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

Endpoint summary

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetics of EDDHMA-Fe

General

EDDHMA-Fe is produced at different EU manufacturing sites. The substance is used as fertilizer.

Toxicological profile of EDDHMA-Fe

Studies with EDDHMA-Fe are available for almost every toxicological endpoint to be addressed. In single cases read across with the non-methylated structural analogue EDDHA-FeNa (CAS no: 84539 -55 -9) was performed instead or additionally. Both substances show very similar physical/chemical properties (high water solubility, low log Kow, no hydrolysis in water) and are thus believed to behave very similar in aqueous solutions.

In three acute oral toxicity studies according to OECD 401 and GLP, the LD50 in rats was determined to be greater than 5000 mg/kg bw. In one of the studies at 2000 mg/kg bw no changes were observed and body weight development was not impaired. In the two other studies at 5000 mg/kg, one out of 10 rats died, in the other study no mortality was observed.

An acute inhalation toxicity study with rats revealed a 4 -h LC50 -value of > 1.24 mg/L (the highest technically achievable concentration). In one acute dermal toxicity study with rats a LD50 of > 2000 mg/kg bw was determined. Four skin irritation/corrosion and eye irritation studies in albino rabbits were performed according to the OECD Guideline No. 404. Application of EDDHMA-Fe to the rabbit skin or eye can be designated as not irritating in these studies.

Six out of eight guinea pig maximisation tests showed no skin sensitising properties of EDDHMA-Fe. All these tests (except for one, Kynoch (1977), pre-GLP) were carried out according to OECD 406 and according to GLP. Two older tests, however, showed skin sensitising properties. One test was carried out in 1990 (Smith), also carried out according to GLP and OECD 406; the other test (Skydsgaard, 1987) was not carried out according to GLP and was a modification of the Magnusson and Kligman test using four topical applications. The fact that more recent studies using higher induction and challenge concentrations did not show sensitising properties whereas two older studies did, allows the conclusion that the older products may have contained one (or more) impurity (/impurities) that had sensitising properties. Overall it is concluded that EDDHMA-Fe is not a skin sensitiser. In addition it is noted that EDDHMA-Fe does not interact with protein, which is considered a requirement for sensitization (needed for haptenisation). Finally, also decades of use of this substance did not result in any reports of people becoming sensitized.

EDDHMA-Fe was examined in two different in vitro genetic toxicity studies (three Ames tests and one Chromosome Aberration Test), all with and without metabolic activation. EDDHMA-Fe did not induce gene mutations in the Ames test. EDDHMA-Fe tested up to cytotoxic concentrations did show an increase in the number of cells with chromosome aberrations only at high and cytotoxic concentrations, and only in the absence of metabolic activation. The structurally related substance EDDHA-FeNa showed no mutagenic effect a a Mouse LYmphoma Assay. Finally, EDDHMA-Fe showed no mutagenic effect in two in vivo Micronucleus test in the mouse (following oral & intraperitoneal adiministration). Overall, EDDHMA-Fe was considered non genotoxic.

In a 90 -day oral (gavage) key repeated dose toxicity study in rats (Schoenmakers, 1996), the NOEL was established at 20 mg/kg bw/day for male rats and 100 mg/kg bw for female rats. In this study, treatment with the test item resulted in slight haematological changes and a slightly increased relative liver weight in male rats treated at 100 mg/kg bw/day. The slight increase in relative kidney weight was, however, not corroborated by histopathological renal effects, and was not seen in female rats at this level. Histopathological kidney effects were observed in both male and female rats at the next higher level of 500 mg/kg bw. In addition, two oral 28-day studies were available. The NOAEL in one of these oral 4 -week studies (Banks, 1988) was 200 mg/kg bw; in the second oral 4 -week study (Korn, 1990) 200 mg/kg bw was a LOAEL, however, the only change observed at that level consisted of slight fatty degenerations of renal tubular epithelial cells; no increase in relative kidney weight was observed at that level. Two other studies were available for the structurally related compound EDDHA-Fe. In the 90 -day study the LOAEL was 50 mg/kg bw.

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 EDDHMA-Fe in rats, the NOEL 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. However, the poor physical condition of animals of this group at 750 mg/kg might have been responsible for these effects, and the NOAEL for reproductive performance/fertility may be set at 750 mg/kg bw.

In a key developmental oral toxicity study with EDDHMA-Fe (Reijnders, 1996), the NOAEL for developmental effects was established at the high dose level of 1000 mg/kg bw/day based on the absence of embryo-/foetotoxic or teratogenic effects. The maternal NOEL was set at 200 mg/kg bw. In a similar oral study with EDDHA-FeNa 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 cresol and ethylenediamine, iron sodium salts (EDDHMA-Fe) consists of odourless, dark red-brown, microgranules. The substance is very soluble in water (> 10 g/L). The log Pow of EDDHMA-Fe was estimated from its solubilities in water and n-octanol to be -1.2. Based on this log Pow a BCF of 3.162 L/kg wet-wt (Log BCF = 0.5) was calculated. EDDHMA-Fe has a low vapour pressure. EDDHMA-Fe is hydrolytically stable but 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 log Pow value EDDHMA-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 is higher than 200, EDDHMA-Fe is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. EDDHMA-Fe showed toxic effects at concentrations above 50 mg/kg bw/day in repeated dose and reproduction toxicity studies when administered orally, respectively. Administered in an acute study EDDHMA-Fe caused limited mortality (10%) up to the limit dose of 5000 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 inhalation exposure is not likely. Only 6.7 % of the particle showed a diameter lower than 100 µm, and only 1.7% of the particles were found less than 10 µm. Thus, it is very unlikely, that large 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). EDDHMA-Fe showed no toxicity after inhalation administration, in a 4 -h acute inhalation toxicity study when applied at a concentration of 1.24 mg/L (technically highest attanaible concentration). 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 EDDHMA-Fe, the substance is not likely to penetrate the skin to a large extent as the very low logPow value of -1.2 suggests that the 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 EDDHMA-Fe to the 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 the structural analogue EDDHA-FeNa, besides 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 EDDHMA-Fe will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value EDDHMA-Fe 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 of phase-II metabolising steps, leading to an even better water solubility for excretion. This is in compliance with the results obtained in the genotoxicity 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 high water solubility and the low log Pow 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, when absorbed, 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.