Registration Dossier

The LD50 of the test item iron oxalate is higher than 2000 mg/ kg body weight by oral route in the rat.

The LD50 of the test item iron oxalate is higher than 2000 mg/ kg body weight by dermal route in the rat.

The LC50 of the test item iron oxalate is higher than 5mg/L by inhalation route in the rat.

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

17/07/2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information in a detailed justification report is included as attachment to the same record.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
For the determination of analogue in this read-across approach, the following points have been considered:
- Chemical speciation and valency (common valency of the cation: Fe2+ compared to Mg2+ or Sr2+).
- The water solubility, as it provides a first indication of the availability of the metal ion in the different compartments of interest. The most simplistic approach to hazard evaluation is to assume that the specific metal-containing compound to be evaluated shows the same hazards as the most water-soluble compounds.
- In fluids of organisms and in aqueous media, dissociation of ferrous oxalate di hydrate takes place immediately, resulting in formation of Ferrous cations (Fe2+) and oxalate anions. Thus, any ingestion or absorption of ferrous oxalate di hydrate by living organisms, in case of systemic consideration, will inevitably result of exposure to the dissociation products.
- Iron is an abundant mineral naturally present in the body. Physiologically, it. exists as an ion in the body as Fe2+ (ferrous ion). It is a necessary trace element used by all known living organisms (Williams 2012, NCBI 2019). Iron-containing enzymes, usually containing heme prosthetic groups, participate in catalysis of oxidation reactions in biology, and in transport of a number of soluble gases (Fraùsto da Silva 2001, NCBI 2019). Iron is an essential constituent of hemoglobin, cytochrome, and other components of respiratory enzyme systems. Its chief functions are in the transport of oxygen to tissue (hemoglobin) and in cellular oxidation mechanisms. Inorganic iron involved in redox reactions is also found in the iron-sulfur clusters of many enzymes, such as nitrogenase (involved in the synthesis of ammonia from nitrogen and hydrogen) and hydrogenase (NCBI 2019). A class of non-heme iron proteins is responsible for a wide range of functions such as ribonucleotide reductase (reduces ribose to deoxyribose; DNA biosynthesis) and purple acid phosphatase (hydrolysis of phosphate esters).
- Counter ions: the assumption that the oxalate ion is responsible for the common property or effect implies that the toxicity or ecotoxicity of the counter ion present in the compound will be largely irrelevant in producing the effects to be assessed.
- Likely common breakdown products via physical and/or biological processes for the targeted substance (ferrous oxalate di hydrate) and the analogues identified cannot present strong differences since the structures are very simple and very similar (formation of Fe2+ or oxalate ion).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical information is provided in the “source” endpoint. No impurity affecting the classification is reported for the source chemical.
Information on the impurities of the target chemical are detailed in the attached report.

3. ANALOGUE APPROACH JUSTIFICATION
The main hypothesis for the analogue approach are verified. They are presented in the detailed report attached. The experimental data performed on the substance (tests performed in this REACH registration) confirms the analogue approach performed (same results on analogues).

4. DATA MATRIX
A data matrix is presented in the detailed report attached.

References :
Fraùsto da Silva J.J.R., Williams R.J.P. 2001 The biological chemistry of the elements, 2nd edition. Oxford University Press, Oxford
NCBI, National Center for Biotechnology Information. PubChem Compound Database; CID=27284, https://pubchem.ncbi.nlm.nih.gov/compound/27284 (accessed Mar. 6, 2019).
Williams R.J.P 2012. Iron in evolution. FEBS Letters. Volume 586, Issue 5, 9 March 2012, Pages 479-484.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: read-across on magnesium oxalate

Mortality:

No effect observed.

Clinical signs:

No effect observed.

Body weight:

No effect observed.

Gross pathology:

No effect observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 is considered higher than 2000 mg/ kg body weight by oral route in the rat.

Executive summary:

The LD50 is considered higher than 2000 mg/ kg body weight by oral route in the rat.

Based on a read-across approach and on an O.E.C.D. Test Guideline No. 423, the LD50 cut-off of the substance may be considered to be higher than 5000 mg/ kg body weight by oral route in the rat.

Ferrous oxalate does not have to be classified in accordance with the Regulation EC No. 1272/2008 on classification, labelling and packaging of substances and mixtures.

No signal word or hazard statement is required.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR INFORMATIONS: Quantitative Structure Activity Relationships (QSAR) are theoretical models that can be used to predict in a qualitative or quantitative manner the physico-chemical, toxicological, ecotoxicological and environmental fate properties of compounds from a knowledge of their chemical structure.
1. SOFTWARE: OECD QSAR ToolBox

2. MODEL (incl. version number) : OECD QSAR ToolBox (version 4.4.1)
Principle of method used:
The OECD QSAR ToolBox is a prediction tool for health and environmental toxicity. It was developed and recommended by OECD and ECHA. The tool allows the prediction of acute toxicity. It is based on available data provided and compiled by OECD and ECHA.
The prediction using the OECD QSAR ToolBox follow the following steps : Selection of the targeted substance, defining the endpoint of interest (LC50, Acute Toxicity on rat), profiling considering the endpoint of interest, category definition, filling information (based on the available data in the OECD QSAR ToolBox database, gap filling approach used: trend analysis), subcategorization and prediction.
The application of this methodology permits the ToolBox to estimates the acute toxicity by inhalation route based on the available information in the OECD and ECHA database implemented in the tool.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS Number : 516-03-0

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
No formal QMRF assessment of the model is currently available, however, the user's guide and the ECHA technical guidance describes all the information.
According to the guidance R.7b - version - June 2017 (page 195) : “The use of QSAR model predictions are of particular relevance and interest when test data are lacking.” Furthermore, the OECD QSAR ToolBox is recommended in this ECHA Guidance.
- Defined endpoint: Actue Toxicity – inhalation route
- Unambiguous algorithm: Defined by OECD and publicly available. - Defined domain of applicability: available in the detailed prediction report - Interpretation: According to the ToolBox, the result is directly expressed as following: 15,5 mg/L

5. APPLICABILITY DOMAIN
The selection of parameters and categorisations when using OECD QSAR ToolBox allow the selection of relevant analogue for deriving relevant result. All information used for prediction is detailed in the prediction report.

6. ADEQUACY OF THE RESULT
The prediction using the OECD QSAR ToolBox provide result allowing classification and use under risk assessment. Therefore it fit with the purpose of this REACH registration dossier.

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Use of the OECD QSAR ToolBox recommanded by ECHA.

Specific details on test material used for the study:

CAS 516-03-0
SMILES: [Fe+2].[O-]C(=O)C([O-])=O

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

195 mg/L air

Based on:

test mat.

95% CL:

173 - 218

Interpretation of results:

GHS criteria not met

Conclusions:

The result is 195 mg/L air, conf.range: (173 ; 218) at 95,0%.

Executive summary:

The result of 195 mg/L of iron oxalate is higer than the cut-off value of 5.0mg/L by inhalation route for rat.

Ferrous oxalate does not have to be classified in accordance with the Regulation EC No. 1272/2008 on classification, labelling and packaging of substances and mixtures.

No signal word or hazard statement is required.

Dose descriptor:

LC50

Value:

5 000 mg/m³

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

25/07/2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information in a detailed justification report is included as attachment to the same record.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
For the determination of analogue in this read-across approach, the following points have been considered:
- Chemical speciation and valency (common valency of the cation: Fe2+ compared to Mg2+ or Sr2+).
- The water solubility, as it provides a first indication of the availability of the metal ion in the different compartments of interest. The most simplistic approach to hazard evaluation is to assume that the specific metal-containing compound to be evaluated shows the same hazards as the most water-soluble compounds.
- In fluids of organisms and in aqueous media, dissociation of ferrous oxalate di hydrate takes place immediately, resulting in formation of Ferrous cations (Fe2+) and oxalate anions. Thus, any ingestion or absorption of ferrous oxalate di hydrate by living organisms, in case of systemic consideration, will inevitably result of exposure to the dissociation products.
- Iron is an abundant mineral naturally present in the body. Physiologically, it. exists as an ion in the body as Fe2+ (ferrous ion). It is a necessary trace element used by all known living organisms (Williams 2012, NCBI 2019). Iron-containing enzymes, usually containing heme prosthetic groups, participate in catalysis of oxidation reactions in biology, and in transport of a number of soluble gases (Fraùsto da Silva 2001, NCBI 2019). Iron is an essential constituent of hemoglobin, cytochrome, and other components of respiratory enzyme systems. Its chief functions are in the transport of oxygen to tissue (hemoglobin) and in cellular oxidation mechanisms. Inorganic iron involved in redox reactions is also found in the iron-sulfur clusters of many enzymes, such as nitrogenase (involved in the synthesis of ammonia from nitrogen and hydrogen) and hydrogenase (NCBI 2019). A class of non-heme iron proteins is responsible for a wide range of functions such as ribonucleotide reductase (reduces ribose to deoxyribose; DNA biosynthesis) and purple acid phosphatase (hydrolysis of phosphate esters).
- Counter ions: the assumption that the oxalate ion is responsible for the common property or effect implies that the toxicity or ecotoxicity of the counter ion present in the compound will be largely irrelevant in producing the effects to be assessed.
- Likely common breakdown products via physical and/or biological processes for the targeted substance (ferrous oxalate di hydrate) and the analogues identified cannot present strong differences since the structures are very simple and very similar (formation of Fe2+ or oxalate ion).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical information is provided in the “source” endpoint. No impurity affecting the classification is reported for the source chemical.
Information on the impurities of the target chemical are detailed in the attached report.

3. ANALOGUE APPROACH JUSTIFICATION
The main hypothesis for the analogue approach are verified. They are presented in the detailed report attached. The experimental data performed on the substance (tests performed in this REACH registration) confirms the analogue approach performed (same results on analogues).

4. DATA MATRIX
A data matrix is presented in the detailed report attached.

References :
Fraùsto da Silva J.J.R., Williams R.J.P. 2001 The biological chemistry of the elements, 2nd edition. Oxford University Press, Oxford
NCBI, National Center for Biotechnology Information. PubChem Compound Database; CID=27284, https://pubchem.ncbi.nlm.nih.gov/compound/27284 (accessed Mar. 6, 2019).
Williams R.J.P 2012. Iron in evolution. FEBS Letters. Volume 586, Issue 5, 9 March 2012, Pages 479-484.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of the test item Magnesium oxalate is higher than 2000 mg/ kg body weight by dermal route in the rat. The test item Magnesium oxalate does not have to be classified in accordance with the Regulation EC No. 1272/2008 on classification, labelling and packaging of substances and mixtures.

Based on a read-across approach and on an O.E.C.D. Test Guideline No. 402, the LD50 is higher than 2000 mg/ kg body weight by dermal route in the rat.
Ferrous oxalate does not have to be classified in accordance with the Regulation EC No. 1272/2008 on classification, labelling and packaging of substances and mixtures.
No signal word or hazard statement is required.

Executive summary:

The test item Magnesium oxalate was applied, as supplied, onto the intact skin of 3 female Sprague Dawley rats at the single dose of 2000 mg/ kg body weight. The experimental protocol was established on the basis of the method as defined in the O.E.C.D. Test Guideline No. 402 dated October 9th, 2017.

No mortality occurred during the study. No systemic clinical sign related to the administration of the test item was observed. The body weight evolution of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal treatment-related changes.

The LD50 of the test item Magnesium oxalate is higher than 2000 mg/ kg body weight by dermal route in the rat. This result is used for iron oxalate based on a read-across approach.

In conclusion, iron oxalate does not have to be classified in accordance with the Regulation EC No. 1272/2008 on classification, labelling and packaging of substances and mixtures. No signal word or hazard statement is required.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

No adverse effect is observed at the highest dose tested (2000 mg/ kg body weight for oral and dermal routes), consequently no classification is needed. Nevertheless, existing harmonised classification (Index Number 607-007-00-3) for “salts of oxalic acid with the exception of those specified elsewhere in this Annex” should apply. Consequently, the substance is classified as Acute Tox. 4 (H302) for oral route and Acute Tox. 4 (H312) for dermal route.