For the oral route uptake is more likely compared to the other routes. Bioaccumulation is not likely to occur based on the physical-chemical properties. Excretion is expected to occur rapidly via the urine and the faeces. No sex differences with regard to toxicity are expected based on data from repeated dose toxicity tests with structural analogue test substances.

Description of key information

Based on physical-chemical characteristics, particularly the high water solubility (≥50 g/L), low octanol-water partition coefficient (log Kow <-1.5) and low vapour pressure (<0.0015 Pa at 20°C), no or only limited absorption by the dermal and inhalation routes is expected. For the oral route uptake is more likely compared to the other routes. Bioaccumulation is not likely to occur based on the physical-chemical properties. Excretion is expected to occur rapidly via the urine and the faeces. No sex differences with regard to toxicity are expected based on data from repeated dose toxicity tests with structural analogue test substances.