Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2010-07-06

Reliability:

1 (reliable without restriction)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2010

Report date:

2010

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 material

Test material information

Constituent 1

Reference substance name:

Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

EC Number:

283-044-5

EC Name:

Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

Cas Number:

84539-55-9

Molecular formula:

non specified (UVCB substance)

IUPAC Name:

Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

Details on test material:

- Name of test material (as cited in study report): Acetic acid,oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts
- CAS no. 84539-55-9
- Molecular formula (if other than submission substance): C6 H6 O. C2 H8 N2. C2 H2 O3. Fe. 2 Na
- Molecular weight (if other than submission substance): 330.075 g/mol
- Physical state: solid
- Purity 100 % (UVCB)

Radiolabelling:

not specified

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Administration / exposure

Duration and frequency of treatment / exposure:

Not applicable

Doses / concentrations

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

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 FeNaEDDHA 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, FeNaEDDHA 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 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 FeNaEDDHA will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value FeNaEDDHA 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.

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

Any other information on results incl. tables

no remarks

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: 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. 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.

Executive summary:

Toxicokinetics of FeNaEDDHA

General

FeNa-EDDHA is produced at different EU manufacturing sites. The substance is used as fertilizer.

Toxicological profile of FeNaEDDHA

Studies with FeNaEDDHA are not available for every toxicological endpoint to be addressed. Read across from the methylated structural analogues FeEDDHMANa (CAS: 149057-66-9) and FeEDDHMAK (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 two acute oral toxicity studies according to OECD 401 and GLP, the LD50 in albino rats and Sprague-Dawley CD strain rats was determined to be greater than 2000 mg/kg bw. Bodyweight development was not impaired. No deaths occurred in both studies.

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

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. Structural analogues and other comparable chelates are not sensitizing, The substance 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 the test substance showed no mutagenic effect in a Mouse Lymphoma assay. Overall, FeNaEDDHA was 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 and indicative of effects on kidneys and/or liver 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.

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 FeEDDHMANa (read across) 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.

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.

Toxicokinetic analysis of FeNaEDDHA

Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts (FeNaEDDHA) is a fine grained, free flowing, homogeneous solid at room temperature with a molecular weight of 435.17 g/mol. The substance is highly soluble in water (150-230 g/L). The logPow of FeNaEDDHA 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. FeNaEDDHA has a very low vapour pressure of < 0.000001 hPa at 20°C.

FeNaEDDHA 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 FeNaEDDHA 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, FeNaEDDHA 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 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.

When reaching the body FeNaEDDHA will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value FeNaEDDHA 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.