Glycine, N,N'-1,2-ethanediylbis-, reaction products with formaldehyde, iron chloride (FeCl3) and phenol, potassium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

weight of evidence

Study period:

2013

Reliability:

1 (reliable without restriction)

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2013

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:

potassium 2-({2-[(carboxymethyl)[(2-hydroxyphenyl)methyl]amino]ethyl}[(2-hydroxyphenyl)methyl]amino)acetic acid iron potassium hydride chloride

EC Number:

938-828-8

Cas Number:

1463474-95-4

Molecular formula:

Not applicable for the reaction product (UVCB)

IUPAC Name:

potassium 2-({2-[(carboxymethyl)[(2-hydroxyphenyl)methyl]amino]ethyl}[(2-hydroxyphenyl)methyl]amino)acetic acid iron potassium hydride chloride

Details on test material:

No test material used

Radiolabelling:

other: not applicable

Test animals

Species:

other: expert statement

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

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 log Kow value this UVCB 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, this UVCB is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. A structurally related UVCB (EDDHMA-Fe; see read across document in section 13) showed toxic effects at concentrations above 50 mg/kg bw/day in repeated dose and reproduction toxicity studies when administered orally. Administered in an acute study this UVCB caused no mortality at 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 inhalation exposure is not likely. Only 9.2% of the particles showed a diameter lower than 100 µm and 0.7% and 0.4% of the particles were found less than 10 or 5 µm, respectively. 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). The structurally related UVCB EDDHMA-Fe showed no toxicity after inhalation administration, in an acute inhalation toxicity study when applied at a technically highest attainable concentration of 1.24 mg/L. 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 this UVCB, the substance is not likely to penetrate the skin to a large extent as the very low log Pow value of -8.97 suggests that the 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 Pow 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 this UVCB in vitro and application of the structurally related UVCB 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 structurally related substance UVCB 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. The UVCB EDDHMA-Fe, applied to the skin of guinea pigs, no sensitising effects were observed, possibly indicating low skin absorption too.

Details on distribution in tissues:

When reaching the body HBED-Fe will be distributed in body liquids due to its high water solubility and very low Pow. As such HBED-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 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 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 absorped, especially if phase-II conjugation takes place e.g. with formation of glucoronid derivates.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Not available

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. When absorbed 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:

General

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

Toxicological profile of HBED-Fe (UVCB)

Studies with the structurally related substance 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 (see also read across document in section 13). All three 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 the acute oral toxicity study with HBED-Fe (UVCB) according to OECD guidelineand GLP, the LD50 in rats was determined to be greater than 2000 mg/kg bw.

An acute inhalation toxicity study with EDDHMA-Fe rats revealed a 4 -h LC50 -value of > 1.24 mg/L (the highest technically achievable concentration). In one acute dermal toxicity study with EDDHMA-Fe in rats a LD50 of > 2000 mg/kg bw was determined. Skin irritation/corrosion and eye irritation studies in vitro were performed with HBED-Fe (UVCB) according to OECD Guidelines and compared with EDDHMA-Fe. Application of both HBED-Fe (UVCB) and EDDHMA-Fe to the rabbit skin or eye can be designated as not irritating in these studies.

A key guinea pig maximisation study showed no skin sensitising properties of EDDHMA-Fe. In addition it is noted that both HBED-Fe (UVCB) and EDDHMA-Fe do not interact with protein, which is considered a requirement for sensitization (needed for haptenisation). Finally, also decades of use of EDDHMA-Fe 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. Finally, EDDHMA-Fe showed no mutagenic effect in two in vivo Micronucleus test in the mouse (following oral & intraperitoneal adiministration). Overall, EDDHMA-Fe and also HBED-Fe are considered non genotoxic.

In a 90 -day oral (gavage) key repeated dose toxicity study with EDDHMA-Fe 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 with EDDHMA-Fe, 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

HBED-Fe (UVCB) consists of dark red-brown, microgranules. The substance is very soluble in water (> 10 g/L). The log Pow was estimated from its solubilities in water and n-octanol to be -8.97.Based on this log Pow a BCF of 3.162 L/kg wet-wt (Log BCF = 0.5) was calculated. HBED-Fe (UVCB)has a low vapour pressure.

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the very low log Pow value HBED-Fe (UVCB) 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, HBED-Fe (UVCB) is very unlikely to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. the structurally related UVCB 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 HBED-Fe (UVCB) caused no mortality at 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 inhalation exposure is not likely. Only 9.2% of the particle showed a diameter lower than 100 µm, and only 0.7% of the particles were found less than 10 µm, and 0.4% less than 5 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). The structurally related UVCB 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 HBED-Fe will be distributed in body liquids due to its high water solubility and very low Pow. Based on its very low BCF value of3.162 L/kg wet-wt (Log BCF = 0.5),

HBED-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.