Acetic acid, 2-oxo-, reaction products with ethylenediamine, iron chloride (FeCl3) and phenol, potassium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

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

GLP compliance:

no

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Administration / exposure

Details on exposure:

Not applicable

Duration and frequency of treatment / exposure:

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

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the very low logPow value FeKEDDHA 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 is higher than 200, FeKEDDHA is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The read across substances FeNaEDDHA and FeNaEDDHMA showed toxic effects at concentration as low as 50 mg/kg bw/day in repeated dose and reproduction toxicity studies when administered orally, respectively. Administered in an acute study FeNaEDDHA and FeNaEDDHMA 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 < 0.000001 hPa inhalation exposure is not likely. Only 2.7 % of the particle showed a diameter lower than 100 µm. 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 (see discussion based on physical and chemical parameters above). FeNaEDDHA 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 FeNaEDDHA, the substance is not likely to penetrate skin to a large extent as the very low logPow value of <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. Very high water solubilities above 10,000 mg/l together with the log P value below 0 further indicate that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. Furthermore, application of FeNaEDDHA to skin of rats and rabbits did not cause irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study and an acute dermal toxicity study. In a repeated dose toxicity study (28 day) beside local effects, only slight systemic effects on body and adrenal weight were observed at a 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. Applied to the skin of guinea pigs, sensitising effects were observed, indicating that at least small amounts of the substance will become available in the body.

Details on distribution in tissues:

When reaching the body FeKEDDHA will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value FeKEDDHA is very unlikely to bioaccumulate in the human body. In addition available studies do not indicate any sex difference with regard to the toxicity of the substance.
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 with FeNaEDDHA and FeNaEDDHMA showing no effects with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely. In addition phase-II metabolite formation is possible.

Details on excretion:

Based on the water solubility and the logPow value, excretion via the urine is likely. As the substance has a molecular weight above 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.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

NA

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation potential based on a toxicokinetic assessment
Based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results with FeNaEDDHA and FeNaEDDHMA. 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 FeNaEDDHA and FeNaEDDHMA.

Executive summary:

Toxicokinetics of FeKEDDHA

General

FeKEDDHA is used as fertilizer.

Toxicological profile of FeKEDDHA

Studies with FeKEDDHA are not available for every toxicological endpoint to be addressed. Read across from FeNaEDDHA and the the methylated structural analogues FeEDDHMANa (CAS: 84539 -53 -7) was performed instead. All 3 substances show very similar physical/chemical properties (high water solubility, low Kow, no hydrolysis in water) and are thus believed to behave very similar in aqueous solutions.

In acute oral toxicity studies with FeNaEDDHA and FeNaEDDHMA according to OECD 401 and GLP, the LD50 in rats was determined to be greater than 2000 mg/kg bw. Bodyweight development was not impaired. No deaths occurred in these studies.

An acute inhalation toxicity study with FeNaEDDHA rats revealed a 4 -h LC50 -value of > 4200 mg/m3 and with FeNaEDDHMA > 1240 mg/m3 (highest technically achievable concentrations). In acute dermal toxicity studies with rats a LD50 of > 2000 mg/kg bw was determined. Skin irritation/corrosion studies in albino rabbits were performed according to the OECD Guideline No. 404. Application of FeNaEDDHA and FeNaEDDHMA to the rabbit skin can be designated as not irritating.

A guinea pig maximation test according to Magnusson and Kligmann and an additional Local Lymph Node Assay (LLNA) revealed ambiguous results regarding skin sensitisation potential of FeNaEDDHA. The available studies indicate either a possible weak, or an ambiguous result for a weak potential for sensitisation of FeNaEDDHA. FeNaEDDHMA and other comparable chelates are not sensitizing, FeNaEDDHA does not interact with protein and decades of use of this substance did not result to any reports of people sensitized to it. In conclusion, in the evaluation of all available information there is no need for classification for skins sensitisation of FeNaEDDHA .

FeNaEDDHA was examined in three different in vitro genetic toxicity studies, all three with and without metabolic activation. The test item did not induce gene mutations by frameshift or base-pair substitution in the examined strains in the Ames test. FeNaEDDHA tested up to cytotoxic concentrations did not induce structural chromosome aberrations in Chinese Hamster ovary cells and was therefore not considered clastogenic in the tested system. Finally FeNaEDDHA showed no mutagenic effect in a Mouse Lymphoma assay. Similar results were obtained for FeNaEDDHMA including an in vivo MN test. Overall, FeNaEDDHA and FeNaEDDHMA are considered non genotoxic.

In a 90 -day oral (gavage) repeated dose toxicity study in rats, the NOEL was established at 5 mg/kg bw/day based on a transient normochromic anaemia present at higher dose levels. Changes in clinical laboratory parameters noted at higher dose levels are indicative of effects on kidneys and/or liver but were without microscopic correlate under the conditions of this study. A supporting and preceding dose range finding subacute oral (gavage) toxicity study in rats provided further indication that the haematopoietic system and, at higher dose levels, the kidney represented target organs following repeated oral exposure. The same was applicable to FeNaEDDHMA but slightly higher dose levels were tested.

In a subacute 28-day dermal toxicity study, the NOEL was established at 100 mg/kg bw/day based on slight effects on the liver and skin and due to increased adrenal weight noted at the high dose level of 1000 mg/kg bw/day. No data on repeated inhalation exposure are available.

In a state of the art one-generation reproduction toxicity study performed with the test item FeNaEDDHMA in rats, the NOAEL for reproductive performance/fertility was established at 200 mg/kg bw/day based on a slight decrease in the conception indices and a minimal delay in precoital time noted at the high and systemically toxic dose level of 750 mg/kg bw/day. In agreement with the read-across approach, this NOAEL is considered to represent a reliable key value for chemical safety assessment of FeNaEDDHA and thus for FeKEDDHA as well.

In a key developmental oral toxicity study with FeNaEDDHA in rats, the NOEL for developmental effects was established at the systemically toxic high dose level of 500 mg/kg bw/day based on the absence of embryo-/foetotoxic or teratogenic effects. Similar results were obtained for FeNaEDDHMA.

Toxicokinetic analysis of FeKEDDHA

FeKEDDHA consist of dark red brown granules and has a molecular weight of 346 g/mol. The substance is highly soluble in water (150 -230 g/L). The logPow of FeKEDDHA was estimated from its solubilities in water and n-octanol to be < -4.2. Based on this log Pow a BCF of 3.162 L/kg wet-wt (Log BCF = 0.5) was calculated. FeKEDDHA has a very low vapour pressure of < 0.000001 hPa at 20°C.

FeKEDDHA is hydrolytically stable but data from the read across substance FeEDDHMANa showed that it is degraded photolytically with a half-life between 40.66 and 35.4 h at 25°C.

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the very low logPow value FeKEDDHA 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 is higher than 200, FeKEDDHA is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The read across substance FeEDDHMANa showed toxic effects at concentration as low as 50 mg/kg bw/day in repeated dose and reproduction toxicity studies when administered orally, respectively. Administered in an acute study FeNaEDDHA and FeNaEDDHMA 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 < 0.000001 hPa inhalation exposure is not likely. Only 9.2% of the particle showed a diameter lower than 100 µm, and only 0.7% was 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 (see discussion based on physical and chemical parameters above). FeNaEDDHA and FeNaEDDHMA showed no toxicity after inhalation expsoure, in acute inhalation toxicity studies when applied at highest technically achievable concentrations of 4200 or 1280 mg/m3, respectively. Together, this indicates low systemic availability after inhalation and if bioavailable, no toxic effects via this route of administration.

Similarly, based on physical – chemical properties of FeKEDDHA, the substance is not likely to penetrate skin to a large extent as the very low logPow value of <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. Very high water solubilities above 10,000 mg/l together with the log P value below 0 further indicate that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. Furthermore, application of FeNaEDDHA or FeNaEDDHMA to skin of rats and rabbits did not cause irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study and an acute dermal toxicity study. In a repeated dose toxicity study (28 day) with FeNaEDDHA beside local effects, only slight systemic effects on body and adrenal weight were observed at a 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.

When reaching the body FeKEDDHA will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value FeKEDDHA is very unlikely to bioaccumulate in the human body. In addition available studies do not indicate any sex difference with regard to the toxicity of the substance.

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 effects with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely. In addition phase-II metabolite formation is possible.

Based on the water solubility and the logPow value, excretion via the urine is likely. As the substance has a molecular weight above 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 water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. 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.