[No public or meaningful name is available]

Endpoint summary

Description of key information

Read-across to manganese salts and specifically sulphate considered acceptable for assessment of acute toxicity 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Remarks:

Read-across to Mn Sulphate

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Source data for read-across
The acute toxicity is considered to be linked to the dissolved Manganese ions
Manganese sulphate is considered a reliable source of data to consider potential toxicity of soluble manganese ions
Results for Chloride and Sulphate are presented to demonstrate importance of Mn ions in toxicity
Data is cited in various review documents and considered reliable
Further animal testing is not justified.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Study involved assessing a number of different metal salts
Results for Chloride and Sulphate are presented to demonstrate importance of Mn ions in toxicity
Animal behaviour assessed

GLP compliance:

no

Remarks:

Pre-dates CLP in India

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Doses:

Actual dose levels are not reported, but were sufficient to allow estimation of LD50

No. of animals per sex per dose:

Not specified

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 3 100 mg/kg bw

Based on:

test mat.

Remarks:

Calculated Mn Glycinate based on Mn SO4

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 150 mg/kg bw

Based on:

test mat.

Remarks:

Manganese sulphate

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 783 mg/kg bw

Based on:

element

Remarks:

Calculated Mn based on sulphate

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 470 mg/kg bw

Based on:

test mat.

Remarks:

Manganese dichloride

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 647 mg/kg bw

Based on:

element

Remarks:

Calculated for Mn ions from chloride

Mortality:

Yes

Clinical signs:

other:

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

In view of dissociation of Mn Glycinate to Mn, Sulphate and Glycine, it is considered valid to estimate acute toxicity based on the dissociated ions.
The Manganese is considered to be the main ion impacting on acute toxicity
No further animal testing can be justified.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

Acute inhalation toxicity is the total of adverse effect caused by substance following the single uninterrupted exposure by inhalation over a short period of time to a substance capable of being inhaled. The aim was to estimate the acute toxicity by inhalation of target substance.

Estimation of the biological activity (acute toxicity by inhalation)
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 4.3
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. Category (source compounds) search based on selected criteria:
a. analogues have the same structural features as the target compound (subcategorization profiles: Sulfate, linear [-O-SO2-O-] Sulfite, linear [-
OS(=O)O-] Suflur {v+4} or {v+6} Miscellaneous metal [Ni, Cu, Zr, Be] Miscellaneous sulfide (=S) or oxide (=O) Zinc, suflur
attach [Zn] (Organic functional groups (US EPA))
b. analogues are structurally similar to the target compound (similarity >40%)
III. Data collection for the analogues (OECD Toolbox database/ECHA CHEM).
IV. Toxicity prediction for the target substance
V. Category consistency check in order to assess the quality of the prediction.
Applied scenario:
Scenario 2
Toxicity prediction for the target substance:
This read-across is based on the fact that the organism is not exposed to common compounds but rather, as a result of similarity, to chemicals which have similar (eco)toxicological and fate properties.
The target substance is an organometallic compound containing manganese (Mn) centres, glycine (Gly) ligands. The metallic centres of the substance are linked by oxygen coordination bonds of the Gly ligands.
The analogues are structurally similar to the target compound in more than 40%. Moreover, analogues and target compound have the same structural features according to profiles: Sulphate, linear [-O-SO2-O-] ; Sulphite, linear [-OS(=O)O-]; Sulphur {v+4} or {v+6} Miscellaneous metal [Ni, Cu, Zr, Be] Miscellaneous sulphide (=S) or oxide (=O) Zinc, sulphur attach [Zn] (Organic functional groups (US EPA)). The MnSO4 was used as the source compound. The acute inhalation toxicity for analogue was measured according to the OECD 403 and this value was taken into account for the prediction.
The acute inhalation toxicity for the source compound was performed according to:
Test guideline: OECD 403
Endpoint: LC50
Test organism: rat
The read-across prediction of the acute inhalation toxicity for the target substance was performed based on the approach “one to one”.

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 QSAR 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 acute inhalation toxicity of the dehydrate manganese (II) glycine sulphate (VI), the read-across hypothesis considers that source and target compounds have the same structural features related to organic functional groups (US EPA). Based on the Dice measure, the structural similarity between analogues and the target compound (besides glycine) was higher than 40%. Therefore, using experimental data of MnSO4 for predicting biological activity for the target compound was justified. Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of “one to one” approach, this criterium would be met only if source and target compounds are the same substance. Thus, information that “target chemical is out of domain” considering this criterium is not critical in this situation.
The structural similarity between the source (MnSO4) and the target compound (Mn(Gly)SO4) equals to 47.1%

Dose descriptor:

LC50

Effect level:

4.45 mg/L air

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute inhalation toxicity for the target substance is predicted at level LC50 = 4.45 mg/L air.

Executive summary:

The target compound has the same structural features as source compound according to organic functional groups (US EPA). The analogues search was performed assuming at least 40% structural similarity between the source and target substances besides glycine. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. Manganese (II) sulphate would have the same structural features (organic functional groups according to US EPA profiler) as well as the experimental data related to its acute inhalation toxicity was available. Therefore, the prediction is based only on the MnSO4.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4.45 mg/L air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

Acute dermal toxicity refers to those adverse effects occurring following a single dermal (skin) exposure to the substance within 24 h.
The aim was to estimate the acute toxicity by dermal route of target substance.

stimation of the biological activity (acute toxicity by dermal route)
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 4.3
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. Category (source compounds) search based on selected criteria:
a. analogues are aliphatic amines according to US-EPA New Chemical Categories
b. analogues are structurally similar to the target compound (similarity >20%)
c. analogues have the same alert “High level” according to the Cramer profile.
III. Data collection for the analogues (OECD Toolbox database/ECHA CHEM).
IV. Toxicity prediction for the target substance
V. Category consistency check in order to assess the quality of the prediction
Applied scenario:
Scenario 2
Toxicity prediction for the target substance:
This read-across is based on the fact that the organism is not exposed to common compounds but rather, as a result of similarity, to chemicals which have similar (eco)toxicological and fate properties.
The target substance is an organometallic compound containing manganese (Mn) centres, glycine (Gly) ligands. The metallic centres of the substance are linked by oxygen coordination bonds of the Gly ligands.
The target and source chemicals are classified as “Aliphatic amines” according to US-EPA New Chemical Categories and have the same “High level” alert responsible for the toxic effect based on the Cramer profiler. Moreover, analogue is structurally similar to the target compound in more than 20%. The sodium (2-aminoethyl)amino]ethanesulphonate was taken into account for the prediction.
The acute dermal toxicity for the source compound was performed according to:
Test guideline: OECD 402
Endpoint: LD50
Test organism: rat
The read-across prediction of the acute dermal toxicity for the target substance was performed based on the approach “one to one”.

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 QSAR Toolbox nomenclature, independently which approach: analogue approach or category approach is used). The category consistency check could be based on the parameters describingthe 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 acute dermal toxicity of the dehydrate manganese (II) glycine sulphate (VI), the read-across hypothesis considers that source and target compounds have the same structural features related to “Aliphatic amines” (US EPA New Chemical Categories) and have the same “High level” alert responsible for the toxic effect based on the Cramer profiler. Based on the Dice measure, the structural similarity between analogues and the target compound was higher than 20%. The sodium 2-[(2-aminoethyl)amino]ethanesulphonate was taken into account for the prediction.
Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of “one to one” approach, this criterium would be met only if source and target compounds are the same substance. Thus, information that “target chemical is out of domain” considering this criterium is not critical in this situation.
The structural similarity between the source (sodium 2-[(2-aminoethyl)amino]ethanesulphonate) and the target compound (Mn(Gly)SO4) equals to 27.3%.

GLP compliance:

no

Remarks:

QSAR

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute dermal toxicity for the target substance is predicted at level LD50 >= 2000 mg/kg

Executive summary:

The source and target compounds have the same structural features related to “Aliphatic amines” (US EPA New Chemical Categories) and have the same “High level” alert responsible for the toxic effect based on the Cramer profiler. The analogues search was performed assuming at least 20% structural similarity between the source and target substances. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. The sodium 2-[(2-aminoethyl)amino]ethanesulphonate would have similar structural features (organic functional groups) and cause similar toxic effect (Cramer profile) as well as the experimental data related to its acute dermal toxicity was available. Therefore, the prediction is based only on the sodium 2-[(2-aminoethyl)amino]ethanesulphonate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw