Iron, bis(glycinato-.kappa.N,.kappa.O)-

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro cytogenicity / micronucleus study

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2020

Reliability:

1 (reliable without restriction)

Justification for type of information:

The computational simulation was performed based on the read-across approach. The readacross is one of the so-called alternative test methods recommended by REACH, where the
predictions are based on the experimental data available for the most similar compounds. The predictions were performed according to the Read-Across Assessment Framework (RAAF),
which assumes six different risk assessment scenarios of chemical compounds.
Applied tool:
The OECD QSAR Toolbox, version 4.4
Procedure of analysis:
VI. Profiling of the target substance in order to retrieve relevant information related to mechanism of action and observed or simulated metabolites
VII. Analogue (source compound) search based on selected criteria:
a. analogue biotransforms similarly like the target compound (dissociation simulator)
b. analogue has the same structural features as the target compound according to:
i. Groups of elements profiler
ii. Chemical elements profiler
iii. Lipinski Rule Oasis profiler
c. analogue has the same alerts according to:
i. Protein binding alerts for Chromosomal aberration by OASIS
VIII. Data collection for the analogues (OECD Toolbox database).
IX. Toxicity prediction for the target substance
X. Category consistency check in order to assess the quality of the prediction
Applied scenario:
Scenario 1
Toxicity prediction for the target substance:
This read-across is based on the fact that target and source compound very easily undergo a rapid dissociation reaction, it is expected that this will be one of the first reactions to which our
target and source chemicals are exposed. As a result, all category members dissociate into transition metal ions and sulphate ions. The target compound - iron (II) glycine sulphate (VI)
trihydrate - dissociates into iron (II) ion, sulphate ion and glycine, however, due to glycine is amino acid, it is not considered as a toxic compound. Hydrogen ions resulted from the degree
of the target compound hydration are neglected. Based on the assumed analogue search criteria, one source compound has been found: FeSO4.
The chromosome aberration for the source compound was performed according to:
Test guideline: OECD 473
Endpoint: chromosome aberration (IV)
Test organism: Chines hamster cells, lung fibroblast (V79)
The read-across prediction of predict the genetic toxicity for the target substance was performed
based on the one to one approach and worst-case scenario (when multiple values are
available, the minimal value is taken in prediction calculations).

Principles of method if other than guideline:

In order to meet regulatory needs, reliability of the predicted results should be assessed. In case of classic quantitative structure-activity relationships (QSAR) modelling, this idea can be
realised by analysing, whether the predicted value is located within so-called applicability domain. The applicability domain is a theoretical region, defined by the range of toxicity values
and structural descriptors for the training compounds, where the predictions may be considered as realistic ones. In a specific case of read-across, the assessment is performed based on the
assessment of degree of similarity between the source and target compounds (in %). Moreover, the internal consistency of the group of source compounds (called category in OECD Toolbox
nomenclature, independently which approach: analogue approach or category approach is used). The category consistency check could be based on the parameters describing the
structural similarity and/or properties as well as mechanistic similarity of the tested compounds.
For example, all members of the category (analogues as well as target substance) need to have the same functional groups and endpoint specific alerts.
In the case of read-across-based prediction of the in vitro cytogenicity of the iron (II) glycine sulphate (VI) trihydrate, the read-across hypothesis considers that all category members
(bio)transform into the same/similar, common compounds: iron (II) ions and sulphate ions. The target as well as source compound have the same/similar results according to the structure
similarity profilers (Chemical elements, Groups of elements, Lipinski Rule Oasis). Moreover, both
category members have no endpoint specific alerts according to Protein binding alerts for
Chromosomal aberration by OASIS. Based on the Dice measure, the structural similarity between
dissociation products of source and target substances (besides glycine) was equal to
47,1%.
Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of Fe(Gly)SO4x3H2O, the log KOW value is available,
however in case of one to one approach, this criterion would be met only if source and target
compound are the same substance. Thus, informarion that target chemical is out of domain is not
critical in this situation.

Species / strain:

mammalian cell line, other:

Metabolic activation:

not specified

Genotoxicity:

other:

Remarks:

QSAR

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

The in vitro mammalian chromosome aberration for the target substance is predicted as positive.

Additional information on results:

The in vitro mammalian chromosome aberration for the target substance is predicted as positive.

Remarks on result:

ambiguous mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The in vitro mammalian chromosome aberration for the target substance is predicted as positive.

Reference 2

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2020

Reliability:

1 (reliable without restriction)

Justification for type of information:

The computational simulation was performed based on the read-across approach. The readacross is
one of the so-called alternative test methods recommended by REACH4, where the
predictions are based on the experimental data available for the most similar compounds. The pre
dictions were performed according to the Read-Across Assessment Framework (RAAF),
which assumes six different risk assessment scenarios of chemical compounds.
Applied tool:
The OECD QSAR Toolbox, version 4.4
Procedure of analysis:
I. Profiling of the target substance in order to retrieve relevant information related to mechanism of
action and observed or simulated metabolites
II. Analogues (source compound) search based on selected criteria:
a. analogue (bio)transforms similarly like the target compound (dissociation simulator)
b. analogue has the same structural features as the target compound according to:
i. Groups of elements profiler
ii. Chemical of elements profiler
iii. Lipinski Rule Oasis profiler
c. analogue has the same alerts according to:
i. DNA binding by OASIS
ii. DNA binding by OECD
iii. In vitro mutagenicity (Ames test) alerts by ISS
iv. OECD HPV Chemical Categories
III. Data collection for the analogues (OECD Toolbox database).
IV. Toxicity prediction for the target substance
V. Category consistency check in order to assess the quality of the prediction
Applied scenario:
Scenario 1
Toxicity prediction for the target substance:
This read-across is based on the fact that target compound very easily undergoes a dissociation
reaction, it is expected that this will be one of the first reactions to which our target chemical is expose
d. Thus, the prediction is based on toxicological data of the dissociation products of the target c
hemical. As a result, all category members dissociate into transition metal ions and
sulphate ions. The target compound - iron (II) glycine sulphate (VI) trihydrate - dissociates into iron (II) ion, sulphate ion and glycine, however, due to glycine is amino acid, it is not considered
as a toxic compound. Hydrogen ions resulted from the degree of the target compound hydration are neglected. Based on the assumed analogue search criteria, two source compounds have been
found: CoSO4 and MnSO4.
The gene mutation for the source compounds were performed according to:
Test guideline: OECD 476
Endpoint: Gene mutation
Test organism: mouse lymphoma L5178Y cells
The read-across prediction of the gene mutation for the target substance was performed based on the many to one approach.
Table. Source compounds for the gene mutation predictions.
No. CAS Name Gene mutation Metabolic activation
Test guideline
1. 10124-43-3 cobalt (II) sulphate 9x negative, Without OECD 476 1x positive
2. 7785-87-7 manganese (III) sulphate negative With and without OECD 476

Principles of method if other than guideline:

In order to meet regulatory needs, reliability of the predicted results should be assessed. In case of classic quantitative structure-activity relationships (QSAR) modelling, this idea can be
realised by analysing, whether the predicted value is located within so-called applicability domain. The applicability domain is a theoretical region, defined by the range of toxicity values
and structural descriptors for the training compounds, where the predictions may be considered as realistic ones. In a specific case of read-across, the assessment is performed based on the
assessment of degree of similarity between the source and target compounds (in %). Moreover, the internal consistency of the group of source compounds (called categoris in OECD Toolbox
nomenclature, independently which approach: analogue approach or category approach is used). The category consistency check could be based on the parameters describing the
structural similarity and/or properties as well as mechanistic similarity of the tested compounds.
For example, all members of the category (analogues as well as target substance) need to have the same functional groups and endpoint specific alerts.
In the case of read-across-based prediction of the gene mutation of the iron (II) glycine sulphate (VI) trihydrate, the read-across hypothesis considers that source and target compounds have the
same/similar (bio)transformation products. All category members dissociate into transition metal ions and sulphate ions. The prediction for the target compound is based on the structural
similariy of category members dissociation products. All category members exhibit the same/similar results according to the structure similarity profilers (Chemical elements, Groups
of elements, Lipinski Rule Oasis). Moreover, all category members have no endpoint specific alerts according to DNA binding by OASIS, DNA binding by OECD, In vitro mutagenicity
(Ames test) alerts by ISS and OECD HPV Chemical Categories. Based on the Dice measure, the
structural similarity between dissociation products of source and target substances (besides
glycine) was equal to 47.1%.
Besides, the category consistencies, the boundaries of the applicability domain are verified by the
critical value of the bioconcentration factor (BCF). In case of Fe(Gly)SO4x3H2O the BCF
is in the range of descriptor .

Species / strain:

mammalian cell line, other:

Genotoxicity:

negative

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The gene mutation for the target substance is predicted as negative.

Executive summary:

The target compound undergoes a dissociation reaction into its basic products: Gly, H2SO4 and Fe(OH)2. Due to the glycine is an amino acid, which is not considered as toxic compound, the analogues search was performed assuming structural similarity between dissociation products of source and target
substances (besides glycine). The transformation products of target and source compounds exhibit physicochemical and structural similarity, undergo dissociation reaction. The category members do not exhibit any structural alerts related to the target endpoint according to the endpoint specific profilers (DNA binding by OASIS, DNA binding by OECD, In vitro mutagenicity (Ames test) alerts by ISS and
OECD HPV Chemical Categories).

Therefore, the target and source compounds have similar toxicological properties and cause similar effects. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox.
Regarding the available and reliable (obtained according to OECD guidelines) data for human health hazards and genetic toxicity (OECD 471, OECD 473, OECD 474) of category members, there is observed a similar trend with exhibited toxicity response between source compounds, that is negative response in majority performed tests. Experimental data gathered for source compounds
were obtained with recommended OECD Guideline 476. The target endpoint for the first source compound, CoSO4, was indicated in majority studies as negative (9x negative, 1x positive) and reliable without restrictions. The target endpoint for the second source compound, MnSO4, was indicated as negative and reliable with restrictions. Nevertheless, results for both source compounds are consistent and could be used in the prediction for the target compound.

Reference 3

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes (incl. QA statement)

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Genotoxicity:

negative

Remarks on result:

other: negative result

Conclusions:

Based on the results obtained under the experimental conditions applied, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used.
In conclusion, the test item IRON GLYCINATE has no mutagenic activity in the bacterial tester strains under the test conditions used in this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

no study available

Justification for classification or non-classification

no